Clinical Trials /

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

NCT02546661

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.

Related Conditions:
  • Bladder Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Open-Label, Randomised, Multi-Drug, Biomarker-Directed, <span class="go-doc-concept go-doc-intervention">Phase 1b</span> Study in Pts w/ Muscle Invasive Bladder Cancer

Title

  • Brief Title: 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)
  • Clinical Trial IDs

    NCT ID: NCT02546661

    ORG ID: D2615C00001

    NCI ID: GU 118

    Trial Conditions

    Muscle Invasive Bladder Cancer

    Trial Interventions

    Drug Synonyms Arms
    AZD4547 Monotherapy AZD4547 Monotherapy
    AZD4547 + MEDI4736 Combination Therapy AZD4547 + MEDI4736 Combination Therapy

    Trial Purpose

    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. The initial module (Module A)
    incorporates an AZD4547 monotherapy arm and MEDI4736+AZD4547 combination therapy arm.

    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 (substudies), each evaluating the safety
    and tolerability of a specific agent or combination. The initial module (Module A)
    incorporates an AZD4547 monotherapy arm and MEDI4736+AZD4547 combination therapy arm. Module
    A will investigate the safety and tolerability of MEDI4736 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 determine the MEDI4736+AZD4547 combination dose(s) for further clinical
    evaluation and confirm 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 in patients with
    muscle invasive bladder cancer, as defined by dose-limiting toxicity. An expansion cohort(s)
    in Module A will enrol additional patients to explore further the safety, tolerability,
    pharmacokinetics and biological activity at the selected AZD4547 plus MEDI4736 dose(s).

    Trial Arms

    Name Type Description Interventions
    AZD4547 Monotherapy Experimental AZD4547 oral AZD4547
    AZD4547 + MEDI4736 Combination Therapy Experimental AZD4547 in combination with MEDI4736 AZD4547 + MEDI4736

    Eligibility Criteria

    Inclusion Criteria:

    1. Fibroblast growth factor receptor (FGFR3) mutation fusion

    2. Histological confirmation of metastatic muscle invasive bladder cancer

    3. Second- or third-line treatment

    4. Failed adjuvant or neo-adjuvant chemotherapy within 1 year

    5. Willingness to provide consent for biopsy samples.

    6. At least 1 lesion that can be accurately measured at baseline as 10 mm in the
    longest diameter (except lymph nodes which must have short axis 15 mm) with CT or
    MRI which is suitable for accurate repeated measurement

    7. WHO performance status of 0-1

    Exclusion Criteria:

    1. Prior exposure to other immunotherapy [e.g., a cytotoxic T-lymphocyte-associated
    protein 4 (CTLA4), PD-1 or PD-L1 inhibitor] before the first dose, any chemotherapy
    or anticancer agents within 4 weeks, radiotherapy of the primary site with a wide
    field of radiation within 4 weeks, or radiotherapy with a limited field of radiation
    for palliation within 2 weeks, any investigational or study drugs from a previous
    study within 30 days.

    2. Major surgery within 4 weeks.

    3. Unresolved toxicities (except alopecia) from prior therapy > CTCAE Grade 1, any prior
    Grade 3 immune-related adverse event (irAE) while receiving immunotherapy, or any
    unresolved irAE >Grade 1

    4. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy

    5. Current or prior immunosuppressive medication within 28 days, with the exceptions of
    intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at
    physiologic doses not to exceed 10 mg/day of prednisone or equivalent

    6. Any of the following immune related criteria:

    - Active or prior documented autoimmune disease within the past 2 years prior to
    screening

    - Active or prior documented inflammatory bowel disease (eg, Crohn's disease,
    ulcerative colitis)

    - History of primary immunodeficiency

    - History of organ transplant that requires use of immunosuppressives

    7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable
    and not requiring steroids for at least 4 weeks

    8. As judged by the investigator, any evidence of severe or uncontrolled systemic
    diseases, including uncontrolled hypertension, active bleeding diatheses, or active
    infection including hepatitis B, hepatitis C and human immunodeficiency virus

    9. Any of the following cardiac criteria:

    - Mean QTc 470 ms

    - Abnormalities in rhythm, conduction or morphology of resting ECG

    - Any factors that increase the risk of QT interval, corrected (QTc) prolongation
    or risk of arrhythmic events

    - Uncontrolled hypertension - BP 150/95 mmHg despite medical therapy

    - Uncontrolled hypotension - systolic BP <90 mmHg and/or diastolic BP <50 mmHg

    - LVEF <55% measured by echocardiography

    - Atrial fibrillation with a ventricular rate >100 bpm on an ECG at rest

    - Symptomatic heart failure - New York Heart Association Grade II-IV

    - Prior or current cardiomyopathy

    - Severe valvular heart disease

    - Uncontrolled angina

    - Stroke or transient ischemic attack in the last 6 months

    - Acute coronary syndrome in the last 6 months

    10. Inadequate bone marrow reserve or organ function as demonstrated by any of the
    following laboratory values:

    - Absolute neutrophil count (ANC) <1.5 x 109/L

    - Platelets <100 x 109/L

    - Hgb <9.0 g/dL

    - Alanine aminotransferase >2.5 times the upper limit of normal (ULN) if no
    demonstrable liver metastases or >5 times ULN in the presence of liver
    metastases

    - Total bilirubin >1.5 times ULN or for patients with documented/suspected
    Gilbert's disease, bilirubin 2 ULN

    - Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min;
    confirmation of creatinine clearance is only required when creatinine is >1.5
    times ULN

    - Corrected calcium >ULN

    - Phosphate >ULN

    11. Known history of tuberculosis

    12. Receipt of any live attenuated vaccination within 30 days prior to study entry or
    within 30 days of receiving MEDI4736.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: 130 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Number of Patients Experiencing Adverse Events

    Change from Baseline in Clinical Chemistry Values

    Change from Baseline in Urinalysis

    Change from Baseline in Haemotology Values

    Change from Baseline in Physical Examination

    Change from Baseline in World Health Organization (WHO) Performance Status

    Change in Baseline in Electrocardiogram (ECG)

    Change from Baseline in Left Ventricular Ejection Fraction (LVEF)

    Change from Baseline in Pulse and Blood Pressure

    Secondary Outcome Measures

    Area under the plasma concentration-time curve (AUC).

    Apparent plasma clearance at steady state (CL).

    Maximum plasma concentration at steady state (Cmax)

    Minimum plasma concentration at steady state (Cmin)

    Time to maximum plasma concentration at steady state (tmax)

    Objective response rate (ORR)

    Disease control rate (DCR)

    Progression free survival (PFS)

    Duration of response (DoR)

    Trial Keywords

    AZD4547, MEDI4736, muscle invasive bladder cancer, MIBC, BISCAY