Details

Details

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)

IRB ZNCA1816

CC 16-1579

Hospital Main Campus

Phase Phase 1

Disease Bladder

Drug AZD1775 , AZD2281 , AZD4547 , Durvalumab

Description

Description

Primary objective
  • To assess the safety and tolerability of study treatments given to selected patients with MIBC who have progressed following prior therapy, and confirm the dose(s) for further clinical evaluation
Secondary objectives
  • To characterise the PK profile(s) of study treatments in selected patients in MIBC population
  • To estimate the overall clinical activity of study treatments in selected patients with MIBC progressing on prior therapy using RECIST 1.1
Exploratory objectives
  • To collect plasma and serum samples for isolation of ctDNA to explore the mutation status of cancer associated genes at screening, during treatment and at discontinuation
  • To collect blood and tissue samples for analysis of peripheral and tumoural biomarkers
  • To collect and store DNA, derived from a blood sample, for future exploratory research into genes/genetic factors that may influence response eg, distribution, safety, tolerability and efficacy of study treatments (optional)
  • To explore potential biomarkers in residual biological samples (eg, tumour, plasma and/or serum) which may influence development of cancer (and associated clinical characteristics) and/or response
Inclusion Criteria

Inclusion Criteria

  1. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses. If a patient declines to participate in any voluntary exploratory research component of the study there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study
  2. Male or female aged 18 years and older. Note: for patients receiving AZD4547 in the Module A sub-study patients must be aged 25 years or older (see the Module A specific criteria in Appendix G)
  3. Histological confirmation of metastatic MIBC involving prostatic urethra, ureters and renal pelvis
  4. Patients may be second- or third-line patients. Patients must have received 1 accepted first-line treatment (eg, methotrexate, vinblastine, doxorubicin, and cisplatin/gemcitabine) in a metastatic setting. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study
  5. Any patient who has failed adjuvant or neo-adjuvant chemotherapy within a year of Screening
  6. Willingness to provide consent for biopsy samples. Tumour biopsies will be required for all patients as described in the CSP. Tumour lesions used for biopsy must not be lesions used as RECIST target lesions (TLs)
    • Tumour sample requirements:
      • Mandatory provision of an unstained, archived tumour tissue sample, taken within 3 years of entry into the study and in a quantity sufficient to allow for analysis. Please refer to the Laboratory Manual for details. A copy of the pathology report related to the archival tissue must also be provided, if available AND
      • Paired pre- and on-drug tumour biopsies resulting in adequate tissue for analysis will be required for all patients enrolled in each treatment arm in each module of the study. This tumour biopsy is mandatory except if associated with unacceptable clinical risk and after discussion with the Medical Monitor.
  7. At least 1 lesion, not previously irradiated, not biopsied during the screening period, 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 computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurement
  8. World Health Organisation performance status of 0 to 1 with no deterioration between Screening and the first dose of study treatment, and a minimum life expectancy of 12 weeks
  9. Females must be using two highly effective contraceptive measures, must not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling 1 of the following criteria at screening:
    • Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
    • Women under 50 years old would be considered postmenopausal if they have been amenorrhoeic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone and luteinising hormone levels in the postmenopausal range for the institution
    • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
  10. Male patients must use barrier contraception (ie, condoms). See Section 3.8 Pharmacogenetic research study (optional) For inclusion in the optional (DNA) genetics research study patients must fulfil the following criteria:
    • Provide informed consent for the genetic sampling and analyses

If a patient declines to participate in the genetics research, there will be no penalty or loss of benefit to the patient. A patient who declines genetics research participation will not be excluded from any other aspect of the main study.

Exclusion Criteria

Exclusion Criteria

  1. Prior exposure to any of the following:
    • Any other immunotherapy (eg, a CTLA-4, PD-1 or PD-L1 inhibitor) before the first dose of study treatment
    • Any other chemotherapy or anticancer agents within 4 weeks before the first dose of study treatment
    • 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 before the first dose of study treatment
    • Any investigational agents or study drugs from a previous clinical study within 30 days before the first dose of study treatment
  2. Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment
  3. With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving immunotherapy, including anti-CTLA-4 treatment, or any unresolved irAE >Grade 1
  4. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. NOTE: local treatment of isolated lesions for palliative intent is acceptable (eg, by local surgery or radiotherapy).
  5. Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, 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. Note: this criterion is only applicable to patients receiving treatment with MEDI4736.
  6. Any of the following immune-related criteria:
    • Active or prior documented autoimmune disease within the past 2 years prior to Screening. NOTE: patients with vitiligo, Grave's disease, Hashimoto's disease, or psoriasis not requiring systemic treatment (within the past 2 years prior to Screening) are not excluded.
    • 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 prior to start of study treatment
  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. Screening for chronic conditions is not required
  9. Any of the following cardiac criteria:
    • Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Friderecia's correction
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block, second degree heart block, first degree heart block
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
    • Uncontrolled hypertension - blood pressure (BP) ≥150/95 mmHg despite medical therapy
    • Uncontrolled hypotension - systolic BP <90 mmHg and/or diastolic BP <50 mmHg
    • Left ventricular ejection fraction <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 to Grade IV
    • Prior or current cardiomyopathy
    • Severe valvular heart disease
    • Uncontrolled angina (Canadian Cardiovascular Society Grade II to Grade IV despite medical therapy)
    • Stroke or transient ischemic attack in the last 6 months prior to Screening
    • Acute coronary syndrome in the last 6 months prior to Screening
  10. Inadequate bone marrow reserve or organ function as demonstrated by any of thefollowing laboratory values:
    • Absolute neutrophil count <1.5x109/L
    • Platelet count <100x109/L
    • Haemoglobin <9.0 g/dL
    • Alanine aminotransferase >2.5x the upper limit of normal (ULN) if no demonstrable liver metastases or >5xULN in the presence of liver metastases
    • Total bilirubin >1.5xULN or for patients with documented/suspected Gilbert's disease, bilirubin ≥2xULN
    • Creatinine >1.5xULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5xULN
    • 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. Note: not applicable to patients not receiving MEDI4736
  13. History of hypersensitivity to active or inactive excipients of any investigational drug in the study or drugs with a similar chemical structure or class to those investigated in the study
  14. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements

Genetics research study (optional)

  • Exclusion criteria for participation in the optional (DNA) genetics research component of the study:
    • Previous allogeneic bone marrow transplant
    • Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection