A Phase 1/2, Open-Label, Dose-Escalation, Dose-Expansion Study of DSP- 5336 in Adult Acute Leukemia Patients with and without Mixed Lineage Leukemia (MLL) Rearrangement or Nucleophosmin 1 (NPM1) Mutation.
Phase 1: Dose-Escalation Objectives:
Primary Objectives:
- To assess the safety and tolerability of DSP-5336 in adult patients with relapsed or refractory acute myeloid leukemia (AML), acute lymphoblastic leukemia (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.
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, fluconazole, or isavuconazonium (prodrug of isavuconazole).
- To evaluate the preliminary clinical activity of DSP-5336 in adult patients with AML, ALL, or acute leukemia of ambiguous lineage
- 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
Exploratory Objectives:
- To assess minimal residual disease (MRD) status
- To assess the pharmacodynamic effect of DSP-5336
- To explore the PK exposure-response (ie, safety, efficacy, or biomarkers) relationship
- To identify the metabolite profile of DSP-5336 in plasma samples
- To identify potential biomarkers capable of predicting clinical efficacy and/or toxicity of DSP-5336
Phase 2: Dose-expansion objectives:
Primary Objective:
- To evaluate the clinical activity of DSP-5336 in adult patients with relapsed/refractory AML who have MLLr and/or NPM1m* by investigator assessment
Secondary Objectives:
- To evaluate the clinical activity of DSP-5336 by central assessment
- To further assess the safety and tolerability of DSP-5336
Exploratory Objectives:
- To assess MRD status
- To further assess the pharmacodynamic effect of DSP-5336
- To identify potential biomarkers capable of predicting clinical efficacy and/or toxicity of DSP-5336
- Rutgers Cancer Institute of New Jersey
- Principal Investigator
- Neil Palmisiano MD
- Principal Investigator
Inclusion Criteria
1. Patients in the Phase 1 dose-escalation portion must have a diagnosis of relapsed or
refractory AML, ALL or acute leukemia of ambiguous lineage, 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. Enrollment to the phase 1 portion of the study may be limited to patients
with certain genetic abnormalities.
Patients in the Phase 2 dose-expansion portion must have a confirmed diagnosis of
relapsed or refractory AML, as determined by pathology review at the treating
institution, and who failed available standard therapies known to be active for
their AML. They must also have a documented KMT2A (MLL)-fusion or NPM1 mutation,
which includes those with coexisting FLT3 genomic alterations and/or IDH1/2
mutations.
2. Be > 18 years of age or 20 years if required by local regulation
3. ECOG < 2
4. WBC below 30,000/μL (hydroxyurea allowed prior to initiation of the study treatment)
5. Clearance of creatinine (CLcr) level ≥ 50 ml/min, assessed by the Cockcroft-Gault
formula
6. Total bilirubin ≤1.5 the upper limit of normal (ULN) (or ≤2.0 ULN for patients with
known Gilbert's syndrome)
7. Aspartate aminotransferase (AST) ≤3.0 times ULN
8. Alanine aminotransferase (ALT) ≤3.0 times ULN
9. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment,
with the exception of ≤Grade 2 alopecia or neuropathy.
10. Be willing to attend study visits as required by the protocol
11. Have an estimated life expectancy ≥3 months, based on the investigator's assessment
12. Females of childbearing potential must have a negative serum pregnancy test. Females
of childbearing potential are defined as women who have (1) experienced menarche and
have not undergone sterilization procedures (hysterectomy, bilateral tubal ligation,
or bilateral oophorectomy), or have (2) 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 mlU/ml).
13. Must agree to use a combination of 2 or more different contraception methods (oral
contraceptives/implantable hormonal contraceptives*, and barrier method*) 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, if male or female patient of
child-producing potential
14. Have AML/ALL material suitable for genomic analysis of AML or ALL genetic
alterations
Exclusion Criteria
1. Has a left ventricular ejection fraction (LVEF) <45%, as determined by ECHO
2. Histological diagnosis of acute promyelocytic leukemia
3. Received systemic calcineurin inhibitors within 4 weeks prior to the first dose of
DSP 5336
4. Has had abnormal ECGs that are clinically significant, such as QT prolongation (QTc
>450 msec for males and >470 msec for females, with QTc corrected according to
Fridericia's formula [QTcF])
5. Has an active, uncontrolled, bacterial, viral, or fungal infection requiring
systemic therapy
6. Receives concurrent sensitive substrates with a narrow safety window or strong
inhibitors or inducers of CYP3A4/5, including specifically: ketoconazole 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.
7. Received immunotherapy, including tumor vaccines and checkpoint inhibitors, within
42 days prior to the first dose of DSP-5336
8. Has been on other investigational treatment within the previous 4 weeks prior to the
first dose of DSP-5336
9. Had major surgery within 28 days prior to the first dose of DSP-5336
10. Has active central nervous system leukemia
11. Previously received menin-MLL inhibitors
12. Has immediately life threatening or severe complications of leukemia
13. 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
14. 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
15. 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
16. Received anthracycline where cumulative doses exceeded the upper limit per the label
approved in each country or investigator discretion (if there is no label
restriction, investigator must state the cumulative dose received for each patient
and sign to indicate that, in his/her medical opinion, stated prior dose of the
agent does not put patient at undue risk of anthracycline-related cardiotoxicity
17. 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; 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
18. Have an active acute or chronic infection, including human immunodeficiency virus
(HIV) as determined by anti-HIV antibodies; and hepatitis B virus (HBV) or hepatitis
C virus (HCV) as determined by hepatitis B surface antigen (HBsAg) or anti-HCV
antibodies, respectively.
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.
19. Have advanced liver disease or cirrhosis (Child-Pugh's Class B or greater)
20. Have one or more active autoimmune diseases requiring immunosuppressive therapy
other than low-dose corticosteroids (equivalent to prednisone 10mg daily) or
azathioprine. Patients on stable immunomodulatory medications may be considered by
the investigator
21. Have active (uncontrolled, metastatic) malignancies of another type
22. Have 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
23. Have cognitive, psychologic, or psychosocial impediment that would impair the
ability of the patient o 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
24. 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
25. Have any history or complication of interstitial lung disease (for sites in Japan
only)
26. Have a history of Torsades de Pointes
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
For further information about clinical trials, please contact us at 732-235-7356.