Momelotinib During and After HCT in Myelofibrosis

Официальное название

A Phase I Study to Evaluate the Safety and Maximum Tolerated Dose of Momelotinib Durind and Following Hematopoietic Cell Transplantation for Patients With Myelofibrosis

Обзор

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).

Подробное описание

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.

Вмешательства

• Препарат Momelotinib
  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.

Первичные конечные точки

• Maximum Tolerated Dose (MTD) of Momelotinib [Срок оценки: From start of study treatment (Day -7) through 28 days.]

Вторичные конечные точки (12)

• Incidence of momelotinib-related toxicities [Срок оценки: Day -7 through 30 days after end of treatment (up to 394 days)]
• Median Duration of Momelotinib Therapy [Срок оценки: Day -7 through end of treatment, up to 364 days.]
• Median time to neutrophil engraftment [Срок оценки: Day 0 (Day of HCT) through Day 60.]
• Median time to platelet engraftment [Срок оценки: Day 0 (Day of HCT) through Day 60.]
• Time to red blood cell transfusion independence [Срок оценки: Day 0 through end of treatment, up to 1 year.]
• Cumulative incidence of primary graft failure [Срок оценки: Day 0 through Day 60.]
• Cumulative incidence of acute graft-versus-host disease (GVHD) [Срок оценки: Day 0 through 2 years after HCT]
• Cumulative incidence of chronic graft-versus-host disease (GVHD) [Срок оценки: Day 0 through 2 years after HCT]
• Incidence of Non-relapse mortality (NRM) [Срок оценки: Day -7 through 2 years post HCT.]
• Progression-free survival (PFS) [Срок оценки: Day -7 through 2 years post HCT.]
• Overall survival (OS) [Срок оценки: Day -7 through 2 years post HCT.]
• GVHD-free, relapse-free survival (GRFS) [Срок оценки: Day -7 through 2 years post HCT]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• Known intolerance or hypersensitivity to any JAK inhibitor, including ruxolitinib, fedratinib, pacritinib, momelotinib or any other JAK inhibitor, its metabolites or formulation excipients.
• Has had any major surgery within 28 days prior to randomization
• Has received treatment with an investigational agent within 4 weeks of the first dose of study intervention
• Has received immunosuppressive agents within 28 days
• Prior allogeneic transplant for any hematopoietic disorder
• Had accelerated phase or leukemic transformation (≥10% blasts in bone marrow any time prior to HCT)
• Has an active, uncontrolled infection
• Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.
• Known diagnosis of active hepatitis B or hepatitis C.
• History of another malignancy(ies), unless:

• the participant has been disease-free for at least 2 years and is deemed by the investigator to be at low risk of recurrence of that malignancy, or
• the cancer has been deemed indolent with no progression over the last 2 years, and deemed by the investigator to be at low risk for further progression during the course of study and follow-up
• the only prior malignancy was cervical cancer in situ and/or basal cell or squamous cell carcinoma of the skin
• Participants without normal organ function defined as follows:

• AST (SGOT), ALT (SGPT) and Alkaline Phosphatase >3 × institutional Upper Limit of Normal (ULN)
• Total bilirubin >1.5 mg/dL, with the exception of participants with Gilbert's Syndrome provided direct bilirubin is ≤1.5x ULN and participant otherwise meets entry criteria.
• Calculated creatinine clearance ≤60 mL/min (Cockcroft-Gault formula)
• Have current or a history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 40%, as measured by MUGA scan or echocardiogram) or clinically significant arrhythmia not controlled by standard of care therapy.
• Not able to take oral medication or having any clinically significant gastrointestinal abnormalities that may alter absorption, e.g., malabsorption syndrome or major resection of the stomach and/or bowels.
• Grade 2 or greater peripheral neuropathy
• Pregnant or lactating women, or women planning to become pregnant or initiating breastfeeding.
• To exclude women of childbearing potential: who are unwilling or unable to practice 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. Highly effective contraceptive measures include:

• stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
• intrauterine device (IUD); intrauterine hormone-releasing system (IUS);
• sexual abstinence;
• intercourse with vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure).
• To exclude sexually active male participants with WOCBP partners who are unwilling to use the one of the following 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:

• vasectomy with medical assessment of surgical success OR consistent use of a condom.
• male participants must also agree not to donate sperm while receiving study drug and for at least 6 months after the last dose.
• Patients receiving strong CYP 3A4 inducers during study period
• Patients with major ABO mismatch donors only

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Massachusetts General Hospital — Boston

Идентификаторы

NCT: NCT07104799 · 25-501

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗