Induction Therapy With Vemurafenib and Cobimetinib to Optimize Nivolumab and Ipilimumab Therapy

NCT02968303 | Unknown Phase 2 DMC

• 1 other identifier: MOMEL27 - COWBOY
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 13

Brief Summary

Rationale: The combination of ipilimumab and nivolumab induces relatively high response rates and promising response depth in late stage melanoma. Nevertheless, it takes time till responses occur and still a significant number of patients do not benefit from treatment, due to rapid progressive disease or resistance to therapy. In contrast to immunotherapies targeted therapies (BRAF or MEK inhibitors), can induce faster and higher response rates, but often of shorter duration, even when combined. Initial attempts of combining vemurafenib or dabrafenib + trametinib with ipilimumab failed due to toxicity. Patients with elevated levels of serum LDH are less likely to respond to immunotherapy compared to patients with normal LDH levels. This does not mean that such patients do not benefit at all from immunotherapy. This raises the question, whether response rates upon immunotherapy can be improved by upfront reduction of tumor burden and normalization of LDH. The investigators postulate that induction therapy with combined BRAF+MEK inhibition, and subsequent LDH normalization, can improve response rates to the rates seen in LDH normal patients. To address this question the investigators have setup a randomized phase 2 trial in metastatic melanoma patients with elevated serum LDH comparing the response rates upon ipilimumab + nivolumab versus ipilimumab + nivolumab preceded by 6 weeks of vemurafenib + cobimetinib induction. Furthermore, less than half of the patients treated with the combination of ipilimumab and nivolumab received maintenance nivolumab, and approximately 40% of all patients discontinued treatment for toxicity. In 70% of patients responses were ongoing despite discontinuation of treatment due to toxicity. This raises the question, to what extent does maintenance therapy add clinical benefit to an ongoing immune response. Preclinical data indicate even that continuous restimulation of T cells can result in activation induced non-responsiveness (anergy). Therefore, a secondary objective of this trial will be, to test a response-driven nivolumab scheme Objectives: Primary Objective • To compare efficacy of induction vemurafenib + cobimetinib followed by ipilimumab + nivolumab (Arm A) versus upfront ipilimumab + nivolumab treatment (Arm B). Secondary Objectives

• To describe duration of response and overall survival induced by vemurafenib + cobimetinib followed by the combination of ipilimumab + nivolumab (Arm A) as compared to ipilimumab + nivolumab (Arm B)
• To describe the rate and quality of toxicity observed in the two study arms
• To describe the rate of ongoing responses upon response-driven flat dose (240mg q2w or 480mg q4w) nivolumab maintenance
• To determine the immune-activating capacity of induction therapy with vemurafenib + cobimetinib followed by the combination of ipilimumab + nivolumab.
• To evaluate the changes in systemic immune competence Study design: This is a two-arm phase 2 study consisting of 200 BRAFV600E/K mutation-positive late-stage melanoma patients with an elevated baseline LDH level (\> ULN, \< 3xULN) randomized 1:1 (stratified according to LDH) to receive either vemurafenib + cobimetinib directly followed by ipilimumab + nivolumab (Arm A) or standard first line ipilimumab + nivolumab (Arm B). Subsequently, patients in both arms will receive flat dose (240mg q2w or 480mg q4w) nivolumab maintenance in a response-driven manner. Study population: Stage IV, or unresectable stage III, BRAFV600E/K mutation positive melanoma patients, naïve for BRAF/MEK, PD-1/PD-L1 or CTLA-4 targeting therapy, 18 years and older. Intervention: Patients will be randomized 1:1 to receive either 6 weeks vemurafenib 960 mg bid + cobimetinib 60 mg QD 21-day on, 7-day off (21/7) schedule, directly followed by 4 courses of ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm A) or first line standard 4 courses of ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm B). Subsequently, patients in both arms will receive nivolumab maintenance flat dose (240mg q2w or 480mg q4w) in a response-driven manner according to their response at week 18. Main study parameters/endpoints: Primary Endpoints
• Compare the best overall response rate (BORR) according to RECIST 1.1 of both arms at week 18 from start of treatment. Secondary Endpoints
• Progression-free survival (PFS) according to RECIST 1.1
• Overall survival (OS)
• Percentage of grade 3/4 toxicities according to CTCv4.03
• Percentage of ongoing response, percentage of patients requiring re-induction, response percentage upon re-induction
• Changes in tumor-specific T cell responses

Conditions

Melanoma, Malignant, of Soft Parts

Outcome Measures

Primary Outcomes (1)

• Best overall response rate (BORR) according to RECIST 1.1

  Week 18 from start of treatment

Secondary Outcomes (6)

• Progression-free survival (PFS) according to RECIST 1.1

  1 and 2 years from start of treatment

• Overall survival (OS)

  1 and 2 years from start of treatment

• Grade 3/4 toxicities according to CTCv4.03

  Week 18 from start of treatment

• Percentage of ongoing response

  1 and 2 years from start of treatment

• Response percentage upon re-induction

  Week 18 from start of treatment

Study Arms (2)

Induction treatment

EXPERIMENTAL

Induction vemurafenib and cobimetinib (6 weeks) directly followed by ipilimumab and nivolumab

Drug: Vemurafenib and Cobimetinib

No induction treatment

NO INTERVENTION

Upfront ipilimumab and nivolumab without induction by vemurafenib and cobimetinib

Interventions

Vemurafenib and Cobimetinib DRUG

Combination of Vemurafenib with Cobimetinib in BRAF V600E/K mutated melanoma patients to normalize LDH and optimize immunotherapy with Nivolumab and Ipilimumab

Induction treatment

Eligibility Criteria

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

You may qualify if:

• Adults 18 years and older
• World Health Organization (WHO) Performance Status 0-2
• Histologically or cytologically confirmed Stage IV, or unresectable stage III, BRAF V600E/K mutated melanoma
• Measurable disease according to RECIST 1.1
• Signed and dated informed consent form
• No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
• No prior BRAFi and/ or MEKi therapy
• No immunosuppressive medications
• Screening laboratory values must meet the following criteria and should be obtained within 10 days prior to randomization:
• WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 5.0 mmol/L
• Creatinine ≤ 2x ULN or creatinine clearance (CrCl) ≥ 40 ml/min
• AST, ALT ≤ 3.0 x ULN (≤5 x ULN for patients with liver metastases)
• Bilirubin ≤ 2.0 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL )
• LDH \> ULN, \< 5.0 x ULN
• No symptomatic brain metastases (asysmptomatic brain metastases, accidentally found during screening can be included)

Sponsors & Collaborators

• Radboud University Medical Center: lead
• The Netherlands Cancer Institute: collaborator
• Isala: collaborator

Study Sites (13)

The Netherlands Cancer Institute

Amsterdam, 1066 CX, Netherlands

RECRUITING

Vrije Universiteit Medisch Centrum

Amsterdam, Netherlands

NOT YET RECRUITING

Amphia Ziekenhuis Breda

Breda, Netherlands

RECRUITING

Maxima MC

Eindhoven, Netherlands

RECRUITING

Medisch Spectrum Twente

Enschede, Netherlands

NOT YET RECRUITING

Universitair Medisch Centrum Groningen

Groningen, Netherlands

RECRUITING

Zuyderland Medisch Centrum Heerlen

Heerlen, Netherlands

RECRUITING

Leids Universitair Medisch Centrum

Leiden, Netherlands

RECRUITING

Maastricht UMC+

Maastricht, Netherlands

RECRUITING

Radboudumc

Nijmegen, 6525GA, Netherlands

RECRUITING

Erasmus MC

Rotterdam, Netherlands

NOT YET RECRUITING

UMC Utrecht

Utrecht, Netherlands

RECRUITING

Isala

Zwolle, 8025 AB, Netherlands

RECRUITING

MeSH Terms

Conditions

Sarcoma, Clear Cell

Interventions

Vemurafenib; cobimetinib

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Central Study Contacts

Rutger HT Koornstra, MD

CONTACT

+31243610354; Rutger.Koornstra@radboudumc.nl

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: Medical Oncologist

Study Record Dates

• First Submitted: November 11, 2016
• First Posted: November 18, 2016
• Study Start: January 27, 2017
• Primary Completion: October 1, 2022
• Study Completion: October 1, 2023
• Last Updated: June 5, 2020

Record last verified: 2020-06

Locations

NL (13)