Bladder Cancer

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A Window-of-opportunity Trial of Abemaciclib Followed by Radical Cystectomy in Patients With Platinum-ineligible Urothelial Carcinoma to Evaluate CDK4/6-dependent Phosphorylation of Pocket Proteins and Clonal Evolution Dynamics


Condition: Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03837821

Sponsor: Weill Medical College of Cornell University

Phase: Early Phase 1

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  1. Age ≥ 18 years old at time of informed consent
  2. Histologically confirmed MIBC (T2-T4) pure or mixed histology urothelial carcinoma [urothelial carcinoma should be the dominant (>50%) histology].
  3. Refusing cisplatin-based chemotherapy or ineligible for cisplatin-based chemotherapy due to at least one of the following:
  4. Creatinine clearance < 60 mL/min (by Cockgroft-Gault calculation and/or measured creatinine clearance)
  5. Hearing loss ≥ grade 2 by CTCAE criteria and/or;
  6. Neuropathy ≥ grade 2 by CTCAE criteria and/or
  7. Heart failure NYHA ≥ III
  8. Medically fit for TURBT and radical cystectomy
  9. Adequate organ and marrow function as defined below: a. Absolute neutrophil count ≥ 1.5 K/mm3 b. White blood cell count (WBC) > 3.0 K/mm3 c. Platelets ≥ 100 K/mm3 d. Hemoglobin ≥ 9 g/dL e. Serum total bilirubin ≤ 1.5 x ULN (Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted) f. ALT and AST ≤ 2.5 x ULN g. Serum creatinine clearance (CrCl) ≥ 30 ml/min using the MDRD or serum creatinine ≤ 2 times ULN.using the Cockcroft-Gault or measurement with 24 hour urine collection
  10. Ability to swallow oral medications
  11. Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and randomization

Exclusion Criteria:

  • 1. Patients with locally advanced unresectable or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within from the date of signed consent, 28 days prior to study enrollment. Low volume (<1.5 cm) suspicious lymph node metastases in the pelvis are allowed if they are in the LN dissection template field. The required radiographic imaging includes: 1. Abdomen/pelvis
  • CT/MRI 2. Chest
  • chest x-ray or CT scan 3. Bone scan or FDG-PET/CT in the presence of bone pain or unexplained elevated alkaline phosphatase 2. Patients with another active second malignancy other than non-melanoma skin cancers and localized prostate cancer. Patients that have completed all necessary therapy and are considered to be <30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment. 3. Patients who have received anti-cancer therapy including chemotherapy, radiotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy 4. Patients who have serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea). 5. Have an active active bacterial infection (especially if requiring IV antibiotics), systemic fungal and/or known viral infection (for example, human immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C antibodies). 6. Subjects who received a strong CYP3A inhibitor within 7 days prior to the first dose of study drug, or patients who require continuous treatment with a strong CYP3A inhibitor 7. The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. 8. Pregnant or breast-feeding women 9. Women who do not agree to use a medically approved contraceptive method during the treatment period and for 3 months following the last dose of Abemaciclib 10. Men who do not agree to use a reliable method of birth control and to not donate sperm during the study and for at least 3 months following the last dose of Abemaciclib 11. Subjects unwilling or unable to comply with the protocol

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Neo-adjuvant Versus Adjuvant Chemotherapy in Upper Tract Urothelial Carcinoma: A Feasibility Phase II Randomized Clinical Trial ("URANUS")"


Condition: Upper Tract Urothelial Carcinoma

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02969083

Sponsor: The European Uro-Oncology Group

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Written informed consent
  • Age > 18 years
  • Histological and radiological defined UTUC: Histologically-confirmed diagnosis of predominantly urothelial carcinoma of the upper urinary tract Patients with UTUC cT2-pT4 cN0-N1 M0 (TNM classification)
  • Women with negative serum pregnancy test within 14 days of first dose of study treatment and agreement to use effective contraception
  • Patients without bladder cancer or with concomitant non muscle invasive bladder cancer
  • Adequate organ system function defined as follows: Hematologic: Absolute neutrophil count (ANC) 1.5 X 109/L; Haemoglobin 5.6 mmol/L (9.02g/dL); Platelets 100 X 109/L; Prothrombin time (PT) or international normalized ratio (INR)b 1.2 X ULN; Activated partial thromboplastin time (aPTT)1.2 X Upper limit of normal (ULN). Hepatic: Total bilirubin 1.5 X ULN; Alanine amino transferase (ALT) and Aspartate aminotransferase (AST) 2.5 X ULN. Renal: GRF 55 ml/min: Electrolytes: potassium and calcium: within normal limits.
  • CT scan of the chest, abdomen and pelvis and Bone scan without evidence of distant metastasis Exclusion Criteria:
  • Histology of pure adenocarcinoma, pure squamous cell carcinoma, sarcomatoid or predominant small cell carcinoma.
  • History of cardiovascular conditions within the past 6 months.
  • Incidentally found asymptomatic pulmonary embolism (PE) or recent deep vein thrombosis (DVT) is not an

Exclusion Criteria:

  • Histology of pure adenocarcinoma, pure squamous cell carcinoma, sarcomatoid or predominant small cell carcinoma.
  • History of cardiovascular conditions within the past 6 months.
  • Incidentally found asymptomatic pulmonary embolism (PE) or recent deep vein thrombosis (DVT) is not an exclusion criteria but requires anticoagulation treatment.
  • Any major contraindication to a surgical procedure.
  • Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
  • Active infection contraindicating chemotherapy
  • Other active neoplasms. Patients with in situ cervical carcinoma, non-melanoma skin cancer or prostate cancer T1 Gleason <7, Prostate specific antigen (PSA) <10. Patients with past medical history of cancer can be included if diagnosed at least 4 years ago.
  • Concomitant muscle invasive bladder cancer
  • Patients who have been or still are on methotrexate treatment.

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A Phase II Trial to Evaluate Combination Therapy With Pemetrexed and Avelumab in Previously Treated Patients With MTAP-Deficient Advanced Urothelial Cancer


Condition: Infiltrating Bladder Urothelial Carcinoma Sarcomatoid Variant, Infiltrating Bladder Urothelial Carcinoma With Glandular Differentiation, Infiltrating Bladder Urothelial Carcinoma With Squamous Differentiation, Infiltrating Bladder Urothelial Carcinoma, Micropapillary Variant, Infiltrating Bladder Urothelial Carcinoma, Plasmacytoid Variant, Metastatic Urothelial Carcinoma, MTAP Negative

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03744793

Sponsor: M.D. Anderson Cancer Center

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Patients must have histologic confirmation of MTAP-deficient metastatic urothelial carcinoma. MTAP-deficiency must be verified by institutional Clinical Laboratory Improvement Act (CLIA)-certified immunohistochemistry (IHC). Histological variants such as glandular, squamous, sarcomatoid, micropapillary, plasmacytoid, and small cell changes will be allowed for this trial if these tumors are MTAP-deficient.
  • Patients can be considered for second line of therapy (after chemotherapy or immune checkpoint inhibitor with PD-[L]1 agent) or for third line of therapy (can have previously received chemotherapy and immune checkpoint inhibitor with PD-[L]1 blockade). Any prior intravesical therapy is allowed and does not count as a prior line of therapy.
  • Patients who received methotrexate-containing chemotherapy (e.g. methotrexate/vinblastine/adriamycin/cisplatin [MVAC]) as neoadjuvant therapy or first-line systemic therapy at least 12 months prior will be allowed for this trial.
  • All patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 and tumors of sufficient sizes for biopsy. In general, liver and lung lesions should be at least 1.0 cm, and patients with lymph node-only disease should have lesions of >= 1.5 cm in shortest dimension. Patients with disease confined to bone may be eligible if a measurable lytic defect is present. The study principal investigator (PI) is the final arbiter in questions related to measurability. Patients with a three-dimensional mass or pelvic sidewall fixation on bladder examination under anesthesia are considered to have measurable disease.
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN), or =< 5 ULN if documented liver metastases are present.
  • Total bilirubin =< 1.5 x ULN, except subjects with Gilbert's syndrome or liver metastases, who must have a baseline total bilirubin =< 3.0 mg/dL.
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.
  • Hemoglobin >= 9 g/dL (may have been transfused).
  • Platelets >= 100 x 10^9/L.
  • Normal serum creatinine, or a creatinine clearance >= 40 ml/min [either measured using a 24 hour urine, calculated using Cockcroft-Gault, or estimated using the MDRD method from the National Kidney Disease Education Program (NKDEP) (the method reported by MD Anderson Cancer Center [MDACC] laboratories).
  • Negative serum or urine pregnancy test at screening for women of child-bearing potential.
  • Females of childbearing potential who are sexually active with a non-sterilized male partner and non-sterilized males must use a highly effective method of contraception for 28 days prior to the first dose of investigational product, and must agree to continue using such precautions for 180 days after the final dose of investigational product; cessation of contraception after this point should be discussed with a responsible physician. They must also refrain from egg cell donation for 180 days after the final dose of investigational product.
  • Non-sterilized males who are sexually active with a female partner of childbearing potential must use a highly effective method of contraception from days 1 through 180 post last dose. In addition, they must refrain from sperm donation for 180 days after the final dose of investigational product.
  • The ability to interrupt nonsteroidal anti-inflammatory drugs (NSAIDS) 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed.
  • The ability to take folic acid, vitamin B12, and dexamethasone according to protocol.
  • Mild autoimmune conditions (such as localized psoriasis) requiring minimal treatment or systemic autoimmune conditions well controlled by target agents such as an anti-IL-17 that do not affect overall immune system. Patients with a history of Hashimoto's thyroiditis only requiring hormone replacement, type I diabetes, or conditions not expected to recur in the absence of an external trigger are allowed to participate.

Exclusion Criteria:

  • Primary central nervous system (CNS) malignancies or CNS metastases, including leptomeningeal metastases, are not allowed. Subjects with previously treated brain metastases will be allowed if the brain metastases have been stable for at least 4 weeks following prior treatment and no ongoing steroid requirement.
  • Any other malignancy from which the patient has been disease-free for less than 2 years, except for non-melanomatous skin cancer, controlled localized prostate cancer, in situ carcinoma of any site.
  • Women who are pregnant or breastfeeding or intend to become pregnant during their participation in the study.
  • Presence of third space fluid which cannot be controlled by drainage. For patients who develop or have baseline clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) before or during initiation of pemetrexed therapy, consideration should be given to draining the effusion prior to dosing. However, if, in the investigator's opinion, the effusion represents progression of disease, the patient should be discontinued from study therapy.
  • Known or suspected autoimmune disease. Patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus or autoimmune vasculitis (e.g., Wegener's granulomatosis) are excluded from this study.
  • Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroids doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • History of primary immunodeficiency.
  • Patients who have prior organ transplantation, including allogeneic stem-cell transplant.
  • Vaccinations within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
  • True positive test results for hepatitis A, B, or C during screening.
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, symptomatic cardiac arrhythmia, or interstitial lung disease.
  • Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medication.
  • Persisting toxicity related to prior therapy (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0 grade > 1); however, alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety risk based on investigator's judgment are acceptable.
  • Uncontrolled psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
  • Known allergy or hypersensitivity to study drug formulations.
  • Major surgical procedure (as defined by the PI or co-PIs within 28 days prior to the first dose of therapy) or still recovering from prior surgery.
  • Patient currently on dialysis.

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A Phase III, Randomized, Open-Label, Multi-Center, Global Study to Determine the Efficacy and Safety of Durvalumab in Combination With Gemcitabine+Cisplatin for Neoadjuvant Treatment Followed by Durvalumab Alone for Adjuvant Treatment in Patients With Muscle-Invasive Bladder Cancer.


Condition: Muscle Invasive Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03732677

Sponsor: AstraZeneca

Phase: Phase 3

Eligibility:

  • Age: minimum 18 Years maximum 130 Years
  • Gender: All

Criteria: Inclusion: - Patient resectable muscle-invasive bladder cancer with clinical stage T2-T4aN0/1M0 with transitional and mixed transitional cell histology - Patients must be planning to undergo a radical cystectomy - Patients who have not received prior systemic chemotherapy or immunotherapy for treatment of MIBC - ECOG performance status of 0 or 1 - Must have a life expectancy of at least 12 weeks at randomization Exclusion: - Evidence of lymph node (N2-N3) or metastatic (M1) disease at time of screening. - Prior pelvic radiotherapy treatment within 2 years of randomization to study - Prior exposure to immune-mediated therapy (with exclusion of Bacillus-Calmette Guerin [BCG]), including but not limited to other anti-CTLA-4, anti-PD-1, anti PD-L1, or anti-PD-L2 antibodies. - Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product (IP). The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection); Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent; Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) - Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. - Uncontrolled intercurrent illness - Active infection including Tuberculosis, Hepatitis B, Hepatitis C, and Human Immunodeficiency

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Evaluation of Non-Invasive Assays for the Detection of Urothelial Cancer of the Bladder and Kidney


Condition: Urothelial Cancer, Cancer, Bladder Neoplasms, Urinary Bladder Cancer

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT00872495

Sponsor: Lahey Clinic

Phase:

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Patients scheduled to have a nephroureterectomy, cystectomy, cytoscopy (newly diagnosed bladder cancer and those with recurrent disease in follow up)
  • Control Group: No known evidence of bladder cancer-one urine sample
  • > than 18 years of age

Exclusion Criteria:

  • < than 18 years of age

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Phase II Study of Pembrolizumab (MK-3475) as First-Line Therapy for High Risk T1 Non-Muscle-Invasive Bladder Cancer


Condition: Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03504163

Sponsor: Memorial Sloan Kettering Cancer Center

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Be willing and able to provide written informed consent/assent for the trial.
  • Histologically confirmed urothelial cancer by TURBT performed at MSKCC.
  • TURBT within 6 weeks of protocol entry with complete resection of all papillary lesions.
  • Patients with high risk, BCG-naïve non-muscle-invasive urothelial cancer defined as having one of the following disease states:
  • T1 on restaging biopsy, plus cis
  • Multiple (≥ 1) T1 recurrences, plus cis
  • Multifocal T1 plus cis
  • T1b, plus cis
  • T1 with lymphovascular invasion plus cis
  • Patient refusal of cystectomy and bilateral pelvic lymphadenectomy
  • No prior intravesical therapy.
  • No prior radiation therapy for bladder cancer. Prior radiation therapy for prostate cancer is allowed.
  • ECOG performance status 0 or 1.
  • Age ≥ 18 years of age
  • Female subjects of childbearing potential should be willing to use 2 methods of birth control, be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of the study medication (reference section 9.5.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for >1 year.
  • Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
  • Patients must not have other invasive malignancies within the past 5 years (with the exception of non-melanoma skin cancers, localized prostate cancer, and carcinoma in situ of the cervix).
  • Required Initial Laboratory Values:
  • Absolute neutrophil count ≥ 1.5 x 10E9/L
  • Platelets ≥ 100 x 10E9/L
  • Hemoglobin ≥ 9 g/dL
  • Bilirubin ≤ 1.5 times the upper limit of normal (x ULN)
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x ULN
  • Calculated creatinine clearance ≥ 30 using the CKD-Epi formula

Exclusion Criteria:

  • Prior treatment with systemic chemotherapy
  • Unstable angina
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure
  • History of myocardial infarction within 6 months
  • History of stroke within 6 months
  • Evidence of bleeding diathesis or coagulopathy
  • Presence of any systemic metastases (ie, nodal, visceral, or central nervous system)
  • Major surgical procedure (other than TURBT) within 28 days prior to the study
  • Pregnant (positive pregnancy test) or lactating
  • Serious, non-healing wound, ulcer, or bone fracture
  • Inability to comply with study and/or follow-up procedures
  • Prior therapy with an anti-PD-1 agent, anti-PD-L1 agent, or other inhibitory or stimulatory agent oriented towards a T-cell receptor
  • Active infection requiring systemic therapy
  • Known history of human immunodeficiency virus (HIV)
  • Known active Hepatitis B or Hepatitis C
  • Received live attenuated vaccines within 30 days prior to start of study treatment. Patients must also agree to avoid live attenuated vaccines during study treatment.
  • Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents. Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren's syndrome will not be excluded from the study.

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A Phase II Study of Gemcitabine Plus Cisplatin Chemotherapy in Patients With Muscle-invasive Bladder Cancer With Bladder Preservation for Those Patients Whose Tumors Harbor Deleterious DNA Damage Response (DDR) Gene Alterations


Condition: Infiltrating Bladder Urothelial Carcinoma, Stage II Bladder Urothelial Carcinoma, Stage III Bladder Urothelial Carcinoma

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03609216

Sponsor: Alliance for Clinical Trials in Oncology

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Step 1 Patient Registration Eligibility Criteria
  • Histologically confirmed muscle-invasive urothelial carcinoma of the bladder. Urothelial carcinoma invading into the prostatic stroma with no histologic muscle invasion is allowed, provided the extent of disease is confirmed via imaging and/or examination under anesthesia (EUA). The diagnostic TURBT sample must have been obtained within 60 days prior to registration
  • 20 unstained slides (10 micron thickness) of formalin-fixed paraffin-embedded (FFPE) pre-treatment diagnostic transurethral resection (TUR) specimen available (for sequencing), with 2 (5 micron) slides at the start and end of the 20 slides, for a total of 22 unstained slides. An FFPE block is also acceptable
  • Clinical stage T2-T4aN0/xM0 disease
  • Medically appropriate candidate for radical cystectomy as assessed by surgeon
  • No concomitant multifocal carcinoma in situ; a single focus is allowed
  • A single muscle-invasive bladder tumor measuring ≤5 cm in size as defined by the surgeons at cystoscopic evaluation. When documented, pathologic size at cystoscopy and TURBT will take precedence over radiographic measurements of tumor size.
  • No clinical or radiographic evidence for locally advanced or metastatic disease
  • No prior anti-PD-1 or anti PD-L1 therapies, or systemic chemotherapy within the past 5 years (prior intravesical induction immunotherapy for non-muscle invasive disease is allowed, defined as BCG x6 doses and maintenance therapy); BCG refractory disease, defined as disease recurrence within 3 months of BCG therapy, is not allowed. Intravesical chemotherapy is allowed.
  • No prior radiation therapy to the bladder or prostate
  • No major surgery or radiation therapy =< 4 weeks of registration (TURBT is allowed).
  • Not pregnant and not nursing. This study involves an agent that has known genotoxic, mutagenic and teratogenic effects. For women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Absolute neutrophil count (ANC) >= 1,000/mm^3
  • Platelet count >= 100,000/mm^3
  • Calculated creatinine clearance ≥ 55 mL/min using formula per institutional standard or investigator's discretion. The same formula should be used to calculate all subsequent creatinine clearances.
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) * (For patients with documented Gilbert's syndrome Total Bilirubin =< 3 x ULN)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN
  • Alkaline phosphatase =< 2.5 x ULN
  • No evidence of New York Heart Association (NYHA) functional class III or IV heart disease
  • No ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade >= 2
  • No pre-existing sensory grade >= 2 neuropathy
  • No pre-existing grade >= 2 hearing loss
  • No serious intercurrent medical or psychiatric illness, including serious active infection
  • None of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack
  • No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the drugs used in this trial. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy, when indicated
  • No history of allergic reaction attributed to compounds of similar chemical or biologic composition to the agents used in this study
  • No concurrent treatment on another clinical trial; supportive care trials or non-therapeutic trials (e.g., quality of life) are allowed
  • No prior malignancy except for: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years. Patients with localized prostate cancer who are being followed by an active surveillance program are also eligible
  • Step 2 Patient Registration Eligibility Criteria
  • Patients must have completed 4 or more cycles of protocol-directed chemotherapy and DDR gene results must be available
  • Step 3 Patient Registration

Eligibility Criteria:

  • Histologically confirmed muscle-invasive urothelial carcinoma of the bladder. Urothelial carcinoma invading into the prostatic stroma with no histologic muscle invasion is allowed, provided the extent of disease is confirmed via imaging and/or examination under anesthesia (EUA). The diagnostic TURBT sample must have been obtained within 60 days prior to registration
  • 20 unstained slides (10 micron thickness) of formalin-fixed paraffin-embedded (FFPE) pre-treatment diagnostic transurethral resection (TUR) specimen available (for sequencing), with 2 (5 micron) slides at the start and end of the 20 slides, for a total of 22 unstained slides. An FFPE block is also acceptable
  • Clinical stage T2-T4aN0/xM0 disease
  • Medically appropriate candidate for radical cystectomy as assessed by surgeon
  • No concomitant multifocal carcinoma in situ; a single focus is allowed
  • A single muscle-invasive bladder tumor measuring ≤5 cm in size as defined by the surgeons at cystoscopic evaluation. When documented, pathologic size at cystoscopy and TURBT will take precedence over radiographic measurements of tumor size.
  • No clinical or radiographic evidence for locally advanced or metastatic disease
  • No prior anti-PD-1 or anti PD-L1 therapies, or systemic chemotherapy within the past 5 years (prior intravesical induction immunotherapy for non-muscle invasive disease is allowed, defined as BCG x6 doses and maintenance therapy); BCG refractory disease, defined as disease recurrence within 3 months of BCG therapy, is not allowed. Intravesical chemotherapy is allowed.
  • No prior radiation therapy to the bladder or prostate
  • No major surgery or radiation therapy =< 4 weeks of registration (TURBT is allowed).
  • Not pregnant and not nursing. This study involves an agent that has known genotoxic, mutagenic and teratogenic effects. For women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Absolute neutrophil count (ANC) >= 1,000/mm^3
  • Platelet count >= 100,000/mm^3
  • Calculated creatinine clearance ≥ 55 mL/min using formula per institutional standard or investigator's discretion. The same formula should be used to calculate all subsequent creatinine clearances.
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) * (For patients with documented Gilbert's syndrome Total Bilirubin =< 3 x ULN)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN
  • Alkaline phosphatase =< 2.5 x ULN
  • No evidence of New York Heart Association (NYHA) functional class III or IV heart disease
  • No ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade >= 2
  • No pre-existing sensory grade >= 2 neuropathy
  • No pre-existing grade >= 2 hearing loss
  • No serious intercurrent medical or psychiatric illness, including serious active infection
  • None of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack
  • No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the drugs used in this trial. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy, when indicated
  • No history of allergic reaction attributed to compounds of similar chemical or biologic composition to the agents used in this study
  • No concurrent treatment on another clinical trial; supportive care trials or non-therapeutic trials (e.g., quality of life) are allowed
  • No prior malignancy except for: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years. Patients with localized prostate cancer who are being followed by an active surveillance program are also eligible
  • Step 2 Patient Registration Eligibility Criteria
  • Patients must have completed 4 or more cycles of protocol-directed chemotherapy and DDR gene results must be available
  • Step 3 Patient Registration Eligibility Criteria (only patients with a DDR gene alteration)
  • Deleterious alteration within 1 or more of 9 pre-defined DDR genes within the pre-treatment TURBT deoxyribonucleic acid (DNA)
  • Cystoscopy and imaging performed to determine stage/treatment assignment

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A Phase 2 Study of Sitravatinib in Combination With PD-(L)1 Checkpoint Inhibitor Regimens in Patients With Advanced or Metastatic Urothelial Carcinoma


Condition: Urothelial Carcinoma, Urothelial Carcinoma Bladder, Urothelial Carcinoma Ureter, Urothelial Carcinoma of the Renal Pelvis and Ureter, Urothelial Carcinoma Urethra

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03606174

Sponsor: Mirati Therapeutics Inc.

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Diagnosis of urothelial carcinoma
  • Adequate bone marrow and organ function

Exclusion Criteria:

  • Uncontrolled tumor in the brain
  • Unacceptable toxicity with prior checkpoint inhibitor
  • Impaired heart function

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Avelumab as Neoadjuvant Therapy in Subjects With Urothelial Muscle Invasive Bladder Cancers


Condition: Non-metastatic Muscle Invasive Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03674424

Sponsor: Jules Bordet Institute

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • 1. Age ≥ 18 years old 2. Must have histologically confirmed muscle invasive urothelial carcinoma (transitional cell carcinoma) or urothelial carcinoma with mixed histology of the bladder, renal pelvis or ureters. Stage permitted: T2, T3 or T4a. T stage is based on the standard of care transurethral resection of the bladder tumour (TURBT) sample 3. Patients may have nodal disease (Nx, N0, N1 or N2) at imagery but there must be no evidence of distant metastases (M0) 4. Performance status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG). 5. Be a medically appropriate candidate for surgery as determined by an attending urologist 6. Adequate bone marrow function as defined below:
  • Absolute neutrophil count ≥1500/µL or 1.5x109/L
  • Hemoglobin ≥ 9 g/dL
  • Platelets ≥100000/µL or 100x109/L 7) 7. Adequate liver function as defined below:
  • Serum total bilirubin ≤ 1.5 x ULN. In case of known Gilbert's syndrome < 3xUNL is allowed
  • AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN 8. Serum pregnancy test (for subjects of childbearing potential) negative within 7 days prior to study treatment administration. 9. Women of childbearing potential must agree to use one highly effective method of contraception prior study entry, during the course of the study and up to 6 months after the last administration of study treatment. Men with childbearing potential partner must agree to use condom during the course of this study and up to 6 months after the last administration of the study treatment. 10. Completion of all necessary screening procedures within 28 days prior to treatment. 11. Availability of biological material for screening and/or translational research activities 12. Signed Informed Consent form (ICF) obtained prior to any study related procedure. Cisplatin-eligible cohort specific criteria: 13. Glomerular filtration rate (GFR) or Creatinine Clearance≥ 60 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) and 14. Peripheral neuropathy ≤ grade 1 and 15. Hearing impaired ≤ grade 1 and 16. Adequate cardiac function (Left Ventricular Ejection Fraction LVEF ≥ 55%) by MUGA (Multiple-Gated Acquisition) scan or echocardiography Cisplatin ineligible cohort specific criteria (if any of the following criteria): 17. Glomerular filtration rate (GFR) or Creatinine Clearance ≥ 30mL/min according to the Cockcroft-Gault formula (or local institutional standard method) or 18. Peripheral neuropathy ≥ grade 2 or 19. Hearing impaired ≥ grade 2 Inclusion criterion specific for France: 20. Patients must be affiliated to a social security system

Exclusion Criteria:

  1. Subjects meeting one of the following criteria are not eligible for this study:
  2. Metastatic disease (M1)
  3. Has had prior systemic chemotherapy, targeted small molecule therapy, or radiation therapy for urothelial carcinoma
  4. Prior treatment with drug specifically targeting T-cell co-stimulation or checkpoint pathways
  5. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  6. Has an active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
  7. Has had a prior organ transplantation including allogenic stem-cell transplantation.
  8. Has an active infection requiring systemic therapy
  9. Has a known history of Human Immunodeficiency Virus (HIV) or known acquired immunodeficiency syndrome.
  10. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA is detected)
  11. Has received vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines such as influenza vaccine.
  12. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 28 days prior to study registration
  13. History of prior invasive malignancy within 2 years (exception of adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localised prostate cancer or ductal carcinoma in situ)
  14. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)
  15. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication."
  16. Pregnant and/or lactating women.
  17. Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator's opinion, may interfere with completion of the study.
  18. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade >1); however, alopecia, sensory neuropathy Grade ≤2, or other Grade ≤2 not constituting a safety risk based on investigator's judgment are acceptable.
  19. Other severe acute chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with the study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. Exclusion criterion specific for France:
  20. Vulnerable persons according to the article L.1121-6 of the CSP, adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the CSP.

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A Pilot Study to Evaluate the Safety of Neoadjuvant Nivolumab Alone or in Combination With Ipilimumab for Cisplatin-Ineligible Patients With Muscle Invasive Bladder Cancer (CA209-9DJ)


Condition: Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03520491

Sponsor: Memorial Sloan Kettering Cancer Center

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Histologically confirmed diagnosis of urothelial carcinoma of the bladder. Variant histology is acceptable if there is a predominant urothelial component.
  • For MUSCLE-INVASIVE UROTHELIAL CANCER OF THE BLADDER (Cohorts 1
  • 3): ° Cystoscopically and radiographically confirmed cT2-4a cN0 cM0 disease. Patients with cT4a disease invading into the prostatic stroma with no cystoscopic confirmation of muscle invasion are eligible.
  • For UROTHELIAL CARCINOMA OF THE UPPER URINARY TRACT (URETER OR RENAL PELVIS) (Cohort U): °Histologically confirmed high grade urothelial carcinoma of the upper tract and/or radiographically visible tumor stage T2-T4a N0/x M0 disease with positive selective urinary cytology. Hydronephrosis associated with tumor on imaging or biopsy will be considered invasive by definition. (Variant histology is acceptable if there is a predominant urothelial component)
  • Patients ineligible for cisplatin based on any of the following criteria:
  • Estimated or calculated creatinine clearance ≥ 30ml/min but < 60 ml/min
  • Grade 2 or above audiometric hearing loss (per CTCAE v4.0)
  • Grade 2 or above peripheral neuropathy (per CTCAE v4.0)
  • Availability of tumor specimen block or 30 unstained slides from diagnosis of muscle-invasive disease. Patients with fewer than 30 slides available may be enrolled after discussion with the Principal Investigator.
  • Karnofsky performance status ≥ 70%.
  • Medically appropriate candidate for radical cystectomy, as per MSK Attending Urologic Oncologist
  • Age ≥ 18 years.
  • Required initial laboratory values:
  • Absolute neutrophil count ≥ 1.5 x 10^9/L
  • Platelets ≥ 100 x 10^9/L
  • Bilirubin ≤1.5 times the upper limit of normal (x ULN)
  • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN
  • PTT/PT ≤1.5 x ULN or INR < 1.7 x ULN for patients who are not receiving therapeutic anticoagulation. Patients receiving therapeutic anticoagulation should be on a stable dose.

Exclusion Criteria:

  • Prior treatment with systemic chemotherapy for urothelial cancer, including immune checkpoint inhibitors for non-muscle invasive bladder cancer. (Prior intravesical treatment such as BCG is allowed.)
  • Prior bladder-directed radiotherapy (exclusion applies only to MIBC Cohorts 1
  • 3).
  • Presence of active autoimmune disease, symptoms, or conditions, with the following exceptions: °Subjects with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, asymptomatic laboratory evidence of autoimmune disease (e.g.: +ANA, +RF, anti-thyroglobulin antibodies), or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  • Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study drug. Inhaled or topical steroids, and adrenal replacement steroid doses are permitted in the absence of active autoimmune disease.
  • Unstable angina.
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure.
  • History of myocardial infarction within 6 months.
  • History of stroke within 6 months.
  • Evidence of bleeding diathesis or coagulopathy. Therapeutic anticoagulation is permitted, but patients must be on a stable dose.
  • Major surgical procedure within 28 days prior to the study. (Transurethral resection of bladder tumor is permitted
  • Serious, non-healing wound, ulcer, or bone fracture.
  • Other prior malignancy active within the previous 2 years except for local or organ-confined early stage cancer that has been definitively treated with curative intent or does not require treatment, does not require ongoing treatment, has no evidence of active disease, and has a negligible risk of recurrence and is therefore unlikely to interfere with the endpoints of the study.
  • Subjects who have received prior therapy with any T cell co-stimulation or checkpoint pathways such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, anti-CD137; or other medicines specifically targeting T cells are prohibited. Prior IL-2 is permitted.
  • Prior therapy with intravesical BCG within 6 weeks of treatment.
  • Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection.
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
  • History of allergy to study drug component or history of severe hypersensitivity reaction to any monoclonal antibody.
  • Women who are breastfeeding or pregnant as evidenced by a positive pregnancy test within 14 days of first dose.
  • Male subjects who are unwilling to use contraception during the treatment and for at least 31 weeks after the last dose of study treatment (5 half-lives of study drug plus 90 days duration of sperm turnover).
  • Women of childbearing potential (WOCBP) not using a medically acceptable means of contraception throughout the study treatment and for at least 23 weeks following the last dose of study treatment (5 half-lives of study drug plus 30 days duration of ovulatory cycle).
  • WOCBP are defined as those who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post-menopausal is defined as:
  • Amenorrhea ≥ 12 consecutive months without another cause, or
  • For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
  • Inability to comply with study and/or follow-up procedures.

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A Phase I Single-Arm Study of the Combination of Durvalumab (MEDI4736) and Vicineum (Oportuzumab Monatox, VB4-845) in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Gu(SqrRoot)(Copyright)Rin (BCG)


Condition: Urinary Bladder Neoplasms

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03258593

Sponsor: National Cancer Institute (NCI)

Phase: Phase 1

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed by NCI Laboratory of Pathology as high grade non-muscle invasive urothelial (transitional cell carcinoma) of the bladder as follows:
  • Carcinoma-in-situ (CIS) with or without papillary tumors
  • High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of the initial dose of study treatment. If multiple bladder biopsies/TURBTs are required to confirm eligibility, the timing of the last bladder biopsy to the initial dose of study treatment must be within 12 weeks.
  • Patients with persistent T1 high grade disease on TURBT following a single induction course of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that the patient is surgically unfit for cystectomy as deemed by the investigator or the patient declines cystectomy.
  • Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and the FDA: Subjects must have received at least two courses of intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat induction course). Please note exception above for persistent T1 disease. There is no upper limit on the amount of prior BCG a subject may have received.
  • Patients who have met eligibility criterion above must have received last BCG dose within a year of enrollment.
  • The investigator must document that he/she believes the subject would not benefit from additional BCG treatment at the time of study entry.
  • Age >= 18 years at time of signing the informed consent form (ICF). Because no dosing or adverse event data are currently available on the use of Vicineum in combination with durvalumab in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. Furthermore, NMIBC does not occur in children.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Adequate organ and marrow function as defined below:
  • Hemoglobin >= 9.0 g/dL
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3)
  • Platelet count >= 75 x 10^9/L (>75,000 per mm^3)
  • Serum bilirubin less than or equal to 1.5 x institutional upper limit of normal (ULN).
  • AST (SGOT)/ALT (SGPT) less than or equal to 2.5 x institutional ULN
  • Creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
  • Males: Creatinine CL (mL/min) = (Weight (kg) x (140
  • Age))/72 x serum creatinine (mg/dL)
  • Females: Creatinine CL (mL/min)= (Weight (kg) x (140
  • Age) x 0.85 )/72 x serum creatinine (mg/dL)
  • Female subjects must either be of non-reproductive potential (i.e., post-menopausal as described below) OR history of surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
  • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
  • Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, or had chemotherapy-induced menopause with last menses >1 year ago
  • The effects of Vicineum and durvalumab on the developing human fetus are unknown. For this reason, all sexually active subjects agree to use barrier contraception (i.e., condoms) while receiving study treatment and for 120 days following their last dose of study treatment. Female subjects of child-bearing potential and male subjects whose sexual partners are WOCBP agree to use barrier contraception and a second form of contraception while receiving study treatment and for 4 months following their last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Written informed consent obtained from the subject prior to performing any protocol- related procedures
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  • Body weight > 30 kg

Exclusion Criteria:

  • Patients who are receiving any other investigational agents.
  • QT interval corrected for heart rate using Fridericia s formula (QTcF) >=470 ms. (Any clinically significant abnormalities detected require triplicate ECG results and a mean QT interval corrected for heart rate using Fridericia s formula (QTcF) >=470 ms calculated from 3 ECGs.)
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to Vicineum or durvalumab or other agents used in the study.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Urinary tract infections (UTIs) are excluded from being an exclusion criterion for treatment unless they are grade 3 or higher.
  • Pregnant women are excluded from this study because it is unknown whether Vicineum and/or durvalumab have any teratogenic effects. In nursing mothers, breastfeeding should be discontinued as these medications may have the potential risk for adverse events in nursing infants secondary to treatment of the mother.
  • Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
  • Evidence of non-bladder urothelial (transitional cell) carcinoma by biopsy, cytology, or radiological imaging within the past 2 years of treatment (e.g. upper tract transitional cell carcinoma, urethral urothelial carcinoma).
  • Subjects with hydronephrosis, except for those subjects where hydronephrosis has been longstanding (i.e., predates the diagnosis of the CIS, Ta, or T1 by more than 2 years) and diagnostic evaluation at screening shows no evidence of tumor causing the hydronephrosis.
  • Any other anticancer therapy (e.g., chemotherapy, biologic therapy, immunotherapy, targeted therapy, endocrine therapy, radiation therapy, intravesical therapy, investigational agent) within 28 days of the first dose of study therapy (and within 6 weeks for nitrosourea or mitomycin C) other than a single dose of intravesical chemotherapy which is permitted between 28 days and 14 days prior to the first dose of study treatment.
  • The subject has a diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancer, localized prostate cancer on active surveillance, or localized solid tumors deemed cured by surgery and not treated with systemic anticancer therapy and not expected to require anticancer therapy in the next 2 years i.e., while the subject may be taking study treatment.
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
  • Subjects with vitiligo or alopecia
  • Subjects with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormonal replacement
  • Any chronic skin condition that does not require systemic therapy
  • Subjects without active disease in the last 5 years may be included but only after consultation with the Principal Investigator
  • Subjects with celiac disease controlled by diet alone
  • History of primary immunodeficiency.
  • History of allogeneic organ transplant.
  • History of hypersensitivity to durvalumab or any excipient
  • History of hypersensitivity to Vicineum or its components
  • Active infection with tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and PPD testing if indicated), hepatitis B (known positive HBV surface antigen (HBsAg) result, hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with HIV are excluded from participating on this clinical trial because their immunodeficiency would confound the evaluation of adverse events which would hinder meeting the primary objective. Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • History of leptomeningeal carcinomatosis
  • Receipt of live attenuated vaccination within 30 days prior to the first dose of Vicineum or durvalumab
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
  • Subjects with uncontrolled seizures
  • Any unresolved toxicity NCI CTCAE Grade >=2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
  • Subjects with Grade >=2 neuropathy will be evaluated on a case-by-case basis after consultation with the Principal Investigator.
  • Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Principal Investigator.

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PhAse 1/2 StuDy of Modern ImmunotherApy in BCG-RelaPsing UroThelial Carcinoma of the BLADDER - (ADAPT-BLADDER) HCRN GU16-243


Condition: Urothelial Carcinoma, Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03317158

Sponsor: Noah Hahn, M.D.

Phase: Phase 1/Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • (All Patients): Subject must meet all of the following applicable criteria to participate in this study:
  • Histologically confirmed non-muscle invasive urothelial carcinoma of the bladder (Ta, T1, or Tis stage) on TURBT obtained within 42 days of registration.
  • ECOG (WHO) performance status 0 or 1
  • Age ≥ 18 years old at time of consent
  • Adequate hematologic, hepatic, and renal function as defined by the following laboratory parameters:
  • White blood cell count (WBC) > 3.0 K/mm^3
  • Absolute neutrophil count (ANC) ≥ 1.5 K/mm^3
  • Platelets ≥ 100 K/mm^3
  • Hemoglobin (Hgb) ≥ 9 g/dL
  • Serum total bilirubin: ≤ 1.5 x ULN
  • ALT and AST ≤ 2.5 x ULN
  • Serum creatinine clearance (CrCl) ≥ 30 mL/min using the Cockcroft-Gault equation, see formula below:
  • CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if subject is female multiply the above by 0.85)
  • Subjects who give a written informed consent obtained according to local guidelines. Inclusion Criteria (Phase 1 Only):
  • In addition to the inclusion criteria required of all patients listed above, the following inclusion criteria are also required of patients enrolling to Phase 1 of the study.
  • BCG-unresponsive disease defined by any of the following:
  • Persistent or recurrent CIS with or without the presence of concurrent Ta or T1 tumors within 12 months of completion of adequate BCG therapy
  • Recurrent high-grade Ta or T1 tumors within 6 months of completion of adequate BCG therapy NOTE: In recognition of the fact that procedure scheduling factors beyond the control of the patient or treating physician may cause unintended delays in disease evaluations, patients with pure papillary tumors (Ta or T1) with no components of CIS with recurrence documented within 9 months of completion of adequate BCG therapy who meet all other

Eligibility Criteria:

  • may be considered for enrollment after consultation with the study chair.
  • Persistent T1 high-grade tumors at the first disease evaluation (e.g. 3- month post-treatment evaluation) following an adequate BCG induction course
  • Prostatic urethra involvement of NMIBC Adequate BCG therapy is defined as at least one of the following:
  • At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 3 doses of maintenance therapy
  • At least 5 of 6 doses of an initial induction BCG course plus at least 2 of 6 doses of a second induction course NOTE: Patients with concurrent non-muscle invasive tumors (CIS, Ta, T1) in the prostatic urethra and/or concurrent non-invasive tumors (CIS, Ta) in the upper urinary tracts (ureter, renal pelvis) are permitted to enroll in Phase 1 of the study. Patients with concurrent T1 tumors in the upper urinary tracts (ureter, renal pelvis) are not eligible to enroll in Phase 1 of the study. Patients who have met the BCG-unresponsive criteria at any time point in their treatment history are permitted to enroll in Phase 1 of the study regardless of the time frame between their most recent BCG treatment administration and study registration dates. Inclusion Criteria (Phase 2 Only):
  • In addition to the inclusion criteria required of all patients listed above, the following inclusion criteria are also required of patients enrolling to Phase 2 of the study. Intermediate or high-risk NMIBC defined according to modified EORTC risk criteria summarized as follows:
  • Low-risk Tumors Initial or recurrent tumor > 12 months after resection with all of the following:
  • Solitary tumor
  • Low-grade
  • < 3 cm
  • No CIS
  • Intermediate-Risk Tumors: All tumors not defined in the two adjacent categories (between the category of low- and high-risk).
  • High-risk Tumors: Any of the following:
  • T1 tumor
  • High-grade
  • CIS
  • Multiple and recurrent and large (> 3 cm) Ta low-grade tumors (all conditions must be met for this point on Ta low-grade tumors).
  • Documented recurrence within 15 months of last exposure to intravesical therapy.
  • Recurrence after 1 prior induction course of intravesical BCG. 8. BCG-relapsing NMIBC defined as recurrent intermediate- or high-risk NMIBC after achievement of a complete response to initial BCG induction therapy which does not meet any of the BCG-unresponsive criteria outlined in section 3.1.2. OR BCG-persistent NMIBC defined as persistent intermediate- or high-risk NMIBC at the first disease evaluation after initial BCG induction therapy (with no intervening achievement of complete response) for which a second course of BCG induction therapy is considered a standard of care (e.g. CIS or high grade Ta tumors) which does not meet any of the BCG-unresponsive criteria outlined in section 3.1.2. NOTE: Patients who have received additional non-BCG based intravesical therapies (e.g. chemotherapy, non-BCG investigational agents) are eligible provided they have received only 1 prior course of BCG induction therapy and satisfy the above BCG-relapsing or BCG-persistent definitions. Inclusion Criteria (Phase 2 Patients with Persistent or Relapsed NMIBC who Cross-Over to Durvalumab Only):
  • In addition to the inclusion criteria described of all patients listed above, the following inclusion criteria are also required of patients originally enrolled in Phase 2 of the study who are noted to have NMIBC in follow up and opt to cross-over to durvalumab monotherapy.
  • Subjects with BCG-unresponsive disease defined by any of the following:
  • Prior treatment with 2 or more adequate courses of BCG (at least 5 of 6 induction installations and at least 2 of 3 maintenance installations for subjects on maintenance therapy).
  • Persistent T1 high-grade disease at the initial 3-month cystoscopy/TURBT assessment in subjects who received 5 of 6 inductions BCG installations.
  • Relapsed NMIBC within 6 months of last exposure to BCG
  • Prostatic urethra involvement of NMIBC Primary Exclusion Criteria: Exclusion Criteria (All Patients):
  • Subjects with muscle-invasive (i.e. T2, T3, T4), locally advanced unresectable, or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 28 days prior to study registration. The required radiographic imaging includes:
  • Abdomen/Pelvis
  • CT scan
  • Chest
  • chest x-ray or CT scan
  • Subjects with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer. Subjects that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment.
  • Subjects who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy.
  • Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria:
  • Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the sponsor-investigator.
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the sponsor-investigator.
  • Subjects who have received prior therapy with PD-1 or PD-L1 directed agents.
  • Subjects who have had any prior radiation to the prostate or pelvis.
  • Subjects who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or subjects who have had minor procedures (i.e. TURBT), percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury.
  • Subjects with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
  • Clinically significant cardiac diseases, including any of the following:
  • History or presence of serious uncontrolled ventricular arrhythmias.
  • Clinically significant resting bradycardia.
  • Any of the following within 3 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE).
  • Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s).
  • Cirrhosis
  • Active Infection (includes chronic active and chronic persistent).
  • Tuberculosis
  • Hepatitis B (known positive HBV surface antigen (HbsAg). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HbsAg) are eligible.
  • Hepatitis C. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Known diagnosis of human immunodeficiency virus (HIV/positive HIV 1/2 antibodies) infection (HIV testing is not mandatory).
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia.
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement.
  • Any chronic skin condition that does not require systemic therapy.
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
  • Patients with celiac disease controlled by diet alone.
  • Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
  • Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted.
  • Pregnant or breast-feeding women. Women of child-bearing potential must have a negative urine or serum test ≤ 14 days prior to starting study drug.
  • Women of child-bearing potential, who are biologically able to conceive, and not employing two forms of highly effective contraception or abstinence. Highly effective contraception or abstinence must be used from the time of informed consent, throughout the trial and up to 180 days after the last dose of durvalumab (e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device). Women of child-bearing potential are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  • Fertile males not willing to use contraception or abstinence, as stated above. Contraception or abstinence must be followed from screening through 180 days after receipt of the final dose of durvalumab therapy.
  • Subjects unwilling or unable to comply with the protocol.
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. Exclusion Criteria (Phase 1 Only):
  • In Phase 1 of the study, there are no additional exclusion criteria beyond those described of all patients in the section listed above. Exclusion Criteria (Phase 2 Only):
  • In addition to the exclusion criteria described of all patients listed above, the following exclusion criteria apply to patients enrolling to Phase 2 of the study.
  • Subjects with BCG-unresponsive disease defined by any of the following:
  • Prior treatment with 2 or more adequate courses of BCG (at least 5 of 6 induction installations and at least 2 of 3 maintenance installations for subjects on maintenance therapy).
  • Persistent T1 high-grade disease at the initial 3-month cystoscopy/TURBT assessment in subjects who received 5 of 6 inductions BCG installations.
  • Relapsed NMIBC within 6 months of last exposure to BCG.
  • Prostatic urethra involvement of NMIBC.
  • Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis) non-invasive urothelial carcinoma. Exclusion Criteria (Phase 2 Patients with Persistent or Relapsed NMIBC who Cross-Over to Durvalumab Only):
  • In addition to the exclusion criteria described of all patients listed above, the following

Exclusion Criteria:

  • Exclusion Criteria (All Patients):
  • Subjects with muscle-invasive (i.e. T2, T3, T4), locally advanced unresectable, or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 28 days prior to study registration. The required radiographic imaging includes:
  • Abdomen/Pelvis
  • CT scan
  • Chest
  • chest x-ray or CT scan
  • Subjects with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer. Subjects that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment.
  • Subjects who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy.
  • Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria:
  • Patients with Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the sponsor-investigator.
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the sponsor-investigator.
  • Subjects who have received prior therapy with PD-1 or PD-L1 directed agents.
  • Subjects who have had any prior radiation to the prostate or pelvis.
  • Subjects who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or subjects who have had minor procedures (i.e. TURBT), percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury.
  • Subjects with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:
  • Clinically significant cardiac diseases, including any of the following:
  • History or presence of serious uncontrolled ventricular arrhythmias.
  • Clinically significant resting bradycardia.
  • Any of the following within 3 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE).
  • Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s).
  • Cirrhosis
  • Active Infection (includes chronic active and chronic persistent).
  • Tuberculosis
  • Hepatitis B (known positive HBV surface antigen (HbsAg). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HbsAg) are eligible.
  • Hepatitis C. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Known diagnosis of human immunodeficiency virus (HIV/positive HIV 1/2 antibodies) infection (HIV testing is not mandatory).
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia.
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement.
  • Any chronic skin condition that does not require systemic therapy.
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
  • Patients with celiac disease controlled by diet alone.
  • Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
  • Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted.
  • Pregnant or breast-feeding women. Women of child-bearing potential must have a negative urine or serum test ≤ 14 days prior to starting study drug.
  • Women of child-bearing potential, who are biologically able to conceive, and not employing two forms of highly effective contraception or abstinence. Highly effective contraception or abstinence must be used from the time of informed consent, throughout the trial and up to 180 days after the last dose of durvalumab (e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device). Women of child-bearing potential are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  • Fertile males not willing to use contraception or abstinence, as stated above. Contraception or abstinence must be followed from screening through 180 days after receipt of the final dose of durvalumab therapy.
  • Subjects unwilling or unable to comply with the protocol.
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. Exclusion Criteria (Phase 1 Only):
  • In Phase 1 of the study, there are no additional exclusion criteria beyond those described of all patients in the section listed above. Exclusion Criteria (Phase 2 Only):
  • In addition to the exclusion criteria described of all patients listed above, the following exclusion criteria apply to patients enrolling to Phase 2 of the study.
  • Subjects with BCG-unresponsive disease defined by any of the following:
  • Prior treatment with 2 or more adequate courses of BCG (at least 5 of 6 induction installations and at least 2 of 3 maintenance installations for subjects on maintenance therapy).
  • Persistent T1 high-grade disease at the initial 3-month cystoscopy/TURBT assessment in subjects who received 5 of 6 inductions BCG installations.
  • Relapsed NMIBC within 6 months of last exposure to BCG.
  • Prostatic urethra involvement of NMIBC.
  • Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis) non-invasive urothelial carcinoma. Exclusion Criteria (Phase 2 Patients with Persistent or Relapsed NMIBC who Cross-Over to Durvalumab Only):
  • In addition to the exclusion criteria described of all patients listed above, the following exclusion criteria apply to patients enrolling to the cross-over to durvalumab portion of the Phase 2 study.
  • Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis) non-invasive urothelial carcinoma.

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Phase II Trial of Neutron Radiotherapy With Concurrent Checkpoint Inhibitor Immunotherapy (Pembrolizumab) in Patients With Advanced Urothelial Carcinoma


Condition: Urothelial Carcinoma

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03486197

Sponsor: University of Washington

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Pathologically proven (either histologic or cytologic) diagnosis of urothelial carcinoma
  • At least two sites of disease that are measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • Eligible for checkpoint inhibitor immunotherapy (pembrolizumab) per standard of care
  • No history of autoimmune disease requiring systemic therapy (e.g. steroids or biologic agents)
  • Absolute neutrophil count (ANC) ≥ 1500 /mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin > 9 g/dL
  • Creatinine ≤ 1.5 x upper limit of normal (ULN) OR ≥ 60 mL/min
  • Total bilirubin ≤ 1.5 ULN OR direct bilirubin ≤ ULN if total bilirubin > 1.5 x ULN
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN OR < 5 x ULN if patient has liver metastasis
  • Albumin >= 2.5 g/dL
  • International normalized ratio (INR) or PT ≤ 1.5 x ULN unless on anticoagulation therapy, in which case prothrombin time (PT) or partial thromboplastin time (PTT) should be in the therapeutic range
  • PTT ≤ 1.5 x ULN unless on anticoagulation therapy, in which case PT or PTT should be in the therapeutic range
  • Eligible for neutron radiation treatment to 1-3 sites of metastatic disease (lesions do not have to be symptomatic)
  • No steroids for at least 2 weeks prior to enrollment, and patient must not be expected to require steroids during the study period
  • Zubrod performance status 0-2
  • Patient must sign study specific informed consent prior to study entry
  • Patients who are sexually active must use medically acceptable forms of contraception
  • Life expectancy must be > 3 months

Exclusion Criteria:

  • Has a known history of active TB (Bacillus tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has a known additional malignancy that is progressing or requires active treatment
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known history of, or any evidence of active, non-infectious pneumonitis
  • Has an active infection requiring systemic therapy
  • Has received a live vaccine within 30 days of planned start of study therapy
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided there is no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

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A Study of Enfortumab Vedotin (ASG-22CE) as Monotherapy or in Combination With Other Anticancer Therapies for the Treatment of Urothelial Cancer


Condition: Carcinoma, Transitional Cell, Urinary Bladder Neoplasms, Urologic Neoplasms, Renal Pelvis Neoplasms, Urothelial Cancer, Ureteral Neoplasms, Urethral Neoplasms

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03288545

Sponsor: Astellas Pharma Global Development, Inc.

Phase: Phase 1/Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Locally advanced or metastatic urothelial cancer (la/mUC)
  • Cohorts A, B, D, E, F, G and K.
  • Histologically documented la/mUC, including squamous differentiation or mixed cell types.
  • An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2: Participants with ECOG performance status of 2 must meet the following additional criteria: hemoglobin ≥10 g/dL, GFR ≥50 mL/min, may not have NYHA Class III heart failure.
  • Eligible for pembrolizumab (Dose-escalation cohorts, Cohorts A, B, G and K Combination Arm).
  • Dose-escalation cohorts: Ineligible for first-line cisplatin-based chemotherapy and no prior treatment for la/mUC, or have disease progression following at least 1 platinum-containing treatment.
  • Cohort A: Ineligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  • Cohort B: Must have disease progression during/following treatment with at least 1 platinum-containing regimen for la/mUC or disease recurrence.
  • Cohort D: Eligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  • Cohort E: Ineligible for cisplatin-based chemotherapy, eligible for carboplatin, and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  • Cohort F: Ineligible for platinum-based chemotherapy, or disease progression during/following at least 1 prior treatment for la/mUC. Eligible for gemcitabine.
  • Cohort G: Eligible for platinum-based chemotherapy (either cisplatin or carboplatin) and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  • Cohort K: Ineligible for cisplatin-based chemotherapy due to at least 1 of the following: Glomerular filtration rate (GFR) <60 mL/min and ≥30 mL/min, ECOG performance status of 2, NCI CTCAE Version 4.03 Grade ≥2 hearing loss, New York Heart Association (NYHA) Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease. No adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
  • Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.
  • Histologically confirmed MIBC with predominant >50% urothelial histology: Cohorts H and J: Clinical stage cT2-T4aN0M0; Cohort L: Clinical stage cT2-T4aN0M0 or cT1-T4aN1M0: Participants with pT1 disease are eligible only if they have N1 disease on imaging. Mixed cell types are eligible if urothelial cancer is predominant (>50%); Participants with plasmacytoid and/or neuroendocrine tumors are ineligible regardless of component percentage. Urothelial tumors not originating in the bladder (eg, upper tract tumors, urethral tumors) are ineligible.
  • Must be cisplatin-ineligible.
  • Cohort-specific eligibility: Cohort J, H, and L: No prior systemic treatment, chemoradiation, or radiation therapy for MIBC. May have received prior intravesical Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy for non-MIBC; Cohort J: Eligible for pembrolizumab.
  • ECOG performance status of 0, 1, or 2.
  • Anticipated life expectancy of ≥3 months.
  • Tumor samples with an associated pathology report from the diagnostic transurethral resection of a bladder tumor done 90 days prior to the first dose of study treatment must be available prior to enrollment and determined to be sufficient for pathology review and biomarker analysis.
  • Participants must be deemed eligible for RC+PLND.

Exclusion Criteria:

  • la/mUC
  • Cohorts A, B, D, E, F, G, and K
  • Received any prior treatment with a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor, except Cohort F.
  • Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, OX-40 agonists, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (except Cohort F).
  • Ongoing sensory or motor neuropathy Grade 2 or higher.
  • Active central nervous system (CNS) metastases.
  • Ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment (including radiotherapy or surgery).
  • Conditions requiring high doses of steroids or other immunosuppressive medications.
  • Prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).
  • Uncontrolled diabetes mellitus.
  • MIBC
  • Cohorts H, J, and L
  • Received prior systemic treatment, chemoradiation, and/or radiation therapy of muscle invasive bladder cancer.
  • Received any prior treatment with a CPI.
  • Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists.
  • For participants in Cohort H, evidence of nodal disease on imaging. For participants in Cohort L, ≥N2 nodal disease on imaging.
  • Participant has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC.
  • Ongoing sensory or motor neuropathy Grade 2 or higher.
  • Conditions requiring high doses of steroids or other immunosuppressive medications.
  • Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer.
  • Participants with a history of another invasive malignancy within 3 years before first dose of study drug.

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A Phase 3, Open-label, Randomized Study of Nivolumab Combined With Ipilimumab, or With Standard of Care Chemotherapy, Versus Standard of Care Chemotherapy in Participants With Previously Untreated Unresectable or Metastatic Urothelial Cancer


Condition: Urothelial Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03036098

Sponsor: Bristol-Myers Squibb

Phase: Phase 3

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Histological or cytological evidence of metastatic or surgically inoperable transitional cell cancer (TCC) of the urothelium involving the renal pelvis, ureter, bladder or urethra
  • No prior systemic chemotherapy for metastatic or surgically inoperable urothelial cancer (UC)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
  • Women and men must agree to follow specific methods of contraception, if applicable Exclusion Criteria:
  • Disease that is suitable for local therapy administered with curative intent
  • Any serious or uncontrolled medical disorder in the opinion of the investigator that may increase the risk associated with study participation or study drug administration or interfere with the interpretation of study results
  • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Other protocol-defined inclusion/

Exclusion Criteria:

  • Disease that is suitable for local therapy administered with curative intent
  • Any serious or uncontrolled medical disorder in the opinion of the investigator that may increase the risk associated with study participation or study drug administration or interfere with the interpretation of study results
  • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Other protocol-defined inclusion/exclusion criteria apply

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Randomized Phase II Study of Neoadjuvant Nivolumab With and Without Urelumab in Cisplatin-Ineligible or Chemotherapy-refusing Patients With Muscle-Invasive Urothelial Carcinoma of the Bladder


Condition: Urothelial Carcinoma, Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02845323

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Electively refusing cisplatin-based neoadjuvant chemotherapy or
  • Ineligible to receive cisplatin-based neoadjuvant chemotherapy based upon at least one of the following criteria:
  • Creatinine clearance < 60 ml/min
  • ECOG status =2
  • Grade > 2 hearing loss
  • Grade > 2 neuropathy
  • New York Heart Association Class III heart failure
  • Age ≥ 18 years old at time of consent
  • Patients must have the following laboratory values: a) Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 (must be stable off any growth factor within 4 weeks of first study drug administration) b) Platelets ≥ 100 K/mm3 (transfusion to achieve this level is not permitted within 2 weeks of first study drug administration) c) Hemoglobin (Hgb) ≥ 9 g/dL d) Serum total bilirubin: ≤ 1.5 x ULN e) ALT and AST ≤ 3.0 x ULN f) Serum creatinine clearance (CrCl) ≥ 30 mL/min using the Cockcroft-Gault equation, see formula below:
  • CrCl = [140-age (years)] x weight (kg) / [72 x serum Cr (mg/dL)] (if patient is female multiply the above by 0.85)
  • Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria:

  • Patients with locally advanced unresectable or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 28 days prior to study registration. The required radiographic imaging includes: a) Abdomen/Pelvis
  • CT scan b) Chest
  • chest x-ray or CT scan
  • Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma.
  • Patients with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer
  • Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
  • Patients who have received prior therapy with immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, anti-LAG3, anti-CTLA-4) or immune costimulatory molecules (e.g. anti-CD137, anti-OX40, anti-GITR) directed agents.
  • Patients who have had radiotherapy ≤ 4 weeks prior to starting study drug, or who have not recovered from radiotherapy toxicities
  • Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting study drug, or patients who have had minor procedures (i.e. TURBT), percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
  • Patients with history of alcoholic or non-alcoholic steatohepatitis (NASH), auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis. (Note: Patients with radiographic evidence of steatohepatitis are excluded unless a liver biopsy is obtained demonstrating no evidence of alcoholic or non-alcoholic steatohepatitis).
  • Patient with history of prior solid organ or allogeneic bone marrow transplant.
  • Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: 1. Clinically significant cardiac diseases, including any of the following: i. History or presence of serious uncontrolled ventricular arrhythmias ii.Clinically significant resting bradycardia iii.Any of the following within 3 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA), Pulmonary Embolism (PE) iv.Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s) b) Cirrhosis, chronic active hepatitis or chronic persistent hepatitis c) Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) d) Known diagnosis of any condition (i.e. post-hematopoietic or organ transplant, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy. Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted. For questions, please consult the study chair. e) Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
  • Pregnant or breast-feeding women
  • Women of child-bearing potential, who are biologically able to conceive, and not employing two forms of highly effective contraception. Highly effective contraception must be used throughout the trial and up to 8 weeks after the last dose of study drug (e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device). Women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 14 days prior to starting study drug
  • Fertile males not willing to use contraception, as stated above
  • Patients unwilling or unable to comply with the protocol

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Phase II Study to Evaluate the Activity of Commercially Available Molecularly Matched Targeted Therapies in Selected Tumor Types Based on Genomic Alterations


Condition: Non-small Cell Lung Carcinoma, Urothelial Carcinoma, Gastrointestinal Carcinoma, Non-colon, Upper Aerodigestive Tract Carcinoma

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02795156

Sponsor: SCRI Development Innovations, LLC

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • 1. Patients with a histologically or cytologically confirmed diagnosis of one of the following tumor types whose disease has progressed following one line of standard therapy and/or for which no standard treatment is available that has been shown to prolong survival: 1. Non-small cell lung cancer 2. Urothelial carcinoma 3. Non-colon gastrointestinal cancers (including hepatobiliary, pancreatic, and gastroesophageal tumors) 4. Upper aerodigestive tract cancers (including lip, tongue, salivary gland, gum, oral cavity, mouth, tonsils, oropharynx, nasopharynx, nasal cavity, sinus, and larynx tumors) 2. Patients must have a predefined genomic alteration that can be targeted with any of the FDA-approved targeted agents used in this study. 3. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 5. Age greater than or equal to 18 years. 6. Adequate hematologic function defined as:
  • Absolute neutrophil count (ANC) ≥1500/μL
  • Platelets ≥75,000/μL 7. Adequate liver function defined as:
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x the upper limit of normal (ULN) or ≤ 5.0 X ULN if liver metastases present
  • Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin elevation due to Gilbert's disease or a similar syndrome involving slow conjugation of bilirubin) 8. Adequate renal function defined as serum creatinine ≤1.5 x the upper limit of normal OR measured or calculated creatinine clearance ≥50 mL/min for patients with creatinine levels greater than or equal to 1.5 x the upper limit of normal. 9. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to receive either regorafenib or afatinib provided that their medication dose and INR/PTT are stable. Close monitoring is mandatory if the patient is receiving anticoagulants. If values are above the therapeutic range the anticoagulant doses should be modified and assessments should be repeated until stable. 10. Male patients with female partners of childbearing potential and women patients of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 90 days following last dose of study drug(s). Male patients must also refrain from donating sperm during their participation in the study and for 90 days after the last dose of study drug. 11. Willingness and ability to comply with study and follow-up procedures. 12. Ability to understand the nature of this study and give written informed consent.

Exclusion Criteria:

  • 1. Two or more prior chemotherapy regimens in the metastatic setting. 2. Most recent chemotherapy ≤ 3 weeks and > Grade 1 chemotherapy-related side effects, with the exception of neuropathy (> grade 2 excluded) and alopecia. 3. Use of a study drug or targeted therapy ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of study treatment. For study drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the study drug and administration of study treatment is required. 4. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy. 5. Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement. 6. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 2 weeks prior to study entry and there is no evidence of central nervous system disease progression, mild neurologic symptoms, and no requirement for chronic corticosteroid therapy. Enzyme-inducing anticonvulsants are contraindicated. 7. Pregnant or lactating 8. Acute or chronic liver, renal, or pancreas disease. 9. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy. 10. Any of the following cardiac diseases currently or within the last 6 months:
  • Unstable angina pectoris
  • Congestive heart failure (New York Heart Association (NYHA) ≥ Grade 2
  • Acute myocardial infarction
  • Conduction abnormality not controlled with pacemaker or medication
  • Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
  • Valvular disease with significant compromise in cardiac function 11. Inadequately controlled hypertension. 12. Thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of start of treatment. 13. Evidence or history of bleeding diathesis or coagulopathy; any haemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of treatment. 14. For patients receiving cabozantinib only: Do not administer cabozantinib to patients that have high risk or at high risk for severe haemorrhage. Examples include: 1. The patient has radiographic evidence of cavitating pulmonary lesion(s). 2. The patient has tumor invading or encasing any major blood vessels. 3. The patient has had hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment. 4. The patient has experienced clinically significant GI bleeding within 6 months of the first dose of study treatment. 5. The patient has experienced any other signs indicative of pulmonary hemorrhage within 3 months of the first dose of study treatment. 15. For patients receiving cabozantinib only: Do not administer cabozantinib to patients that have high risk or at high risk of perforation or fistula: 1. The patient has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction. 2. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose. 3. The patient has pre-existing fistula of head and neck area. Note: Treatment areas should be healed with no sequelae from prior radiation therapy that would predispose to fistula formation. 4. The patient has pre-existing osteonecrosis of the jaw. 16. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors. [Patients receiving cabozantinib only] 17. Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12 weeks before randomization, and who have had no complications from a thromboembolic event or the anticoagulation regimen.Presence of a non-healing wound, non-healing ulcer, or bone fracture. 18. Patients with phaeochromocytoma. 19. Serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment. 20. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C. 21. Presence of other active cancers unless indolent and not requiring therapy. Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma are eligible, as are patients with history of non-melanoma skin cancer. 22. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

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Peking University First Hospital


Condition: Upper Tract Urothelial Carcinoma, Bladder Recurrence

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02740426

Sponsor: Peking University First Hospital

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • Suspected UTUC patients without history of bladder tumor.
  • Suspected UTUC patients without synchronous bladder tumor.
  • Suspected UTUC patients without contralateral UTUCs.

Exclusion Criteria:

  • Patients with history of bladder tumor.
  • Patients with synchronous bladder tumor.
  • Patients with contralateral UTUCs.
  • Patients with advanced stage (T4).
  • Patients with other malignant tumors.

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A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of INCB054828 in Subjects With Advanced Malignancies (FIGHT-101)


Condition: Lung Cancer, Solid Tumor, Gastric Cancer, Urothelial Cancer, Endometrial Cancer, Multiple Myeloma, Myeloproliferative Neoplasms, Breast Cancer, Cholangiocarcinoma, UC, MPN

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02393248

Sponsor: Incyte Corporation

Phase: Phase 1/Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • 1. Male or female subjects, age 18 years or older on day of signing consent 2. Part 1: Any advanced solid tumor malignancy; Part 2: Subjects with squamous non-small cell lung cancer, cholangiocarcinoma/gastric cancer, urothelial cancer, breast/endometrial cancer, multiple myeloma, or MPNs that have a tumor or malignancy that has been evaluated and confirmed to harbor genetic alterations in FGF or FGFR genes. A subject's fibroblast growth factor (FGF) or fibroblast growth factor receptor (FGFR) alteration may be based on local or central laboratory results. Part 3: Dose finding: subjects with solid tumor malignancies who qualify for combo therapy; dose-expansion: FGF/FGFR+ subjects qualified to receive combo therapy 3. Has progressed after prior therapy and there is no further effective standard anticancer therapy available (including subject refuses or is intolerant) 4. Life expectancy > 12 weeks 5. Eastern Cooperative Oncology Group (ECOG) performance status:
  • Part 1: 0 or 1
  • Part 2 and 3: 0, 1, or 2

Exclusion Criteria:

  1. Treatment with other investigational study drug for any indication for any reason, or receipt of anticancer medications within 21 days or 5 half-lives before first dose of study drug
  2. Prior receipt of a selective FGFR inhibitor
  3. History of a calcium/phosphate homeostasis disorder
  4. History and/or current evidence of ectopic mineralization/calcification
  5. Current evidence of corneal disorder/keratopathy
  6. Has a history or presence of inadequate liver, renal, hematopoietic and/or cardiac function parameters outside protocol-defined range
  7. Prior radiotherapy within 2 weeks of study treatment

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Prospective Randomized Phase II Trial: Single Instillation Versus Long-term Prophylactic Intravesical Instillation of Pirarubicin in the Prevention of Bladder Recurrence After Nephroureterectomy for Primary Upper Tract Urothelial Carcinoma


Condition: Intravesical Instillation

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT03030157

Sponsor: RenJi Hospital

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

Inclusion Criteria:

  • clinically diagnosed with upper tract urothelial carcinoma
  • have no distant metastasis
  • have an ECOG 0 to 2
  • expected to receive radical nephroureterectomy

Exclusion Criteria:

  • a prior history of bladder or synchronous bladder cancer
  • administration of neoadjuvant chemotherapy
  • the presence of severe complications
  • deny to receive cytoscopy
  • patients with advanced stage (T4)
  • patients with contralateral UTUCs

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