| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The primary objective of the study is to compare the of OS rate at 12 months of Nivolumab combined with Ipilimumab to Standard of Care in patients with previously untreated and advanced non-clear cell RCC. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Survival of patients with kidney cancer. |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038415 |
| E.1.2 | Term | Renal cell carcinoma stage unspecified |
| 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 |
| The primary objective of the study is to compare the of OS rate at 12 months of Nivolumab combined with Ipilimumab to Standard of Care in patients with previously untreated and advanced non-clear cell RCC. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to examine if the following is achieved:
To compare the OS rate at 6 and 18 months of Nivolumab combined with Ipilimumab to Standard of Care in previously untreated and advanced non-clear cell RCC
Duration of reponse (DOR) for both arms and subgroups
To compare the PFS of Nivolumab combined with Ipilimumab to Standard of Care with previously untreated metastatic non-clear cell RCC
To compare the medianOS of Nivolumab combined with Ipilimumab to Standard of Care in subjects with previously untreated metastatic non-clear cell RCC C (based on hazard ratio)
To estimate the objective response rate (ORR) of Nivolumab combined with Ipilimumab to Standard of Care in subjects with previously untreated mRCC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
2. Target Population
a) Histological confirmation of non-clear RCC with at least 50% non-clear cell component according to actual WHO classification36
b) Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
c) Karnofsky > 70% (See Appendix 2, 14.2)
d) Measurable disease as per RECIST v 1.1 (See Appendix 3, 14.3) documented by an English radiology report
e) Tumor tissue (FFPE archival or recent acquisition) must be available and sent to the central pathological reviewer (see Table 6) in order to confirm the diagnosis. (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for submission).
f) Patients with all risk categories will be eligible for the study. Patients will be stratified for papillary or non-papillary non-clear cell histology and IMDC risk score Patients will be categorized according to favorable versus intermediate versus poor risk status at registration according to the International Metastatic RCC Database Consortium (IMDC) criteria:
i. KPS equal to 70%
ii. Less than 1 year from diagnosis to randomization
iii. Hemoglobin less than the lower limit of normal (LLN)
iv. Corrected calcium concentration greater than the upper limit of normal (ULN)
v. Absolute neutrophil count greater than the ULN
vi. Platelet count greater than the ULN
If none of the above factors are present, subjects are only eligible for the favorable-risk cohort, if
1-2 factors are present subjects are catogerized as intermediate risk and > 3 factors as poor risk.
3. Age and Reproductive Status
a) Males and Females, ≥ 18 years of age
b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half-lives. The terminal half-lives of Nivolumab and Ipilimumab are up to 25 days and 18 days, respectively. The terminal half-life of the active metabolite of Sunitinib is up to 110 hours. The terminal half-life of other standard of care agents has to be derived from the product information.
i. WOCBP randomized to receive Nivolumab + Ipilimumab should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug.
ii. WOCBP randomized to receive a standard of care agent should use an adequate method to avoid pregnancy for at least 8 weeks (30 days plus the time required for the active metabolite of the standard of care agent to undergo five half-lives)
e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half-lives. The terminal half-lives of Nivolumab and Ipilimumab are up to 25 days and 18 days, respectively. The terminal half-life of the active metabolite of Sunitinib is up to 110 hours.
i. Males randomized to receive Nivolumab combined with Ipilimumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug.
ii. Males randomized to receive standard of care who are sexually active with WOCBP must continue contraception for at least16 weeks (90 days plus the time required for the active metabolite of the standard of care agent to undergo five half-lives) after the last dose of investigational drug.
f) Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy
testing as described in this section. |
|
| E.4 | Principal exclusion criteria |
1) Any active brain metastases requiring systemic corticosteroids.
2) Tumors with a clear-cell component of > 50% Medical History and Concurrent Diseases
3) Prior systemic treatment with VEGF or VEGF receptor targeted therapy (including, but not limited to, Sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab) or prior treatment with an mTOR inhibitor or cytokines.
4) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
5) Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone
replacement are permitted to enroll.
6) Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
7) Uncontrolled adrenal insufficiency.
8) Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 msec for males and > 470 msec for females, where QTcF = QT / 3√RR
9) Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥ 150 mmHg or diastolic blood pressure (DBP) of ≥ 90 mmHg), despite antihypertensive therapy.
10) History of any of the following cardiovascular conditions within 12 months of enrollment:
cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery by-pass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association.
11) History of cerebrovascular accident including transient ischemic attack within the past 12 months.
12) History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin
13) History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks.
14) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.
15) Serious, non-healing wound or ulcer.
16) Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days.
17) Any requirement for anti-coagulation, except for low molecular weight heparin.
18) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
19) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
20) Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
21) Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
22) Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
23) Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.
24) Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
25) Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Sunitinib
26) Left ventricular ejection fraction (LVEF) less than the LLN as assessed by echocardiography or multigated acquisition (MUGA) scan.
27) Any of the following laboratory test findings:
i. WBC < 2,000/mm3
ii. Neutrophils < 1,500/mm3
iii. Platelets < 100,000/mm3
iv. AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
v. Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
vi. Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula):
28) History of severe hypersensitivity reaction to any monoclonal antibody.
29) Subjects who are incompetent to understand and sign the informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the overall survival rate at 12 months (OS12) (landmark). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after start of treatment of patient. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints were:
OS rate at 6 and 18 months in overall population and histological and prognostic subgroups.
Overall survival (OS)
Progression-free survival (PFS)
Objective response rate (ORR)
Safety/tolerability
Quality of Life (QoL) as assessed by FKSI-DRS questionnaire |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints were:
OS rate at 6 and 18 months in overall population and histological and prognostic subgroups.
Overall survival (OS)
Progression-free survival (PFS)
Objective response rate (ORR)
Safety/tolerability
Quality of Life (QoL) as assessed by FKSI-DRS questionnaire |
|
| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 17 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 study will end 18 months after the last patient is in. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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