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Report for Clinical Trial NCT02410863

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Biopsy- and Biology-driven Optimization of Targeted Therapy of Metastatic Melanoma in BRAF Inhibitor Non-pretreated and Pretreated Subjects With Advanced, Non-resectable (STAGE IIIC) or Metastatic (StAGE IV) BRAF Mutation-positive Melanoma

This is an open-label, multi-center, clinical phase II study to explore the correlation of the genetic make-up of the treated tumor before start of therapy and to correlate clinical response at 8 weeks as well as metabolic response at 2 and 8 weeks with genetic features of the tumor. It will be conducted as a rationale optimization of targeted therapy in BRAF naïve and pretreated patients. Prerequisite for all patients is the availability of tumor sample at start of treatment in order to determine the underlying driver mutation (BRAF mutational status) as well as molecular composition by next generation sequencing (NGS) and assessable lesions for biopsy at week 2. Melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment and treated with dabrafenib and trametinib (cohort A and B)

NCT02410863 Malignant Melanoma
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

2 Interventions

Name: Dabrafenib

Description: 150 mg twice daily

Type: Drug

Cohort A (BRAFi naïve) Cohort B (BRAFi / MEKi rechallenge)

Name: Trametinib

Description: 2 mg daily

Type: Drug

Cohort A (BRAFi naïve) Cohort B (BRAFi / MEKi rechallenge)


Primary Outcomes

Description: To broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial or complete response according to RECIST) at week 8 of targeted therapy in different pre-treated patients with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.

Measure: Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies.

Time: Week 8

Secondary Outcomes

Description: To correlate the tumor´s molecular composition to metabolic responses and biological effects on the downstream signaling cascade in order to get first insights into an adaptive mechanism in the downstream signaling of an oncogenic driver mutation upon its selective inhibition.

Measure: Correlation of the tumor´s molecular composition to metabolic responses

Time: Baseline, week 2 and 8

Description: Occurrence of adverse events and reactions

Measure: Safety / toxicity according to the Common Toxicity Criteria (CTC, Version 4.0)

Time: 1 year

Description: Proportion of patients with PFS after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs first.

Measure: Progression free survival rate

Time: 6 and 12 months

Description: Time after date of the first dose of study medication until documented date of death

Measure: Overall survival

Time: 6 and 12 months

Description: Time after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs

Measure: Progression free survival according to RECIST criteria

Time: 6 and 12 months

Description: Proportion of patients with PR and CR

Measure: Overall response rate according to RECIST criteria

Time: 6 and 12 months

Description: Proportion of patients with SD, PR and CR

Measure: Disease control rate according to RECIST criteria

Time: 6 and 12 months

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There is one SNP

SNPs


1 V600E

Prerequisite for all patients is the availability of tumor sample at start of treatment in order to determine the underlying driver mutation (BRAF mutational status) as well as molecular composition by next generation sequencing (NGS) and assessable lesions for biopsy at week 2. Melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment and treated with dabrafenib and trametinib (cohort A and B) Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies.. To broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial or complete response according to RECIST) at week 8 of targeted therapy in different pre-treated patients with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.. Correlation of the tumor´s molecular composition to metabolic responses. --- V600E ---

3. Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive by the central laboratory. --- 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