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Report for Clinical Trial NCT02968303

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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

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) 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) 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) 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

NCT02968303 Melanoma, Malignant, of Soft Parts
MeSH: Melanoma Sarcoma, Clear Cell
HPO: Cutaneous melanoma Melanoma

1 Interventions

Name: Vemurafenib and Cobimetinib

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

Type: Drug

Induction treatment


Primary Outcomes

Measure: Best overall response rate (BORR) according to RECIST 1.1

Time: Week 18 from start of treatment

Secondary Outcomes

Measure: Progression-free survival (PFS) according to RECIST 1.1

Time: 1 and 2 years from start of treatment

Measure: Overall survival (OS)

Time: 1 and 2 years from start of treatment

Measure: Grade 3/4 toxicities according to CTCv4.03

Time: Week 18 from start of treatment

Measure: Percentage of ongoing response

Time: 1 and 2 years from start of treatment

Measure: Response percentage upon re-induction

Time: Week 18 from start of treatment

Measure: Changes in tumor-specific T cell responses

Time: Week 18 from start of treatment

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 V600E

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. --- V600E ---

Inclusion Criteria: - 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) - No leptomeningeal metastases - No active autoimmune disease requiring systemic treatment in the past 3 months or a documented history of autoimmune disease, or history of syndrome that required systemic steroids, at daily dose of ≥10mg prednisone or equivalent, or immunosuppressive medications. --- V600E ---

- No underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events Inclusion Criteria: - 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) - No leptomeningeal metastases - No active autoimmune disease requiring systemic treatment in the past 3 months or a documented history of autoimmune disease, or history of syndrome that required systemic steroids, at daily dose of ≥10mg prednisone or equivalent, or immunosuppressive medications. --- V600E ---



HPO Nodes


HPO:
Cutaneous melanoma
Genes 15
HRAS MITF CDKN2A BRAF NRAS NRAS WRN CDKN2A CXCR4 BAP1 POLH CDK4 ERCC3 XPC MC1R
Melanoma
Genes 98
MGMT NRAS POT1 NRAS XPA CTSC BRCA1 SDHC ERCC4 CXCR4 RAD51C CDKN2B ERCC3 XPC PALLD ERCC2 ERCC2 CHEK2 CDKN2A RAD51D GNAQ SDHD KRAS MBTPS2 BAP1 BAP1 CYSLTR2 RNF43 BAP1 CDKN2A PTPN11 CDK4 BRCA2 ERCC3 MITF TERF2IP ERCC4 CHEK2 BRCA1 TRPV3 POT1 OCA2 TERT CDKN2A AKT1 CDKN2A SF3B1 ERCC6 ERCC5 ERCC5 MDM2 BRCA2 BAP1 GNA11 ACD BRIP1 HRAS MRE11 BRAF TYR TP53 KLLN SEC23B PTEN PIK3CA XPA PERP MITF RAF1 BRAF POLH TP53 BARD1 NRAS SMAD4 RAD50 DDB2 ERCC2 NBN TERT MC1R SLC45A2 WRN PALB2 DDB2 PALB2 CDKN2A SDHB MC1R RAD51 TP53 XPC ERCC3 PTEN CDKN2A POLH CDK4 MC1R