Clinical trial NCT02546661: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer
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).
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Muscle Invasive Bladder Cancer
Keywords: Durvalumab
Olaparib
Vistusertib
Selumetinib
Muscle invasive bladder cancer
MIBC
BISCAY
MEDI4736
AZD4547
AZD2281
AZD1775
AZD2014
AZD9150
AZD6244
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2015-09-11
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Eligibility 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.

Primary outcomes:
measure: Module A: The frequency and nature of adverse events related to AZD4547 monotherapy.
timeFrame: 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.
measure: Module A: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral AZD4547.
timeFrame: 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.
measure: Module B: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral olaparib.
timeFrame: 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.
measure: Module C: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral AZD1775.
timeFrame: 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.
measure: Module D: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) monotherapy.
timeFrame: 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.
measure: Module E: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral vistusertib.
timeFrame: 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.
measure: Module F: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and intravenous AZD9150.
timeFrame: 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.
measure: Module G: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral selumetinib.
timeFrame: 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.
measure: All Modules: Change from baseline in clinical chemistry parameters.
timeFrame: 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.
measure: All Modules: Change from baseline in haematology parameters.
timeFrame: 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.
measure: All Modules: Change from baseline in urinalysis results.
timeFrame: 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.
measure: All Modules: Change from baseline in vital signs.
timeFrame: Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.
measure: All Modules: Change from baseline in physical examination findings.
timeFrame: Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.
measure: All Modules: Change from baseline in ECG findings.
timeFrame: ECGs will be collected at screening, Day 1, Cycle 1and then Day 1 of each cycle from Cycle 2 onwards.
measure: All Modules: Change from baseline in ejection fraction determined by assessing ECHO/MUGA scans.
timeFrame: 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.
measure: All Modules: Change from baseline in coagulation parameters
timeFrame: 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.
measure: All Modules: Change from baseline in lipid profile
timeFrame: 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.
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: 16 weeks and 52 weeks
measure: Disease control rate (DCR)
timeFrame: 16 weeks and 52 weeks
measure: Progression free survival (PFS)
timeFrame: up to 12 months
measure: Duration of response (DoR)
timeFrame: up to 12 months
measure: Overall survival (OS) rate at 1 year
timeFrame: 1 year
measure: Plasma concentration of AZD4547 (Module A)
timeFrame: Blood samples will be taken pre-dose on Days 1 and 8 of Cycle 1; pre-dose and 2, 3, 4 and 6 hours post-dose on Day 1 of Cycle 2; and pre-dose and 2 to 4 hours post-dose on Day 1 of Cycle 3.
measure: Plasma concentration of MEDI4736 (durvalumab) (Module A)
timeFrame: Blood samples will be taken pre-dose and end of infusion for Day 1 of Cycles 1 to 7 and for the post-Cycle 7 8-weekly assessments, and pre-dose for Day 8 of Cycle 1.
measure: Plasma concentration of olaparib (Module B)
timeFrame: Blood samples will be taken on Day 3 of Cycles 1 and pre-dose and 4 hr post-dose. Serial samples on Day 3 of Cycle 3, pre-dose, 1, 2, 4, 6, 8, and 10 hr post-dose.
measure: Plasma concentration of AZD1775 (Module C)
timeFrame: Blood samples will be taken on Day 8 at steady state at the following time points: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hr post-dose.
measure: Plasma concentration of MEDI4736 (durvalumab) (Module C)
timeFrame: Blood samples will be taken on Days 1 and 8 of Cycle 1 pre-dose and at the end of infusion (1 hour). Samples will also be collected on Day 1 of Cycles 2 to 7 pre-dose and at the end of infusion.
measure: Plasma concentration of MEDI4736 (durvalumab) (Module D)
timeFrame: Blood samples will be taken on Days 1 and 8 of Cycle 1
measure: Plasma concentration of vistusertib (Module E)
timeFrame: Blood samples will be collected pre-dose, and 2 and 4 hr post-dose on Day 1 of Cycle 1; and pre-dose and 2 to 6 hr post-dose (matched to biopsy) on Day 2 of Cycle 2.
measure: Plasma concentration of Medi4736 (durvalumab) (Module E).
timeFrame: Blood samples will be taken pre-dose and end of infusion for Day 1 of Cycles 1 to 7 and every 8 weeks thereafter and pre-dose for Day 8 of Cycle 1.
measure: Plasma concentration of AZD9150 (Module F)
timeFrame: Blood samples will be taken pre-dose of Days -7, -5, and -3 of the lead-in portion and thereafter prior to dosing and at the ned of infusion on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 (approximately 8 months).
measure: Plasma concentration of MEDI4736 (durvalumab) (Module F).
timeFrame: Blood samples will be taken pre-dose and end of infusion for Day 1 of Cycles 1 to 7 and every 8 weeks thereafter and pre-dose for Day 8 of Cycle 1.
measure: The presence of Anti-Drug Antibodies (ADA) and ADA neutralising antibodies to MEDI4736 will be assessed in patients receiving MEDI4736 in any sub-study module.
timeFrame: Blood samples will be collected prior to MEDI4736 dosing on Day 1 of Cycles 1, 2 and 4 and every 12 weeks thereafter (up to 12 months).
Other outcomes:
measure: Mutation status of cancer associated genes in circulating tumour DNA (ctDNA).
timeFrame: Blood samples for assessment of ctDNA will be collected at screening, on Day 1 of Cycles 1, 2, 3, and 4 (up to 91 days) and at disease progression.
measure: Biomarker Analysis of Blood and Tissue
timeFrame: Up to 12 months
measure: Correlation of biomarkers to response and/or development of cancer
timeFrame: Throught out study (up to 18 months)
measure: Estimate overall survival (OS)
timeFrame: Up to 18 months
measure: Objective Response Rate (ORR) (by modified RECIST 1.1)
timeFrame: 16 weeks and 52 weeks
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: New Haven
country: United States
facility: Research Site
state: Connecticut
city: Fort Myers
country: United States
facility: Research Site
state: Florida
city: New York
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Cleveland
country: United States
facility: Research Site
state: Ohio
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Bordeaux
country: France
facility: Research Site
city: Caen
country: France
facility: Research Site
city: LYON cedex 08
country: France
facility: Research Site
city: Marseille Cedex 9
country: France
facility: Research Site
city: Saint Herblain Cedex
country: France
facility: Research Site
city: Toulouse Cedex
country: France
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Southampton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Barts Cancer Center, Barts and The London School of Medicine and Denistry
name: Thomas Powles, MBBS, MRCP, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sarah Cannon Research Institute, UK
name: Hendrik-Tobias Arkenau, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Powles T, Carroll D, Chowdhury S, Gravis G, Joly F, Carles J, Flechon A, Maroto P, Petrylak D, Rolland F, Cook N, Balar AV, Sridhar SS, Galsky MD, Grivas P, Ravaud A, Jones R, Cosaert J, Hodgson D, Kozarewa I, Mather R, McEwen R, Mercier F, Landers D. An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. Nat Med. 2021 May;27(5):793-801. doi: 10.1038/s41591-021-01317-6. Epub 2021 May 3.
citation: Maia MC, Salgia M, Pal SK. Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers. Nat Rev Urol. 2020 May;17(5):271-291. doi: 10.1038/s41585-020-0297-9. Epub 2020 Mar 17.