Myelofibrosis, Hematopoietic Cell Transplantation (HCT)
Conditions
Keywords
myelofibrosis, allogeneic hematopoietic cell transplantation (HCT), HCT
Brief summary
This is a single-center, open-label, phase I study to determine the safety and tolerability of momelotinib in patients with myelofibrosis during and after hematopoietic cell transplantation (HCT).
Detailed description
The purpose of this study is to test the safety, effects, and recommended dose of an investigational drug, momelotinib, during and after undergoing allogeneic HCT. This study will enroll up to 28 participants with myelofibrosis that are planned to undergo standard of care allogeneic hematopoietic cell transplantation (HCT). Participants may receive momelotinib or other JAK inhibitors prior to HCT and may adjust momelotinib dosing per protocol as follows: Multiple dose cohorts (100 mg daily, 150 mg daily and 200 mg daily) will be investigated in the peri-transplant period. Participants not previously on momelotinib will begin this drug at the initiation of conditioning therapy (Day -7 from HCT). Once participants have achieved hematopoietic recovery and are at least Day 21(cycle 2 day 1) after HCT, participants, receiving lower doses will increase the dose to 200 mg daily. Patients will remain on momelotinib for a total of 13 cycles (28 days per cycle, until approximately 1 year after transplant). After HCT, participants will be followed for up to 2 years.
Interventions
DRUGMomelotinib
Administered orally once per day during each 28-day cycle. This will start on day -7 (7 days before HCT) and continue for up to 13 cycles. Dose cohorts (100 mg daily, 150 mg daily, 200 mg daily) will be investigated in the peri-transplant period. Once participants have achieved hematopoietic recovery and are at least Day 21 after HCT, participants will increase the dose to 200 mg daily.
Sponsors
Massachusetts General Hospital
GlaxoSmithKline
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
* Participants must have pathologically confirmed primary myelofibrosis (PMF) according to WHO criteria or secondary myelofibrosis as defined by the IWG-MRT criteria. * Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) Plus criteria OR * Intermediate-1 risk disease with at least one of the following unfavorable features known to impact the survival adversely * Red cell transfusion dependency * Unfavorable Karyotype * Platelet count ≤100 x 10\^9/L * Presence of a high risk molecular marker associated with worsened overall survival (ASXL1, EZH2, IDH1/2, SRSF2, U2AF1, p53) * Participants do not have to be receiving treatment with JAK inhibitors for MF at the time of enrollment. If participants are receiving JAK inhibitor therapy with agents other momelotinib, participants must agree to be switched to momelotinib to begin Cycle 1 Day 1 on Day -7 from HCT (at the initiation of conditioning). * Age \>18 years * Participants must be designated to undergo allogeneic HCT with: * reduced intensity conditioning regimen, and * peripheral blood stem cells as a graft source * Participants who will undergo HCT from the following donor types are eligible: * 6/6 (HLA-A, B, DR) fully matched related donor or * 8/8 (HLA-A, B, DR, C) fully matched unrelated donor. Matching in the unrelated setting must be at the allele level * ECOG performance status ≤2 (Karnofsky ≥60%) * The effects of momelotinib on the developing human fetus are unknown. Female patients of childbearing potential must have a negative pregnancy test, as measured by serum or urine testing. Women of childbearing potential: must agree to use highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 1 week after the last dose of momelotinib. Male participants with women of child bearing potential partners must agree to use one of the forms of medically acceptable birth control at start of the first treatment, during the study, and for at least 6 months after the last dose. See
Exclusion criteria
for effective contraception and birth control. \- Ability to understand and the willingness to sign a written informed consent document.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Momelotinib | From start of study treatment (Day -7) through 28 days. | MTD is defined as the highest dose level at which 0 or 1 of 6 patients experience a Dose Limiting Toxicity (DLT). Toxicities will be graded and documented according to NCI CTCAE version 5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of momelotinib-related toxicities | Day -7 through 30 days after end of treatment (up to 394 days) | Toxicity will be categorized and graded per NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. |
| Median Duration of Momelotinib Therapy | Day -7 through end of treatment, up to 364 days. | Median duration of momelotinib therapy during and after allogeneic HCT will be calculated and is the duration of study treatment which divides the shortest 50% and longest 50% of treatment durations. |
| Median time to neutrophil engraftment | Day 0 (Day of HCT) through Day 60. | Neutrophil engraftment will be defined as first of 3 successive days with an absolute neutrophil count of greater than or equal to 0.5 x 10\^9/l after post-HCT nadir. Median time to neutrophil engraftment for participants receiving momelotinib during allogeneic HCT will be calculated. |
| Median time to platelet engraftment | Day 0 (Day of HCT) through Day 60. | Platelet engraftment will be defined as first of 3 successive days with platelet count of greater than or equal to 20 x 10\^9/l in the absence of platelet transfusion for 7 consecutive days. Median time to platelet engraftment for participants receiving momelotinib during allogeneic HCT will be calculated. |
| Time to red blood cell transfusion independence | Day 0 through end of treatment, up to 1 year. | Transfusion independence is defined as clinical hematologic recovery requiring no transfusion in the past 7 days. The time from Day 0 to transfusion independence will be reported. |
| Cumulative incidence of primary graft failure | Day 0 through Day 60. | Primary graft failure will be defined as lack of achievement of an absolute neutrophil count of greater than or equal to 0.5 x 10\^9/l by Day +30 after HCT with associated pancytopenia. Incidence of primary graft failure in participants receiving momelotinib during and after allogeneic HCT will be reported. |
| Cumulative incidence of acute graft-versus-host disease (GVHD) | Day 0 through 2 years after HCT | Clinical stage and grade of acute graft-versus-host-disease (GVHD) is based on MAGIC Criteria. The incidence of acute GVHD grade II-IV and grade III-IV will be estimated for each treatment group using the cumulative incidence estimate, treating death prior to acute GVHD as a competing event. Incidence of acute GVHD in participants receiving momelotinib during and after allogeneic HCT will be reported. |
| Cumulative incidence of chronic graft-versus-host disease (GVHD) | Day 0 through 2 years after HCT | Chronic GVHD will be assessed as per the 2014 National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease. The incidence of chronic GVHD will be estimated for each treatment group using the cumulative incidence estimate, treating death prior to chronic GVHD as a competing event. |
| Incidence of Non-relapse mortality (NRM) | Day -7 through 2 years post HCT. | Clinical response is evaluated using the using the Revised IWG-MRT, ELN response criteria for Myelofibrosis, and recently defined endpoints for MF based on recently defined consensus criteria. The incidence of non-relapse mortality (NRM) will be estimated for each treatment group using the cumulative incidence estimate, treating disease relapse or progression as a competing event. NRM will be estimated in the context of a competing risks framework. Gray test will be used for group comparison of cumulative incidence of NRM. |
| Progression-free survival (PFS) | Day -7 through 2 years post HCT. | Clinical response is evaluated using the using the Revised IWG-MRT, ELN response criteria for Myelofibrosis, and recently defined endpoints for MF based on recently defined consensus criteria. Progression-free survival is defined as the time from first dose of study drug to the earlier of disease relapse or death due to any cause. Participants alive and progression-free are censored at the date of last disease evaluation. |
| Overall survival (OS) | Day -7 through 2 years post HCT. | Overall Survival is defined as the time from first dose of study drug to the date of death due to any cause. Participants who are alive at the analysis / cutoff date will be censored at the last contact date. OS will be estimated using the Kaplan-Meier method and compared using log-rank test. |
| GVHD-free, relapse-free survival (GRFS) | Day -7 through 2 years post HCT | GVHD, relapse-free survival is defined as the time from first dose of study drug to the earlier of grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, leukemia relapse or death due to any cause. Participants alive and without one of these three events are censored at the date of last disease evaluation. GRFS will be estimated using the Kaplan-Meier method and compared using log-rank test. |
Countries
United States
Contacts
CONTACTGabriela Hobbs, MD
PRINCIPAL_INVESTIGATORGabriela Hobbs, MD
Massachusetts General Hospital
Outcome results
None listed