A Phase 1/2 Study of Enzomenib (DSP 5336) in Adults with Relapsed or Refractory Acute Leukemia, Including MLL-Rearranged or NPM1-Mutated Subtypes

Trial ID: 2022-502741-10-00
Protocol: DSP-5336-101
Sponsor: Sumitomo Pharma America Inc.

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Diseases & Conditions

Acute leukaemia

Objectives

The primary objectives are to assess the safety and tolerability of enzomenib monotherapy in patients with relapsed or refractory acute myeloid leukemia, acute lymphoblastic leukemia, or acute leukemia of ambiguous lineage. This phase aims to establish the recommended phase 2 dose based on the maximum tolerated dose or the dose providing optimal biologic and clinical effect. The second phase evaluates the clinical activity of the agent in patients with relapsed or refractory acute leukemia presenting with MLL rearrangement or NPM1 mutation. 5, 3

Secondary objectives include:

Characterization of pharmacokinetic profiles, including interactions with concomitant azoles such as posaconazole, voriconazole, or fluconazole. 6
Evaluation of preliminary clinical activity in patients with acute myeloid leukemia, acute lymphoblastic leukemia, or acute leukemia of ambiguous lineage. 5
Assessment of continuous safety and tolerability profiles. 4
Determination of cardiac safety through 12-lead electrocardiogram monitoring. 4

Participants

This study involves 404 participants diagnosed with acute leukemia, specifically acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or acute leukemia of ambiguous lineage. The study population includes both male and female individuals aged 18 years or older. Participants must have relapsed or refractory disease following standard therapies and must possess a documented KMT2A (MLL) fusion or NPM1 mutation. Key inclusion requirements include an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2, adequate renal and hepatic function, and an estimated life expectancy of at least 3 months. For the monotherapy component, the white blood cell count must be below 30,000/μL at enrollment. Additionally, patients must have bone marrow material suitable for genomic analysis. Phase 2 participants are further required to have a blast percentage of ≥5% and must not have received prior exposure to a menin inhibitor.

Plans and Procedures

This Phase 1/2, open-label, dose-escalation, and dose-expansion study evaluates the safety, tolerability, and clinical activity of enzomenib in adult patients diagnosed with acute leukemia, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The first phase aims to determine the maximum tolerated dose and the recommended Phase 2 dose by monitoring dose-limiting toxicities and treatment-emergent adverse events. The second phase focuses on evaluating clinical activity, specifically the complete remission rate, in patients with mixed lineage leukemia (MLL) rearrangement or nucleophosmin 1 (NPM1) mutation. Following a screening visit to confirm diagnosis and genomic alterations, participants receive enzomenib as a monotherapy via an oral route. The study involves multiple follow-up visits to monitor pharmacokinetics, vital signs, and hematologic parameters. Participation duration is contingent upon clinical response and safety profiles, and early termination may occur due to adverse events or disease progression. Endpoints include safety assessments, overall survival, and event-free survival.

Treatment

The experimental medication is Enzomenib, administered in tablet form. This substance is delivered via the oral route.

Efficacy

Efficacy in Phase 2 will be evaluated by measuring clinical activity in patients with relapsed or refractory acute leukemia featuring mixed lineage leukemia rearrangement or acute myeloid leukemia with nucleophosmin 1 mutation. The primary efficacy endpoints for Phase 2 include the rates of complete remission (CR), complete remission with incomplete hematologic recovery (CRh), complete remission with incomplete hematologic recovery (CRi), partial response (PR), and morphologic leukemia cell leukemia blast reduction (MLFS) as defined by ELN 2017 criteria. Additional secondary efficacy parameters consist of the overall response rate (ORR), time to complete remission or CRh, time to ORR, duration of complete remission or CRh, duration of ORR, treatment interruption (TI), overall survival (OS), and event-free survival (EFS).

In Phase 1, biologic efficacy is assessed through pharmacokinetics (PK), specifically by analyzing plasma concentration-time profiles and parameters such as area under the curve (AUC), maximum concentration (Cmax), time to maximum concentration (tmax), and half-life (t1/2). Clinical response in Phase 1 is also evaluated based on ELN 2017 criteria and FDA guidance for CRh, including CR, CRh, CRi, PR, MLFS, CR plus CRh, combined complete response (CRc), and ORR.

Inclusion and Exclusion Criteria

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Inclusion Criteria

For patients in Phase 1: Have a confirmed diagnosis of refractory or relapsed AML, ALL, or acute leukemia of ambiguous lineage and whose disease has progressed after available standard therapies known to be active for their AML, ALL, or acute leukemia of ambiguous lineage. Participants must have a documented KMT2A (MLL) fusion or NPM1 mutation including those with coexisting FLT3 genomic alterations and/or IDH1/2 mutation.Participants who are candidates for stem cell transplantation must have been offered this therapeutic option
For patients in Phase 2: Have a confirmed diagnosis of refractory or relapsed AML or ALL according to WHO 2022 classification, as determined by pathology review at the treating institution, and who have ≥5% blasts by morphologic assessment in the bone marrow. Patients must have received clinically applicable standard therapies with confirmed survival benefit. Patients must not have had prior exposure to a menin inhibitor
For patients in Phase 2: Have a documented KMT2A (MLL)-fusion or NPM1 mutation assessed at relapse or immediately prior to the determination of refractory status
For all patients: Be ≥18 years of age. For countries and sites where permitted, for DSP-5336 monotherapy, acute leukemia patients ≥12 years of age who weigh ≥40 kg may be enrolled.
For all patients: Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
For all patients: For DSP-5336 monotherapy, white blood cell (WBC) count must be below 30,000/μL at the time of enrollment and prior to starting study treatment. (Hydroxyurea and steroid for cytoreduction purpose will be allowed prior to enrollment and during study treatment).
For all patients: Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia or neuropathy
For all patients: Have adequate renal and hepatic function at Screening as determined by: a. Clearance of creatinine (CLcr) level ≥ 50 ml/min, assessed by the Cockcroft-Gault formula b. Total bilirubin ≤1.5 times the upper limit of normal (ULN) (or ≤2.0 times ULN for patients with known Gilbert’s syndrome) c. Aspartate aminotransferase (AST) ≤3.0 times ULN d. Alanine aminotransferase (ALT) ≤3.0 times ULN
For all patients: Be willing to attend study visits as required by the protocol
For all patients: Have an estimated life expectancy ≥3 months, based on the investigator’s assessment
For all patients: Females of childbearing potential must have a negative serum or urine pregnancy test.
For all patients: Must agree to use one highly effective contraception method or 2 acceptable methods of birth control (each partner to use one method) or use prevention of pregnancy measures (ie, sexual abstinence, when this is the usual and preferred lifestyle of the patient) during the study and for 6 months (for females and males alike) after the last dose of study drug, if the male or female patient is of child-producing potential
For all patients: Have bone marrow material suitable for genomic analysis (eg, MLLr or NPM1 mutations) of AML or ALL genetic alterations. Note: if a bone marrow material is insufficient, an alternative suitable tissue (eg, peripheral blood) must be provided.

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Exclusion Criteria

Have a histologic diagnosis of acute promyelocytic leukemia
Have a cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient to receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent/assent process, protocol, or protocol-required visits and procedures
Have a history of Grade ≥ 2 drug-induced interstitial lung disease or Grade ≥ 2 non-infectious pneumonitis within 6 months of starting study treatment.
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336.
Receive concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5. Other antifungals that are used as standard of care to prevent or treat infections are permitted Note: If a patient is on one of the excluded azole class antifungals and can be switched to a permitted azole 7 or more days prior to study, that patient could be allowed on study (Arm B).
Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of a hepatitis B surface antigen, all being indicative of active infection.
In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results; these conditions include, but are not limited to: clinically significant non-healing or healing wounds; concurrent congestive heart failure (New York Heart Association Functional Classification Class III or IV; see Section 21.7); concurrent unstable angina; concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation); recent (within the prior 6 months) myocardial infarction; acute coronary syndrome within the previous 6 months; significant pulmonary disease (shortness of breath at rest or on mild exertion), eg, due to concurrent severe obstructive pulmonary disease, concurrent hypertension not controlled with concomitant medication, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 6 months.
Have a history of Torsades de Pointes
Have abnormal ECGs at screening that are clinically significant, such as QTc >480 with QTc corrected according to Fridericia’s formula [QTcF]).
Are pregnant or breastfeeding or planning to become pregnant Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug. .
Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP 5336, or receiving immunosuppressive therapy post-HSCT at the time of Screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD.
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336
Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
Had major surgery within 28 days prior to the first dose of DSP-5336
Have active central nervous system leukemia (prophylactic intrathecal chemotherapy is allowed).
Have a known intolerance or hypersensitivity reaction to components of any of the investigational medicinal products
Have a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO
Have an active and uncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy
Have known severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication