Study of DSP-5336 in Patients with Adult Acute Leukemia.

JRCT ID: jRCT2031210594

Registered date:05/02/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Phase1: AML, ALL, or acute leukemia of ambiguous lineage Phase2: AML
• Date of first enrollment: 28/03/2022
• Target sample size: 100
• Countries of recruitment: United States,Japan,Canada,Japan
• Study type: Interventional
• Intervention(s): Patients will receive DSP-5336 orally at a dose of 40/60/80/100/120/140180/240/320/420/560/740 mg twice daily. The study will be divided into 28-day cycles for safety and response assessments.

Outcome(s)

Primary Outcome

Dose escalation part (Phase 1):
1.Assess the safety and tolerability of DSP-5336 in adult patients with relapsed or refractory AML, ALL, or acute leukemia of ambiguous lineage
2.Determine the RP2D of DSP-5336 based on the lowest dose of DSP-5336 that provides the maximum biologic and clinical effect, or the MTD, whichever is lower
Dose expansion part (Phase 2):
1.Evaluate the clinical activity of DSP-5336 in adult patients with relapsed/refractory AML who have MLLr and/or NPM1

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

For patients in Phase 1 (dose-escalation) of the study:
1) Have a confirmed diagnosis of refractory or relapsed AML, ALL, or acute leukemia of ambiguous lineage according to World Health Organization (WHO) 2022 classification, as determined by pathology review at the treating institution, and who failed available standard therapies known to be active for their AML, ALL or acute leukemia of ambiguous lineage. Participants who are candidates for stem cell transplantation must have been offered this therapeutic option.
a) Refractory is defined as: patient did not achieve complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), defined by the 2017 European LeukemiaNet (ELN) guideline under initial intensive therapy, or did not achieve CR, CRi, morphologic leukemia free state (MLFS) or partial remission (PR) after an initial sufficient time course of treatment with hypomethylating agents (HMA) or lowdose cytarabine (LDAC), with sufficient time course defined as at least 4 cycles of HMA or LDAC therapy, or at least 2 cycles of combination therapy (ie, HMA or LDAC in combination with venetoclax or glasdegib)
b) Relapse is defined as: relapse diagnosed by bone marrow assessment or by the appearance of peripheral blasts after the achievement of CR or CRi, defined by 2017 ELN guideline, with or without consolidation or maintenance, and with or without HSCT
For patients in Phase 2 (dose-expansion) of the study:
2) Have a confirmed diagnosis of refractory or relapsed AML according to WHO 2022 classification, as determined by pathology review at the treating institution, and who failed available standard therapies known to be active for their AML. Participants who are candidates for stem cell transplantation must have been offered this therapeutic option. See Criterion 1 for definitions of refractory and relapsed.
3) Have a confirmed KMT2A (MLL)-fusion or NPM1 mutation, which includes those with coexisting FLT3 genomic alterations and/or IDH1/2 mutations
For all patients:
4) Be >= 18 years of age
5) Have an Eastern Cooperative Oncology Group (ECOG) performance status <= 2
6) White blood cell (WBC) count must be below 30,000/u L at the time of enrollment and prior to starting study treatment (hydroxyurea will be allowed prior to enrollment and during study treatment)
7) Any prior treatment-related toxicities resolved to <= Grade 1 prior to enrollment, with the exception of <= Grade 2 alopecia or neuropathy
8) 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 the upper limit of normal (ULN) (or <=2 .0 ULN for patients with known Gilberts syndrome)
c) Aspartate aminotransferase (AST) <= 3.0 times ULN
d) Alanine aminotransferase (ALT) <= 3.0 times ULN
9) Be willing to attend study visits as required by the protocol
10) Have an estimated life expectancy >= 3 months, based on the investigators assessment
11) Female patients of childbearing potential must have a negative serum or urine pregnancy test.
Females of childbearing/child-producing potential are defined as women who have (1) experienced menarche and have not undergone sterilization procedures (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or (2) have not experienced menopause (defined as having amenorrhea continuously for more than 12 months that is not determined to be drug-induced, or who are taking hormone replacement therapy with serum follicle-stimulating hormone >35 mIU/mL).
12) Male or female patients of child-producing potential must agree to use a combination of two or more contraception (oral contraceptives, implantable hormonal contraceptives, or barrier methods*) or use prevention of pregnancy measures (ie, agreement to refrain completely from heterosexual intercourse) during the study and for 6 months (for females and males alike) after the last dose of study drug.
*For sites in Japan only: Implantable hormonal contraceptives, a diaphragm with spermicide, cervical cap with spermicide and contraceptive sponge (spermicide is already in the contraceptive sponge) included in the barrier contraceptive method are not approved and cannot be used in Japan.
13) Have AML/ALL material (eg, bone marrow or peripheral blood) suitable for genomic analysis (eg, MLLr orNPM1 mutations) of AML or ALL genetic alterations.

Exclude criteria

1) Has 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) 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
4) 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) within 14 days prior to the first dose of DSP-5336
5) Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of DSP-5336
6) Received immunotherapy, including tumor vaccines and checkpoint inhibitors, within 42 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336
7) Has been on other investigational treatment within the previous 4 weeks prior to the first dose of DSP-5336
8) Had major surgery within 28 days prior to the first dose of DSP-5336
9) Has active central nervous system leukemia
10) Has had abnormal ECGs at screening that are clinically significant, such as QT prolongation (QTc >450 msec for males and >470 msec for females, with QTc corrected according to Fridericias formula [QTcF])
11) Has a left ventricular ejection fraction (LVEF) <45%, as determined by ECHO
12) Has a history of Torsades de Pointes
13) In the opinion of the treating investigator, patient has 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); 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
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
For sites in Japan only: Hepatitis B core (HBc) antibody or hepatitis B surface (HBs) antibody test should be performed if HBsAg is negative. If HBc antibody or HBs antibody test is positive, HBV DNA quantification test should be performed to confirm that HBV DNA is negative.
15) Has an active, uncontrolled, bacterial, viral, or fungal infection requiring systemic therapy
16) Has 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
17) Has 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 process, protocol, or protocol-required visits and procedures
18) Receives concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5, including specifically: ketoconazole, itraconazole and isavuconazole. 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 (>=7 days for ketoconazole and itraconazole, >=21 days for isavuconazole) , that patient could be allowed on study (Arm B) with approval of the medical monitor
19) Is 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
20) Patients with any history or complication of interstitial lung disease (for sites in Japan only)

Related Information

• Primary Sponsor: Tada Tomohiro
• Secondary ID(s): NCT04988555