Ignite Creation Date:
2024-05-06 @ 9:23 AM
Last Modification Date:
2024-10-26 @ 12:13 PM
Study NCT ID:
NCT02968303
Status:
UNKNOWN
Last Update Posted:
2020-06-05
First Post:
2016-11-11
Brief Title:
Induction Therapy With Vemurafenib and Cobimetinib to Optimize Nivolumab and Ipilimumab Therapy
Sponsor:
Radboud University Medical Center
Organization:
Radboud University Medical Center
Study Overview
Official Title:
Phase 2 Study With COmbination of Vemurafenib With Cobimetinib in B-RAF V600EK Mutated Melanoma Patients to Normalize LDH and Optimize Nivolumab and Ipilimumab therapY
Status:
UNKNOWN
Status Verified Date:
2020-06
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
COWBOY
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 BRAFMEK 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 BRAFV600EK mutation-positive late-stage melanoma patients with an elevated baseline LDH level ULN 3xULN randomized 11 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 BRAFV600EK mutation positive melanoma patients naïve for BRAFMEK PD-1PD-L1 or CTLA-4 targeting therapy 18 years and older
Intervention
Patients will be randomized 11 to receive either 6 weeks vemurafenib 960 mg bid cobimetinib 60 mg QD 21-day on 7-day off 217 schedule directly followed by 4 courses of ipilimumab 3mgkg q3wk nivolumab 1mgkg q3wk Arm A or first line standard 4 courses of ipilimumab 3mgkg q3wk nivolumab 1mgkg 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 parametersendpoints
Primary Endpoints
Compare the best overall response rate BORR according to RECIST 11 of both arms at week 18 from start of treatment
Secondary Endpoints
Progression-free survival PFS according to RECIST 11
Overall survival OS
Percentage of grade 34 toxicities according to CTCv403
Percentage of ongoing response percentage of patients requiring re-induction response percentage upon re-induction
Changes in tumor-specific T cell responses
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 BRAFMEK 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 BRAFV600EK mutation-positive late-stage melanoma patients with an elevated baseline LDH level ULN 3xULN randomized 11 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 BRAFV600EK mutation positive melanoma patients naïve for BRAFMEK PD-1PD-L1 or CTLA-4 targeting therapy 18 years and older
Intervention
Patients will be randomized 11 to receive either 6 weeks vemurafenib 960 mg bid cobimetinib 60 mg QD 21-day on 7-day off 217 schedule directly followed by 4 courses of ipilimumab 3mgkg q3wk nivolumab 1mgkg q3wk Arm A or first line standard 4 courses of ipilimumab 3mgkg q3wk nivolumab 1mgkg 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 parametersendpoints
Primary Endpoints
Compare the best overall response rate BORR according to RECIST 11 of both arms at week 18 from start of treatment
Secondary Endpoints
Progression-free survival PFS according to RECIST 11
Overall survival OS
Percentage of grade 34 toxicities according to CTCv403
Percentage of ongoing response percentage of patients requiring re-induction response percentage upon re-induction
Changes in tumor-specific T cell responses
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None