Bladder Cancer Clinical Trial

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

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.

View Full Description

Full 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.

View Eligibility Criteria

Eligibility Criteria

Inclusion Criteria 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:

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:

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.

Exclusion Criteria for all Modules:

Immunotherapy, chemotherapy, anticancer agents, radiotherapy <4 weeks, or radiotherapy for palliation <2 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 mLmin; 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 inhibitorsinducers of CYP3A4, CYP2D6 or substrates 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 CYP3A4.
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 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 strongmoderate inhibitorsinducers of CYP3A45, Pgp (MDR1) and BRCP if taken within washout periods 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:

1. 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.

Study is for people with:

Bladder Cancer

Phase:

Phase 1

Estimated Enrollment:

156

Study ID:

NCT02546661

Recruitment Status:

Active, not recruiting

Sponsor:

AstraZeneca

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There are 27 Locations for this study

See Locations Near You

Research Site
Los Angeles California, 90095, United States
Research Site
New Haven Connecticut, 06510, United States
Research Site
Fort Myers Florida, 33901, United States
Research Site
New York New York, 10029, United States
Research Site
New York New York, 10032, United States
Research Site
New York New York, 10116, United States
Research Site
Cleveland Ohio, 44195, United States
Research Site
Nashville Tennessee, 37203, United States
Research Site
Edmonton Alberta, T6G 1, Canada
Research Site
Vancouver British Columbia, V5Z 4, Canada
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Toronto Ontario, M5G 2, Canada
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Montreal Quebec, H3T 1, Canada
Research Site
Bordeaux , 33075, France
Research Site
Caen , 14000, France
Research Site
LYON cedex 08 , 69373, France
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Marseille Cedex 9 , 13273, France
Research Site
Saint Herblain Cedex , 44805, France
Research Site
Toulouse Cedex , 31100, France
Research Site
Badalona , 08003, Spain
Research Site
Barcelona , 08035, Spain
Research Site
Barcelona , 08041, Spain
Research Site
Madrid , 28040, Spain
Research Site
Glasgow , G12 0, United Kingdom
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London , EC1M , United Kingdom
Research Site
London , W1G 6, United Kingdom
Research Site
Manchester , M20 4, United Kingdom
Research Site
Southampton , SO16 , United Kingdom

How clear is this clinincal trial information?

Study is for people with:

Bladder Cancer

Phase:

Phase 1

Estimated Enrollment:

156

Study ID:

NCT02546661

Recruitment Status:

Active, not recruiting

Sponsor:


AstraZeneca

How clear is this clinincal trial information?

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