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Title A Phase 3, Multinational, Randomized, Open-Label, Parallel-Arm Study Of Avelumab (Msb0010718c) In Combination With Axitinib (Inlyta®) Versus Sunitinib (Sutent®) Monotherapy In The First-Line Treatment Of Patients With Advanced Renal Cell Carcinoma

IRB PFIZ2816

CC 16-573

Hospital Main Campus

Phase Phase 3

Disease Renal

Drug Avelumab , Axitinib, Sunitinib

Description

Primary Objective

• To demonstrate that avelumab in combination with axitinib is superior to sunitinib monotherapy in prolonging PFS in the first-line treatment of patients with aRCC.

Secondary Objectives

• To compare avelumab in combination with axitinib to sunitinib monotherapy in the first-line treatment of patients with aRCC, with respect to overall survival.
• To evaluate other measures of efficacy of avelumab in combination with axitinib and sunitinib monotherapy in the first-line treatment of aRCC patients.
• To evaluate the overall safety profile of avelumab in combination with axitinib and sunitinib monotherapy in the first-line treatment of aRCC patients.
• To evaluate the population pharmacokinetics of avelumab and axitinib when administered in combination.
• To evaluate candidate predictive biomarkers in pre-treatment tumor tissue that may aid in the identification of a patient subpopulation most likely to benefit from treatment with avelumab in combination with axitinib and sunitinib monotherapy.
• To assess the immunogenicity of avelumab when combined with axitinib.
• To evaluate the effects of avelumab in combination with axitinib and sunitinib monotherapy on patient-reported outcomes.

Exploratory Objectives

• To explore the predictive and pharmacodynamic characteristics of peripheral blood and additional tumor tissue biomarkers that may be relevant to the mechanism of action of, or resistance to, avelumab in combination with axitinib and sunitinib monotherapy, including but not limited to biomarkers related to anti-tumor immune response or target modulation.
• To explore immune-related RECIST (irRECIST)-defined anti-tumor activity of avelumab in combination with axitinib and of sunitinib monotherapy in the first-line treatment of aRCC patients.

Inclusion Criteria

1. Diagnosis:
   • Histologically or cytologically confirmed advanced or metastatic renal cell carcinoma with a clear cell component. Advanced RCC patients are patients affected by unresectable disease either unresectable locally advanced or metastatic disease;
   • Availability of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block: an FFPE tumor tissue block from a de novo tumor biopsy obtained during screening will be required (biopsied tumor lesion should not be a RECIST target lesion). Alternatively, a recently obtained archival FFPE tumor tissue block (cut slides not acceptable) from a primary or metastatic tumor resection or biopsy can be provided if the following criteria are met: 1) the biopsy or resection was performed within 1 year of randomization AND 2) the patient has not received any intervening systemic anti-cancer treatment from the time the tissue was obtained and randomization onto the current study (see Section 6.1.1);
   • Availability of an archival FFPE tumor tissue 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 (see Section 6.1.1);
   • At least one measureable lesion as defined by RECIST version 1.1 that has not been previously irradiated.
2. Evidence of a personally 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.
3. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
4. Age ≥18 years (≥20 years in Japan).
5. Estimated life expectancy of at least 3 months.
6. ECOG PS 0 or 1.
7. No evidence of uncontrolled hypertension as documented by 2 baseline blood pressure (BP) readings taken at least 1 hour apart. The baseline systolic BP readings must be ≤140 mm Hg, and the baseline diastolic BP readings must be ≤90 mm Hg. Use of antihypertensive medications to control BP is allowed.
8. 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).
9. Adequate renal function, including:
   • Estimated creatinine clearance ≥50 mL/min as calculated using the Cockcroft-Gault (CG) equation.
   • Urinary protein <2+ by urine dipstick. If dipstick is ≥2+, then 24-hour urinary protein <2 g per 24 hours.
10. Adequate liver function, including:
    • Total serum bilirubin ≤1.5 x ULN;
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN.
11. Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) as assessed by either multigated acquisition (MUGA) scan or echocardiogram (ECHO).
12. Serum pregnancy test (for females of childbearing potential) negative at screening.
13. 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 (see Section 4.3.1) throughout the study and for at least 90 days after the last dose of assigned treatment.

Exclusion Criteria

1. The following prior therapies are excluded:
   • Prior systemic therapy directed at advanced or metastatic RCC.
   • Prior adjuvant or neoadjuvant therapy for RCC if disease progression or relapse has occurred during or within 12 months after the last dose of treatment.
   • Prior immunotherapy with IL-2, IFN-α, or anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
   • Prior therapy with axitinib and/or sunitinib as well as any prior therapies with other VEGF pathway inhibitors.
2. Participation in other therapeutic studies within 4 weeks prior to randomization.
3. Patients with known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior torandomization, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.
4. Major surgery ≤4 weeks or major radiation therapy ≤2 weeks prior to randomization. Prior palliative radiotherapy (≤10 fractions) to metastatic lesion(s) is permitted, provided it has been completed at least 48 hours prior to patient randomization.
5. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1; however, sensory neuropathy Grade ≤2 is acceptable.
6. 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).
7. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partially controlled asthma Global Initiative for Asthma 201136).
8. Known prior or suspected hypersensitivity to study drugs or any component in their formulations.
9. 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 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation, or castration).
10. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
11. Gastrointestinal abnormalities including:
    • Inability to take oral medication;
    • Requirement for intravenous alimentation;
    • Prior surgical procedures affecting absorption including total gastric resection;
    • Treatment for active peptic ulcer disease in the past 6 months;
    • Active gastrointestinal bleeding, unrelated to cancer, as evidenced by clinically significant hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy;
    • Malabsorption syndromes.
12. Active infection requiring systemic therapy.
13. Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
14. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection.
15. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines).
16. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access device or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.
17. Evidence of inadequate wound healing.
18. Grade ≥3 hemorrhage within 4 weeks of patient randomization.
19. Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant pericardial effusion, cerebrovascular accident, transient ischemic attack.
20. Any of the following in the previous 6 months: deep vein thrombosis or symptomatic pulmonary embolism.
21. Evidence of tumor involvement of the myocardium or pericardium or tumor thrombus extending to the heart.
22. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2 or prolongation of the QTc interval to >500 msec.
23. Current use or anticipated need for treatment with drugs or foods that are known strong CYP3A4/5 inhibitors, including their administration within 10 days prior to patient randomization (eg, grapefruit juice or grapefruit/grapefruit-related citrus fruits [eg, Seville oranges, pomelos], ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan). The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed.
24. Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, including their administration within 10 days prior to patient randomization, eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, St John's wort.
25. Patients who are investigational site staff members directly involved in the conduct of the trial 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.
26. Pregnant female patients; breastfeeding female patients.
27. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, and pneumonitis or 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 investigational product 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.