Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (NCT02546661) — Spain Trial Details

Condition(s) studied

Muscle Invasive Bladder Cancer

Investigational drug(s) / intervention(s)

AZD4547 →MEDI4736 →Olaparib →AZD1775 →Vistusertib →AZD9150 →Selumetinib →

AZD4547: AZD4547 Monotherapy vs. MEDI4736 (durvalumab) + AZD4547 1:1 Randomization.

MEDI4736: MEDI4736

Olaparib: MEDI4736 (durvalumab) + Olaparib

AZD1775: MEDI4736 (durvalumab) + AZD1775

Vistusertib: MEDI4736 (durvalumab) + Vistusertib

AZD9150: MEDI4736 (durvalumab) + AZD9150

Selumetinib: MEDI4736 (durvalumab) + Selumetinib

Study summary

This is an open label, multi-drug, biomarker-directed, multi-centre, multi-arm, Phase 1b study in patients with muscle invasive bladder cancer (MIBC) (urothelial) who have progressed on prior treatment. This study is modular in design, allowing evaluation of the safety, tolerability, pharmacokinetics and anti-tumour activity of multiple agents as monotherapy and as combinations of different novel anti-cancer agents.

The study will consist of a number of study modules (sub-studies), each evaluating the safety and tolerability of a specific agent or combination.

Eligibility

Sex

ALL

Min age

18 Years

Max age

130 Years

Healthy volunteers

No

Inclusion Criteria for all Modules: 1. Metastatic MIBC 2. 2nd/3rd line 3. Failed adjuvant/neo-adjuvant chemotherapy \<1 yr 4. 1 lesion ≥10 mm at baseline in the longest diameter suitable for accurate repeated measurement 5. WHO perf. status 0-1 For Module A: 1. M/F ≥25 2. Confirmation of FGFR3 mutation or FGFR fusion For Module B: 1. Hgb ≥10 g/dL 2. Deleterious mutation, deletion or truncation in any HRR genes For Module C: 1\. 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: 1\. Contraception must be sustained throughout treatment with vistusertib and 16 wks after last dose For Module F: 1. Adequate organ and marrow function, defined as Leukocytes ≥3.0x10(exp9)/L; ANC ≥1.5x10(exp9)/L; platelets ≥100x10(exp9)/L 2. Contraceptive measures must be sustained throughout treatment with AZD9150 and for 180 days after the last dose. Exclusion Criteria for all Modules: 1. Immunotherapy, chemotherapy, anticancer agents, radiotherapy \<4 weeks, or radiotherapy for palliation \<2 weeks, any study drugs \<30 days. 2. Major surgery \<4 weeks 3. Unresolved toxicities from prior therapy 4. Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy 5. Immunosuppressive drugs \<28 days 6. Any of the following: Autoimmune disease ≤2 yr; IBD; primary immunodeficiency; organ transplant requiring immunosuppressives 7. Spinal cord compression or brain metastases, treated and stable \& not requiring steroids for at least 4 weeks 8. Severe or uncontrolled systemic disease 9. 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 10. 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 11. 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. 12. Live attenuated vaccination \<30 days For Module A: 1. 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 2. 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 3. Refractory nausea/vomiting, chronic GI diseases, or previous bowel resection For Module B: 1. Transfusion \<120 days 2. Concurrent medications that are strong inhibitors of cytochrome P450 (CYP) 3A (CYP3A) or strong inducers of CYP3A4. 3. Previous treatment with PARP inhibitor, including olaparib 4. Patients with history of MDS or AML For Module C: 1. 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 2. 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 3. Herbal preparations 4. Refractory nausea and vomiting or chronic GI diseases 5. Cardiac disease \<6 months For Module E: 1. Minor surgery \<14 days of first dose 2. 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 3. Haemopoietic growth factors (filgrastim, sargramostim, GM-CSF) \<14 days prior to treatment 4. Other mTOR inhibitors 5. Renal disease or renal tubular acidosis 6. Uncontrolled Type 1 or 2 diabetes For Module F: 1\. AST ≤ 2.5xULN or ≤5xULN with liver metastases For Module G: 1. Have had prior treatment with a MEK, Ras or Raf inhibitor. 2. 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) 3. 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. 4. Previous moderate or severe impairment of LVEF (\<45% on echocardiography or equivalent on MUGA) even if full recovery has occurred. 5. 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. 6. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD. 7. Receiving or have received systemic therapy with nitrosoureas, mitomycin or suramin within 6 weeks prior to starting study treatment.

Primary outcome measure(s)

Module A: The frequency and nature of adverse events related to AZD4547 monotherapy. — Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of AZD4547 monotherapy given orally to selected patients with MIBC who have progressed following prior therapy.
Module A: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral AZD4547. — Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with AZD4547 given orally to selected patients with MIBC who have progressed following prior therapy.
Module B: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral olaparib. — Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with olaparib given orally to selected patients with MIBC who have progressed following prior therapy.
Module C: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral AZD1775. — Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with AZD1775 given orally to selected patients with MIBC who have progressed following prior therapy.
Module D: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) monotherapy. — Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) monotherapy given intravenously to selected patients with MIBC who have progressed following prior therapy.
Module E: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral vistusertib. — Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI 4736 (durvalumab) given intravenously in combination with vistusertib given orally to selected patients with MIBC who have progressed following prior therapy.
Module F: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and intravenous AZD9150. — Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of intravenous MEDI4736 (durvalumab) in combination with intravenous AZD9150 in selected patients with MIBC who have progressed following prior therapy.
Module G: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral selumetinib. — Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.
The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI 4736 (durvalumab) given intravenously in combination with selumetinib given orally to selected patients with MIBC who have progressed following prior therapy.
All Modules: Change from baseline in clinical chemistry parameters. — Days 1, 8, 15, and 22 of Cycle 1, Days 1, 15, and 22 of Cycles 2 and 3 and every 4 weeks thereafter, and at discontinuation.
Changes from baseline in clinical chemistry parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.
All Modules: Change from baseline in haematology parameters. — Days 1, 8, 15, and 22 of Cycle 1, Days 1, 15, and 22 of Cycles 2 and 3 and every 4 weeks thereafter, and at discontinuation.
Changes from baseline in haemotology parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.
All Modules: Change from baseline in urinalysis results. — Days 1, 8, 15, and 22 of Cycle 1, Days 1, 15, and 22 of Cycles 2 and 3 and every 4 weeks thereafter, and at discontinuation.
Changes from baseline in urinalysis findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.
All Modules: Change from baseline in vital signs. — Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.
Changes from baseline in vital signs will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.
All Modules: Change from baseline in physical examination findings. — Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.
Changes from baseline in physical examination findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.
All Modules: Change from baseline in ECG findings. — ECGs will be collected at screening, Day 1, Cycle 1and then Day 1 of each cycle from Cycle 2 onwards.
Changes from baseline in ECG findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.
All Modules: Change from baseline in ejection fraction determined by assessing ECHO/MUGA scans. — Ejection fraction will be measured at screening, on Day 1, Cycle 1, and every 12 weeks thereafter (relative to the first dose of study drug) up to Cycle 7, and then every 16 weeks thereafter.
Changes from baseline in ejection fraction determined by assessing ECHO/MUGA scans will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.
All Modules: Change from baseline in coagulation parameters — Coagulation parameters will be measured at screening, on Day 1, Cycle 1, and every 12 weeks thereafter (relative to the first dose of study drug) up to Cycle 7, and then every 16 weeks thereafter.
Changes from baseline in coagulation parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.
All Modules: Change from baseline in lipid profile — Lipid profile will be measured at screening, on Day 1, Cycle 1, and every 12 weeks thereafter (relative to the first dose of study drug) up to Cycle 7, and then every 16 weeks thereafter.
Changes from baseline in lipid profile will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

Trial sites (27)

Facility	City	Region
Research Site	Los Angeles	California
Research Site	New Haven	Connecticut
Research Site	Fort Myers	Florida
Research Site	New York	New York
Research Site	New York	New York
Research Site	New York	New York
Research Site	Cleveland	Ohio
Research Site	Nashville	Tennessee
Research Site	Edmonton	Alberta
Research Site	Vancouver	British Columbia
Research Site	Toronto	Ontario
Research Site	Montreal	Quebec
Research Site	Bordeaux	France
Research Site	Caen	France
Research Site	Lyon	France
Research Site	Marseille	France
Research Site	Saint-Herblain	France
Research Site	Toulouse	France
Research Site	Badalona	Spain
Research Site	Barcelona	Spain
Research Site	Barcelona	Spain
Research Site	Madrid	Spain
Research Site	Glasgow	United Kingdom
Research Site	London	United Kingdom
Research Site	London	United Kingdom
Research Site	Manchester	United Kingdom
Research Site	Southampton	United Kingdom

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