A Phase 1/2 study of Enzomenib (DSP-5336) in Adult Patients with Acute leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sumitomo Pharma America Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

26 Jan 2024 → ongoing

Decision date (initial)

2023-09-04

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Sumitomo Pharma America, Inc.

External identifiers

EU CT number

2022-502741-10-00

WHO UTN

U1111-1285-3199

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Pharmacokinetic, Safety

Phase 1:
To assess the safety and tolerability of DSP-5336 monotherapy in patients with relapsed or refractory AML, ALL, or acute leukemia of ambiguous lineage.
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
Phase 2:
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 3

1. Phase 1: 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 Phase 2: To evaluate the 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
2. ​​Phase 1: ​To evaluate the preliminary clinical activity of DSP-5336 monotherapy in patients with AML, ALL, or acute leukemia of ambiguous lineage ​ ​Phase 2: ​To further assess the safety and tolerability of DSP-5336
3. ​​Phase 1: ​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​

Conditions and MedDRA coding

Acute Leukemia with Mixed Lineage Leukemia (MLL)-rearrangement or Nucleophosmin 1 (NPM1) Mutation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 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
2. 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
3. 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
4. For all patients: Be ≥18 years of age
5. For all patients: Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
6. 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).
7. ​​For all patients: ​Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia or neuropathy ​
8. ​​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
9. ​​For all patients: ​Be willing to attend study visits as required by the protocol ​
10. ​​For all patients: ​Have an estimated life expectancy ≥3 months, based on the investigator’s assessment ​
11. For all patients: Females of childbearing potential must have a negative serum or urine pregnancy test.
12. 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
13. 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.

Exclusion criteria 24

1. Have a histologic diagnosis of acute promyelocytic leukemia
2. 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.
3. Have any history or complication of interstitial lung disease (for sites in Japan only) and, for clinical sites operating under the European Medicines Agencies, a history of Grade ≥ 2 drug-induced interstitial lung disease or Grade ≥ 2 non-infectious pneumonitis within 6 months of starting study treatment
4. Have a known intolerance or hypersensitivity reaction to components of any of the investigational medicinal products
5. Have a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO
6. 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 .
7. Received systemic calcineurin inhibitors within 42 weeks prior to the first dose of DSP 5336.
8. Have an active and uncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy
9. 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
10. 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
11. Have a history of Grade ≥ 2 drug-induced interstitial lung disease or Grade ≥ 2 non-infectious pneumonitis within 6 months of starting study treatment.
12. 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.
13. 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).
14. 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.
15. 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.
16. Have a history of Torsades de Pointes
17. Have abnormal ECGs at screening that are clinically significant, such as QTc >480 with QTc corrected according to Fridericia’s formula [QTcF]).
18. 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. .
19. 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
20. 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.
21. 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
22. Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
23. Had major surgery within 28 days prior to the first dose of DSP-5336
24. Have active central nervous system leukemia (prophylactic intrathecal chemotherapy is allowed).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Phase 1: Safety: Dose-limiting toxicities (DLTs) as assessed by (NCI CTCAE), version 5.0 Phase 2: CR + CRh
2. Phase 1: Safety: Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)
3. Phase 1: Safety: Changes in vital signs, clinical laboratory values (hematology, clinical chemistry, urinalysis), electrocardiogram (ECG) parameters, echocardiogram (ECHO) parameters
4. Phase 1: Tolerability: Dose interruptions, dose reductions, and/or dose discontinuations
5. Phase 1: Biologic Efficacy: see corresponding secondary endpoints for PK and clinical activity

Secondary endpoints 3

1. Phase 1: Plasma DSP-5336 concentration-time profiles, plasma PK parameters of DSP-5336 (ie, AUC, Cmax, tmax, t1/2, and other parameters, as data allow) Phase 2: CR; CRi; PR; MLFS defined by ELN 2017. CRc (CR or CRh or CRi); ORR (= CR or CRi or MLFS); time to CR/CRh; time to ORR; duration of CR/CRh, duration of ORR; TI; OS; EFS
2. Phase 1: For acute leukemias: Response according to ELN 2017 criteria and criteria for CRh defined by the FDA guidance: CR; CRh; CRi; PR; MLFS; CR+ CRh; ; CRc (CR or CRh or Cri); ORR (=CR or CRi or MLFS); time to CR/CRh;time to ORR; duration of CR/CRh, duration of ORR; TI;OS;EFS Phase2: • TEAEs and SAEs • Changes in vital signs, clinical laboratory values (hematology, clinical chemistry), ECG parameters, Dose modifications
3. Phase 1: QT interval changes and morphology, assessed in patients receiving DSP-5336 as a single agent or in the presence of azoles QT interval correction will be performed using Fridericia’s formula (QTcF) from triplicate ECGs

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sumitomo Pharma America Inc.

Sponsor organisation

Sumitomo Pharma America Inc.

Address

84 Waterford Drive

City

Marlborough

Postcode

01752-7010

Country

United States

Scientific contact point

Organisation

Sumitomo Pharma America Inc.

Contact name

Clinical Development

Public contact point

Organisation

Sumitomo Pharma America Inc.

Contact name

Clinical Development

Third parties 15

Locations

4 EU/EEA countries · 36 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 64 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

15 submissions — initial application plus substantial / non-substantial modifications