| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023400 |
| E.1.2 | Term | Kidney cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Evaluate the efficacy of atezolizumab (MPDL3280A)+bevacizumab
compared with sunitinib as measured by the co-primary endpoints of
investigator assessed progression-free survival (PFS) per Response
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and overall
survival (OS) in the PD-L1 selected population and ITT population |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of atezolizumab + bevacizumab versus
sunitinib as measured by Independent Review Committee (IRC)−
assessed PFS according to RECIST v1.1
-To evaluate the efficacy of atezolizumab bevacizumab versus sunitinib
as measured by investigator-assessed PFS, DOR, and ORR per modified
RECIST |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Unresectable advanced or metastatic RCC with clear-cell histology and/orcomponent of sarcomatoid carcinoma
•Measurable disease, as defined by RECIST v1.1
•Karnofsky performance status ≥ 70
•Adequate hematologic and end organ function, defined by the following laboratory results obtained within 28 calendar days prior to randomization:
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 the upper limit of normal (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)
• 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.
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive 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 atezolizumab and
bevacizumab or 30 days after the last dose of sunitinib
- For men: agreement to remain abstinent (refrain from heterosexual
intercourse) or use contraceptive measures that result in a failure rate of < 1% per year, and agreement to refrain from donating sperm, for at
least 6 months after the last dose of atezolizumab or bevacizumab or 30 days after the last dose of sunitinib
|
|
| E.4 | Principal exclusion criteria |
•Prior treatment with active or experimental systemic agents for treatment of RCC, including treatment in the neoadjuvant or adjuvant setting. Prior treatment with placebo in adjuvant setting is allowed.
•Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic resonance imaging evaluation during screening and prior radiographic assessments
•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 corrected serum calcium greater than the upper limit of normal]) or symptomatic hypercalcemia refractory to bisphosphonate therapy or denosumab
•Pregnant and lactating , or intending to become pregnant during the study
•History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
•Malignancies other than RCC within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death, treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated with curative intent, ductal carcinoma in situ of the breast treated surgically with curative intent). Contact the Medical Monitor if there are concerns or if clarification is needed.
•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, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see the protocol 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
•Patients with active or chronic hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or Patients with active hepatitis C
•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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) in the PD-L1- selected population
2. Overall Survival (OS) in the ITT populaiton and the PD-L1- selected population |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. The primary analysis of PFS is projected to occur at 228 PFS events in
the PD-L1-selected population
2. The primary analysis of OS is projected to occur at 246 OS events in
the PD-L1-selected population and 639 events in the ITT population |
|
| E.5.2 | Secondary end point(s) |
1. PFS based on IRC assessment of radiographic progression per RECIST
v1.1
2. ORR, defined as the proportion of patients with an objective response (either complete response or partial response, confirmation not required) as determined by investigator per RECIST v1.1
3. DOR, defined as the time from the first documented response to
documented disease progression as determined by the investigator per
RECIST v1.1 or death due to any cause, whichever occurs first
4. ORR and DOR based on IRC assessment per RECIST v1.1
5. PFS, ORR, and DOR based on investigator assessment per modified
RECIST criteria
6. PFS by investigator (patients with sarcomatoid histology, RECIST
v1.1)
7. OS (patients with sarcomatoid histology)
8. Change from baseline in symptom interference (from the MDASI Part
II) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-8. The end of study will occur when the number of deaths required for
the final analysis of OS (246 and 639 deaths in the PD-L1-selected and
ITT population respectively) have been observed |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
|
| 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
|
| The end of study will occur when the number of deaths required for the final analysis of OS has been observed. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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