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Report for Clinical Trial NCT01726738

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations

This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at baseline and at progression.If a subject is removed from the study for one of a variety of reasons including, but not limited to, an inability to tolerate the combination of dabrafenib and trametinib, a need to receive other therapy or completion of 3-years of study treatment without progression, and the subject later receives, as part of his/her standard of care, the combination of dabrafenib and trametinib and progresses on the standard of care regimen, then the subject may be contacted by the treating physician to be put back on to the LCCC 1128 protocol and have a progression biopsy at this progression time point. Markers of resistance will be explored by performing near kinome-wide profiling on tumor samples, and in patients who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA sequencing technology. Overall response rate and duration to this combination will also be assessed.

NCT01726738 Stage III Melanoma Stage IV Melanoma Unresectable Melanoma BRAF Mutant Melanoma
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

1 Interventions

Name: BRAF inhibitor dabrafenib and MEK inhibitor trametinib

Description: Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

Type: Drug

BRAF (dabrafenib) and MEK (trametinib) inhibitors


Primary Outcomes

Description: The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry.

Measure: Kinase Expression

Time: One year post treatment

Secondary Outcomes

Description: The secondary outcome measure is to explore whether resistance to BRAF and MEK inhibition is associated with new functional mutations in the approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of the tumors (using NextGen DNA sequencing technology) in the subset of patients who co-enroll in a correlative study, with particular focus on one of five established resistance genes (BRAF, NRAS, MEK1, MAP3K8 or COT, and PTEN).

Measure: BRAF and MEK inhibition associated with new functional mutations in the approximately 150 oncogenes

Time: One year

Description: Prediction analysis of microarrays (PAM) based on nearest shrunken centroid will also be carried out to identify a subset of kinases that predicts resistance to BRAF+MEK inhibition.

Measure: Kinome signature predictive of resistance

Time: One year post treatment

Description: To determine the disease overall response rate (ORR: complete response + partial response) as measured radiographically via RECISTv1.1. The response rate will be estimated and 95% confidence interval will be computed.

Measure: Overall Response Rate (ORR)

Time: One year post treatment

Description: Patients will enter the follow-up phase every 3 months for up to 1 year from study entry to document survival (no tumor measurement per study protocol will be necessary after progression). Response measured radiographically via RECISTv1.1.

Measure: Duration of Overall Response Rate (ORR)

Time: One year post treatment

Description: Patients who come off therapy for reasons other than progression will enter the follow-up phase every 3 months for up to 1 year from study entry to document survival.Response measured radiographically via RECISTv1.1. Progression-free survival will be evaluated using the Kaplan-Meier statistical method

Measure: Progression Free Survival (PFS)

Time: One year post treatment

Description: Patients will enter the follow-up phase every 3 months for up to 1 year from study entry to document survival.

Measure: Rate of Overall Survival (OS)

Time: One year post treatment

Purpose: Treatment

Single Group Assignment


There are 2 SNPs

SNPs


1 V600E

Patients will enter the follow-up phase every 3 months for up to 1 year from study entry to document survival.. Main Study Inclusion Criteria: Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2 Normal organ function as defined by the following: - Absolute neutrophil count >1.2 × 109/L - Hemoglobin >9 g/dL, platelets >75 × 109/L - PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment) - Albumin >2.5 g/dL - Total bilirubin <1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded) - AST and ALT < 2.5× ULN - CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. --- V600E ---

Main Study Inclusion Criteria: Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2 Normal organ function as defined by the following: - Absolute neutrophil count >1.2 × 109/L - Hemoglobin >9 g/dL, platelets >75 × 109/L - PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment) - Albumin >2.5 g/dL - Total bilirubin <1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded) - AST and ALT < 2.5× ULN - CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. --- V600E ---


2 V600K

Patients will enter the follow-up phase every 3 months for up to 1 year from study entry to document survival.. Main Study Inclusion Criteria: Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2 Normal organ function as defined by the following: - Absolute neutrophil count >1.2 × 109/L - Hemoglobin >9 g/dL, platelets >75 × 109/L - PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment) - Albumin >2.5 g/dL - Total bilirubin <1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded) - AST and ALT < 2.5× ULN - CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. --- V600E --- --- V600K ---

Main Study Inclusion Criteria: Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2 Normal organ function as defined by the following: - Absolute neutrophil count >1.2 × 109/L - Hemoglobin >9 g/dL, platelets >75 × 109/L - PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment) - Albumin >2.5 g/dL - Total bilirubin <1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded) - AST and ALT < 2.5× ULN - CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. --- V600E --- --- V600K ---



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