SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT01711632

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

A Phase II Study of the BRAF Inhibitor, Vemurafenib, in Patients With Relapsed or Refractory Hairy Cell Leukemia

The purpose of this study is to find out what effects, good and/or bad, treatment with vemurafenib (also known as Zelboraf™) has on the patient and on leukemia. Specifically, the researchers want to know how well vemurafenib eliminates leukemia from the blood.

NCT01711632 Hairy Cell Leukemia
MeSH: Leukemia Leukemia, Hairy Cell
HPO: Leukemia

1 Interventions

Name: Vemurafenib

Description: Patients will receive vemurafenib at a dose of 960mg orally b.i.d. continuously in cycles of 4 weeks (28 days) as outpatient. A bone marrow aspirate and/or biopsy will be performed after the first cycle for research purposes only. After the completion of the third cycle, a repeat bone marrow aspirate and/or biopsy will be performed for assessment of response and evaluation of MRD. Following the third cycle assessments, patients who achieve complete response (CR) with detectable MRD or partial response (PR) may continue with vemurafenib for up to 3 additional cycles at the treating physician's discretion (Cycles 4-6). Patients who achieve CR without MRD will be observed as part of post-treatment followup, and may be re-treated with vemurafenib after relapse (as per below). Patients who achieve no response (NR) after the initial 3 cycles of vemurafenib will be removed from the study. They will be followed every 3 months as part of posttreatment followup for a total of 12 months.

Type: Drug

Vemurafenib


Primary Outcomes

Description: as assessed by overall response rates after three months of treatment in patients with relapsed or refractory HCL.

Measure: efficacy of vemurafenib

Time: 3 months

Secondary Outcomes

Description: Toxicity will be graded and recorded using the NCI Common Toxicology Criteria version 4.0.

Measure: Toxicity (safety and tolerability)

Time: 2 years

Description: Peripheral blood and/or bone marrow aspirate samples from pretreatment and post-treatment at specified time points will be assessed by Western Blot or by phospho-flow for the downstream targets of BRAF (MEK, pMEK, ERK, pERK) to assess the ontarget effect of the Vemurafenib.

Measure: To assess the pharmacodynamics

Time: 2 years

Description: Reactivation of MAPK pathways: Increased expression of the other RAF isoforms CRAF and ARAF), and MAPK (MAPK8 or COT) will be analyzed by Western Blot and/or real-time PCR39,40. Secondary BRAF mutations (all 18 BRAF exons) and RAS mutations40 will be analyzed by bidirectional Sanger sequencing and by Raindance multiplex PCR and Illumina next generation sequencing, respectively. Activation of RTKs (i.e. PDGFRβ and IGF-IR) will be assessed by Western Blot. Cell Biosciences NanoPro 1000 technology will be used to examine quantitative signaling on the entire MAPK, PI3K and JAK-STAT pathways41.

Measure: evaluate biomarkers

Time: 2 years

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 V600E

Exclusion Criteria: - Pregnant or breast-feeding - Have had chemotherapy (including purine analogs, rituximab, and other investigational agents) within six weeks prior to entering the study - Major surgery within 4 weeks prior to entering the study - Invasive malignancy within the past 2 years prior to first study drug administration, except for adequately treated (with curative intent) basal or squamous cell carcinoma, melanoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug - Prior treatment with MEK or BRAF inhibitors - Active HIV, hepatitis B and hepatitis C - Patients with HCL variant (as defined by absence of expression of CD25 or absence of BRAF V600E mutation) Inclusion Criteria: - ≥ 18 years of age - Histologically confirmed classical HCL with one of the following: - Intolerance to purine analogs or considered to be poor candidates for purine analog-based therapy - Failure to achieve any response (CR or PR) to the initial purine analog-based therapy - Relapse ≤ 2 years of purine analog-based therapy - ≥ 2 relapses Histologic confirmation of diagnosis will be performed at MSKCC or a participating site. --- V600E ---

Exclusion Criteria: - Pregnant or breast-feeding - Have had chemotherapy (including purine analogs, rituximab, and other investigational agents) within six weeks prior to entering the study - Major surgery within 4 weeks prior to entering the study - Invasive malignancy within the past 2 years prior to first study drug administration, except for adequately treated (with curative intent) basal or squamous cell carcinoma, melanoma, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, or limited stage bladder cancer or other cancers from which the patient has been disease-free for at least 2 years - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug - Prior treatment with MEK or BRAF inhibitors - Active HIV, hepatitis B and hepatitis C - Patients with HCL variant (as defined by absence of expression of CD25 or absence of BRAF V600E mutation) Hairy Cell Leukemia Leukemia Leukemia, Hairy Cell null --- V600E ---



HPO Nodes


HPO:
Leukemia
Genes 125
MPL RNASEH2B KRAS NPM1 TET2 MYD88 TSR2 RPL26 RPL27 TREX1 EFL1 PIGL SCN11A FLT3 PMS2 RPL35A EVC2 ABL1 CEBPA RARA NRAS WAS WIPF1 ATRX SH2B3 PDGFRA RB1 RNASEH2A PDGFRB CALR ARHGAP26 SH3GL1 RPS7 RPS10 NUMA1 GATA1 GATA2 RPS15A APC NSD1 ETV6 TCIRG1 DNAJC21 EVC SRP54 RPS17 NBN RPS19 SAMHD1 MSH2 RPS24 NUP214 RPS26 RPS27 RPS28 RPS29 MLLT10 RUNX1 XRCC4 CBFB CBL BCR ADAR TRIP13 ADA2 NSUN2 CREBBP PICALM GFI1 F13A1 F13B FANCA FANCC BLM FANCD2 FANCE NUTM1 JAK2 IFIH1 TYROBP MSH6 FANCG LIG4 PTPN11 SAMD9L THPO NF1 STS PIGA BRCA2 DYNC2LI1 PIK3CA SBDS GLI1 PIK3R1 BRD4 SETBP1 RNASEH2C LPP BUB1 BUB1B SCN9A SCN10A TREM2 MLF1 MLH1 ELANE DKC1 ATM HAX1 RPL35 GNB1 BUB3 CEP57 TAL1 KIT TAL2 RPL5 EP300 TP53 RPL11 KIF11 RPL15 DNMT3A RPL18