Details

Details

Title A Phase 3, Multicenter, Multinational, Randomized, Open-Label, Parallel-Arm Study Of Avelumab* (MSB0010718C) Plus Best Supportive Care Versus Best Supportive Care Alone As A Maintenance Treatment In Patients With Locally Advanced Or Metastatic Urothelial Cancer Whose Disease Did Not Progress After Completion Of First-Line Platinum-Containing Chemotherapy

IRB PFIZ1816

CC 16-397

Hospital Main Campus

Phase Phase 3

Disease Bladder, Urothelial

Drug Avelumab

Description

Description

Primary Objective
  • To demonstrate the benefit of maintenance treatment with avelumab plus BSC vs. BSC alone in prolonging overall survival (OS) in patients with unresectable locally advanced or metastatic UC whose disease did not progress on or following completion of first-line platinum-containing chemotherapy in each co-primary UC patient population: 1) patients determined to have PD-L1-positive tumors (including infiltrating immune cells) by a verified GMP PD-L1 IHC test, and 2) all randomized patients.
Secondary Objectives
  • To compare the PFS of avelumab plus BSC vs. BSC alone in patients determined to have PD-L1-positive tumors (including infiltrating immune cells) by a verified GMP PD-L1 IHC test, and in all randomized patients.
  • To evaluate the anti-tumor activity of avelumab plus BSC and BSC alone according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in patients determined to have PD-L1-positive tumors (including infiltrating immune cells) by a verified GMP PD-L1 IHC test, and in all randomized patients.
  • To evaluate the overall safety profile of avelumab plus BSC and BSC alone.
  • To evaluate the PK of avelumab in each of the co-primary UC patient populations treated with avelumab.
  • To assess the immunogenicity of avelumab in each of the co-primary UC patient populations treated with avelumab.
  • To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab in pre-treatment tumor tissue in each of the co-primary UC patient populations treated with avelumab.
  • To evaluate the effect of avelumab plus BSC and BSC alone on patient-reported outcomes (PROs) in each of the co-primary UC patient populations.
Exploratory Objectives
  • To explore the predictive and/or pharmacodynamic (PD) characteristics of peripheral blood and additional tumor tissue biomarkers relevant to the mechanism of action of or resistance to avelumab.
  • To explore the anti-tumor activity of avelumab plus BSC and BSC alone in each of the co-primary UC patient populations according to immune-related RECIST (irRECIST) [Nishino et al, 2014].
Inclusion Criteria

Inclusion Criteria

  1. Diagnosis:
    • Histologically confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium.
    • Documented Stage IV disease (per American Joint Committee on Cancer/ International Union for Cancer Control Tumor Node Metastasis (TNM) system, 7th edition) at the start of first-line chemotherapy.
    • Measurable disease prior to the start of first-line chemotherapy by RECIST v1.1.
  2. Prior first-line chemotherapy must have consisted of at least 4 cycles and no more than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin. No other chemotherapy regimens are allowed in this study.
    • The last dose of first-line chemotherapy must have been received no less than 4 weeks, and no more than 10 weeks, prior to randomization in the present study.
  3. Patients without progressive disease as per RECIST v1.1 guidelines (ie, with an ongoing CR, PR, or SD) following completion of 4 to 6 cycles of first-line chemotherapy.
    • Eligibility based on this criterion will be determined by investigator review of prechemotherapy and postchemotherapy radiological assessments (CT/MRI scans); see Study Overview, Section 3.1.
  4. Provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (slides not acceptable) from the most recent primary or metastatic tumor biopsy or resection obtained prior to treatment with first line chemotherapy but within one year of randomization, with no intervening systemic anti-cancer therapy. If a suitable tissue sample is not otherwise available, then an FFPE tissue block from a de novo biopsy (core needle or excisional) must have been obtained for research purposes prior to randomization in this study.
  5. Provision of an archival FFPE tumor tissue block from primary tumor resection specimen (if not provided per above). If an FFPE tissue block cannot be provided, 15 unstained slides (10 minimum) will be acceptable. If a suitable tissue sample is not otherwise available, then a de novo biopsy (core needle or excisional) must have been obtained for research purposes prior to randomization in this study. Note: tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material) or bone metastases are not acceptable and should not be submitted.
  6. Evidence of a signed and dated informed consent document indicating that the patient (or a legally acceptable representative, as allowed by local guideline/practice) has been informed of all pertinent aspects of the study.
  7. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
  8. Age ≥18 years (≥20 years in Japan).
  9. Estimated life expectancy of at least 3 months.
  10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (Appendix 1).
  11. Adequate bone marrow function, including:
    • Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;
    • Platelets ≥100,000/mm3 or ≥100 x 109/L;
    • Hemoglobin ≥9 g/dL (may have been transfused).
  12. Adequate renal function, defined as estimated creatinine clearance ≥30 mL/min as calculated using the Cockcroft-Gault equation (Appendix 5) or by 24-hour urine collection for creatinine clearance or according to the local institutional standard method.
  13. Adequate liver function, including:
    • Total serum bilirubin ≤1.5 x upper limit of normal (ULN);
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN, or, for patients with documented metastatic disease to the liver, AST and ALT levels ≤ 5 x ULN.
  14. Serum pregnancy test (for females of childbearing potential) negative at screening.
  15. Male patients able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception (Section 4.3.1) throughout the study and for at least 60 days after the last dose of assigned treatment.
Exclusion Criteria

Exclusion Criteria

  1. Patients whose disease progressed by RECIST v1.1 on or after first-line chemotherapy for urothelial cancer.
  2. Prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization.
  3. Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
  4. Major surgery ≤4 weeks or major radiation therapy ≤2 weeks prior to randomization. Prior palliative radiotherapy is permitted, provided it has been completed at least 48 hours prior to patient randomization.
  5. Patients with known symptomatic central nervous system (CNS) metastases requiring steroids. Patients with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to randomization, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.
  6. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1; however, sensory neuropathy Grade ≤2 is acceptable, or other Grade ≤2 adverse events not constituting a safety risk based on the investigator's judgment are acceptable.
  7. Diagnosis of any other malignancy within 5 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, or low-grade (Gleason ≤6) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration), or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms.
  8. Participation in other studies involving investigational drug(s) within 4 weeks prior to randomization. Observational studies are permitted.
  9. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypoor hyperthyroid disease not requiring immunosuppressive treatment are eligible.
  10. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
  11. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or symptomatic pulmonary embolism.
  12. Active infection requiring systemic therapy.
  13. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of asthma symptom control per the Global Initiative for Asthma 2015).
  14. Known prior or suspected hypersensitivity to study drugs or any component in their formulations.
  15. Current or prior use of immunosuppressive medication within 7 days prior to randomization, EXCEPT the following:
    • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection);
    • Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent;
    • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
  16. Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
  17. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
  18. Vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivate vaccines (for example, inactivated influenza vaccines).
  19. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees directly involved in the conduct of the study.
  20. Pregnant female patients; breastfeeding female patients; male patients able to father children, and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in the protocol for the duration of the study and for at least 60 days after the last dose of investigational product.
  21. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, and pneumonitis; psychiatric condition including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.