Randomized Phase-II Study of Nivolumab Plus Ipilimumab vs. Standard of Care in Untreated and Advanced Non-clear Cell RCC

  • STATUS
    Recruiting
  • End date
    Dec 31, 2023
  • participants needed
    306
  • sponsor
    Nicola Goekbuget
Updated on 25 January 2021
platelet count
vasectomy
cancer
sunitinib
measurable disease
metastasis
nivolumab
ipilimumab
fine needle aspiration
clear cell renal cell carcinoma

Summary

SUNNIFORECAST (Sunitinib vs. Nivolumab + Ipilimumab as First line treatment Of REnal cell CAncer of non-clear cell SubTypes) is a Phase II, randomized, open-label investigator initiated trial (IIT) of Nivolumab (BMS-936558) combined with Ipilimumab vs standard of care in subjects with previously untreated and advanced (unresectable or metastatic) non-clear cell renal cell carcinoma (nccRCC).

Description

SUNNIFORECAST (Sunitinib vs. Nivolumab + Ipilimumab as First line treatment Of REnal cell CAncer of non-clear cell SubTypes) is a Phase II, randomized, open-label investigator initiated trial (IIT) of Nivolumab (BMS-936558) combined with Ipilimumab vs standard of care in subjects with previously untreated and advanced (unresectable or metastatic) non-clear cell renal cell carcinoma (nccRCC). In the Phase I setting, Nivolumab combined with Ipilimumab has demonstrated substantially greater clinical activity, as measured by objective response rate (ORR), than either agent alone in metastatic RCC (mRCC). Given the durability of responses associated with immunotherapies, Nivolumab combined with Ipilimumab is hypothesized to lead to greater clinical benefit, as measured by overall survival (OS) rate at 12 months as primary endpoint and OS at 6 months and 18 months, progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) as secondary endpoints compared to standard of care in this patient population. This study will allow for direct comparison of OS rate at 12 months between both arms.

Details
Condition Metastatic Renal Cell Carcinoma, Metastatic Kidney Cancer
Treatment Sunitinib, Ipilimumab plus nivolumab
Clinical Study IdentifierNCT03075423
SponsorNicola Goekbuget
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have Metastatic Renal Cell Carcinoma?
Do you have any of these conditions: Metastatic Renal Cell Carcinoma or Metastatic Kidney Cancer?
Signed Written Informed Consent a) Subjects must have signed and dated an approved written informed consent form according to the Institutional Review Board (IRB) and 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
Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
Target Population a) Histological confirmation of non-clear cell renal cell carcinoma (nccRCC) with at least 50% non-clear cell component according to actual World Health Organization (WHO) classification
Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) nccRCC c) Performance status: Karnofsky (KPS) > 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)
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. < 1 year from diagnosis to randomization iii. Hemoglobin < 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 categorized as intermediate risk and > 3 factors as poor risk
Age and Reproductive Status
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
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
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 Sunitinib should use an adequate method to
avoid pregnancy for 8 weeks (30 days plus the time required for the active
metabolite of Sunitinib 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 Sunitinib who are sexually active and women of
childbearing potential (WOCBP) must continue contraception for 16 weeks (90
days plus the time required for the active metabolite of Sunitinib 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
Investigators shall counsel WOCBP and male subjects who are sexually active
with WOCBP on the importance of pregnancy prevention and the implications of
an unexpected pregnancy Investigators shall advise WOCBP and male subjects who
are sexually active with WOCBP on the use of highly effective methods of
contraception. Highly effective methods of contraception have a failure rate
of < 1% when used consistently and correctly
At a minimum, subjects must agree to the use of two methods of contraception
with one method being highly effective and the other method being either
highly effective or uncertain effective as listed below
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Male condoms with spermicide
Hormonal methods of contraception including combined oral contraceptive pills
vaginal ring, injectables, implants and intrauterine devices (IUDs) by WOCBP
subject or male subject's WOCBP partner
Female partners of male subjects participating in the study may use hormone
based contraceptives as one of the acceptable methods of contraception since
they will not be receiving study drug
Nonhormonal IUDs
Tubal ligation
Vasectomy
Complete Abstinence
Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence
UNCERTAIN METHODS OF CONTRACEPTION Diaphragm with spermicide Cervical cap with
spermicide
Vaginal sponge
Male Condom without spermicide
Progestin only pills by WOCBP subject or male subject's WOCBP partner
Female Condom. A male and female condom must not be used together

Exclusion Criteria

Target Disease Exceptions
Any active brain metastases requiring systemic corticosteroids. Baseline imaging of the brain by MRI is required in patients with clinical signs of potential central nerve system (CNS) involvement within 28 days prior to randomization
Tumors with a clear-cell component of > 50%
Medical History and Concurrent Diseases
\. Prior systemic treatment with vascular endothelial growth factor (VEGF) or
VEGF receptor targeted therapy (including, but not limited to, Sunitinib
pazopanib, axitinib, tivozanib, and bevacizumab) or prior treatment with an
mammilian target of rapamycin (mTOR) inhibitor or cytokines
\. Prior treatment with an immune checkpoint inhibitor as anti-programmed
cell death (PD)PD-1, anti-PD-L1, anti-PD-L2, anti cytotoxic T-lymphocyte-
associated Protein 4 (CTLA 4) antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways
\. 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
\. 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
\. Uncontrolled adrenal insufficiency
\. 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
RR
\. Poorly controlled hypertension (defined as systolic blood pressure (SBP)
of > 150 mmHg or diastolic blood pressure (DBP) of > 90 mmHg), despite
antihypertensive therapy
\. 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
\. History of cerebrovascular accident including transient ischemic attack
within the past 12 months
\. History of deep vein thrombosis (DVT) unless adequately treated with low
molecular weight heparin
\. History of pulmonary embolism within the past 6 months unless stable
asymptomatic, and treated with low molecular weight heparin for at least 6
weeks
\. History of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess within the past 6 months
\. Serious, non-healing wound or ulcer
\. Evidence of active bleeding or bleeding susceptibility; or medically
significant hemorrhage within prior 30 days
\. Any requirement for anti-coagulation, except for low molecular weight
heparin
\. 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
\. Known history of testing positive for human immunodeficiency virus (HIV)
or known acquired immunodeficiency syndrome (AIDS)
\. Any positive test for hepatitis B or hepatitis C virus indicating acute
or chronic infection
\. 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
\. Major surgery (eg, nephrectomy) < 28 days prior to the first dose of
study drug
\. Anti-cancer therapy < 28 days prior to the first dose of study drug or
palliative, focal radiation therapy < 14 days prior to the first dose of study
drug
\. Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors (See
Appendix 4, 14.4)
\. Impairment of gastrointestinal function or gastrointestinal disease that
may significantly alter the absorption of Sunitinib (eg, malabsorptive
disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or
small bowel resection)
\. Hypersensitivity to sunitinib or any of the excipients
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