Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in pts w/ Muscle Invasive Bladder Cancer - BISCAY

Study identifier:D2615C00001

ClinicalTrials.gov identifier:NCT02546661

EudraCT identifier:2015-002228-25

CTIS identifier:N/A

Recruitment Complete

Official Title

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).

Medical condition

Muscle invasive bladder cancer

Phase

Phase 1

Healthy volunteers

Study drug

AZD4547, MEDI4736, Olaparib, AZD1775, Vistusertib, AZD9150, Selumetinib

Sex

All

Actual Enrollment

156

Study type

Interventional

Age

18 Years - 130 Years

Date

Study Start Date: 03 Oct 2016

Primary Completion Date: 18 Mar 2020

Estimated Study Completion Date: 28 Jun 2024

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

Verification:

Verified 01 Mar 2024 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

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.

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 in patients whose tumours express specific genomic alterations relevant to the molecules under investigation and whose disease has progressed following prior therapy. The allocation of patients to specific modules will depend on the specific eligible genomic alterations identified in their tumours. Each module will determine the appropriate combination dose for further clinical evaluation based on safety, tolerability and efficacy profile. A maximum tolerated dose will be defined and each arm expanded appropriately to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected combination doses. Module A includes an AZD4547 monotherapy arm and a MEDI4736 (durvalumab) + AZD4547 combination therapy arm and will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with AZD4547 given orally to selected patients with MIBC with tumours that have fibroblast growth factor receptor mutations or fibroblast growth factor receptor fusions. Module B will investigate the safety and tolerability of MEDI4736 given intravenously in combination with olaparib (AZD2281, Lynparza) given orally to selected patients with MIBC whose tumors have mutations in a homologous recombination repair gene panel and whose disease had progressed following prior therapy. Module C will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with AZD1775 given orally to selected patients with MIBC whose tumours have mutations in genes involved in cell cycle regulation (e.g., loss of either retinoblastoma 1 or cyclin-dependent kinase inhibitor 2A or amplification of cyclin E1 or MYC family genes). Module D will investigate the safety and tolerability of MEDI4736 given intravenously as monotherapy to patients with MIBC who do not qualify for Modules A, B or C. Module E will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with vistusertib (AZD2014) given orally to patients with MIBC whose tumours do not show genomic alterations that would be eligible for other study modules. Patients whose MIBC tumours harbour the following genomic alterations that have potential to respond to a mammalian target of rapamycin (mTOR) inhibitor will also be included in Module E: RICTOR amplification, or TSC1/1 mutations. Module F will investigate the safety and tolerability of MEDI4736 given intravenously in combination with AZD9150 given intravenously to patients with MIBC whose tumours do not show genomic alterations that would be eligible for other modules. Module G will investigate the safety and tolerability of MEDI4736 given intravenously in combination with selumetinib (AZD6244) given orally to patients with MIBC. Patients in this module will not be selected for any specific tumour genomic alteration.

No locations available

Arms	Assigned Interventions
Experimental: Module A: AZD4547 Monotherapy AZD4547 will be given orally twice daily until disease progression. Patients who receive AZD4547 as monotherapy will have the option to cross over to durvalumab as monotherapy at the point of objective progression, as long as the following criteria are met: • The investigator believes it is in the patient’s interest to receive durvalumab; • The patient consents to the continued treatment; • It is clinically appropriate for the patient to continue on durvalumab treatment; • The patient satisfies the key eligibility criteria for receiving durvalumab treatment.	Drug: AZD4547 AZD4547 Monotherapy vs. MEDI4736 (durvalumab) + AZD4547 1:1 Randomization.
Experimental: Module A: MEDI4736 (durvalumab) + AZD4547 AZD4547 will be given orally twice daily until disease progression. Patients will also receive MEDI 4736 (durvalumab) by IV infusion once every 4 weeks.	Drug: AZD4547 AZD4547 Monotherapy vs. MEDI4736 (durvalumab) + AZD4547 1:1 Randomization. Drug: MEDI4736 MEDI4736 Other Name: Durvalumab
Experimental: Module B: MEDI4736 (durvalumab) + Olaparib MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. Olaparib will be given orally twice daily.	Drug: MEDI4736 MEDI4736 Other Name: Durvalumab Drug: Olaparib MEDI4736 (durvalumab) + Olaparib Other Name: Lynparza
Experimental: Module C: MEDI4736 (durvaluamb) + AZD1775 MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. AZD1775 will be given orally in approximate 12 hour intervals over 3 days (6 doses) on Days 1-3, 8-10, and 15-17 of 28 day cycles.	Drug: MEDI4736 MEDI4736 Other Name: Durvalumab Drug: AZD1775 MEDI4736 (durvalumab) + AZD1775
Experimental: Module D: MEDI4736 (durvalumab) monotherapy MEDI 4736 (durvalumab) will be given by IV infusion once every 4 weeks.	Drug: MEDI4736 MEDI4736 Other Name: Durvalumab
Experimental: Module E: MEDI4736 (durvalumab) + Vistusertib MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. Vistusertib will be given orally twice per day on an intermittent schedule (2 days on, 5 days off).	Drug: MEDI4736 MEDI4736 Other Name: Durvalumab Drug: Vistusertib MEDI4736 (durvalumab) + Vistusertib
Experimental: Module F: MEDI4736 (durvaluamb) + AZD9150 AZD9150 will be given as monotherapy on Days -7, -5, and -3 of a one week lead-in period. Combination dosing with IV AZD9150 followed by IV MEDI4736 (durvalumab) begins on Day 1 of each 28 day cycle. Thereafter AZD9150 is given weekly and MEDI4736 is given once every 4 weeks.	Drug: MEDI4736 MEDI4736 Other Name: Durvalumab Drug: AZD9150 MEDI4736 (durvalumab) + AZD9150
Experimental: Module G: MEDI4736 + Selumetinib	Drug: MEDI4736 MEDI4736 Other Name: Durvalumab Drug: Selumetinib MEDI4736 (durvalumab) + Selumetinib

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Contact Backup

AstraZeneca Cancer Study Location Service

1-877-400-4656