Bladder Cancer

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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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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) and Bacillus Calmette-Guérin (BCG) as First-Line Treatment for High-Risk T1 Non-Muscle- Invasive Bladder Cancer (NMIBC) and High- Grade Non-Muscle- Invasive Upper Tract Urothelial Cell Carcinoma (NMI-UTUCC)


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 MSK for patients in the T1 bladder cancer cohort or by high-grade cytology/biopsy by ureteroscopy performed at MSK for patients in the NMI-UTUC cohort.
  • TURBT within 8 weeks of protocol entry with complete resection of all papillary lesions for patients in the T1 bladder cancer cohort and ureteroscopy within 8 weeks of protocol entry with complete ablation of all papillary lesions with ureteroscopy or through antegrade percutaneous access for patients in the NMI-UTUC cohort..
  • Patients in the T1 bladder cancer cohort must have 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 (extensive/deep invasion into lamina propria) plus CIS
  • Lymphovascular invasion plus CIS
  • T1 with variant histology: including micropapillary, nested variant, poorly differentiated, squamous, and glandular differentiation (the presence of variant histology will be based on MSKCC review), plus CIS.
  • T1 with urothelial carcinoma of prostatic urethra (Ta, Tis, or T1 within prostatic urethra), plus CIS
  • Large (≥3 cm) T1 tumor, plus CIS
  • Patients in the NMI-UTUC cohort must have high risk, BCG naïve NMI-UTUC, defined by having one of the following disease states:
  • Histologic confirmed ureteroscopic biopsy with clinical stage Tis (also known as CIS), Ta, or T1 disease in the renal pelvis. Concomitant ureteral disease will be allowed if completely treated endoscopically.
  • Clinical stage Tis confirmed by a positive high-grade selective cytology, coupled with ureteroscopic evaluation, confirming only flat eryethematous lesions and the absence of papillary tumors.
  • Patients must have cross sectional imaging (CT or MRI urogram) within 3 months of protocol entry demonstrating no evidence of metastasis or radiographic evidence of muscle invasive disease.
  • Patient refusal of cystectomy and bilateral pelvic lymphadenectomy for the T1 bladder cancer cohort, or refusal of radical nephroureterectomy for NMI-UTUC cohort.
  • No prior intravesical BCG therapy for patients in the T1 bladder cancer cohort.
  • No prior radiation therapy for bladder cancer for patients in the T1 bladder cancer cohort. Prior radiation therapy for prostate cancer is allowed.
  • ECOG performance status of 0 or 1.
  • Age ≥ 18 years.
  • Female subjects of childbearing potential must 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 CIS of the cervix).
  • Required initial laboratory values:
  • Absolute neutrophil count ≥ 1.5 x 10^9/L
  • Platelets ≥ 100 x 10^9/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:

  • Current or History of muscle invasive bladder cancer or prostatic stromal invasion.
  • 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 (i.e, nodal, visceral, or central nervous system)
  • Major surgical procedure (other than TURBT or ureteroscopy) 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.
  • Known contraindications to BCG, defined as one of the following:
  • History of systemic hypersensitivity reaction or history of febrile systemic BCG reaction
  • Febrile illness or persistent gross hematuria
  • Active tuberculosis
  • Immunosuppression due to congenital or acquired immune deficiency, concurrent immune suppressive disease, systemic cancer therapy, or chronic immunosuppressive therapy other than topical or inhaled corticosteroids

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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 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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PhAse 1/2 StuDy of Modern ImmunotherApy in BCG-Unresponsive, BCG-RelaPsing, and High-Risk BCG-Naive Non-muscle Invasive UroThelial Carcinoma of the BLADDER


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 60 days of registration. NOTE: Mixed histologies are permitted, provided a component of urothelial carcinoma is present. Patients with histologically confirmed non- muscle invasive urothelial carcinoma of the bladder (Ta, T1, or Tis stage) on prior TURBT who undergo re-resection of the tumor base to confirm the diagnosis and/or exclude the presence of muscle-invasive disease (T2 or greater) who do not have appreciable tumor in the re-resection TURBT are eligible to enroll provided their re-resection was obtained within 60 days of registration and they meet all other eligibility criteria.
  • 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/mm3
  • Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
  • Platelets ≥ 100 K/mm3
  • 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 modified Cockcroft- Gault equation
  • 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 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 above, the following inclusion criteria are also required of patients enrolling to Phase 2 of the study. • High-risk NMIBC defined according to modified EORTC risk criteria summarized as follows: NOTE: Intermediate- and Low-risk tumors as defined below are not eligible. NOTE: Patients with concurrent non-muscle invasive tumors (CIS, Ta, T1) in the prostatic urethra are permitted to enroll in Phase 2 of the study. At least half of the subjects enrolled to each cohort must have a component of CIS present.
  • 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) • BCG-unresponsive, BCG-relapsing, BCG-persistent, or high-risk BCG-naïve NMIBC defined as follows: NOTE: Patients enrolling to phase 2 will enroll separately into a maximum of three expanded cohorts defined by the BCG exposure population eligibility criteria defined below (BCG-unresponsive, BCG-relapsing, BCG-persistent, and high-risk BCG-naïve). The three possible cohorts for each regimen expanded to phase 2 enrollment will be: BCG-unresponsive, BCG-relapsing and/or BCG-persistent (combined within a single cohort), and high-risk BCG-naïve. It is not anticipated that all three possible phase 2 expansion cohort populations will be pursued for every regimen entering phase 2 expansion. Questions regarding phase 2 expansion cohort populations and patient eligibility should be directed to the study chair. The individual eligibility for phase 2 expanded cohorts according to BCG exposure history are summarized below. o BCG-unresponsive NMIBC phase 2 expanded cohort. BCG-unresponsive NMIBC is 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 high-grade 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 o 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
  • BCG-relapsing and/or BCG-persistent NMIBC phase 2 expanded Cohort. BCG-relapsing and/or BCG-persistent NMIBC is defined by either of the following: • BCG-relapsing NMIBC is defined as recurrent high-risk NMIBC after achievement of a complete response to BCG induction therapy which does not meet any of the BCG-unresponsive criteria outlined in the protocol.
  • BCG-persistent NMIBC is defined as persistent 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 the protocol.
  • High-risk BCG-naive NMIBC cohort. High-risk BCG-naive NMIBC is defined as high-risk NMIBC in a patient that has never received intravesical BCG therapy. NOTE: Patients who satisfy the above definition of BCG-unresponsive NMIBC continue to be considered BCG-unresponsive regardless of the receipt of any intervening or additional non-BCG based intravesical therapies (e.g. chemotherapy, non-BCG investigational agents) 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 60 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 v4.03 for Cohorts 1-3 and v5.0 for cohorts 4-6 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, PD-L1, or CTLA-4 directed agents.
  • Subjects who have had any prior radiation to the prostate or pelvis. NOTE: The exclusion of patients who have had any prior radiation to the prostate or pelvis applies to both phase 1 and 2 of the trial only within radiation containing study regimens. Patients with a prior history of prostate or pelvic radiation who meet all other

Eligibility Criteria:

  • .
  • 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/mm3
  • Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
  • Platelets ≥ 100 K/mm3
  • 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 modified Cockcroft- Gault equation
  • 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 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 above, the following inclusion criteria are also required of patients enrolling to Phase 2 of the study. • High-risk NMIBC defined according to modified EORTC risk criteria summarized as follows: NOTE: Intermediate- and Low-risk tumors as defined below are not eligible. NOTE: Patients with concurrent non-muscle invasive tumors (CIS, Ta, T1) in the prostatic urethra are permitted to enroll in Phase 2 of the study. At least half of the subjects enrolled to each cohort must have a component of CIS present.
  • 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) • BCG-unresponsive, BCG-relapsing, BCG-persistent, or high-risk BCG-naïve NMIBC defined as follows: NOTE: Patients enrolling to phase 2 will enroll separately into a maximum of three expanded cohorts defined by the BCG exposure population eligibility criteria defined below (BCG-unresponsive, BCG-relapsing, BCG-persistent, and high-risk BCG-naïve). The three possible cohorts for each regimen expanded to phase 2 enrollment will be: BCG-unresponsive, BCG-relapsing and/or BCG-persistent (combined within a single cohort), and high-risk BCG-naïve. It is not anticipated that all three possible phase 2 expansion cohort populations will be pursued for every regimen entering phase 2 expansion. Questions regarding phase 2 expansion cohort populations and patient eligibility should be directed to the study chair. The individual eligibility for phase 2 expanded cohorts according to BCG exposure history are summarized below. o BCG-unresponsive NMIBC phase 2 expanded cohort. BCG-unresponsive NMIBC is 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 high-grade 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 o 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
  • BCG-relapsing and/or BCG-persistent NMIBC phase 2 expanded Cohort. BCG-relapsing and/or BCG-persistent NMIBC is defined by either of the following: • BCG-relapsing NMIBC is defined as recurrent high-risk NMIBC after achievement of a complete response to BCG induction therapy which does not meet any of the BCG-unresponsive criteria outlined in the protocol.
  • BCG-persistent NMIBC is defined as persistent 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 the protocol.
  • High-risk BCG-naive NMIBC cohort. High-risk BCG-naive NMIBC is defined as high-risk NMIBC in a patient that has never received intravesical BCG therapy. NOTE: Patients who satisfy the above definition of BCG-unresponsive NMIBC continue to be considered BCG-unresponsive regardless of the receipt of any intervening or additional non-BCG based intravesical therapies (e.g. chemotherapy, non-BCG investigational agents) 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 60 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 v4.03 for Cohorts 1-3 and v5.0 for cohorts 4-6 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, PD-L1, or CTLA-4 directed agents.
  • Subjects who have had any prior radiation to the prostate or pelvis. NOTE: The exclusion of patients who have had any prior radiation to the prostate or pelvis applies to both phase 1 and 2 of the trial only within radiation containing study regimens. Patients with a prior history of prostate or pelvic radiation who meet all other eligibility criteria may be considered for phase 1 and phase 2 enrollment to non-radiation containing study regimens after consultation with the study chair.
  • 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. For questions, please consult the sponsor-investigator.
  • Pregnant or breast-feeding women. Women of child-bearing potential must have a negative serum test ≤ 14 days prior to starting study drug.
  • Women of child-bearing potential, who are biologically able to conceive, and not employing contraception as described in the protocol.
  • Fertile males not willing to use contraception, as stated in the protocol.
  • Subjects unwilling or unable to comply with the protocol
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. NOTE: Patients, if enrolled, should not receive live vaccine whilst receiving study drugs and up to 30 days after the last dose of study drug. • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 3.2.2 Exclusion Criteria (Cohorts 4 and 5 Only) • Subjects who have received prior intravesical therapy with BOTH gemcitabine and docetaxel NOTE: Patients who have received either intravesical gemcitabine or intravesical docetaxel (or other taxanes) but not both remain eligible. For example, patients receiving post-TURBT single dose intravesical gemcitabine administration are eligible. Similarly, patients treated with intravesical gemcitabine induction and/or maintenance are eligible. While we typically do not see patients treated with intravesical docetaxel (or other taxanes) monotherapy, if such a patient were identified and screened, they would be eligible. Patients who have received treatment with separate courses of intravesical gemcitabine monotherapy and intravesical docetaxel (or other taxanes) monotherapy are not eligible, unless such therapies occurred more than 24 months ago. Exclusion Criteria (Phase 1 Only) In Phase 1 of the study, there are no additional exclusion criteria beyond those described of all patients above. Exclusion Criteria (Phase 2 Only) In addition to the exclusion criteria described of all patients 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 60 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 v4.03 for Cohorts 1-3 and v5.0 for cohorts 4-6 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, PD-L1, or CTLA-4 directed agents.
  • Subjects who have had any prior radiation to the prostate or pelvis. NOTE: The exclusion of patients who have had any prior radiation to the prostate or pelvis applies to both phase 1 and 2 of the trial only within radiation containing study regimens. Patients with a prior history of prostate or pelvic radiation who meet all other eligibility criteria may be considered for phase 1 and phase 2 enrollment to non-radiation containing study regimens after consultation with the study chair.
  • 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. For questions, please consult the sponsor-investigator.
  • Pregnant or breast-feeding women. Women of child-bearing potential must have a negative serum test ≤ 14 days prior to starting study drug.
  • Women of child-bearing potential, who are biologically able to conceive, and not employing contraception as described in the protocol.
  • Fertile males not willing to use contraception, as stated in the protocol.
  • Subjects unwilling or unable to comply with the protocol
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. NOTE: Patients, if enrolled, should not receive live vaccine whilst receiving study drugs and up to 30 days after the last dose of study drug. • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 3.2.2 Exclusion Criteria (Cohorts 4 and 5 Only) • Subjects who have received prior intravesical therapy with BOTH gemcitabine and docetaxel NOTE: Patients who have received either intravesical gemcitabine or intravesical docetaxel (or other taxanes) but not both remain eligible. For example, patients receiving post-TURBT single dose intravesical gemcitabine administration are eligible. Similarly, patients treated with intravesical gemcitabine induction and/or maintenance are eligible. While we typically do not see patients treated with intravesical docetaxel (or other taxanes) monotherapy, if such a patient were identified and screened, they would be eligible. Patients who have received treatment with separate courses of intravesical gemcitabine monotherapy and intravesical docetaxel (or other taxanes) monotherapy are not eligible, unless such therapies occurred more than 24 months ago. Exclusion Criteria (Phase 1 Only) In Phase 1 of the study, there are no additional exclusion criteria beyond those described of all patients above. Exclusion Criteria (Phase 2 Only) In addition to the exclusion criteria described of all patients above, the following exclusion criteria apply to patients enrolling to Phase 2 of the study. • Subjects with concurrent upper urinary tract (i.e. ureter, renal pelvis) high-grade urothelial carcinoma. NOTE: Subjects with concurrent low-grade non-invasive (Ta) upper urinary tract urothelial carcinoma are eligible. Similarly, patients with a history of high-grade upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.

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A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) and Pembrolizumab in Combination With Other Investigational Agents in Subjects With High Risk Non-muscle-Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy


Condition: Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02625961

Sponsor: Merck Sharp & Dohme LLC

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

  • Histologically-confirmed diagnosis of high risk non-muscle-invasive (T1, high grade Ta and / or carcinoma in situ [CIS]) transitional cell carcinoma of the bladder (mixed histology tumors allowed if transitional cell histology is predominant histology).
  • Fully resected disease at study entry (residual CIS acceptable)
  • BCG-unresponsive high risk non-muscle-invasive bladder cancer after treatment with adequate BCG therapy
  • Ineligible for radical cystectomy or refusal of radical cystectomy
  • Available tissue from a newly obtained core biopsy of a tumor lesion not previously irradiated
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Adequate organ function
  • Female participants of childbearing potential have a negative urine or serum pregnancy test and must be willing to use an adequate method of contraception
  • Male participants must be willing to use an adequate method of contraception

Exclusion Criteria:

  • Centrally assessed muscle-invasive, locally advanced nonresectable, or metastatic urothelial carcinoma (i.e., T2, T3, T4, and / or stage IV)
  • Centrally assessed concurrent extra-vesical (i.e., urethra, ureter, or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium
  • Currently participating or has participated in a study of an investigational agent and received study therapy or received investigational device within 4 weeks prior to the first dose of study treatment
  • Received intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy / Transurethral Resection of Bladder Tumor (TURBT) to starting study treatment
  • Received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to starting study treatment or not recovered from adverse events due to a previously administered agent
  • Known additional malignancy that is progressing or requires active treatment excepting basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with definitive intent (surgically or through radiation therapy) is acceptable provided that the following criteria are met: Stage T2N0M0 or lower; Gleason score ≤7 and prostatic-specific antigen (PSA) undetectable for at least 1 year while off androgen deprivation therapy that was either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study allocation
  • Active autoimmune disease that has required systemic treatment in the past 2 years
  • Evidence of interstitial lung disease or active non-infectious pneumonitis
  • Active infection requiring systemic therapy
  • Pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial through 120 days after the last dose of study treatment
  • Prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-ligand 2 (L2) agent, or with an agent directed to another co-inhibitory T-cell receptor
  • Known human immunodeficiency virus (HIV)
  • Known active Hepatitis B or C infection
  • Received a live virus vaccine within 30 days of planned start of study treatment
  • Has had an allogeneic tissue/solid organ transplant

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A Phase II Trial of sEphB4-HSA in Combination With Anti PD1 Antibody Pembrolizumab (MK-3475) for Solid Tumors


Condition: Stage IV Bladder Urothelial Carcinoma, Prostate Cancer, Urothelial Carcinoma

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02717156

Sponsor: University of Southern California

Phase: Phase 2

Eligibility:

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

Inclusion Criteria:

  • (for all Cohorts):
  • Be willing and able to provide written informed consent/assent for the trial
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
  • Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30mL/min for subject with creatinine levels > 1.5 X institutional upper limit of normal (ULN)
  • Serum total bilirubin =< 1.5 X ULN or direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN or =< 5 X ULN for subjects with liver metastases
  • Albumin >= 2.5 mg/dL
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
  • Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Recovered to grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies
  • Female subject of childbearing potential should have a negative urine or serum pregnancy; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Female subjects of childbearing potential must be willing to use adequate method of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
  • Male subjects must 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 Criteria specific to 2nd line and 3rd line and beyond cohorts (Cohorts A and B):
  • Advanced (metastatic or recurrent) pathologically proven urothelial carcinoma which is refractory to platinum based due to disease progression on a platinum containing regimen; patients progressing within 12 months of their last dose of platinum-based neoadjuvant or adjuvant chemotherapy will be considered platinum refractory
  • Have measurable disease based on RECIST 1.1
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained for up to 12 weeks (84 days) after discontinuation of previous systemic therapy and prior to initiation of treatment on day 1 on this study; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor; an optional core biopsy will be requested from an accessible metastatic site after 2 cycles of treatment and prior to progression of disease to help the investigators better understand the activity of these drugs in tumor tissue. Criteria specific to the neoadjuvant urothelial cohort (Cohort C):
  • Must have tumor stage ≥T2 AND ≤T4a, N0, M0 (AJCC 8th edition) urothelial carcinoma of the bladder deemed resectable and planned for radical cystectomy with curative intent. T4 due to infiltration of the prostate is allowed.
  • Must have TURBT specimen obtained within 12 weeks prior to the first day of treatment on the study and the specimen must include muscle. Subjects for whom a TURBT specimen within 12 weeks of C1D1 cannot be provided, but an older specimen is available (e.g. unlikely to be able to obtain adequate specimen or subject safety concern) may submit an archived specimen only upon written agreement from the Sponsor.
  • Prior intravesical therapy is allowed. However, patients who have received prior systemic therapy within 12 months enrollment are excluded. Criteria specific to the neoadjuvant prostate cohort (Cohort D):
  • Must have biopsy proven prostate cancer (Gleason Score ≥7, and PSA >4.0 ng/mL- rare cases can be reviewed and approved with a written agreement from the Sponsor) amenable to radical prostatectomy.
  • Must have appropriate staging imaging showing no evidence of distant metastatic disease. Choice of imaging is per treating physician- some acceptable imaging examples include MRI of pelvis, CT of abdomen and pelvis, bone scan, Axumin PET CT, and PSMA PET CT. For Cohort D, the imaging studies may be considered valid for enrollment beyond the 28 days at the discretion of the treating physician and no longer than 90 days.

Exclusion Criteria:

  • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
  • Has a known history of active TB (bacillus tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (ie, =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (ie, =< grade 1 or at baseline) from adverse events due to a previously administered agent; Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study; Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have 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
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment
  • Has known history of, or any evidence of active, non-infectious pneumonitis
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or sEsphB4-HSA
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active Hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (eg, hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has New York Heart Association (NYHA) class 3 or 4, myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months; or any other intercurrent medical condition that contraindicates treatment with sEphB4HSA or pembrolizumab (MK-3475) or places the patient at undue risk for treatment related complications
  • Has received a live vaccine within 30 days of planned start of study therapy; Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (eg, flu-mist) are live attenuated vaccines, and are not allowed
  • Uncontrolled hypertension is excluded- systolic blood pressure >140mmHg or diastolic >90mmHg. Patients experiencing white coat hypertension in the office, may be considered eligible if blood pressure log at home is within acceptable limits AND upon review and agreement from the Sponsor.

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A Study of Intravesical Bacillus Calmette-Guerin (BCG) in Combination With ALT-803 (N-803) in Patients With Non-Muscle Invasive Bladder Cancer


Condition: Non-muscle Invasive Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02138734

Sponsor: ImmunityBio, Inc.

Phase: Phase 1/Phase 2

Eligibility:

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

Inclusion Criteria:

  • 1. Histologic confirmation of non-muscle invasive bladder cancer of the transitional cell carcinoma high-grade subtype (mixed histology tumors allowed if transitional cell histology is predominant histology). 1. Cohort A: Histologically confirmed CIS (with or without Ta/T1 disease); Cohort B: Histologically confirmed high-grade papillary disease (Ta/T1 only). 2. Patients are eligible if the diagnostic biopsy was done within 3 months of treatment start and a cystoscopy demonstrating no resectable disease was done within 6 calendar weeks (inclusive of 48 days) of treatment start (residual CIS is acceptable; patients with T1 disease must undergo repeat resection if muscularis propria is not present in each biopsy sample). Patients with high-grade Ta and/or T1 disease should have complete resection before study treatment. 3. Upper tract imaging within 6 months prior to study entry must not be suspicious for upper tract malignancy. 2. Currently eligible for intravesical BCG therapy. 3. Age ≥ 18 years. 4. Performance status: ECOG performance status of 0, 1, or 2. 5. Laboratory tests performed within 21 days of treatment start: 1. Absolute neutrophil count (AGC/ANC) ≥ 1,000/µL 2. Platelets ≥ 100,000/µL [Patients may be transfused to meet this requirement] 3. Hemoglobin ≥ 8 g/dL [Patients may be transfused to meet this requirement] 4. Calculated glomerular filtration rate (GFR*) >40 mL/min or Serum creatinine ≤ 1.5 x ULN 5. Total bilirubin ≤ 2.0 X ULN 6. AST, ALT, ALP ≤ 3.0 X ULN 6. Adequate pulmonary function without any clinical sign of severe pulmonary dysfunction. PFT > 50% FEV1 if clinically indicated by the investigator. 7. Negative serum pregnancy test if female and of childbearing potential (non-childbearing is defined as greater than one year postmenopausal or surgically sterilized). 8. Female participants of childbearing potential must adhere to using a medically accepted method of birth control prior to screening and agree to continue its use during the study or be surgically sterilized (e.g., hysterectomy or tubal ligation) and males must agree to use barrier methods of birth control while on study. 9. Provide signed informed consent and HIPPA authorization and agree to comply with all protocol-specified procedures and follow-up evaluations.
  • using the following Cockcroft-Gault equation to calculate the eGFR for this study: eGFR in mL/min = {(140-age in years) x (weight in kg) x F}/(serum creatinine in mg/dL x 72) Where F =1 if male; and 0.85 if female

Exclusion Criteria:

  1. Prior BCG treatment or known hypersensitivity to BCG. Patients who have received more than a single-dose post-operative treatment of mitomycin-C or gemcitabine following the most recent screening TURBT/biopsy are excluded.
  2. Concurrent use of other investigational agents (not including FDA-authorized drugs for the prevention and treatment of COVID-19).
  3. History of or evidence of muscle-invasive, locally advanced, metastatic and/or extravesical bladder cancer or any other cancer within the past 5 years, except: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage 1 or 2 cancer from which the patient is currently in complete remission, or stable prostate cancer (under active surveillance or hormone control).
  4. Symptomatic congestive heart failure (CHF), NYHA (New York Heart Association) Class III or IV or other clinical signs of severe cardiac dysfunction.
  5. Severe/unstable angina pectoris, or myocardial infarction within 6 months prior to study entry.
  6. History or evidence of uncontrollable CNS disease.
  7. Known HIV-positive.
  8. Active systemic infection requiring parenteral antibiotic therapy. All prior infections must have resolved following optimal therapy.
  9. Concurrent febrile illness, active urinary tract infection, active tuberculosis, a history of hypotension or anaphylactic reactions.
  10. Ongoing chronic systemic steroid therapy required (>10 mg oral prednisone daily or equivalent).
  11. Women who are pregnant or nursing. Female patients of childbearing potential must have a negative pregnancy test and must adhere to using a medically acceptable method of birth control prior to screening and agree to continue its use during the study and for 30 days after the last dose of study drug, or be surgically sterilized (e.g., hysterectomy or tubal ligation). Women of childbearing potential are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause. Males must agree to use barrier methods of birth control while on study and for 90 days post last dose of study drug.
  12. Psychiatric illness/social situations that would limit compliance with study requirements.
  13. Other illness that in the opinion of the investigator would exclude the patient from participating in this study.

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Personalized NK Cell Therapy in Cord Blood Transplantation


Condition: Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Acute Biphenotypic Leukemia, Acute Lymphoblastic Leukemia, Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia With Myelodysplasia-Related Changes, Acute Myeloid Leukemia With Variant MLL Translocations, B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, Chemotherapy-Related Leukemia, Chronic Myelomonocytic Leukemia, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, ISS Stage II Plasma Cell Myeloma, ISS Stage III Plasma Cell Myeloma, Myelodysplastic Syndrome, Myelodysplastic Syndrome With Excess Blasts, Myelodysplastic Syndrome With Gene Mutation, Myelodysplastic/Myeloproliferative Neoplasm, Previously Treated Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Hodgkin Lymphoma, Recurrent Non-Hodgkin Lymphoma, Refractory Acute Lymphoblastic Leukemia, Refractory Adult Acute Lymphoblastic Leukemia, Secondary Acute Myeloid Leukemia, Therapy-Related Myelodysplastic Syndrome

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02727803

Sponsor: M.D. Anderson Cancer Center

Phase: Phase 2

Eligibility:

  • Age: minimum 15 Years maximum 80 Years
  • Gender: All

Inclusion Criteria:

  • Patients must have one of the following hematologic malignancies: acute myelogenous leukemia (AML), induction failure, high-risk for relapse first remission (with intermediate-risk or high-risk cytogenetics including complex karyotype, abnormal [abn][3q], -5/5q-, -7/7q-, abn[12p], abn[17p], myeloid/lymphoid or mixed-lineage leukemia [MLL] gene re-arrangement and t [6;9]47, fms related tyrosine kinase 3 [flt3] mutation positive and/or evidence of minimal residual disease by flow cytometry), secondary leukemia from prior chemotherapy and/or arising from myelodysplastic syndromes (MDS), any disease beyond first remission
  • Myelodysplastic syndrome (MDS): Primary or therapy related, including patients that will be considered for transplant; these include any of the following categories: 1) revised International Prognostic Scoring System (IPSS) intermediate and high risk groups, 2) malondialdehyde (MDA) with transfusion dependency, 3) failure to respond or progression of disease on hypomethylating agents, 4) refractory anemia with excess of blasts, 5) transformation to acute leukemia, 6) chronic myelomonocytic leukemia, 7) atypical MDS/myeloproliferative syndromes, 8) complex karyotype, abn(3g), -5/5g-, -7/7g-, abn(12p), abn(17p)
  • Acute lymphoblastic leukemia (ALL): Induction failure, primary refractory to treatment (do not achieve complete remission after first course of therapy) or are beyond first remission including second or greater remission or active disease; patients in first remission are eligible if they are considered high risk, defined as any of the following detected at any time: with translocations 9;22 or 4;11, hypodiploidy, complex karyotype, secondary leukemia developing after cytotoxic drug exposure, and/or evidence of minimal residual disease or acute biphenotypic leukemia, or double hit non-Hodgkin's lymphoma
  • Non-Hodgkin's lymphoma (NHL) in second or third complete remission, or relapse (including relapse post autologous hematopoietic stem cell transplant); relapsed double hit lymphomas; patients with options for treatment that are known to be curative are not eligible
  • Small lymphocytic lymphoma (SLL), or chronic lymphocytic leukemia (CLL) with progressive disease following a minimum of two lines of standard therapy
  • Chronic myeloid leukemia (CML) second chronic phase or accelerated phase
  • Hodgkin's disease (HD): Induction failures, after first complete remission, or relapse (including relapse post autologous hematopoietic stem cell transplant), or those with active disease
  • Multiple myeloma: stage II or III, symptomatic, secretory multiple myeloma requiring treatment
  • A person (such as a haploidentical family member) or unit of cord blood must be identified as a source of back-up cells source in case of engraftment failure
  • Patient age criteria: age >= 15 and =< 45 years (myeloablative regimen 1; age >= 15 and =< 80 years (nonmyeloablative regimen 2) at the discretion of the investigator(s); age >= 15 and =< 80 years old that in the opinion of the investigator(s) would preclude myeloablative therapy may receive reduced intensity regimen 3
  • Performance score of at least 60% by Karnofsky
  • Left ventricular ejection fraction of at least 40% (myeloablative regimen 1, reduced intensity regimen 3)
  • Left ventricular ejection fraction of at least 30% (nonmyeloablative regimen 2)
  • Pulmonary function test (PFT) demonstrating an adjusted diffusion capacity of least 50% predicted value for hemoglobin concentration (myeloablative regimen 1, reduced intensity regimen 3)
  • Serum creatinine within normal range, or if serum creatinine outside normal range, then renal function (measured or estimated creatinine clearance or glomerular filtration rate [GFR]) > 40mL/min/1.73 m^2
  • Serum glutamate pyruvate transaminase (SGPT)/bilirubin < to 2.0 x normal (myeloablative regimen 1), reduced intensity regimen 3; SGPT/bilirubin < to 4.0 x normal (nonmyeloablative regimen 2)
  • Negative beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential defined as not post-menopausal for 12 months
  • Patients with options for treatment that are known to be curative are not eligible
  • Patients enrolled in this study may be enrolled on other supportive care investigational new drug (IND) studies at the discretion of the principal investigator (PI)

Exclusion Criteria:

  • Human immunodeficiency virus (HIV) positive; HIV results will be determined by nucleic acid testing
  • Uncontrolled serious medical condition such as persistent septicemia despite adequate antibiotic therapy, decompensated congestive heart failure despite cardiac medications or pulmonary insufficiency requiring intubation (excluding primary disease for which cord blood [CB] transplantation is proposed), or psychiatric condition that would limit informed consent
  • Active central nervous system (CNS) disease in patient with history of CNS malignancy
  • Availability of appropriate, willing, human leukocyte antigen (HLA)-matched related stem cell donor

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Phase I Study of Hypofractionated Radiotherapy and Anti-PD1 Antibody (Pembrolizumab) in the Treatment of Advanced Bladder Cancer


Condition: Invasive Bladder Cancer

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02560636

Sponsor: Royal Marsden NHS Foundation Trust

Phase: Phase 1

Eligibility:

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

Inclusion Criteria:

  1. Histologically confirmed invasive bladder.carcinoma (T2-4,N0-3,M0-1).
  2. Be willing and able to provide written informed consent for the trial.
  3. Be ≥ 18 years of age on day of signing informed consent.
  4. Have measurable disease based on RECIST 1.
  5. , or, in group A, disease assessable by cystoscopic assessment.
  6. Have consented to analysis of tissue from an archival tissue sample
  7. Have a performance status of 0-1 on the ECOG Performance Scale.
  8. Planned for hypofractionated radiotherapy
  9. Demonstrate adequate organ function as defined in table 2 (please see protocol) all screening blood tests should be performed within 10 days of confirmation of eligibility.
  10. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to confirmation of study eligibility. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  11. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  12. 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 if their partner has childbearing potential (as defined by not being surgically sterilized or have not been free from menses for > 1 year).

Exclusion Criteria:

  • The subject must be excluded from participating in the trial if the subject: 1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment. 2. Previous pelvic radiotherapy, history of inflammatory bowel disease or other conditions that would in the opinion of the investigator would preclude the safe administration of pelvic radiotherapy. 3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (>dose equivalent to 10mg of Prednisolone/day) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 4. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent or therapy.
  • Note: Subjects with ≤ Grade 2 neuropathy or chemotherapy induced alopecia/nail changes are an exception to this criterion and may qualify for the study.
  • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 6. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, localized prostate cancer (≤T2 ≤ Gl3+4) or in situ cervical cancer that has undergone potentially curative therapy. Patients may have received treatment for previous urothelial malignancy. 7. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. 8. 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 steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. 9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 10. Has an active infection requiring systemic therapy. 11. 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. 12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 15. Has a known history of Human Immunodeficiency Virus (HIV). 16. Has known clinical history of Hepatitis B or Hepatitis C . 17. Has received a live vaccine within 30 days prior to the first dose of trial treatment.

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Molecular Correlates of Sensitivity and Resistance to Therapy in Genitourinary Malignancy


Condition: Localized Renal Pelvis and Ureter Urothelial Carcinoma, Malignant Solid Neoplasm, Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Neoplasm in the Soft Tissues, Metastatic Renal Pelvis and Ureter Urothelial Carcinoma, Recurrent Bladder Carcinoma, Recurrent Prostate Carcinoma, Recurrent Renal Pelvis and Ureter Urothelial Carcinoma, Stage IV Bladder Cancer AJCC v7, Stage IV Bladder Urothelial Carcinoma AJCC v7, Stage IV Prostate Cancer AJCC v7

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT01050504

Sponsor: University of Washington

Phase:

Eligibility:

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

Inclusion Criteria:

  • Patients with localized and/or metastatic bladder/urothelial or prostate cancer who have disease in the primary organ, biopsy accessible bone metastases (collaborating radiologists will determine if bone metastasis is appropriate for biopsy) or soft tissue metastases are eligible; men and women without cancer are eligible to have blood or normal tissue collected if acquired as part of non-research procedures (e.g. transurethral resection of the prostate or bladder); in patients without malignancy, no additional tissue beyond that necessary for care will be procured
  • Ability to adequately understand and give informed consent
  • Local or metastatic disease to soft tissue or bone at sites accessible to biopsy with minimal risk of complications Or the ability to obtain tissue with minimal risk of complication from a surgical procedure being conducted as a part of another research study Or for standard of care purposes or patients who have archival tissue collected for research or standard of care who are willing to donate archival tissue for this study
  • Alternatively, men and women without cancer or who are at risk of developing cancer are eligible to have blood or normal tissue collected if acquired; tissue will only be acquired as part of non-research procedures (e.g. transurethral resection of the prostate or bladder; in patients without malignancy, no additional tissue beyond that necessary for care will be procured
  • Platelet count > 50,000
  • White blood cell (WBC) > 1,500
  • Hemoglobin (Hgb) > 8.0
  • International normalized ratio (INR) < 1.5
  • Partial thromboplastin time (PTT) < 45
  • No history of excessive unexplained bleeding from previous surgery

Exclusion Criteria:

  • Patients unable to stop chronic anticoagulation with warfarin or Lovenox for less than 3 days
  • Serious or uncontrolled infection
  • Treatment with a vascular endothelial growth factor (VEGF) inhibitor (such as Avastin) within the past 28 days

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A Genotype-Phenotype Urothelial Cancer Registry


Condition: Urothelial Cancer, Renal Pelvis Cancer, Ureter Cancer, Bladder Cancer

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT00902590

Sponsor: Memorial Sloan Kettering Cancer Center

Phase:

Eligibility:

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

Inclusion Criteria:

  • Urothelial Cancer Cases
  • Must be ≥ 18 years of age AND
  • Must have a diagnosis of urothelial cancer AND
  • Must be an English-speaker Non-Cancer Control Group
  • Must be ≥ 18 years of age AND
  • Must not have cancer or a personal history of cancer, with the exception of skin cancer. AND
  • Must not be a blood relative of cases AND
  • Must not be a blood relative of another control AND
  • Must be an English-speaker Family Member Control Group: In select kindreds with a high prevalence of bladder cancer and/or very early onset bladder cancer, first- and second-degree family members of probands may be contacted by the MSKCC study team and invited to complete the questionnaire and submit a saliva sample.
  • Must be ≥ 18 years of age AND
  • Must be a blood relative of a case participant AND
  • Must be an English-speaker

Exclusion Criteria:

  • Have any condition, which in the opinion of the primary MSKCC clinician or investigators precludes their ability to provide informed consent.

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