An Open-Label Phase 1/2 Multi-Arm Study of DS-1594b as a Single-Agent and in Combination With Azacitidine and Venetoclax or Mini-HCVD for the Treatment of Patients With Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL)
An Open-Label Phase 1/2 Multi-Arm Study of DS-1594b as a Single-Agent and in Combination With Azacitidine and Venetoclax or Mini-HCVD for the Treatment of Patients With Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL)
This phase I/II trial studies the effect of DS-1594b with or without azacitidine, venetoclax, or mini-HCVD in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia that has come back (recurrent) or not responded to treatment (refractory). Chemotherapy drugs, such as azacitidine, venetoclax, and mini-HCVD, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. DS-1594b may inhibit specific protein bindings that cause blood cancer. Giving DS-1594b, azacitidine, and venetoclax, or mini-HCVD may work better in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia.
OUTLINE: This is a phase I, dose-escalation study of DS-1594b followed by a phase II study.
PHASE I: Patients receive DS-1594b orally (PO) twice daily (BID) on days 1-28 in the absence of disease progression or unacceptable toxicity.
PHASE II: Patients are assigned to 1 of 4 cohorts.
COHORT A: Patients with MLLr receive DS-1594b PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
COHORT B: Patients with NPM1m receive DS-1594b PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
COHORT C: Patients receive DS-1594b PO BID on days 1-28, venetoclax PO QD on days 1-28, and azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
COHORT D: Patients receive DS-1594b PO BID on days 1-28. For cycles 1, 3, 5, 7, patients also receive cyclophosphamide IV over 3 hours on days 1-3, mesna IV over 24 hours on days 1-3, vincristine IV on days 1 and 11, dexamethasone PO or IV on days 1-4 and 11-14, filgrastim SC on days 1-28, methotrexate intrathecally (IT) on day 2 of cycles 1 and 3, and cytarabine IT on day 7 of cycles 1 and 3. For cycles 2, 4, 6, 8, patients also receive methotrexate IV over 24 hours on day 1, cytarabine BID IV over 3 hours on days 2 and 3, leucovorin IV or PO every 6 hours (Q6H) starting 12 hours after completion of methotrexate, filgrastim SC days 1-28, cytarabine IT on day 5-8 of cycles 2 and 4 and methotrexate IT on days 8-11 of cycles 2 and 4. Patients with CD20 expression may also receive rituximab IV on days 1 and 11 of cycles 1 and 3 and days 1 and 8 of cycles 2 and 4. Cycles repeat every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients may then receive DS-1594b PO BID on days 1-28, vincristine IV over 15 minutes on day 7 and prednisone PO BID on days 1-5. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at days 30 and 100.
Inclusion Criteria:
Provision of written (signed) informed consent form (ICF) by the subject or legal guardian prior to the performance of any study-specific procedures, according to International Council on Harmonisation (ICH) and local regulatory requirements. Subject must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible toxicities) and must sign and date an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent form (ICF)(including Health Insurance Portability and Accountability Act authorization [HIPAA], if applicable) before performance of any study-specific procedures or examinations
Subjects must be willing and able to comply with the protocol
Subjects with AML or ALL, diagnosed according to the 2016 criteria by the World Health Organization (WHO) who are refractory or relapsed (any salvage) with no available therapies or not candidates for available therapies. For subjects with prior MDS or chronic myelomonocytic leukemia (CMML) or MPN who transformed to AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy for AML except for MDS or CMML treated with HMAs. Subjects with MDS or CMML treated with HMA therapies who progress to AML and have no available therapies or are not candidates for available therapies, will be eligible at the time of progression to AML. In Phase 1: all R/R AML or R/R ALL subjects irrespective of mutations will be eligible. In Phase 2 Cohort A only R/R AML with MLLr will be eligible. In Phase 2 Cohort B only R/R AML with NPM1m will be eligible. In Phase 2 Cohorts C and D: Only R/R AML or R/R ALL subjects with an MLLr or NPM1m will be eligible
Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is permitted
Age 18 years or older
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
Total bilirubin =< 1.5 times upper limit of normal (x ULN)
Aspartate aminotransferase or alanine aminotransferase =< 2.5 x ULN (aspartate aminotransferase or alanine aminotransferase =< 5.0 x ULN if deemed related to leukemia by the treating physician)
Creatinine clearance >= 50 mL/min as calculated using the modified Cockcroft-Gault equation
Serum electrolytes within the institution's normal limits: potassium, calcium (total calcium, calcium corrected for serum albumin in case of hypoalbuminemia or ionized calcium) and magnesium. If outside of the institution's normal range, subject will be eligible when electrolytes are corrected
In the absence of rapidly progressive disease, the interval from prior treatment to the time of initiation of protocol therapy will be at least 14 days for prior anti-leukemic therapy with the exception of hydroxyurea as noted below OR at least 5 half-lives for cytotoxic/noncytotoxic agents, whichever is shorter. The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochure's, or drug-administration manuals) and will be documented in the protocol eligibility document. Since the effect of therapy may be delayed, use of hydroxyurea for subjects with rapidly proliferative disease is allowed before the start of study therapy and on study and hydroxyurea will not require a washout
Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted. Subjects with a known history of CNS disease or leukemic brain metastasis must have been treated locally, have at least 3 consecutive lumbar punctures (LPs) with no evidence of CNS leukemia, and must be clinically stable for at least 4 weeks prior to enrollment and have no ongoing neurological symptoms that in the opinion of the treating physician are related to the CNS disease (sequelae that are a consequence of the treatment of the CNS disease are acceptable)
Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment
Women of childbearing potential must agree to use an adequate method of contraception during the study and until 4 months after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment. Adequate methods of contraception include:
Total abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
Combination of any of the two following (a+b or a+c or b+c)
In case of use of oral contraception, women should have been stable on the same pill before taking study treatment.
Note: Oral contraceptives are allowed but should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential
Exclusion Criteria:
Subjects with a known allergy, hypersensitivity, or contraindication to the protocol therapies or any of their components to be used in the arm the subject is to be enrolled on
Uncontrolled or significant cardiovascular disease, including any of the following:
Persisting toxicity related to prior therapy of grade > 1 NCI-CTCAE v 5.0; however, alopecia and sensory neuropathy grade 2 or lower is acceptable
Underwent HSCT within 90 days of the first dose of protocol therapy, or subjects with clinically significant (grade 2 or greater) graft-versus-host disease (GVHD) (the use of topical steroids for ongoing cutaneous GVHD is permitted)
Subjects with symptomatic CNS leukemia or subjects with poorly controlled CNS leukemia
Active and uncontrolled disease (active infection requiring systemic therapy, fever likely secondary to infection within prior 48 hours, uncontrolled hypertension despite adequate medical therapy as judged by the treating physician)
Active (uncontrolled, metastatic) other malignancies
Major surgery within 28 days prior to the first dose of protocol therapy
Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (test at screening only if required by local regulations)
Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with active Hepatitis B or C infection at screening (positive HBV surface antigen or HCV ribonucleic acid [RNA] if anti-HCV antibody screening test positive)
Vaccination within 4 weeks of the first dose of study drug and while on trials is prohibited except for administration of inactivated vaccines
Subjects who are currently receiving treatment with medication that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of DS-1594b treatment:
Subjects who consume grapefruit products, Seville oranges, or star fruit within 3 days prior to the first DS-1594b administration and until the last day of DS-1594b is completed
SUB-STUDIES: Subjects who are currently receiving moderate inhibitors or inducers of CYP3A who cannot discontinue at least one week prior to the start of DS-1594b treatment till the end of sub-study period
SUB-STUDIES: Subjects who are currently receiving proton pump inhibitors who cannot discontinue at least 2 days prior to the start of DS-1594b treatment till the end of sub-study period
Other severe acute or chronic medical conditions that is active and not well controlled including renal, skeletal muscle, adrenal insufficiency, colitis, inflammatory bowel disease, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study
Subjects unwilling or unable to comply with the protocol, including:
Acute promyelocytic leukemia (APL)
Uncontrolled or poorly controlled adrenal or pituitary disease (including adrenal insufficiency, Addison's disease, Cushing's disease)