An Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Multi-Centre, Multi-arm Phase 1b Study in Patients With Muscle Invasive Bladder Cancer (MIBC) Who Have Progressed on Prior Treatment (BISCAY).
Condition: Muscle Invasive Bladder Cancer
Study Type: Interventional
Clinical Trials Identifier NCT 8-digits: NCT02546661
Phase: Phase 1
- Age: minimum 18 Years maximum 130 Years
- Gender: All
- for all Modules:
- Metastatic MIBC
- 2nd/3rd line
- Failed adjuvant/neo-adjuvant chemotherapy <1 yr
- 1 lesion ≥10 mm at baseline in the longest diameter suitable for accurate repeated measurement
- WHO perf. status 0-1 For Module A:
- M/F ≥25
- Confirmation of FGFR3 mutation or FGFR fusion For Module B:
- Hgb ≥10 g/dL
- Deleterious mutation, deletion or truncation in any HRR genes For Module C:
- Tumour harbours a deletion or inactivating mutation of the CDKN2A or RB1 genes and/or amplification of CCNE1, MYC, MYCL or MYCN genes For Module E:
- Contraception must be sustained throughout treatment with vistusertib and 16 wks after last dose For Module F:
- Adequate organ and marrow function, defined as Leukocytes ≥3.0x10(exp9)/L; ANC ≥1.5x10(exp9)/L; platelets ≥100x10(exp9)/L
- Contraceptive measures must be sustained throughout treatment with AZD9150 and for 180 days after the last dose.
- for all Modules:
- Immunotherapy, chemotherapy, anticancer agents, radiotherapy <4 weeks, or radiotherapy for palliation <2 weeks, any study drugs <30 days.
- Major surgery <4 weeks
- Unresolved toxicities from prior therapy
- Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy
- Immunosuppressive drugs <28 days
- Any of the following: Autoimmune disease ≤2 yr; IBD; primary immunodeficiency; organ transplant requiring immunosuppressives
- Spinal cord compression or brain metastases, treated and stable & not requiring steroids for at least 4 weeks
- Severe or uncontrolled systemic disease
- Any of the following: Mean QTc ≥470 ms; abnormalities in resting ECG; factors that increase the risk of QTc prolongation or arrhythmia; uncontrolled hyper/hypotension; LVEF <55%; atrial fibrillation; NYHA Grade II-IV; severe valvular disease; uncontrolled angina; stroke/TIA <6 months; acute coronary syndrome <6 months
- Any of the following laboratory values: ANC <1.5x10(exp9)/L; Platelets <100x10(exp9)/L; Hgb <9.0 g/dL; ALT >2.5xULN or >5xULN with liver mets; Total bilirubin >1.5 times ULN or with Gilbert's disease ≥2×ULN; Creatinine >1.5xULN concurrent with creatinine clearance <50 mL/min; Corrected Ca >ULN, PO4 >ULN
- Active infection including tuberculosis, hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus. Patients with a past or resolved HBV infection are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- Live attenuated vaccination <30 days For Module A:
- Prior exposure to: Nitrosourea or mitomycin C <6 weeks; any agent with FGFR inhibition as its primary pharmacology; AZD4547; potent inhibitors/inducers of CYP3A4, inhibitors of CYP2D6 or substrates of CYP3A4 <2 wks
- Ophthalmological criteria: RPED; laser treatment or intraocular injection for macular degeneration; age-related macular degeneration; retinal vein occlusion; retinal degenerative disease; other clinically relevant chorioretinal defect
- Refractory nausea/vomiting, chronic GI diseases, or previous bowel resection For Module B:
- Transfusion <120 days
- Concurrent medications that are strong inhibitors of cytochrome P450 (CYP) 3A (CYP3A) or strong inducers of CYP3A
- Previous treatment with PARP inhibitor, including olaparib
- Patients with history of MDS or AML For Module C:
- Prior exposure to any of the following: Nitrosourea or mitomycin C <6 wks; any agent with Wee1 inhibition as its primary pharmacology; prior treatment with AZD1775
- Any drugs or products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with narrow therapeutic index, or moderate to strong inhibitors/inducers of CYP3A4
- Herbal preparations
- Refractory nausea and vomiting or chronic GI diseases
- Cardiac disease <6 months For Module E:
- Minor surgery <14 days of first dose
- Exposure to specific substrates of OATP1B1, OATP1B3, MATE1 and MATE2K <5x half-life before treatment. Exposure to strong/moderate inhibitors/inducers of CYP3A4/5, Pgp (MDR1) and BRCP if taken within washout periods before the first dose
- Haemopoietic growth factors (filgrastim, sargramostim, GM-CSF) <14 days prior to treatment
- Other mTOR inhibitors
- Renal disease or renal tubular acidosis
- Uncontrolled Type 1 or 2 diabetes For Module F:
- AST ≤ 2.5xULN or ≤5xULN with liver metastases For Module G:
- Have had prior treatment with a MEK, Ras or Raf inhibitor.
- Any of the following ophthalmic criteria: Current or past history of central serous retinopathy, detachment of retinal pigmented epithelium, or retinal vein occlusion; intraocular pressure (IOP) >21 mmHg; uncontrolled glaucoma (irrespective of IOP)
- Baseline left ventricular ejection fraction (LVEF) <55% measured by echocardiogram (ECHO) or, if allowed, a multigated acquisition (MUGA) scan. Appropriate correction to be used if a MUGA is performed.
- Previous moderate or severe impairment of LVEF (<45% on echocardiography or equivalent on MUGA) even if full recovery has occurred.
- Male or female patients with reproductive potential and, as judged by the investigator, are not employing an effective method of birth control and female patients who are breastfeeding.
- Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
- Receiving or have received systemic therapy with nitrosoureas, mitomycin or suramin within 6 weeks prior to starting study treatment.
View trial on ClinicalTrials.gov