A BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer

NCT02960906 | Completed Phase 2 DMC

• 1 other identifier: BIONIKK
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 16

Brief Summary

Disease and Stage: naïve metastatic kidney cancer. A multicenter, randomized, a Phase 2 BIOmarker driven trial with Nivolumab and Ipilimumab or VEGFR tKi in naïve metastatic Kidney cancer

Conditions

Clear Cell Metastatic Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment

  ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment (nivolumab monotherapy, nivolumab combined with ipilimumab, or TKI: sunitinib or pazopanib), based on Investigator assessments.

  54 months

Secondary Outcomes (14)

• Progression-free survival (PFS)

  54 months

• Overall Survival

  54 months

• Objective response rate at 22 weeks

  at 22 weeks

• Duration of treatment (DOT)

  54 months

• Duration of response (DOR)

  54 months

Study Arms (8)

ccRCC molecular subgroup 1: 1A

EXPERIMENTAL

ccRCC molecular subgroup 1 -\> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol. Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab

ccRCC molecular subgroup 1: 1B

EXPERIMENTAL

ccRCC molecular subgroup 1 -\> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol. Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab; Drug: Ipilimumab

ccRCC molecular subgroup 4: 4A

EXPERIMENTAL

ccRCC molecular subgroup 4 -\> randomisation: subjects with ccRCC1 treated with nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol. Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab

ccRCC molecular subgroup 4: 4B

EXPERIMENTAL

ccRCC molecular subgroup 4 -\> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol. Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab; Drug: Ipilimumab

ccRCC molecular subgroup 2: 2C

EXPERIMENTAL

ccRCC molecular subgroup 2 -\> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Drug: Pazopanib; Drug: Sunitinib

ccRCC molecular subgroup 2: 2B

EXPERIMENTAL

ccRCC molecular subgroup 2 -\> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol. Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab; Drug: Ipilimumab

ccRCC molecular subgroup 3: 3B

EXPERIMENTAL

ccRCC molecular subgroup 3 -\> randomisation: subjects with ccRCC1 treated with nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab 240mg IV every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol. Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Drug: Nivolumab; Drug: Ipilimumab

ccRCC molecular subgroup 3: 3C

EXPERIMENTAL

ccRCC molecular subgroup 3 -\> randomisation: TKI (sunitinib 50mg daily or Pazopanib 800mg daily) according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Drug: Pazopanib; Drug: Sunitinib

Interventions

Nivolumab DRUG

For Arms 1A and 4A: Nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol. For Arms 1B, 2B, 3B and 4B: Nivolumab administered IV over 60 minutes at 3 mg/kg combined with ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 60 minutes at 240 mg every 2 weeks until disease progression, unacceptable toxicity or other reasons specified in the protocol. Starting from the Cycle 7 possibility to switch from nivolumab 240 mg every 2 weeks to 480 mg every 4 weeks according to the Investigator's preference.

Also known as: BMS-936558, Opdivo

ccRCC molecular subgroup 1: 1A; ccRCC molecular subgroup 1: 1B; ccRCC molecular subgroup 2: 2B; ccRCC molecular subgroup 3: 3B; ccRCC molecular subgroup 4: 4A; ccRCC molecular subgroup 4: 4B

Ipilimumab DRUG

For Arms 1B, 2B, 3B and 4B: Ipilimumab administered IV over 30 minutes at 1 mg/kg every 3 weeks combined with Nivolumab administered IV over 60 minutes at 3 mg/kg for 4 doses until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Also known as: YERVOY, BMS-734016

ccRCC molecular subgroup 1: 1B; ccRCC molecular subgroup 2: 2B; ccRCC molecular subgroup 3: 3B; ccRCC molecular subgroup 4: 4B

Pazopanib DRUG

For Arms 2C and 3C (TKI pazopanib or sunitinib): Pazopanib 800 mg orally QD until disease progression, unacceptable toxicity or other reasons specified in the protocol

Also known as: Votrient

ccRCC molecular subgroup 2: 2C; ccRCC molecular subgroup 3: 3C

Sunitinib DRUG

For Arms 2C and 3C (TKI pazopanib or sunitinib): Sunitinib 50 mg orally QD until disease progression, unacceptable toxicity or other reasons specified in the protocol

Also known as: Sutent

ccRCC molecular subgroup 2: 2C; ccRCC molecular subgroup 3: 3C

Eligibility Criteria

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

You may qualify if:

• Histological confirmation of RCC with a clear-cell component. Patients with TFE3 or TFEB translocation proven by cytogenetic analysis or by fluorescence in situ hybridization (FISH) are eligible.
• Metastatic (American Joint Committee on Cancer \[AJCC\] Stage IV) RCC
• No prior systemic therapy for mRCC
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2
• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Frozen tumor samples (primary tumor and/or metastasis biopsies) must be available and received by the central laboratory (Cordelier Research Center) to determine molecular groups. (Note: fine needle aspiration \[FNA\] and bone metastases samples are not acceptable for submission).
• Molecular group has to be determined prior to randomization.
• Formalin-fixed, paraffin-embedded (FFPE) tumor tissue available for biomarker (gene expression and immunohistochemistry (IHC)) analysis.

You may not qualify if:

• Any untreated CNS metastases. Patients with CNS metastases will be eligible if they are: asymptomatic, without significant oedema, not on corticosteroids, not eligible for radiation therapy/surgery or have already received radiation therapy.
• 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) except in an adjuvant setting with a free interval of more than 1 year.
• Prior treatment with an anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti-PD-L2, anti-CD137, or 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 1 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.
• Known history of COPD (of any stage).
• Known history of uveitis or complaint of double vision.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months.

Sponsors & Collaborators

• Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie: lead

Study Sites (16)

Hôpital Saint André, CHU de Bordeaux

Bordeaux, 33075, France

Location

Centre Francois Baclesse

Caen, 14000, France

Location

CHU Henri-Mondor

Créteil, 94000, France

Location

Centre OSCAR LAMBRET LILLE

Lille, 59000, France

Location

Institut Paoli Calmettes (IPC)

Marseille, 13009, France

Location

Centre Antoine Lacassagne

Nice, 06100, France

Location

Institut de Cancérologie du Gard - CHU Caremeau

Nîmes, 30029, France

Location

Institut Mutualiste Montsouris

Paris, 75014, France

Location

Hôpital Européen Georges Pompidou

Paris, 75015, France

Location

Hôpital Cochin

Paris, 75679, France

Location

Centre Hospitalier Lyon Sud - Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL)

Pierre-Bénite, 69310, France

Location

Centre Eugene Marquis

Rennes, 35042, France

Location

Hôpitaux universitaires de Strasbourg

Strasbourg, 67000, France

Location

Hopital Foch

Suresnes, 92151, France

Location

Institut Claudius Regaud

Toulouse, 31059, France

Location

CHU Bretonneau

Tours, 37000, France

Location

Related Publications (3)

• Davidson G, Helleux A, Vano YA, Lindner V, Fattori A, Cerciat M, Elaidi RT, Verkarre V, Sun CM, Chevreau C, Bennamoun M, Lang H, Tricard T, Fridman WH, Sautes-Fridman C, Su X, Plassard D, Keime C, Thibault-Carpentier C, Barthelemy P, Oudard SM, Davidson I, Malouf GG. Mesenchymal-like Tumor Cells and Myofibroblastic Cancer-Associated Fibroblasts Are Associated with Progression and Immunotherapy Response of Clear Cell Renal Cell Carcinoma. Cancer Res. 2023 Sep 1;83(17):2952-2969. doi: 10.1158/0008-5472.CAN-22-3034.

  PMID: 37335139 DERIVED

• Vano YA, Elaidi R, Bennamoun M, Chevreau C, Borchiellini D, Pannier D, Maillet D, Gross-Goupil M, Tournigand C, Laguerre B, Barthelemy P, Coquan E, Gravis G, Houede N, Cancel M, Huillard O, Beuzeboc P, Fournier L, Mejean A, Cathelineau X, Doumerc N, Paparel P, Bernhard JC, de la Taille A, Bensalah K, Tricard T, Waeckel T, Pignot G, Braychenko E, Caruso S, Sun CM, Verkarre V, Lacroix G, Moreira M, Meylan M, Bougouin A, Phan L, Thibault-Carpentier C, Zucman-Rossi J, Fridman WH, Sautes-Fridman C, Oudard S. Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial. Lancet Oncol. 2022 May;23(5):612-624. doi: 10.1016/S1470-2045(22)00128-0. Epub 2022 Apr 4.

  PMID: 35390339 DERIVED

• Epaillard N, Simonaggio A, Elaidi R, Azzouz F, Braychenko E, Thibault C, Sun CM, Moreira M, Oudard S, Vano YA. BIONIKK: A phase 2 biomarker driven trial with nivolumab and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naive metastatic kidney cancer. Bull Cancer. 2020 Jun;107(5S):eS22-eS27. doi: 10.1016/S0007-4551(20)30283-6.

  PMID: 32620212 DERIVED

MeSH Terms

Conditions

Clear-cell metastatic renal cell carcinoma

Interventions

Nivolumab; Ipilimumab; pazopanib; Sunitinib

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Yann-Alexandre VANO, MD

  Hôpital Européen Georges Pompidou; Oncology department of Pr Stéphane OUDARD

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2016
• First Posted: November 10, 2016
• Study Start: May 31, 2017
• Primary Completion: February 15, 2021
• Study Completion: February 15, 2021
• Last Updated: April 26, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

FR (16)