Ziftomenib treatment after blood cancer transplant

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

This study is testing if ziftomenib can help people with acute myeloid leukemia feel better and stay healthy after a blood cancer transplant.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 22 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Massachusetts General Hospital (Academic / other)
• Locations: 2 sites (Boston, Massachusetts and 1 other locations)
• Trial ID: NCT06440135 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the safety and effectiveness of ziftomenib as a maintenance therapy following allogeneic hematopoietic cell transplantation (allo-HCT) for patients with acute myeloid leukemia (AML). The study is divided into two parts: a dose escalation phase to determine the highest safe dose of ziftomenib, followed by an expansion cohort where participants receive the established dose. The goal is to assess whether ziftomenib can improve patient outcomes by enhancing the body's immune response against leukemia cells after transplantation.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with a confirmed diagnosis of acute myeloid leukemia in complete remission or with incomplete count recovery, and who have specific molecular mutations.

Not a fit: Patients who do not have acute myeloid leukemia or are not in remission may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could lead to better survival rates and reduced relapse in patients with acute myeloid leukemia after transplantation.

How similar studies have performed: While ziftomenib is being tested in this novel approach, similar studies targeting residual leukemia cells post-transplant have shown promise in improving outcomes.

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.

Where this trial is running

Boston, Massachusetts and 1 other locations

• Massachusetts General Hospital — Boston, Massachusetts, United States (Recruiting)
• Ohio State University Wexner Medical Center- James Cancer Hospital — Columbus, Ohio, United States (Recruiting)

Study contacts

• Principal investigator: Zachariah DeFilipp, MD — Massachusetts General Hospital
• Study coordinator: Zachariah DeFilipp, MD

Conditions Acute Myeloid Leukemia; Acute Myeloid Leukemia in Remission; NPM1 Mutation; KMT2A Rearrangement; Allogeneic hematopoietic cell transplantation; Allo-HCT