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Report for Clinical Trial NCT01711632

Developed by Shray Alag, 2020.
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 190
ATM KRAS KIT RPS15A NF1 MPL RPL35A RPL11 RPL18 DDX41 SBDS LPP ETV6 BUB1B F13A1 DNMT3A JAK2 NUP214 FANCD2 MSH6 FANCA PIGL NRAS TCIRG1 BUB1 TET2 FLT3 TAL1 ATRX TREX1 PDGFRA SRP54 RPS29 PTPN11 CALR FANCE WIPF1 SF3B1 GATA2 GLI1 STS SH3GL1 XRCC4 MPL SH2B3 EFL1 PIGA TREM2 CBL MPL RUNX1 MPL PIGL THPO FANCG NSD1 BRD4 NSUN2 SH2B3 RARA GATA2 NPM1 CBL CHIC2 ERBB3 GFI1 TERT KIT BCR ARHGAP26 DYNC2LI1 EVC SCN10A GATA1 ELANE RNASEH2B RPS14 SH2B3 JAK2 RPL15 SBDS NRAS RPL26 RPL27 ADA2 RPS7 TYROBP F13B MSH2 BCR WAS TERC TP53 TRIP13 MYD88 NUTM1 RPS24 GNB1 TP53 DNMT3A TERT NUMA1 NUP214 RPL5 SAMD9L TET2 CFTR POT1 FANCC RPS10 EP300 EVC2 BUB1B CEBPA BRCA2 DNAJC21 CALR SCN9A LIG4 ADAR BLM TET2 JAK2 SMPD1 RNASEH2C SCN11A GATA2 BUB3 PRSS1 KIF11 BCR RPL35 TAL2 SRP54 IFIH1 ABL1 PDGFRB KRAS RNASEH2A TET2 MLLT10 SRP54 DNAJC21 DKC1 RUNX1 APC LIG4 CBFB BLM THPO CALR NBN JAK2 MLH1 RPS19 ELANE SAMD9L RPL31 PMS2 ASXL1 TSR2 MLF1 PIK3CA DNAJC21 RUNX1 GFI1 SRSF2 SETBP1 HAX1 RPS26 RPS17 FLT3 RPS27 PIK3R1 KRAS CEP57 PICALM CREBBP GATA2 CTRC MYD88 TET2 RPS28 ABL1 RB1 SPINK1 GATA1 NBN JAK2 SAMHD1