Ziftomenib Maintenance Post Allo-HCT

Official title

An Open Label Phase I Study of Ziftomenib as Maintenance Therapy Following Allogeneic Hematopoietic Cell Transplantation

Overview

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

Detailed description

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.

Interventions

• Drug Ziftomenib
  Taken orally once per day

Primary outcome measures

• Maximum Tolerated Dose (Dose Escalation) [Time frame: 28 days]

Secondary outcome measures (11)

• Occurrence of ziftomenib-related toxicities [Time frame: Day 0 to last treatment dose, up to 336 days]
• Incidence of acute Graft versus Host Disease (GVHD) during treatment [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 [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) [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) [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) [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) [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 [Time frame: 30 days (Screening to Day 0)]
• 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 [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 [Time frame: Day 0 to end of treatment visit, up to 366 days (336 days of treatment + 30 days end of treatment)]

Eligibility criteria

Inclusion criteria

• 18 years or older.
• Pathologically confirmed diagnosis of acute myeloid leukemia (AML).
• Complete remission (CR) or complete remission with incomplete count recovery (CRi) at screening.

• Complete remission (CR):

• no circulating blasts in peripheral blood and <5% blasts in bone marrow
• no extramedullary disease
• platelet count ≥100 x 10(9)/L and/or absolute neutrophil count ≥1000/µL
• Complete remission with incomplete count recovery (CRi):

• no circulating blasts in peripheral blood and <5% blasts in bone marrow
• no extramedullary disease
• platelet count <100 x 10(9)/L and/or absolute neutrophil count <1000/µL
• Presence of at least one of the following molecular mutations:

• KMT2A rearrangement

• Eligibility and enrollment will be based on local mutational testing.
• The presence of a KMT2A rearrangement (excluding partial tandem duplication \[PTD\]) at the time of initial diagnosis or any other time thereafter is sufficient.
• Participants may receive additional treatment for AML between consent and transplant.
• NPM1 mutation

• Eligibility and enrollment will be based on local mutational testing.
• For participants being transplanted in CR1, the presence of a NPM1 mutation at screening is necessary for the purposes of eligibility.
• For participants being transplanted in greater than or equal to CR2, the presence of a NPM1 mutation at the time of consent is not necessary for eligibility and its presence at the time of initial diagnosis or any other time thereafter is sufficient.
• Participants may receive additional treatment for AML between consent and transplant.
• Treatment with a menin inhibitor prior to transplant is permitted. However, patients who experienced AML relapse or progression while being treated with a menin inhibitor prior to transplant are ineligible.
• Will undergo first allogeneic HCT for their malignancy.
• Transplantation will be performed with the use of conventional myeloablative (MAC) or reduced intensity conditioning (RIC).
• HCT Donor will be one of the following:

• 5/6 or 6/6 (HLA-A, B, DR) matched related donor
• 7/8 or 8/8 (HLA-A, B, DR, C) matched unrelated donor. Matching in the unrelated setting must be at the allele level.
• Haploidentical related donor, defined as ≥ 3/6 (HLA-A, B, DR) matched
• ≥ 4/6 (HLA-A, B, DR) umbilical cord blood (UCB). Matching in the UCB setting is at the antigen level. Recipients may receive either one or two UCB units. In the case of 2 UCB units, both units must have been at least 4/6 matched with the recipient.
• Any non-investigational GVHD prophylaxis regimen is allowed.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Participants must have normal organ and function as defined below:

• AST (SGOT), ALT (SGPT) and Alkaline phosphatase < 3x institutional upper limit of normal (ULN)
• Total bilirubin < 1.5 x institutional ULN (with the exception of subjects with a history of Gilbert's syndrome, for which the total bilirubin must be < 5 x ULN)
• Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula)
• LVEF must be ≥50%, as measured by MUGA scan or echocardiogram.
• Female patients of childbearing potential must have a negative pregnancy test, as measured by serum or urine testing.
• The effects of ziftomenib on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during the entire study treatment period and through 6 months after the last dose of treatment.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• History of other 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
• Known diagnosis of active hepatitis B or hepatitis C
• Current or history of congestive heart failure New York Heart Association (NHYA) class 3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF < 50%, as measured by multigated acquisition (MUGA) scan or echocardiogram)
• Current or history of ventricular or life-threatening arrhythmias or diagnosis of long-QT syndrome
• Systemic uncontrolled infection
• Known dysphagia, short-gut syndrome, gastroparesis, or other condition(s) that limits the ingestion or gastrointestinal absorption of drugs administered orally
• Uncontrolled hypertension (systolic blood pressure \[BP\] > 180 mmHg or diastolic BP > 100 mmHg)
• QTc interval (i.e., Friderica's correction \[QTcF\]) ≥ 480 ms or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening
• Uncontrolled intercurrent illness that would limit compliance with study requirements.
• Persons who are pregnant or lactating.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 2 centers

• Massachusetts General Hospital — Boston
• Ohio State University Wexner Medical Center- James Cancer Hospital — Columbus

Identifiers

NCT: NCT06440135 · 24-096

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗