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Title A Phase III, open-label, randomized study of MPDl3280a (anti-pd-l1 antibody) in combination with bevacizumab versus sunitinib in patients with untreated advanced renal cell carcinoma

IRB GENE1815

CC 15-361

Hospital Main Campus

Phase Phase 3

Disease Renal

Drug Bevacizumab , MPDL3280A

Description

EFFICACY OBJECTIVES

Primary Efficacy Objective
• To evaluate the efficacy of MPDL3280A+ bevacizumab compared with sunitinib as measured by investigator-assessed PFS per RECIST v1.1.

• Secondary Efficacy Objectives
  • To evaluate the efficacy of MPDL3280A+ bevacizumab versus sunitinib as measured by Independent Review Committee (IRC)-assessed PFS according to RECIST v1.1
  • To evaluate the efficacy of MPDL3280A + bevacizumab versus sunitinib as measured by overall survival (OS)
  • To evaluate tiredness severity as measured by worst fatigue, Question 3 in the Brief Fatigue Inventory (BFI)
  • To assess symptom interference (from the M.D. Anderson Symptom Inventory [MDASI]), tiredness interference (from the BFI), diarrhea severity (from the MDASI), treatment side-effects subscale (from the FKSI-19)
  • To evaluate the efficacy of MPDL3280A+ bevacizumab versus sunitinib as measured by investigator-assessed ORR (complete+ partial response rates) per RECIST v1.1
  • To evaluate the efficacy of MPDL3280A+ bevacizumab versus sunitinib as measured by investigator-assessed DOR among patients with an objective response per RECIST v1.1
  • To evaluate the efficacy of MPDL3280A+ bevacizumab versus sunitinib as measured by IRC-assessed ORR and DOR according to RECIST v1.1
  • To evaluate the efficacy of MPDL3280A+ bevacizumab versus sunitinib as measured by investigator-assessed PFS, DOR, and ORR per modified RECIST (see Appendix 4)
  • To evaluate the efficacy of MPDL3280A+ bevacizumab versus sunitinib in patients who have detectable PD-L1 expression as measured by OS and investigator-assessed PFS per RECIST v1.1

SAFETY OBJECTIVES

• To evaluate the safety and tolerability of MPDL3280A + bevacizumab versus sunitinib
• To evaluate the incidence of anti-therapeutic antibodies (ATAs) against MPDL3280A and to explore the potential relationship of immunogenicity response with pharmacokinetics, safety, and efficacy

PHARMACOKINETIC OBJECTIVES

• To characterize the pharmacokinetics of MPDL3280A when administered in combination with bevacizumab
• To characterize the pharmacokinetics of bevacizumab when administered in combination with MPDL3280A

PATIENT-REPORTED OUTCOME OBJECTIVES

• To assess symptom severity and functional interference associated with MPDL3280A+ bevacizumab versus sunitinib in patients with RCC as measured by the MDASI and BFI
• To obtain general measures of health as measured by the EuroQoL 5 Dimensions (EQ-5D) questionnaire for health economic modeling of MPDL3280A + bevacizumab versus sunitinib in patients with RCC

EXPLORATORY OBJECTIVES

• To evaluate the relationship between the expression of other candidate predictive immune, angiogenic, or hypoxia biomarkers, as defined by IHC or quantitative polymerase chain reaction (qPCR), and efficacy as defined by PFS and ORR
• To evaluate the efficacy of MPDL3280A+ bevacizumab versus sunitinib among patients with tumor Fuhrman Grade 4 or sarcomatoid histology (defined by investigator-assessed conventional histopathology) as measured by PFS and ORR
• To assess immune-mediated predictive and prognostic exploratory biomarkers in tumor tissue and blood from archival specimens, fresh biopsy specimens, or specimens obtained during the study and their association with disease status and/or efficacy as defined by PFS and ORR

Inclusion Criteria

• Signed Informed Consent Form
• Unresectable advanced or metastatic RCC with clear-cell histology and/or component of sarcomatoid carcinoma Renal cell carcinoma with any component of high-grade malignant spindle cells consistent with sarcomatoid histology is eligible. (See Appendix 15 for further guidelines regarding defining sarcomatoid histology.)
• Evaluable MSKCC risk score (i.e., "Motzer" score, see Appendix 9). All MSKCC risk scores are included. Patients with good risk MSKCC (risk score 0) will comprise no more than 20% of the study population
• Definitive diagnosis of RCC on the basis of a representative, formalin-fixed, paraffin-embedded tumor specimen accompanied by an associated pathology report collected within 24 months prior to Cycle 1, Day 1 available at the study site that allows determination of PD-L1 expression status (IC) (required prior to randomization)The archival specimen must contain adequate viable tumor tissue to establish PD-L1 expression status by a central laboratory prior to randomization. The specimen may consist of a tissue block (preferred) or at least 15 unstained, serial sections. Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. For core needle biopsy specimens, at least three cores embedded into a single paraffin block should be submitted for evaluation. Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable. If the archival tissue was acquired > 24 months prior to Cycle 1, Day 1, the patient may still be eligible provided the patient is willing to consent to and undergo a pre-treatment core or excisional biopsy of the tumor. If the location of the tumor renders the tumor biopsy medically unsafe, eligibility may be provided with Medical Monitor approval. A local analysis to confirm the diagnosis of RCC is required.
• Measurable disease, as defined by RECIST v1.1 (see Appendix 3)
• Age ≥ 18 years
• KPS ≥ 70 (see Appendix 5)
• Ability and capacity to comply with study and follow-up procedures
• Adequate hematologic and end-organ function, defined by the following laboratoryresults obtained within 28 calendar days prior to the first study treatment:
  • ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
  • WBC counts ≥ 2500/μL
  • Lymphocyte count ≥ 300/μL
  • Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
  • Hemoglobin ≥ 9.0 g/dL
  • AST, ALT, and alkaline phosphatase ≤ 2.5 x ULN, with the following exceptions:
    • Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
    • Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 x ULN
  • Serum bilirubin ≤ 1.5 x ULN
    • Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled.
  • INR and aPTT ≤ 1.5 x ULN, unless on a stable dose of warfarin
  • Serum albumin > 2.5 g/dL
  • Creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula or based on 24-hour urine collection)
• For women who are not postmenopausal (≥ 12 months of non-therapy-inducedamenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent (refrain from heterosexual intercourse) or use single or combined contraception methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of MPDL3280A + bevacizumab or 30 days after the last dose of sunitinib, according to treatment assignment. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices.
• For men: agreement to remain abstinent or use a condom during the treatment period and for at least 90 days after the last dose of study drug and agreement to refrain from donating sperm during this same period Men with a pregnant partner must agree to remain abstinent or use a condom for the duration of the pregnancy. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
• Patients with a history of treated asymptomatic central nervous system (CNS) metastases are eligible, provided they meet all of the following criteria:
  • Evaluable or measurable disease outside the CNS
  • Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, pons, medulla or spinal cord)
  • No history of intracranial or spinal cord hemorrhage
  • No evidence of significant vasogenic edema
  • No ongoing requirement for corticosteroids as therapy for CNS disease
  • No stereotactic radiation within 14 days
  • No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study
  • Patients with new asymptomatic CNS metastases detected at the screening scan must receive radiation therapy and/or surgery for CNS metastases.
  • Following treatment, these patients may then be eligible without the need for an additional brain scan prior to enrollment [or randomization], if all other criteria are met.

Exclusion Criteria

• Prior treatment with active or experimental systemic agents, including treatment in the neoadjuvant or adjuvant setting. Prior treatment with placebo in adjuvant setting is allowed.
• Radiotherapy for RCC within 14 calendar days prior to Cycle 1, Day 1
• Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated at least 14 days prior to Cycle 1, Day 1.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL) or symptomatic hypercalcemia refractory to bisphosphonate therapy or denosumab. Patients who are currently receiving bisphosphonate therapy without current hypercalcemia (corrected serum calcium greater than the upper limit of normal) are eligible. Patients currently receiving denosumab must substitute a bisphosphonate (if eligible)
• Malignancies other than RCC within 5 years prior to Cycle 1, Day 1:
  • Patients with localized low risk prostate cancer (defined as stage ≤ T2b, Gleason score ≤ 7, and PSA at prostate cancer diagnosis ≤ 20 ng/mL) treated with curative intent and without prostate-specific antigen (PSA) recurrence are eligible
  • Patients with low risk prostate cancer (defined as Stage T1/T2a,Gleason score ≤ 6 and PSA ≤ 10 ng/mL) who are treatment-na�ve and undergoing active surveillance are eligible
  • Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of metastasis or death <5% at 5 years) are eligible provided they meet all of the following criteria:
    • Malignancy treated with expected curative intent (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent)
    • No evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers

General Medical Exclusions

• Life expectancy of < 12 weeks
• Current, recent (within 4 weeks of Cycle 1, Day 1), or planned participation in another experimental drug study
• Pregnant and lactating, or intending to become pregnant during the study
• Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 7 days prior to initiation of study drug.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
• History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 6 for a more comprehensive list of autoimmune diseases). Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan; however, history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Positive test for HIV
• Patients with active or chronic hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening). Patients with past/resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. A negative HBV DNA test must be obtained in patients with positive hepatitis B core antibody prior to Cycle 1, Day 1.
• Patients with active hepatitis C Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) analysis is negative for HCV RNA.
• Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Signs or symptoms of infection (including active tuberculosis) within 2 weeks prior to Cycle 1, Day 1
• Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
• Patients receiving routine antibiotic prophylaxis (e.g., to prevent chronic obstructive pulmonary disease exacerbation or for dental extraction) are eligible.
• Significant cardiovascular or cerebrovascular disease, such as New York Heart Association cardiac disease (Class II or greater), unstable angina, myocardial infarction or cerebrovascular events within the previous 6 months or unstable arrhythmias within the previous 3 months. Patients with known coronary artery disease, arrhythmias, congestive heart failure not meeting the above criteria must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate. Baseline evaluation of left ventricular ejection fraction should be considered for all patients, especially in those with cardiac risk factors and/or history of coronary artery disease. Patients with known left ventricular ejection fraction < 50%
• Major surgical procedure other than for diagnosis within 21 days prior to Cycle 1, Day 1, or planned procedure or surgery during the study
• Prior allogeneic stem cell or solid organ transplant
• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 Influenza vaccination should be given during influenza season only. Patients must agree not to receive live, attenuated influenza vaccine within 28 days prior to randomization, during treatment or within 90 days following the last dose of atezolizumab (for patients randomized to atezolizumab).
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications

Exclusion Criteria Related to Medications

• Prior treatment with CD137 agonists, anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
• Treatment with systemic immunostimulatory agents (including but not limited to IFN α, IL-2) for the treatment of non-malignant conditions within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
• Any prior use of systemic immunostimulatory agents for the management of metastatic RCC is excluded.
• Treatment with systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) or physiologic replacement doses (i.e., prednisone 5-7.5 mg/day) for adrenal insufficiency may be enrolled in the study. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed.

Bevacizumab- and Sunitinib-Specific Exclusions

• Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg)
• Anti-hypertensive therapy to maintain a systolic blood pressure <150mmHg and/or diastolic blood pressure <100mmHg is permitted.
• Prior history of hypertensive crisis or hypertensive encephalopathy
• New York Heart Association Class II or greater congestive heart failure (see Appendix 7)
• History of stroke or transient ischemic attack within 6 months prior to Cycle 1, Day 1
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1
• Patients with a baseline ECG demonstrating a QTc >460 ms
• Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence of therapeutic anticoagulation)
• Current or recent (within 10 calendar days prior to Cycle 1, Day 1) use of dipyramidole, ticlopidine, clopidogrel, or cilostazol
• Prophylactic or therapeutic use of low molecular-weight heparin (e.g., enoxaparin), direct thrombin inhibitors, or warfarin are permitted, provided, where appropriate anticoagulation indices are stable. Patients should have been on a stable dose (for therapeutic use) for at least two weeks (or until reaching steady state level of the drug) prior to the first study treatment
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 calendar days prior to the first dose of bevacizumab
• History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 months prior to Cycle 1, Day 1
• Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
• Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
• Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour urine collection. All patients with ≥2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein.