A Phase 2, Randomized, Open-Label Study of Nivolumab Combined with Ipilimumab Versus Standard of Care in Subjects with Previously Untreated and Advanced (unresectable or metastatic) non-clear Cell Renal Cell Carcinoma
- Conditions
- 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 RCCMedDRA version: 20.0Level: LLTClassification code 10038415Term: Renal cell carcinoma stage unspecifiedSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2016-000706-12-FR
- Lead Sponsor
- Goethe University Frankfurt
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 306
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
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 / 3vRR
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method