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
- kidney cancer10038364renal cancer
- Registration Number
- NL-OMON55837
- Lead Sponsor
- Goethe University Frankfurt
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 31
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% nonclear 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 inst
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
intraabdominal 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 he
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary endpoint of this study is the overall survival rate at 12 months<br /><br>(OS12).</p><br>
- Secondary Outcome Measures
Name Time Method <p>• OS rate at 6 and 18 months in overall population and histological and<br /><br>prognostic subgroups.<br /><br>• Overall survival (OS)<br /><br>• Progression-free survival (PFS)<br /><br>• Objective response rate (ORR)<br /><br>• Safety/tolerability<br /><br>• Quality of Life (QoL) as assessed by FKSI-DRS questionnaire</p><br>