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

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ClinicalTrials.gov Identifier: NCT02960906

Recruitment Status : Completed

First Posted : November 10, 2016

Last Update Posted : April 26, 2021

View this study on the modernized ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

Tracking Information

First Submitted Date ^ICMJE

August 18, 2016

First Posted Date ^ICMJE

November 10, 2016

Last Update Posted Date

April 26, 2021

Actual Study Start Date ^ICMJE

May 31, 2017

Actual Primary Completion Date

February 15, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

ORR evaluation according to molecular groups (ccRCC1 to 4) and assigned treatment [ Time Frame: 54 months ]

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.

Original Primary Outcome Measures ^ICMJE

Change History

Current Secondary Outcome Measures ^ICMJE

Progression-free survival (PFS) [ Time Frame: 54 months ]
progression-free survival (PFS) in subjects with previously untreated mRCC according to molecular groups and assigned treatment, based on Investigator radiological assessments.
Overall Survival [ Time Frame: 54 months ]
To evaluate OS in subjects with previously untreated mRCC according to molecular groups and assigned treatment.
Objective response rate at 22 weeks [ Time Frame: at 22 weeks ]
To evaluate objective response rate at 22 weeks as a surrogate of other endpoints according to molecular groups and assigned treatment.
Duration of treatment (DOT) [ Time Frame: 54 months ]
To evaluate the duration of treatment (DOT) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1&4 vs 2&3).
Duration of response (DOR) [ Time Frame: 54 months ]
To evaluate the duration of response (DOR) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1&4 vs 2&3).
Number of Participants With Treatment-Related Adverse Events [ Time Frame: 54 months ]
To estimate the incidence of AEs associated with nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in all treated subjects with previously untreated mRCC.
Gene expression of immune population markers [ Time Frame: at baseline at progression (36 months maximum) ]
To assess gene expression of immune population markers in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable.populations (CD3, CD8...) and regulatory markers (PD-1, LAG-3…) within the primary tumor, and metastases whenever possible, using frozen and FFPE tumor tissue.
Gene expression levels obtained from FFPE [ Time Frame: at the end of the study (36 months) ]
Gene expression levels obtained from FFPE tumor tissue (exploratory method) will be compared to those obtained with frozen tumor tissue (standard method).
Functional status of peripheral blood lymphocytes (PBL) [ Time Frame: at baseline, at cycle 2 and at progression (36 months maximum) ]
To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry, before treatment initiation, during treatment, and at progression.
Association between non-immune tissue and circulating biomarkers and outcomes [ Time Frame: 36 months maximum ]
To explore the association between non-immune tissue and circulating biomarkers and outcomes (ORR, ORR at 22 weeks, OS and PFS).
Mutation and methylation analysis of circulating tumor DNA [ Time Frame: 36 months maximum ]
The initial rate of ctDNA and its evolution will be correlated to the clinical evolution of patients and progression-free survival.
Genetic and epigenetic alterations [ Time Frame: 36 months maximum ]
To identify genetic and epigenetic alterations associated with either response or resistance to immune checkpoint inhibitors and tyrosine kinase inhibitors.
association between immune cells composing tumor microenvironment and response and/or resistance [ Time Frame: 36 months maximum ]
To evaluate the association between immune cells composing tumor microenvironment and response and/or resistance to immune checkpoint inhibitors or tyrosine kinase inhibitors.
additional genetic and epigenetic tumor alterations [ Time Frame: 36 months maximum ]
To evaluate additional genetic and epigenetic tumor alterations at resistance/progression or after resection of residual mass.

Original Secondary Outcome Measures ^ICMJE

Progression-free survival (PFS) [ Time Frame: 36 months ]
progression-free survival (PFS) in subjects with previously untreated mRCC according to molecular groups and assigned treatment, based on Investigator radiological assessments.
Overall Survival [ Time Frame: 36 months ]
To evaluate OS in subjects with previously untreated mRCC according to molecular groups and assigned treatment.
Objective response rate at 22 weeks [ Time Frame: at 22 weeks ]
To evaluate objective response rate at 22 weeks as a surrogate of other endpoints according to molecular groups and assigned treatment.
Duration of treatment (DOT) [ Time Frame: 36 months ]
To evaluate the duration of treatment (DOT) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1&4 vs 2&3).
Duration of response (DOR) [ Time Frame: 36 months ]
To evaluate the duration of response (DOR) of nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in subjects with previously untreated mRCC according to their molecular subgroup (1&4 vs 2&3).
Number of Participants With Treatment-Related Adverse Events [ Time Frame: 36 months ]
To estimate the incidence of AEs associated with nivolumab combined with ipilimumab or nivolumab alone or cabozantinib in all treated subjects with previously untreated mRCC.
Gene and protein expression of immune populations (CD3, CD8...) and regulatory markers (PD-1, LAG-3…) [ Time Frame: at baseline, at week 6, and at progression (36 months maximum) ]
To evaluate the association between exploratory biomarkers and outcomes; Exploratory biomarkers include: gene and protein expression of immune populations (CD3, CD8...) and regulatory markers (PD-1, LAG-3…) within the primary tumor, and metastases whenever possible, using frozen and FFPE tumor tissue.

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

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

Official Title ^ICMJE

A Phase 2 BIOmarker Driven Trial With Nivolumab and Ipilimumab or VEGFR tKi in Naïve Metastatic Kidney Cancer

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

Detailed Description

Research Hypothesis: Molecular groups of ccrcc will define patients who will respond to nivolumab alone, nivolumab combined with ipilimumab, or VEGFR-TKI (sunitinib or pazopanib) in subjects with previously untreated metastatic renal cell carcinoma (mRCC).

Conditions:

Advanced or metastatic RCC: previously untreated in metastatic setting.
Frozen tumor samples available for molecular group determination.
Determination of molecular subgroup prior to randomization.

Product(s):

ARM A: nivolumab alone administered IV over 60 minutes at 240 mg every 2 weeks (molecular group 1 and 4).
ARM B : 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

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 (Arm A and B),

- ARM C: TKI (molecular group 2 and 3), pazopanib or sunitinib according to investigator's choice until disease progression, unacceptable toxicity or other reasons specified in the protocol.

Biological assessments:

Molecular groups (1 to 4) will be determined for all patients from frozen tumor tissue samples or from fresh tumor samples immediately stored in "RNA later" medium.

Further exploratory biological assessments will be performed in order to define predictive biomarkers of response to N+I, N alone or TKI (sunitinib or pazopanib) by analyzing tumor specimens and blood samples:

To assess gene expression of immune population markers in the primary tumor as well as in the metastases before beginning treatment, and at progression if safely achievable.
Gene expression analysis will be performed from frozen and FFPE tumor tissue in order to compare the two methods.
To assess the density and phenotype of selected immune populations (CD8, CD3/CD20, PD-1, TIM-3, LAG3, FoxP3) as well as the phenotype of tumor cells (PD-L1, PD-L2) by immunohistochemistry (IHC) in the primary tumor and metastases, before treatment initiation and at progression if safely achievable.
To assess the functional status of peripheral blood lymphocytes (PBL) by flow cytometry, before treatment initiation, during treatment, and at progression.
To quantify plasmatic angiogenesis-related (i.e. VEGF-A, VEGF-C its soluble receptors VEGFR-1 and 2 and co-receptors neuropilin 1 and 2, angiopoietins, SDF-1, PDGFs…)) and endothelial cell-derived molecules (i.e. endoglin, VE-cadherin) before treatment initiation, during treatment, and at progression.
To correlate plasmatic angiogenesis-related molecules with tumor vascularization studied by immunofluorescence (IF) and a multi-spectral analyzer (Vectra technology) on tumor tissue.
To investigate a predictive role of the response of CXCL7 and sCD146 to TKI, nivolumab and/or nivolumab+ipilimumab.
To determine whether the mutation and methylation analysis of circulating tumor DNA can be used as predictive biomarker of response, resistance to treatment or progression.
Identify genetic and epigenetic alterations associated with either response or resistance to immune checkpoint inhibitors and tyrosine kinase inhibitors
Evaluate association between immune cells composing tumor microenvironment and response and/or resistance to immune checkpoint inhibitors or tyrosine kinase inhibitors
Evaluate additional genetic and epigenetic tumor alterations at resistance/progression or after resection of residual mass.

Statistical Considerations:

An adaptative design will be used to ensure that conclusions can be made with a limited number of patients in each molecular group, which is the major constraint of the study.

Sample Size: Approximately 150 patients are planned to be treated. Given an expected failure rate of molecular grouping of less than 20%, 150-200 patients must be included.

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

Clear Cell Metastatic Renal Cell Carcinoma

Intervention ^ICMJE

Drug: Nivolumab
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.
Other Names:
- BMS-936558
- Opdivo
Drug: Ipilimumab
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.
Other Names:
- YERVOY
- BMS-734016
Drug: Pazopanib
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

Other Name: Votrient
Drug: Sunitinib
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

Other Name: Sutent

Study Arms ^ICMJE

Experimental: ccRCC molecular subgroup 1: 1A
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.

Intervention: Drug: Nivolumab
Experimental: ccRCC molecular subgroup 1: 1B
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.
Interventions:
- Drug: Nivolumab
- Drug: Ipilimumab
Experimental: ccRCC molecular subgroup 4: 4A
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.

Intervention: Drug: Nivolumab
Experimental: ccRCC molecular subgroup 4: 4B
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.
Interventions:
- Drug: Nivolumab
- Drug: Ipilimumab
Experimental: ccRCC molecular subgroup 2: 2C
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.
Interventions:
- Drug: Pazopanib
- Drug: Sunitinib
Experimental: ccRCC molecular subgroup 2: 2B
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.
Interventions:
- Drug: Nivolumab
- Drug: Ipilimumab
Experimental: ccRCC molecular subgroup 3: 3B
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.
Interventions:
- Drug: Nivolumab
- Drug: Ipilimumab
Experimental: ccRCC molecular subgroup 3: 3C
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.
Interventions:
- Drug: Pazopanib
- 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

Completed

Actual Enrollment ^ICMJE

200

Original Estimated Enrollment ^ICMJE

150

Actual Study Completion Date ^ICMJE

February 15, 2021

Actual Primary Completion Date

February 15, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Key Inclusion Criteria:

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.

Key Exclusion Criteria:

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.
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 (e.g., 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.
Known history of hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory, neuropathy, and polyneuropathy.
Major surgery (e.g., nephrectomy) less than 35 days prior to the first dose of study drug.
Focal radiation therapy less than 14 days prior to the first dose of study drug.
Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of cabozantinib (e.g., malabsorptive disorder, ulcerative disease, uncontrolled nausea, vomiting, diarrhea, or small bowel resection).
Any of the following laboratory test findings:
1. WBC <2,000/mm3
2. Hemoglobin ≤9.0 g/dL
3. Neutrophils <1,500/mm3
4. Platelets <100,000/mm3
5. AST or ALT >3 x ULN (>5 x ULN if liver metastases are present)
6. Lipase and amylase > 1.5 ULN
7. Total Bilirubin >1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL)
8. Serum creatinine >1.5 x ULN or creatinine clearance <40 mL/min (measured or calculated by Cockroft-Gault formula)
9. Proteinuria: patients with ≥2+ protein on urine dipstick at baseline must undergo a 24-hour urine collection for protein then if > 1.0 g of protein patient will not be included.

Sex/Gender ^ICMJE

Sexes Eligible for Study:

All

Ages ^ICMJE

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact information is only displayed when the study is recruiting subjects

Listed Location Countries ^ICMJE

France

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT02960906

Other Study ID Numbers ^ICMJE

BIONIKK

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:

Current Responsible Party

Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

Original Responsible Party

Same as current

Current Study Sponsor ^ICMJE

Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

Original Study Sponsor ^ICMJE

Same as current

Collaborators ^ICMJE

Not Provided

Investigators ^ICMJE

Principal Investigator:

Yann-Alexandre VANO, MD

Hôpital Européen Georges Pompidou; Oncology department of Pr Stéphane OUDARD

PRS Account

Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

Verification Date

April 2021

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

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