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

NCT03075423 | Completed Phase 2 DMC

• 1 other identifier: SUNNIFORECAST
• Study Type: interventional
• Target: 316
• Locations: 7 countries
• Sites: 30

Brief Summary

SUNNIFORECAST (Standard of Care 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).

Conditions

Metastatic Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• Overall survival rate at 12 months (OS12) (landmark)

  The overall survival rate at 12 months will be compared in both arms. OS is calculated from date of randomization to death.

  12 months

Secondary Outcomes (6)

• OS rate at 6 and 18 months in overall population and histological and prognostic subgroups

  6 and 18 months

• Overall survival (OS)

  5 years

• Progression-free survival (PFS)

  5 years

• Objective response rate (ORR)

  4 years

• Incidence of treatment related adverse events

  5 years

Study Arms (2)

Ipilimumab plus nivolumab

EXPERIMENTAL

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 fixed dose of 240 mg nivolumab every two weeks or 480 mg every four weeks until progression.

Drug: Ipilimumab plus nivolumab

Standard of Care therapy

ACTIVE COMPARATOR

Standard of Care therapy is administered according to the physician´s decision.

Drug: Standard Therapy

Interventions

Ipilimumab plus nivolumab DRUG

Ipilimumab every 3 weeks for 4 times Nivolumab every 3 weeks for 4 times followed by maintenance therapy with nivolumab every 2nd or 4th week

Also known as: Yervoy plus Opdivo

Ipilimumab plus nivolumab

Standard Therapy DRUG

Standard of Care therapy is administered according to the physician´s decision.

Standard of Care therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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% 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 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.
• 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 the Standard of Care agent should use an adequate method to avoid pregnancy for 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 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:

You may not qualify if:

• \. 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 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 / 3√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.

Sponsors & Collaborators

• Goethe University: lead

Study Sites (30)

Gent University Hospital (Universitair Ziekenhuis Gent)

Ghent, Belgium

Location

University Hospital Hradec Králové

Hradec Králové, Czechia

Location

Thomayer Hospital

Prague, Czechia

Location

Centre Hospitalier Universitaire de Bordeaux

Bordeaux, France

Location

Centre François Baclesse

Caen, France

Location

Centre Hospitalier Départemental de Vendée

La Roche-sur-Yon, France

Location

Centre Leon Berard

Lyon, France

Location

Institut Gustave Roussy

Paris, France

Location

Les Hoptaux Universitaires de Strasbourg

Strasbourg, France

Location

Medizinische Hochschule Hannover

Hanover, Lower Saxony, 30625, Germany

Location

Charite Berlin (Campus Virchow-Klinikum)

Berlin, Germany

Location

Heine University

Düsseldorf, Germany

Location

University Hospital Erlangen

Erlangen, 91054, Germany

Location

Universitätsklinikum Essen

Essen, Germany

Location

Goethe University Frankfurt

Frankfurt am Main, D-60590, Germany

Location

University Hospital Greifswald

Greifswald, Germany

Location

Nationales Zentrum für Tumorerkrankungen (NCT)

Heidelberg, 69120, Germany

Location

University Hospital

Homburg/Saar, Germany

Location

Klinik für Urologie, Universitätsklinik

Jena, Germany

Location

Klinikum Rechts der Isar der TU München

München, Germany

Location

University of Muenster

Münster, 48149, Germany

Location

Universitätsklinik Tübingen

Tübingen, Germany

Location

Netherlands Cancer Institute

Amsterdam, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Hospita de la Santa Creu i Sant Pau

Barcelona, Spain

Location

Hospital Clinic de Barcelona

Barcelona, Spain

Location

Hospital Vall d'Hebron

Barcelona, Spain

Location

Hospital Univeritario 12 de Octubre

Madrid, Spain

Location

Royal Free London NHS Foundation Trust

London, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

Related Publications (6)

• Bergmann L, Albiges L, Ahrens M, Gross-Goupil M, Boleti E, Gravis G, Flechon A, Grimm MO, Bedke J, Barthelemy P, Castellano D, Mellado B, Ivanyi P, Rottey S, Florcken A, Suarez C, Maroto P, Grunwald V, Oosting SF, Kopecky J, Zschabitz S, Boegemann M, Buchler T, Niegisch G, Goebell PJ, Waddell T, Joly F, Priou F, Retz M, Siemer S, Zimmermann U, Deckbar D, Burkholder I, Hartmann A, Haanen JB; Interdisciplinary Renal Cell Carcinoma Working Group of the DKG (IAGN). Prospective randomized phase-II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer - results of the SUNNIFORECAST trial. Ann Oncol. 2025 Jul;36(7):796-806. doi: 10.1016/j.annonc.2025.03.016. Epub 2025 Apr 1.

  PMID: 40180121 BACKGROUND

• Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015 Nov 5;373(19):1803-13. doi: 10.1056/NEJMoa1510665. Epub 2015 Sep 25.

  PMID: 26406148 BACKGROUND

• Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016 Mar;17(3):378-388. doi: 10.1016/S1470-2045(15)00515-X. Epub 2016 Jan 13.

  PMID: 26794930 BACKGROUND

• Vera-Badillo FE, Templeton AJ, Duran I, Ocana A, de Gouveia P, Aneja P, Knox JJ, Tannock IF, Escudier B, Amir E. Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and meta-analysis. Eur Urol. 2015 Apr;67(4):740-9. doi: 10.1016/j.eururo.2014.05.010. Epub 2014 Jun 2.

  PMID: 24882670 BACKGROUND

• Ahrens M, Scheich S, Hartmann A, Bergmann L; IAG-N Interdisciplinary Working Group Kidney Cancer of the German Cancer Society. Non-Clear Cell Renal Cell Carcinoma - Pathology and Treatment Options. Oncol Res Treat. 2019;42(3):128-135. doi: 10.1159/000495366. Epub 2019 Feb 23.

  PMID: 30799404 BACKGROUND

• Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthelemy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.

  PMID: 29562145 BACKGROUND

Related Links

• Results published in EU Clinical Trial Register

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

Ipilimumab; Nivolumab; Standard of Care

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Lothar Bergmann, MD

  Goethe University (Hospital) Frankfurt

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 6, 2017
• First Posted: March 9, 2017
• Study Start: November 1, 2017
• Primary Completion: November 23, 2023
• Study Completion: November 23, 2023
• Last Updated: September 26, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (2); NL (2); BE (1); FR (6); DE (13); ES (4); GB (2)