Hairy Cell Leukemia
Conditions
Keywords
VEMURAFENIB, BRAF Inhibitor, 12-200, Zelboraf™
Brief summary
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.
Interventions
DRUGVemurafenib
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.
Sponsors
National Cancer Institute (NCI)
Northwestern University
Ohio State University
Dana-Farber Cancer Institute
Scripps Clinic
Northwell Health
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. * Patients who meet the standard treatment initiation criteria, as defined by ANC ≤1.0, Hgb ≤ 10.0 or PLT ≤100K * ECOG performance status of 0-2 * Acceptable pre-study organ function during screening as defined as: Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x ULN, and serum creatinine ≤ 1.5x ULN * Electrocardiogram (ECG) without evidence of clinically significant ventricular arrhythmias or ischemia as determined by the investigator and a rate-corrected QT interval (QTc, Bazett's formula) of \< 480 msec. * For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of vemurafenib * For men with female partners of childbearing potential, agreement to use a latex condom and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of vemurafenib * Negative serum pregnancy test within 7 days of commencement of treatment in premenopausal women. * Agreement not to donate blood or blood products during the study and for at least 6 months after discontinuation of vemurafenib; for male partners, agreement not to donate sperm during the study and for at least 6 months after discontinuation of vemurafenib * Ability to understand and willingness to sign a written informed consent document. * Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Vemurafenib | 3 months | as assessed by overall response rates after three months of treatment in patients with relapsed or refractory HCL. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity (Safety and Tolerability) | 2 years | Toxicity will be graded and recorded using the NCI Common Toxicology Criteria version 4.0. |
| To Assess the Pharmacodynamics Change From Baseline | 2 years | 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. The droplet digital PCR assay was performed to quantify the concentration of molecules with mutated BRAF V600E DNA at baseline and again at 12 weeks of vermurafenib therapy. |
| Evaluate Biomarkers of Resistance | 2 years | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vemurafenib Eligible patients will receive vemurafenib at a dose of 960mg orally twice daily (b.i.d.) continuously in cycles of 4 weeks (28 days). | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Death | 3 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | No follow up required in re-treatment | 3 |
| Overall Study | Progressive disease | 2 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Vemurafenib |
|---|---|
| Age, Continuous | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 33 Participants |
| Region of Enrollment United States | 36 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 36 |
| other Total, other adverse events | 22 / 36 |
| serious Total, serious adverse events | 13 / 36 |
Outcome results
Primary
Efficacy of Vemurafenib
as assessed by overall response rates after three months of treatment in patients with relapsed or refractory HCL. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Time frame: 3 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vemurafenib | Efficacy of Vemurafenib | Complete Response | 10 Participants |
| Vemurafenib | Efficacy of Vemurafenib | Partial Response | 14 Participants |
| Vemurafenib | Efficacy of Vemurafenib | No CR or PR | 12 Participants |
Secondary
Evaluate Biomarkers of Resistance
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.
Time frame: 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vemurafenib | Evaluate Biomarkers of Resistance | Participants with KRAS mutations | 1 Participants |
| Vemurafenib | Evaluate Biomarkers of Resistance | Participants without KRAS mutations | 35 Participants |
Secondary
To Assess the Pharmacodynamics Change From Baseline
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. The droplet digital PCR assay was performed to quantify the concentration of molecules with mutated BRAF V600E DNA at baseline and again at 12 weeks of vermurafenib therapy.
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vemurafenib | To Assess the Pharmacodynamics Change From Baseline | Pts with a decrease of the concentration of molecules with mutated BRAF V600E DNA at 12 wks | 24 participants |
| Vemurafenib | To Assess the Pharmacodynamics Change From Baseline | Pts without decrease of the concentration of molecules with mutated BRAF V600E DNA at 12 wks | 12 participants |
Secondary
Toxicity (Safety and Tolerability)
Toxicity will be graded and recorded using the NCI Common Toxicology Criteria version 4.0.
Time frame: 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Vemurafenib | Toxicity (Safety and Tolerability) | Dose reduction to 720mg twice daily | 2 Participants |
| Vemurafenib | Toxicity (Safety and Tolerability) | Dose reduction to 480mg twice daily | 10 Participants |
| Vemurafenib | Toxicity (Safety and Tolerability) | Dose reduction to 240mg twice daily | 1 Participants |
| Vemurafenib | Toxicity (Safety and Tolerability) | Did not need a dose reduction | 23 Participants |