Induction Therapy With Vemurafenib and Cobimetinib to Optimize Nivolumab and Ipilimumab Therapy (COWBOY)
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|ClinicalTrials.gov Identifier: NCT02968303|
Recruitment Status : Recruiting
First Posted : November 18, 2016
Last Update Posted : June 5, 2020
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
Primary Objective • To compare efficacy of induction vemurafenib + cobimetinib followed by ipilimumab + nivolumab (Arm A) versus upfront ipilimumab + nivolumab treatment (Arm B).
- 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
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.
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.
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:
• Compare the best overall response rate (BORR) according to RECIST 1.1 of both arms at week 18 from start of treatment.
- 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
|Condition or disease||Intervention/treatment||Phase|
|Melanoma, Malignant, of Soft Parts||Drug: Vemurafenib and Cobimetinib||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||200 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase 2 Study With COmbination of Vemurafenib With Cobimetinib in B-RAF V600E/K Mutated Melanoma Patients to Normalize LDH and Optimize Nivolumab and Ipilimumab therapY|
|Actual Study Start Date :||January 27, 2017|
|Estimated Primary Completion Date :||October 2022|
|Estimated Study Completion Date :||October 2023|
Experimental: Induction treatment
Induction vemurafenib and cobimetinib (6 weeks) directly followed by ipilimumab and nivolumab
Drug: Vemurafenib and Cobimetinib
Combination of Vemurafenib with Cobimetinib in BRAF V600E/K mutated melanoma patients to normalize LDH and optimize immunotherapy with Nivolumab and Ipilimumab
No Intervention: No induction treatment
Upfront ipilimumab and nivolumab without induction by vemurafenib and cobimetinib
- Best overall response rate (BORR) according to RECIST 1.1 [ Time Frame: Week 18 from start of treatment ]
- Progression-free survival (PFS) according to RECIST 1.1 [ Time Frame: 1 and 2 years from start of treatment ]
- Overall survival (OS) [ Time Frame: 1 and 2 years from start of treatment ]
- Grade 3/4 toxicities according to CTCv4.03 [ Time Frame: Week 18 from start of treatment ]
- Percentage of ongoing response [ Time Frame: 1 and 2 years from start of treatment ]
- Response percentage upon re-induction [ Time Frame: Week 18 from start of treatment ]
- Changes in tumor-specific T cell responses [ Time Frame: Week 18 from start of treatment ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02968303
|Contact: Rutger HT Koornstra, MD||+31243610354||Rutger.Koornstra@radboudumc.nl|
|The Netherlands Cancer Institute||Recruiting|
|Amsterdam, Netherlands, 1066 CX|
|Contact: Christian U Blank, Prof MD PhD +31205129111 email@example.com|
|Principal Investigator: Christian U Blank, Prof MD PhD|
|Vrije Universiteit Medisch Centrum||Not yet recruiting|
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|Universitair Medisch Centrum Groningen||Recruiting|
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|Leids Universitair Medisch Centrum||Recruiting|
|Contact: Ellen Kapiteijn, MD, PhD 071 526 91 11 H.W.Kapiteijn@lumc.nl|
|Principal Investigator: Ellen Kapiteijn, MD, PhD|
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|Nijmegen, Netherlands, 6525GA|
|Contact: Rutger HT Koornstra, MD +31243610354 Rutger.Koornstra@radboudumc.nl|
|Contact: Hettie Maters, MSc +31243655388 firstname.lastname@example.org|
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|Erasmus MC||Not yet recruiting|
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|Zwolle, Netherlands, 8025 AB|
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|Principal Investigator: Johannes WB de Groot, MD PhD|