| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced renal cell carcinoma (aRCC). |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023405 |
| E.1.2 | Term | Kidney cancer stage IV |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023404 |
| E.1.2 | Term | Kidney cancer stage III |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The study is a Phase 3 to evaluate the efficacy and safety of avelumab, an anti-PD-L1 monoclonal antibody (mAb), in combination with axitinib (Inlyta®) with the primary objective to demonstrate that the combination of avelumab with axitinib (Inlyta®) is superior to sunitinib (Sutent®) monotherapy in prolonging progression-free survival (PFS) or Overall Survival (OS) based on Blinded Independent Central Review (BICR) assessment per RECIST v.1.1 in the first-line treatment of PD-L1 positive patients with advanced renal cell cancer (aRCC). |
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| E.2.2 | Secondary objectives of the trial |
To demonstrate avelumab combined with axitinib is superior to sunitinib in prolonging PFS and OS in first-line treatment of aRCC patients unselected for PD-L1 expression;
To evaluate other measures of efficacy of avelumab combined with axitinib and sunitinib monotherapy in the first-line treatment of aRCC patients;
To evaluate PFS on next-line of therapy (PFS2);
To evaluate the overall safety profile of the IMPs in the first-line treatment of aRCC patients;
To evaluate the pop PK of avelumab and axitinib when in combination;
To evaluate the time to treatment discontinuation/failure due to toxicity and the proportion of patients who discontinued treatment due to toxicity;
To evaluate candidate predictive biomarkers in pre-treatment tumor tissue that may aid in the id of a patient subpopulation most likely to benefit from treatment;
To assess the immunogenicity of avelumab combined with axitinib;
To evaluate the effects of the IMPs on PRO |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histological or cytological diagnosis of advanced/metastatic renal cell carcinoma (aRCC) with a clear cell component. A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from a de novo tumor biopsy during screening will be required. Alternatively, a recently obtained archival FFPE tumor tissue block (not cut slides) from a primary or metastatic tumor resection or biopsy can be provided. If an FFPE tissue block cannot be provided as per documented regulations then 15 unstained slides will be acceptable. Availability of an archival FFPE tumor tissue block from primary diagnosis specimen (or 15 unstained slides). At least one measurable lesion defined by RECIST that has not been previously irradiated;
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;
3. Estimated life expectancy of at least 3 months;
4. Adequate bone marrow, renal and liver function;
5. No evidence of uncontrolled hypertension documented by 2 baseline blood pressure (BP) readings taken at least 1 hour apart;
6. Left ventricular ejection fraction (LVEF) above or equal to the lower limit of normal (LLN);
7. Negative serum pregnancy test at screening (females of childbearing potential);
8. Male and female patients able to have children must agree to use 2 highly effective methods of contraception throughout the study and for at least 90 days after the last dose of assigned treatment
9. Evidence of a personally signed and dated informed consent;
10. Patients willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures;
11. Age above 18 years.
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|
| E.4 | Principal exclusion criteria |
1. Systemic therapy directed at advanced or metastatic RCC prior to study entry, including adjuvant or neoadjuvant therapy for RCC if disease progression or relapse has occured during or within 12 months after the last dose of treatment, immunotherapy or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways;
2. Therapy with axitinib and/or sunitinib as well as any prior therapies with other VEGF pathway inhibitors prior to study entry;
3. Patients with newly diagnosed brain metastases or patients with known symptomatic brain metastases requiring steroids;
4. Major surgery within 4 weeks or major radiation therapy within 2 weeks prior to study entry;
5. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1;
6. Current or prior use of immunosuppressive medication within 7 days prior to study entry;
7. Known prior or suspected hypersensitivity to investigational products, including known severe hypersensitivity reactions to monoclonal antibodies (Grade >= 3) and any history of anaphylaxis;
8. 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;
9. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent;
10. Gastrointestinal abnormalities;
11. Active infection requiring systemic therapy;
12. Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy;
13. Known HIV or AIDS-related illness;
14. Positive HBV or HCV test indicating acute or chronic infection;
15. Administration of live vaccine within 4 weeks prior to study entry and during study participation;
16. Requirement of anticoagulant therapy with oral vitamin K antagonists;
17. Evidence of inadequate wound healing;
18. Grade >= 3 hemorrhage within 4 weeks of patient study entry;
19. Any of the following in the previous 12 months prior to study entry: 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 prior to study entry: 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 medicines or foods that are known strong CYP3A4/5 inhibitors, including their administration within 10 days prior to study entry;
24. Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, including their administration within 10 days prior to study entry;
25. Patients who are 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 and breastfeeding female patients;
27. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, uncontrolled asthma and pneumonitis or psychiatric condition including recent 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;
28. Participation in other studies involving investigational product(s) within 4 weeks prior to study entry and/or during study participation.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-Free Survival (PFS), defined as the time from randomization to the first occurrence of disease progression, based on Blinded Independent Central Review (BICR) assessment per RECIST v.1.1., for PD-L1 positive patients.
Overall Survival (OS) for PD-L1 positive patients.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Disease progression will be assessed through radiological tumor assessment conducted at screening, at 6 weeks from randomization, then every 6 weeks up to 18 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression. |
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| E.5.2 | Secondary end point(s) |
1. PFS by BICR assessment per RECIST v1.1 for patients unselected for PD-L1 expression.
2. Overall Survival (OS) for patients unselected for PD-L1 expression.
3. Objective Response (OR), Disease Control (DC), Time to Tumor Response (TTR), Duration of Response (DR) based on BIRC and investigator assessment per RECIST v1.1
4. Progression-Free Survival (PFS) based investigator assessment per RECIST v1.1
5. Progression-Free Survival on next-line therapy (PFS2)
6. Adverse events (AEs), laboratory abnormalities, and vital signs
7. Time to treatment discontinuation/failure due to toxicity
8. Treatment discontinuation due to toxicity
9. PK parameters including trough concentrations (Ctrough) of avelumab
10. Trough concentrations (Ctrough) and maximum concentrations (Cmax) of axitinib.
11. Tumor tissue biomarkers
12. Measures of clinical outcome (PFS, OS, OR, DC, TTR, and DR) in biomarker-positive and biomarker-negative subgroups
13. Anti-drug antibodies (ADAs; nAbs) of avelumab when in combination with axitinib
14. Patient-Reported Outcomes (PRO): FACT-Kidney Symptom Index (FKSI-19), EuroQol 5 Dimension (EQ 5D). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 -5 and 7 - 8. Baseline up to approximately 24 months;
6. Recorded at each visit through and including 90 calendar days after the last administration of the study drug;
9. Pre-dose on Days 1, 15 and 29 of Cycle 1, on Day 1 and 29 of Cycles 2, 3 and 4, and on Day 1 of Cycle 6 and then every 2 cycles thereafter, plus 1 month after end of avelumab treatment
10. Two hours post-dose on Day 1 then at pre-dose and 2 hours post-dose on Day 15 and 29 of Cycle 1
11. Pre-dose at screening, Day 1 of Cycles 1, 2 and 3
12. Baseline up to approximately 24 months
13. Pre-dose on Days 1, 15 and 29 of Cycle 1, on Day 1 and 29 of Cycles 2, 3 and 4, on Day 1 of Cycle 6 and then every 2 cycles thereafter, plus 1 month after end of avelumab treatment
14. On Day 1 of each Cycle
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| New Zealand |
| Romania |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of trial in a Member State of the European Union (EU) is defined as the time at which it is deemed that a sufficient number of participants have been recruited and completed the study as stated in the regulatory application (i.e., clinical trial application (CTA)) and ethics committee application in the Member State.
End of trial in all participating countries is defined as Last Subject Last Visit. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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