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BRIEF TITLE: Study in Patients With Muscle Invasive Bladder Cancer (MIBC) Who Have Progressed on Prior Treatment (BISCAY).

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).


  • Org Study ID: D2615C00001
  • Secondary ID: GU 118,BISCAY
  • NCT ID: NCT02546661
  • NCT Alias:
  • Sponsor: AstraZeneca - Industry
  • Source: AstraZeneca

Brief Summary

This is an open label, multi-drug, biomarker-directed, multi-centre, multi-arm, randomised Phase 1b study in patients with muscle invasive bladder cancer (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 in patients with muscle invasive bladder cancer. The study will consist of a number of study modules (substudies), 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, randomised
Phase 1b study in patients with muscle invasive bladder cancer (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 in patients with muscle
invasive bladder cancer. 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 mutations 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 mutations identified in their tumours.

Module A includes an AZD4547 monotherapy arm and a durvalumab + AZD4547 combination therapy
arm. Patients who receive AZD4547 monotherapy will have the option to cross over to
durvalumab as a monotherapy treatment at the point of objective progression. Module A will
investigate the safety and tolerability of durvalumab given intravenously, in combination
with AZD4547 given orally to selected patients with muscle invasive bladder cancer with
tumours that have fibroblast growth factor receptor mutations or fibroblast growth factor
receptor fusions and whose disease has progressed following prior therapy. Specifically the
following fibroblast growth factor receptor 3 activating mutations are eligible, R248C,
S249C, G370C, Y373C, S371C, G3780R, as are fibroblast growth factor receptor 1, 2, 3 gene
fusions resulting in removal of the c-terminal of the fibroblast growth factor receptor while
encoding an intact tyrosine kinase domain, an example being the fibroblast growth factor
receptor 3-transforming acidic coiled-coil 3 fusions identified in bladder cancer and
glioblastoma. Module A will evaluate the durvalumab + AZD4547 combination dose(s) for further
clinical evaluation and assess the safety, tolerability and efficacy of AZD4547 given orally
to selected patients with muscle invasive bladder cancer who have progressed following prior
therapy. In the combination arm, a maximum tolerated dose will be defined by dose-limiting
toxicity. An expansion cohort(s) in Module A will enroll additional patients to explore
further the safety, tolerability, pharmacokinetics and biological activity at the selected
AZD4547 plus durvalumab dose(s). 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 investigator believes it is in the patient's interest to continue MEDI4736
monotherapy.

Module B will evaluate durvalumab + olaparib combination dose(s) to confirm the safety and
tolerability of durvalumab given intravenously in combination with olaparib (AZD2281).
Olaparib will be given orally to selected patients with muscle invasion bladder cancer (MIBC)
whose tumors have deleterious mutations, deletions or truncations in any one of a panel of
homologous recombination repair (HRR) genes, and whose disease had progressed following prior
therapy.

Module C will evaluate durvalumab + AZD1775 combination doses(s) to confirm the safety and
tolerability of durvalumab given intravenously, in combination with AZD1775 given orally to
selected patients with MIBC whose tumours have mutations in genes involved in cell cycle
regulation (eg, loss of either retinoblastoma 1 or cyclin-dependent kinase inhibitor 2A or
amplification of cyclin E1 or MYC family genes).

Module D will evaluate durvalumab monotherapy treatment to confirm the safety and
tolerability of durvalumab given intravenously as monotherapy to patients with MIBC who do
not qualify for Modules A, B or C. This sub-study will not be restricted to any PD-L1 defined
sub-population and it is intended to perform retrospective analysis of PD-L1 so that patients
with positive PD-L1 status are included in this monotherapy module.

Module E will evaluate the safety and tolerability of durvalumab given intravenously, in
combination with vistusertib (AZD2014) given orally to patients with MIBC whose disease has
progressed following prior therapy. Patients who enter this sub study will be those whose
tumours do not show mutations that would be eligible for other study modules, with the
exception of the following mutations that have potential to respond to an mTOR inhibitor:
RICTOR amplification, or TSC1/2 mutations.

Module F will investigate the safety and tolerability of intravenous durvalumab in
combination with intravenous AZD9150 in patients with MIBC whose tumours do not show genomic
alterations that would be eligible for other modules.

Overal Status Start Date Phase Study Type
Recruiting October 3, 2016 Phase 1 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: The frequency and nature of adverse events related to AZD4547 monotherapy.

Primary Outcome 1 - Time Frame: Adverse events will be assessed at each clinic visit up to 12 weeks, and at study discontinaution and 90 days after the end of treatment.

Primary Outcome 2 - Measure: The frequency and nature of adverse events related to the combination of intravenous durvalumab and oral AZD4547.

Primary Outcome 2 - Time Frame: Adverse events will be assessed at each clinic visit up to 12 weeks, and at study discontinaution and 90 days after the end of treatment.

Primary Outcome 3 - Measure: The frequency and nature of adverse events related to the combination of intravenous durvalumab and oral olaparib.

Primary Outcome 3 - Time Frame: Adverse events will be assessed at each clinic visit up to 12 weeks, and at study discontinaution and 90 days after the end of treatment.

Primary Outcome 4 - Measure: The frequency and nature of adverse events related to intravenous durvalumab when given in combination with oral AZD1775.

Primary Outcome 4 - Time Frame: Adverse events will be assessed at each clinic visit up to 12 weeks, and at study discontinaution and 90 days after the end of treatment.

Primary Outcome 5 - Measure: The frequency and nature of adverse events related to intravenous durvalumab monotherapy.

Primary Outcome 5 - Time Frame: Adverse events will be assessed at each clinic visit up to 12 weeks, and at study discontinaution and 90 days after the end of treatment.

Primary Outcome 6 - Measure: The frequency and nature of adverse events related to intravenous durvalumab when given in combination with oral vistusertib.

Primary Outcome 6 - Time Frame: Adverse events will be assessed at each clinic visit up to 12 weeks, and at study discontinaution and 90 days after the end of treatment.

Primary Outcome 7 - Measure: Change from baseline in clinical chemistry parameters.

Primary Outcome 7 - Time Frame: 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.

Primary Outcome 8 - Measure: Change from baseline in haematology parameters.

Primary Outcome 8 - Time Frame: 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.

Primary Outcome 9 - Measure: Change from baseline in urinalysis results.

Primary Outcome 9 - Time Frame: 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.

Primary Outcome 10 - Measure: Change from baseline in vital signs.

Primary Outcome 10 - Time Frame: Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.

Primary Outcome 11 - Measure: Change from baseline in physical examination findings.

Primary Outcome 11 - Time Frame: Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.

Primary Outcome 12 - Measure: Change from baseline in ECG findings.

Primary Outcome 12 - Time Frame: ECGs will be collected at screening, Day 1, Cycle 1and then Day 1 of each cycle from Cycle 2 onwards.

Primary Outcome 13 - Measure: Change from baseline in ejection fraction determined by assessing ECHO/MUGA scans.

Primary Outcome 13 - Time Frame: 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.

Primary Outcome 14 - Measure: The frequency and nature of adverse events related to the combination of intravenous durvalumab and intravenous AZD9150.

Primary Outcome 14 - Time Frame: Adverse events will be assessed at each clinic visit up to 12 weeks, and at study discontinaution and 90 days after the end of treatment.

Condition:

  • Muscle Invasive Bladder Cancer

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 wks, or radiotherapy
for palliation <2 wks, any study drugs <30 days.

2. Major surgery <4 wk

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 mets
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Gender: All

Minimum Age: 18 Years

Maximum Age: 130 Years

Healthy Volunteers: No

Official Information

Name: Thomas Powles, MBBS, MRCP, MD

Role: Principal Investigator

Affiliation: Barts Cancer Center, Barts and The London School of Medicine and Denistry

Overall Contact

Name: AstraZeneca Clinical Study Information Center

Phone: 1-877-240-9479

Email: information.center@astrazeneca.com

Locations

Facility Status Contact
Research Site
Los Angeles, California 90095
United States
Recruiting
Research Site
New Haven, Connecticut 06510
United States
Recruiting
Research Site
Baltimore, Maryland 21231
United States
Withdrawn
Research Site
Baltimore, Maryland 21287-0013
United States
Recruiting
Research Site
Detroit, Michigan 48202
United States
Not yet recruiting
Research Site
Kansas City, Missouri 64132
United States
Not yet recruiting
Research Site
New York, New York 10029
United States
Recruiting
Research Site
New York, New York 10032
United States
Recruiting
Research Site
New York, New York 10116
United States
Recruiting
Research Site
Cincinnati, Ohio 45243
United States
Withdrawn
Research Site
Cleveland, Ohio 44195
United States
Recruiting
Research Site
Nashville, Tennessee 37203
United States
Recruiting
Research Site
Milwaukee, Wisconsin 53226
United States
Recruiting
Research Site
Edmonton, Alberta T6G 1Z2
Canada
Recruiting
Research Site
Vancouver, British Columbia V5Z 4E6
Canada
Recruiting
Research Site
Toronto, Ontario M5G 2M9
Canada
Recruiting
Research Site
Montreal, Quebec H3T 1E2
Canada
Not yet recruiting
Research Site
Bordeaux, 33075
France
Recruiting
Research Site
Caen, 14000
France
Recruiting
Research Site
LYON cedex 08, 69373
France
Recruiting
Research Site
Marseille Cedex 9, 13273
France
Recruiting
Research Site
Saint Herblain Cedex, 44805
France
Recruiting
Research Site
Toulouse Cedex, 31100
France
Recruiting
Research Site
Badalona, 08003
Spain
Recruiting
Research Site
Barcelona, 08035
Spain
Recruiting
Research Site
Barcelona, 08041
Spain
Recruiting
Research Site
Madrid, 28040
Spain
Recruiting
Research Site
Cardiff, CF14 2TL
United Kingdom
Recruiting
Research Site
Glasgow, G12 0YN
United Kingdom
Recruiting
Research Site
London, EC1M 6BQ
United Kingdom
Recruiting
Research Site
London, W1G 6AD
United Kingdom
Recruiting
Research Site
Manchester, M20 4BX
United Kingdom
Recruiting
Research Site
Plymouth, PL6 8DH
United Kingdom
Not yet recruiting
Research Site
Southampton, SO16 6YD
United Kingdom
Recruiting