A Phase 2, Randomized, Open-Label Study of Nivolumab Combined with Ipilimumab Versus Standard of Care in Subjects with Previously Untreatedand Advanced (unresectable or metastatic) non-clear Cell Renal Cell Carcinoma
- Conditions
- Advanced (unresectable or metastatic) non-clear Cell Renal Cell CarcinomaMedDRA version: 21.1Level: LLTClassification code 10038415Term: Renal cell carcinoma stage unspecifiedSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2016-000706-12-BE
- Lead Sponsor
- Goethe University Frankfurt
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 306
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.
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%
d) Measurable disease as per RECIST v 1.1 documented by an
English radiology report
e) Tumor tissue (FFPE archival or recent acquisition) must be
available and sent to the central pathological 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:
1. KPS equal to 70%
2. Less than 1 year from diagnosis to randomization
3. Hemoglobin less than the lower limit of normal (LLN)
4. Corrected calcium concentration greater than the upper limit
of normal (ULN)
5. Absolute neutrophil count greater than the ULN
6. 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 categorized 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 Sun
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%
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 hepatitis C virus indicating
acute or chronic infection. u) Known medical condition (
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