A Study Investigating the Safety, Tolerability and Efficacy of ASP7517 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML) and Relapsed/Refractory Higher Risk Myelodysplastic Syndrome (MDS)

The purpose of this study was to evaluate the safety and tolerability and to determine the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) of ASP7517.

This study also evaluated the clinical response of ASP7517 as well as other measures of anticancer activity of ASP7517.

This study consisted of 2 parts: phase 1 dose escalation and phase 2 dose expansion.

Phase 1 Dose Escalation:

Approximately 18 subjects with either relapsed/refractory (R/R) AML or R/R higher risk MDS were enrolled. Participants received 2 single doses of ASP7517 via intravenous infusion. Dosing occured on day 1 of each cycle. Each cycle was defined as 28 days with a total of 2 treatment cycles.

Participants were managed under hospitalization for at least 7 days during the first cycle of the dose escalation phase. In addition, prior to hospital discharge, participant safety was ensured by performing medical tests and procedures listed on day 7 of cycle 1 and tests considered clinically necessary to evaluate the participant's general condition and adverse event (AE) resolution. The participant was also followed on an outpatient basis on planned visits during cycles 1 and 2 after hospital discharge during the dose limiting toxicity (DLT) assessment period to closely monitor any AEs. Participants were hospitalized days 1 to 7 during cycle 2.

Phase 2 Dose Expansion:

Approximately 104 participants per dose level were enrolled. Each dose level enrolled up to 52 R/R AML participants and up to 52 R/R higher risk MDS participants. Both groups of participants were enrolled in parallel and independently. The number of dose levels investigated during phase 2 were based upon the data from phase 1. When escalation and expansion cohorts were both open for enrollment, enrollment into escalation cohorts took priority such that participants who were eligible for both were preferentially enrolled in the escalation cohorts.

Eligibility Criteria:
Inclusion Criteria:

* Subject diagnosed with R/R AML or R/R higher risk MDS is defined as:

  * R/R AML: Morphologically documented primary or secondary AML by the WHO criteria (2016); and refractory to at least 2 cycles of induction chemotherapy/not a candidate for re-induction or relapsed after achieving remission with a prior therapy; and received all standard therapies including targeted therapies (unless the therapy is contraindicated or intolerable) which are known to provide clinical benefit in the opinion of the treating investigator; and received salvage therapy or is not a candidate for salvage therapy.
  * R/R higher risk MDS: Has MDS by the WHO criteria (2016); and either relapsed after achieving remission or refractory to standard therapies, including ≥ 4 cycles of hypomethylating agents (unless the therapy is contraindicated or intolerable); and is classified as higher risk MDS with a score of \> 3.5 by Revised International Prognostic Scoring System (IPSS-R) in MDS.
* Subject has an Eastern Cooperative Oncology Group performance status of ≤ 2.
* Subject must meet the following criteria as indicated on the clinical laboratory tests during screening period:

  * Serum aspartate aminotransferase and alanine aminotransferase ≤ 2.5 × upper limit of normal (ULN).
  * Serum total bilirubin ≤ 1.5 × ULN.
  * Serum creatinine ≤ 1.5 × ULN or an estimated glomerular filtration rate of \> 50 mL/min as calculated by the Modification of Diet in Renal Disease equation.
  * Platelets ≥ 50,000/μL at cycle 1 day 1 (C1D1) in the dose escalation cohorts only.
* Subject has a life expectancy of ≥ 12 weeks at the time of screening.
* Subjects with AML must have peripheral blood absolute blast count of \< 20,000/μL at C1D1. Note: Blast count can be controlled by hydroxyurea during screening period.
* Female subject is not pregnant and at least 1 of the following conditions apply:

  * Not a woman of childbearing potential (WOCBP).
  * WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 180 days after final study treatment administration.
* Female subject must agree not to breastfeed starting at screening and throughout the study period and for 180 days after the final study treatment administration.
* Female subject must not donate ova starting at first dose of investigational product (IP) and throughout the study period and for 180 days after final study treatment administration.
* Male subject with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 180 day after final study treatment administration.
* Male subject must not donate sperm during the treatment period and for 180 days after the final study treatment administration.
* Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 180 days after final study treatment administration.
* Subject agrees not to participate in another interventional study while receiving study treatment in the present study.

Exclusion Criteria:

* Subject was diagnosed with acute promyelocytic leukemia.
* Subject has breakpoint cluster region-Abelson-positive leukemia (BCR-ABL).
* Subject has persistent non-hematological toxicities of ≥ grade 2 (National Cancer Institute's Common Terminology Criteria for Adverse Events \[NCI-CTCAE\], version 5.0), with symptoms and objective findings from prior AML or MDS treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation or surgery).
* Subject has received any of the following therapies:

  * Systemic immunomodulators or immunosuppressive drugs including steroids ≤ 28 days prior to C1D1 (steroids can be used if not intended for treatment of AML or MDS; steroids for AML/MDS related symptoms can be used at low doses \[less than 10 mg/day dexamethasone\]).
  * Cytotoxic agents (except hydroxyurea given for controlling blast cells) ≤ 28 days prior to C1D1.
  * Investigational products for the treatment of AML or MDS within 5 half-lives prior to screening visit.
  * Hematopoietic stem cell transplant (HSCT).
  * Radiation therapy ≤ 28 days prior to C1D1.
* Subject has clinically active nervous system leukemia.
* Subject has active or prior documented autoimmune or inflammatory disorders requiring systemic treatment.
* Subject has ongoing, untreated malignancy with the exception of the following:

  * Subjects with treated non-melanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed.
  * Subjects with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy.
* Subject with left ventricular ejection fraction of \< 45% on echocardiogram or multigated acquisition scan (MUGA) performed within 28 days of screening.
* Subject has laboratory abnormalities, or clinical evidence of disseminated intravascular coagulation, or ongoing history of coagulation disorder manifested by bleeding or clotting.
* Subject has an active uncontrolled infection.
* Subject is known to have human immunodeficiency virus infection.
* Subject has active hepatitis B or C or other active hepatic disorder.
* Subject has any condition which makes the subject unsuitable for study participation.
* Subject has a known or suspected hypersensitivity to bovine-derived protein or has suspected hypersensitivity to any ingredients of ASP7517.
* Subject is eligible for HSCT.