IRB Study Number 23-939
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
• To determine the safety and tolerability of ziftomenib combined with SOC treatments in adults with newly diagnosed NPM1-m or KMT2A-r AML and for ziftomenib combined with SOC treatments in NPM1-m or KMT2A-r patients with relapsed or refractory AML
• To determine the antileukemic activity of ziftomenib combined with SOC treatments in adults with newly diagnosed NPM1-m or KMT2A-r AML and for ziftomenib combined with SOC treatments in NPM1-m or KMT2A-r patients with relapsed or refractory AML
Secondary Objectives
• To evaluate survival, disease control outcomes and additional markers of antileukemic activity for ziftomenib combined with SOC treatments in adults with newly diagnosed NPM1-m or KMT2A-r AML and for ziftomenib combined with SOC treatments in NPM1-m or KMT2A-r patients with relapsed or refractory AML
• Characterize the pharmacokinetics of ziftomenib and metabolites when administered in combination with SOC treatments in adults with newly diagnosed NPM1-m or KMT2A-r AML and for ziftomenib combined with SOC treatments in NPM1-m or KMT2A-r patients with relapsed or refractory AML
• To evaluate the potential drug interaction of ziftomenib on venetoclax (i.e., potential inhibition of CYP3A4 metabolism of venetoclax by ziftomenib)
Inclusion Criteria
- Adults, age ≥18 years at study entry, diagnosed with AML per the WHO Classification of Hematolymphoid Tumors (5th Edition) with a documented NPM1 mutation or KMT2A rearrangement (excluding partial tandem duplication [PTD]). Patients with isolated myeloid sarcoma may also be enrolled on an exploratory basis.
a. Newly diagnosed NPM1-m patients that are FLT3 wild-type or ITD ratio of <0.05 (i.e., are not eligible for FLT3 targeted treatment) and have high-risk disease, based on at least one of the following:
A. Adverse risk genetics per ELN criteria (Döhner et al. 2022)
B. Age ≥ 60 years
C. Treatment-related AML (regardless of age)
a. For R/R cohorts: must have been refractory to prior therapy or have had reappearance of ≥ 5% blasts in the BM or reappearance of blasts in the blood in at least 2 peripheral blood samples at least one week apart; or development of new extramedullary disease and have failed at least one prior line of therapy
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (Appendix 3)
AST < 5 × upper limit of normal (ULN), ALT < 5 × ULN, and total bilirubin ≤ 1.5 × ULN (except for patients with known Gilbert’s syndrome) for the local laboratory. If due to disease, higher values may be approved after discussion with the Kura Medical Monitor.
Adequate renal function as defined by calculated creatinine CL (according to the Cockcroft-Gault equation) ≥ 50 mL/min
Ejection fraction by transthoracic echocardiogram or multi-gated acquisition scan
i. Front-line setting (i.e., zifto/7+3): ≥ 50%
ii. R/R (i.e., zifto/ven/aza; zifto/ven): ≥40%
Patients, or their legally authorized representative, must be able to understand and provide informed consent
Female patients of childbearing potential (i.e., any premenopausal woman who has begun menstruation and is capable of getting pregnant) must agree to use adequate contraception from screening visit until 180 days following the last dose of study intervention (Appendix 2). Male patients capable of having intercourse with females of childbearing potential must agree to abstain from heterosexual intercourse or have their partner use adequate contraception from the screening visit until 90 days after the last dose of study intervention. Female patients must also agree not to donate eggs throughout the study and for 180 days after the last dose of study treatment. They must also refrain from sperm donation from the screening visit until 90 days following the last dose of study intervention.
Patient’s life expectancy attributed to AML must be greater than 3 months. If the patient has comorbid illness or malignancy (ie, condition other than AML), life expectancy attributed to this other condition(s) must be greater than 2 years.
For newly diagnosed patients who are not a candidate for intensive induction chemotherapy. Potential reasons for this designation may include:
• ≥ 75 years of age; OR
• ≥ 18 to 74 years of age with at least 1 of the following comorbidities:
− ECOG Performance Status of 2;
− Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina;
− Diffusing capacity of the lungs for carbon monoxide ≤ 65% or forced expiratory volume in 1 second ≤ 65%;
− Moderate hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 × ULN;
− Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis
Exclusion Criteria
Diagnosis of either acute promyelocytic leukemia or blast chronic myelomonocytic leukemia
Known history of BCR-ABL alteration
Advanced malignant hepatic tumor [for patients receiving ven/aza combination]
Administration of live attenuated vaccines within 14 days prior to, during, or after treatment until B-cell recovery
Active central nervous system (CNS) involvement by AML. Those patients with evidence of CNS disease at baseline/screening may continue to receive intrathecal prophylaxis per institutional practices.
Clinical signs/symptoms of leukostasis or WBC > 25 × 109/L.
a. Note: Hydroxyurea and/or leukapheresis are permitted to meet this criterion.
Patients who have not recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicities except for alopecia
Known clinically active human immunodeficiency virus, active hepatitis B or active hepatitis C infection
For newly diagnosed cohorts: has received prior chemotherapy for leukemia, except hydroxyurea and/or leukapheresis to control leukocytosis, prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia, or non-HMA therapy for prior myelodysplastic syndrome
For R/R cohorts: has received chemotherapy, immunotherapy, radiotherapy (unless if given for management of CNS leukemia), or any ancillary therapy that is considered to be investigational (ie, used for non-approved indications(s) and in the context of a research investigation) < 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug
Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study intervention and follow-up
Patients who are otherwise determined unable to comply with the protocol, in the opinion of the Investigator
Any other significant medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient participating in the study or would confound the interpretation of the results of the study
Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic CHF, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction with evidence of residual abnormalities within 6 months prior to enrollment (Troponin leak alone not included if no residual dysfunction), New York Heart Association Class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
Mean corrected QT interval corrected for heart rate by Fredericia’s formula (QTcF) >480 ms on triplicate ECGs performed within 5 minutes of each other.
As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control.
Hypersensitivity to azacitidine or mannitol [for zifto/ven/aza; zifto/ven]
Women who are pregnant or lactating. All female patients must have a negative serum pregnancy test within 72 hours prior to start of study intervention.
Patients who have an active malignancy currently receiving chemotherapy for that malignancy or whose disease is uncontrolled/progressing.
Patients who have active GVHD and those on immunosuppressive drugs for the treatment of GVHD. Patients may not receive calcineurin inhibitors for at least 4 weeks prior to study treatment to be eligible.
