The purpose of this study is to test the safety, effects, and recommended dose of an investigational drug, ziftomenib, in addition to the standard treatment on blood cancer with Allogeneic Hematopoietic Cell Transplantation (allo-HCT). This study plans to learn more about ziftomenib, which targets and inhibits negative interactions within cancer cells related to AML, when given after allo-HCT, to determine if it improves outcomes following allo-HCT. The name of the study drug involved in this study is: • Ziftomenib
This is a prospective, multi-center, open-label, phase I study of ziftomenib as maintenance therapy following allogeneic hematopoietic cell transplantation (HCT). This study is testing whether ziftomenib, combined with the standard allo-HCT treatment, is safe and effective in treating blood cancer. This study will test if ziftomenib improves outcomes after allo-HCT. The study drug is given after the allo-HCT, in combination with standard treatment and aftercare. This study consists of 2 parts: Part A (Dose Escalation): The investigators are looking to find the highest dose of the study intervention that can be administered safely without severe or unmanageable side effects, not everyone who participates in this research study will receive the same dose of the study intervention. The dose given will depend on the number of participants who have been enrolled prior and how well the dose was tolerated. Once determined, this highest dose will then be used in the dose expansion part of the study. Part B (Expansion Cohort): Participants will be treated at the respective dose as determined during Part A(Dose Escalation). Ziftomenib administered after allo-HCT may work to enhance graft-versus-leukemia effects, selectively target residual leukemic cells, or suppress leukemic stem cells, among other mechanisms. The U.S. Food and DrugAdministration (FDA) has not currently approved ziftomenib as a treatment for any disease but it is being studied in Phase 1/2 interventional clinical trials for participants with relapsed or refractory acute myelogenous leukemia. The estimated length of the study is 2 years. Participants will begin treatment 30 to 90 days after allo-HCT, and treatment will continue for up to 12 months. Then they will be followed for 12 to 24 months after study treatment ends. It is expected that about 22 people will take part in this research study.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Taken orally once per day
Massachusetts General Hospital
Boston, Massachusetts, United States
RECRUITINGMaximum Tolerated Dose (Dose Escalation)
Defined as the highest dose level at which 1 or 0 of 6 patients experience a Dose Limiting Toxicity (DLT). Toxicities will be graded and documented according to NCI CTCAE version 5.0. A non-hematologic DLT is any grade 3 adverse event (AE) lasting \>72 hours or any grade greater than or equal to 4 AE that is at least possibly related to the study drug with exceptions. Any ≥ grade 2 non-hematologic toxicity that the participant finds intolerable or renders the participant unable to take 75% or more of the assigned doses (e.g. multiple dose interruptions) during the first cycle will be considered a DLT.
Time frame: 28 days
Occurrence of ziftomenib-related toxicities
Defined as ziftomenib-related toxicities detected and categorized according to severity. Toxicities will be graded and documented according to NCI CTCAE version 5.0.
Time frame: Day 0 to last treatment dose, up to 336 days
Incidence of acute Graft versus Host Disease (GVHD) during treatment
Defined as cumulative incidence of acute GVHD from start of ziftomenib in subjects receiving maintenance therapy after allogeneic HCT. Clinical stage and grade of acute graft-versus-host-disease (GVHD) is based on MAGIC Criteria (Harris 2016). 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.
Time frame: Day 0 to end of treatment visit, up to 366 days (336 days of treatment + 30 days end of treatment)
Incidence of chronic Graft versus Host Disease (GVHD) during treatment
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. 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 (Jagasia 2015).
Time frame: Day 0 to end of treatment visit, up to 366 days (336 days of treatment + 30 days end of treatment)
Non-relapse mortality (NRM)
The incidence of non-relapse mortality will be estimated for each treatment group using the cumulative incidence estimate, treating disease relapse or progression as a competing event. AML treatment response is based on 2022 ELN recommendations (Dohner 2022).
Time frame: Day 0 to end of treatment visit, up to 1086 days (336 days of treatment + 30 days end of treatment + 24 months follow-up))
Leukemia-Free Survival (LFS)
Leukemia-Free Survival is defined as the time from first dose of study drug to the earlier of leukemia relapse or death due to any cause. Participants alive and leukemia-free are censored at the date of last disease evaluation. AML treatment response is based on 2022 ELN recommendations (Dohner 2022).
Time frame: Day 0 to end of treatment visit, up to 1086 days (336 days of treatment + 30 days end of treatment + 24 months follow-up))
Overall Survival (OS)
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.
Time frame: Day 0 to end of treatment visit, up to 1086 days (336 days of treatment + 30 days end of treatment + 24 months follow-up))
GVHD-free, relapse-free survival (GRFS)
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. AML treatment response is based on 2022 ELN recommendations (Dohner 2022).
Time frame: Day 0 to end of treatment visit, up to 1086 days (336 days of treatment + 30 days end of treatment + 24 months follow-up))
Proportion of successfully screened that do not reach study treatment
Defined as proportion of subjects who successfully screen for study prior to transplantation but who do not reach the maintenance phase due to transplant-related morbidity or mortality.
Time frame: 30 days (Screening to Day 0)
Plasma Concentration of ziftomenib and metabolites
Characterize the pharmacokinetics (PK) of ziftomenib and metabolites when ziftomenib is given as maintenance therapy after allogeneic HCT by measuring the plasma concentration of ziftomenib and metabolites.
Time frame: Up to 62 days (Cycle 1 Day 1 - Cycle 3 Day 1 (+/- 5 days)
Plasma Concentration of oral immunosuppressive agents and ziftomenib
Assess PK drug-drug interaction between ziftomenib and oral systemic immunosuppressive agents performed by measuring plasma concentrations.
Time frame: Up to 34 days (Day -7 to -14 after HCT prior to co-administration and on Cycle 1 Day 1 and Day 15 (+/- 5 days) of co-administration)
Number of Participants with Treatment-Related Adverse Events
The severity/intensity of adverse events will be graded based upon the subject's symptoms according to the current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0). All participants will be followed and assessed for adverse events 30 days after removal from protocol therapy or until death, whichever occurs first.
Time frame: Day 0 to end of treatment visit, up to 366 days (336 days of treatment + 30 days end of treatment)
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