Clinical Trial 23640

• Overview

  Study Title:

  A Phase 1/2, Open-Label, Dose-Escalation, Dose-Expansion Study of Enzomenib (DSP-5336) in Adult Patients with Acute Leukemia and Other Selected Hematologic Malignancies, with and without Mixed Lineage Leukemia (MLL) rearrangement or Nucleophosmin 1 (NPM1) Mutation

  Summary:

  A phase 1/2 dose escalation / dose expansion study of Enzomenib (DSP-5336) in patients with acute leukemia.

  Objective:

  Phase 1: Relapsed/Refractory Primary Objectives: To assess the safety and tolerability of DSP-5336 monotherapy in patients with relapsed or refractory AML, ALL, acute leukemia of ambiguous lineage, and, in selected sites and regions, also in patients with high-risk relapsed or refractory MDS, or relapsed/refractory MM. To determine the recommended Phase 2 dose (RP2D) of DSP-5336 based on the lowest dose of DSP-5336 that provides the maximum biologic and clinical effect, or the maximum tolerated dose (MTD), whichever is lower. To determine the safety, tolerability, and RP2D of DSP-5336 administered in combination with venetoclax/azacitidine in adult patients with relapsed or refractory AML To determine the safety, tolerability, and RP2D of DSP-5336 administered in combination with gilteritinib in adult patients with relapsed or refractory AML. Secondary Objectives: To characterize the PK profiles of DSP-5336, including the PK profile in the presence of concomitant use of selected azoles, ie, posaconazole, voriconazole, or fluconazole. To assess the effect of food (high-fat diet) on DSP-5336 PK/exposures. To assess the PK characteristics of DSP-5336 administered in combination with venetoclax and azacitidine. To assess the PK characteristics of DSP-5336 administered in combination with gilteritinib. To assess the PK characteristics of venetoclax administered in combination with DSP-5336. To assess the PK characteristics of gilteritinib administered in combination with DSP-5336. To evaluate the preliminary clinical activity of DSP-5336 monotherapy in patients with AML, ALL, acute leukemia of ambiguous lineage, and, in selected sites and regions, also in patients with high-risk relapsed or refractory MDS or relapsed/refractory MM. To evaluate the preliminary clinical activity of DSP-5336 in combination with venetoclax/azacitidine. To evaluate the preliminary clinical activity of DSP-5336 in combination with gilteritinib. To determine the cardiac safety of DSP-5336 administered as a single agent by 12-lead safety and intensive ECG monitoring, and in the presence of azoles by 12-lead safety ECG monitoring. Frontline (DSP-5336 with Venetoclax/Azacitidine) Primary Objectives: To optimize the dose of DSP-5336 administered in combination with venetoclax/azacitidine in adult patients with newly diagnosed AML Frontline (DSP-5336 with 7+3) Primary Objectives: To determine the safety, tolerability, and RP2D of DSP-5336 administered in combination with 7+3 in adult patients with newly diagnosed AML. Secondary Objectives: To evaluate the preliminary clinical activity of DSP-5336 in combination with a 7+3 chemotherapy regimen in adult patients with newly diagnosed AML. To explore mechanisms and biomarkers of resistance to menin inhibition. Phase 2: Primary Objectives: To evaluate the clinical activity of DSP-5336 monotherapy in patients with relapsed/refractory acute leukemia with an MLLr or patients with relapsed/refractory AML with an NPM1m. Secondary Objectives: To evaluate additional clinical activity of DSP‑5336 monotherapy in patients with relapsed/refractory acute leukemia with an MLLr or patients with relapsed/refractory AML with an NPM1m. To further assess the safety and tolerability of DSP-5336.

• Treatments

  Therapies:

  BCL-2 inhibitor; Chemotherapy (NOS); DNA methyltransferase inhibitor; FLT3 kinase inhibitor; Menin-MLL inhibitor

  Medications:

  Azacitidine (5-azacitidine); Cytarabine (Cytosine Arabinoside); DSP-5336 (); Daunomycin (daunorubicin); GDC-0199 (Venetoclax); Gilteritinib (); Idarubicin (); Venetoclax (); Zevados (Idarubicin); daunorubicin ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Have a diagnosis of relapsed or refractory AML, ALL or acute leukemia of ambiguous lineage according to World Health Organization (WHO) 2022 classification, or, in selected sites and regions, a diagnosis of MDS or MM as determined by pathology review at the treating institution, and whose disease has progressed after available standard therapies known to be active for their AML, ALL, or acute leukemia of ambiguous lineage or, in selected sites and regions, for MM or MDS. If acute leukemia patients are transformation from MDS or other hematologic malignancies, patients need to receive available standard therapies as acute leukemia after AML transformation and before enrolling this trial. In regions or countries where required by regulatory authorities, 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.
  • Patients with MDS must have bone marrow blasts ≥ 5%.
  • Patients with MDS must have relapsed or refractory disease and have exhausted available standard therapies including at least 2 cycles of treatment with HMA.
  • Have measurable disease as defined in the protocol.
  • Meet the laboratory parameters set in the protocol.
  • Additional Criteria will apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Has a left ventricular ejection fraction (LVEF) > Histological diagnosis of acute promyelocytic leukemia.
  • Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336.
  • Have abnormal ECGs at screening that are clinically significant, such as (QTc >480 msec, with QTc corrected according to Fridericia's formula (QTcF). For clinical sites in the UK, have abnormal ECGs at screening that are clinically significant, such as QTc ≥470 msec and ≥450 msec with QTc corrected according to Fridericia's formula (QTcF), for females and males, respectively. In addition, patients with a history of prolonged QT syndrome or who are required to take therapies associated with QT-interval prolongation are excluded.
  • Has an active and uncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy. Note: Patients must be afebrile with negative blood cultures at least 72 hours prior to Cycle 1 Day 1.
  • Receives concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5, including specifically: ketoconazole, isavuconazole and itraconazole. Other antifungals that are used as standard of care to prevent or treat infections are permitted. If a patient is on one of the excluded azole class antifungals, he/she can be taken off or switched to a permitted azole 7 or more days prior to first dose, then the patient could be allowed on study (Arm B) with approval of the medical monitor.
  • Had major surgery within 28 days prior to the first dose of DSP-5336.
  • Has active central nervous system leukemia (prophylactic intrathecal chemotherapy is allowed).
  • 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. For clinical sites in the UK, underwent CAR-T therapy or other modified T-cell therapy within 6 months prior to the first dose of DSP-5336.
  • 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 7 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336.
  • 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 21.2); 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.
  • Additional Criteria will apply.

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