| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 | 20.0 |
| 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 |
| 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
- To compare the OS rate at 6 and 18 months of Nivolumab combined with Ipilimumab to standard of caremonotherapy 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 classification
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, greater than or equal 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 |
Exclusion Criteria
Target Disease Exceptions
a) Any active brain metastases requiring systemic corticosteroids. Baseline imaging of the
brain by MRI is required in patients with clinical signs of potential CNS involvement
within 28 days prior to randomization.
b) Tumors with a clear-cell component of > 50%
Medical History and Concurrent Diseases
c) 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.
d) 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.
e) 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.
f) 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.
g) Uncontrolled adrenal insufficiency.
h) 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
i) Poorly controlled hypertension (defined as systolic blood pressure (SBP) of 150 mmHg
or diastolic blood pressure (DBP) of 90 mmHg), despite antihypertensive therapy.
j) 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.
k) History of cerebrovascular accident including transient ischemic attack within the past
12 months.
l) History of deep vein thrombosis (DVT) unless adequately treated with low molecular
weight heparin
m) History of pulmonary embolism within the past 6 months unless stable, asymptomatic,
and treated with low molecular weight heparin for at least 6 weeks.
n) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within the past 6 months.
o) Serious, non-healing wound or ulcer.
p) Evidence of active bleeding or bleeding susceptibility; or medically significant
hemorrhage within prior 30 days.
q) Any requirement for anti-coagulation, except for low molecular weight heparin.
r) 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.
s) Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).
t) Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
u) 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.
v) Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
w) 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.
x) Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors (See
Appendix 4, 14.4).
y) Impairment of gastrointestinal function or gastrointestinal disease that may significantly
alter the absorption of the standard of care agent (eg, malabsorptive disorder, ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
z) Hypersensitivity to standard of care agents or any of the excipients
|
|
| 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
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 | 14 |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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