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

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ClinicalTrials.gov Identifier: NCT03075423
Recruitment Status : Recruiting
First Posted : March 9, 2017
Last Update Posted : June 2, 2020
Sponsor:
Information provided by (Responsible Party):
Nicola Goekbuget, Goethe University

Tracking Information
First Submitted Date  ICMJE March 6, 2017
First Posted Date  ICMJE March 9, 2017
Last Update Posted Date June 2, 2020
Actual Study Start Date  ICMJE November 1, 2017
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 6, 2017)
Overall survival rate at 12 months (OS12) (landmark) [ Time Frame: 12 months ]
The overall survival rate at 12 months will be compared in both arms. OS is calculated from date of randomization to death.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 8, 2017)
  • OS rate at 6 and 18 months in overall population and histological and prognostic subgroups [ Time Frame: 6 and 18 months ]
    The overall survival rate at 6 and 18 months will be compared in both arms. OS is calculated from date of randomization to death.
  • Overall survival (OS) [ Time Frame: 5 years ]
    The overall survival will be compared in both arms by Kaplan-Meyer plots. OS is calculated from date of randomization to death.
  • Progression-free survival (PFS) [ Time Frame: 5 years ]
    PFs will be compared in both arms. PFS is calculated from date of randomization to progression.
  • Objective response rate (ORR) [ Time Frame: 4 years ]
    ORR will be compared in both both arms. ORR will be assessed by regular tumor imaging as CT or magnetic resonance tomography (MRT).
  • Incidence of treatment related adverse events [ Time Frame: 5 years ]
    Adverse events (AEs) and serious adverse event (SAEs) will be recorded in both arms and the frequency will be compared.
  • Quality of Life (QoL) as assessed by patient outcome measurement (FKSI-DRS) questionnaire [ Time Frame: 5 years ]
    Quality of life will be assessed during therapy using the FKSI-DRS questionnaire and evaluated over time and in comparison of both arms.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2017)
  • OS rate at 6 and 18 months in overall population and histological and prognostic subgroups [ Time Frame: 6 and 18 months ]
    The overall survival rate at 6 and 18 months will be compared in both arms. OS is calculated from date of randomization to death.
  • Overall survival (OS) [ Time Frame: 5 years ]
    The overall survival will be compared in both arms by Kaplan-Meyer plots. OS is calculated from date of randomization to death.
  • Progression-free survival (PFS) [ Time Frame: 5 years ]
    PFs will be compared in both arms. PFS is calculated from date of randomization to progression.
  • Objective response rate (ORR) [ Time Frame: 4 years ]
    ORR will be compared in both both arms. ORR will be assessed by regular tumor imaging as CT or magnetic resonance tomography (MRT).
  • Safety/tolerability [ Time Frame: 5 years ]
    Adverse events (AEs) and serious adverse event (SAEs) will be recorded in both arms and the frequency will be compared.
  • Quality of Life (QoL) as assessed by patient outcome measurement (FKSI-DRS) questionnaire [ Time Frame: 5 years ]
    Quality of life will be assessed during therapy using the FKSI-DRS questionnaire and evaluated over time and in comparison of both arms.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomized Phase-II Study of Nivolumab Plus Ipilimumab vs. Standard of Care in Untreated and Advanced Non-clear Cell RCC
Official Title  ICMJE 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 (nccRCC)
Brief 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).
Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Renal Cell Carcinoma
Intervention  ICMJE
  • Drug: Ipilimumab plus nivolumab
    Ipilimumab every 3 weeks for 4 times Nivolumab every 3 weeks for 4 times followed by maintenance therapy with nivolumab every 2nd week
    Other Name: Yervoy plus Opdivo
  • Drug: Sunitinib
    Sunitinib is administered orally 50 mg tablets for 4 weeks on and 2 weeks off
    Other Name: Sutent
Study Arms  ICMJE
  • Experimental: Ipilimumab plus nivolumab
    Ipilimumab 1mg/kg plus nivolumab 3mg/kg, both, will be administered i.v. every 3 weeks for 4 times as an induction therapy followed by a maintenance therapy with a flat dose of 240 mg nivolumab biweekly until progression.
    Intervention: Drug: Ipilimumab plus nivolumab
  • Active Comparator: Sunitinib
    Sunitinib will be administered at a starting dose of 50 mg/die p.o. for 4 weeks on and 2 weeks off per cycle until progression.
    Intervention: Drug: Sunitinib
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 6, 2017)
306
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2023
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. 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.

    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 cell renal cell carcinoma (nccRCC) with at least 50% non-clear cell component according to actual World Health Organization (WHO) classification.

    b) 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).

    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. < 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.

  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.

    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 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:

1. Target Disease Exceptions

  1. 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.
  2. Tumors with a clear-cell component of > 50%

    Medical History and Concurrent Diseases

  3. 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.
  4. 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.
  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 intra-abdominal 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 hepatitis B or hepatitis C virus indicating acute or chronic infection.
  21. 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.
  22. Major surgery (eg, nephrectomy) < 28 days prior to the first dose of study drug.
  23. 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.
  24. Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors (See Appendix 4, 14.4).
  25. 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).
  26. Hypersensitivity to sunitinib or any of the excipients
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lothar Bergmann, MD +49 69 63015121 L.Bergmann@em.uni-frankfurt.de
Contact: Nicola Goekbuget, MD +49 69 63016365 goekbuget@em.uni-frankfurt.de
Listed Location Countries  ICMJE Belgium,   Czechia,   France,   Germany,   Netherlands,   Spain,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03075423
Other Study ID Numbers  ICMJE EUDRACT: 2016-000706-12
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Nicola Goekbuget, Goethe University
Study Sponsor  ICMJE Nicola Goekbuget
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Lothar Bergmann, MD Goethe University (Hospital) Frankfurt
PRS Account Goethe University
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP