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)

Study Overview
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Brief Summary
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The purpose of this study is 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 will also evaluate the clinical response of ASP7517 as well as other measures of anticancer activity of ASP7517.

Detailed Description
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This study consists 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 will be enrolled. Participants will receive 2 single doses of ASP7517 via intravenous infusion. Dosing will occur on day 1 of each cycle. Each cycle is defined as 28 days with a total of 2 treatment cycles. Participants must be 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 must be 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 should also be 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 may be hospitalized days 1 to 7 during cycle 2. Phase 2 Dose Expansion: Approximately 104 participants per dose level will be enrolled. Each dose level may enroll up to 52 R/R AML participants and up to 52 R/R higher risk MDS participants. Both groups of participants will enroll in parallel and independently. The number of dose levels investigated during phase 2 will be based upon the data from phase 1. When escalation and expansion cohorts are both open for enrollment, enrollment into escalation cohorts takes priority such that participants who are eligible for both will be preferentially enrolled in the escalation cohorts.

Official Title
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A Phase 1/2 Open-label 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)

Conditions
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Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: ASP7517


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 ASP7517 Dose Escalation<br>Two single doses of ASP7517 will be administered intravenously at up to 3 dose levels and will be based on the assessment of safety variables, including the occurrence of dose limiting toxicities (DLTs). | Biological: ASP7517<br>* Intravenous (IV)<br>|
| Experimental: Phase 2 ASP7517 Dose Expansion<br>Up to six single doses of ASP7517 will be administered intravenously at the dose levels determined from the Dose Escalation phase. | Biological: ASP7517<br>* Intravenous (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) | A DLT is defined as any of the following events that occur within 28 days starting with the first dose on cycle 1 day 1 (C1D1) and that is considered to be related to investigation product (IP). The severity of AEs will be assessed according to National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. DLT is defined as follows: non-hematologic AEs that are ≥ grade 3; confirmed Hy's law case; new onset of grade 4 thrombocytopenia (with minimum of 2 grade worsening from baseline) within 24 hours of dosing; prolonged myelosuppression, defined as absolute neutrophil count (ANC) < 500/μL for more than 28 days off therapy and in the absence of evidence of active leukemia or MDS in the marrow or blood, will be considered as a DLT. | 28 days | 
| Number of participants with adverse events (AEs) | An AE is any untoward medical occurrence in a participant administered a study drug, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product whether or not considered related to the medicinal product. AEs will be graded using NCI-CTCAE guidelines, version 5.0. | Up to 2 years | 
| Number of participants with serious adverse events (SAEs) | An AE is considered serious if the event: results in death; is life-threatening (An AE is considered life-threatening if its occurrence places the subject at immediate risk of death; it does not include an AE that, had it occurred in a more severe form, might have caused death.); results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly, or birth defect; requires inpatient hospitalization (except for planned procedures as allowed per study) or leads to prolongation of hospitalization (except if prolongation of planned hospitalization is not caused by an AE); other medically important events. | Up to 2 years | 
| Number of participants with laboratory value abnormalities and/or AEs | Number of participants with potentially clinically significant laboratory values. | Up to 2 years | 
| Number of participants with 12-lead electrocardiogram (ECG) abnormalities and/or AEs | Routine 12-lead ECGs will be taken after the subject has been resting in the supine position for at least 5 minutes. Routine 12-lead ECGs will be taken in triplicate during the Screening and Treatment Periods, and as a single assessment (in triplicate, if deemed necessary) during the Observation Periods 1 and 2. | Up to 2 years | 
| Number of participants with vital sign abnormalities and/or AEs | Number of participants with potentially clinically significant vital sign values. | Up to 2 years | 
| Number of participants with physical exam abnormalities and/or AEs | Number of participants with potentially clinically significant physical exam values. | Up to 2 years | 
| Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status | The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 5 (dead). Negative change scores indicate an improvement. Positive scores indicate a decline in performance. | Up to 2 years | 
| Composite complete remission (CRc) rate for participants with R/R AML (phase 2) | CRc rate is defined for AML subjects as the number of participants who achieve the best response of CRc (complete remission [CR], complete remission with incomplete platelet recovery [CRp] or complete remission with incomplete hematological recovery [CRi]) divided by the number of participants in the analysis population. | Up to 2 years | 
| Complete remission + bone marrow complete remission + partial remission (CR + BM CR + PR) rate for participants with R/R higher risk MDS (phase 2) | CR + BM CR + PR rate is defined for MDS participants as the number of participants who achieve the best response of CR + BM CR + PR divided by the number of subjects in the analysis population. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of remission for participants with AML | Duration of remission for participants with AML includes duration of CRc, duration of CR/complete remission with partial hematologic recovery (CRh), duration of CRh, duration of CR, and duration of response (i.e., CRc + PR). | Up to 2 years | 
| Duration of remission for participants with MDS | Duration of remission for MDS includes duration of CR and duration of response (i.e., CR + PR). | Up to 2 years | 
| Number of participants with event-free survival (EFS) | EFS is defined as the time from the date of first dose until the date of documented relapse, treatment failure or death from any cause within 30 days after the last dose of study drug (whichever occurs first earliest of [relapse date, treatment failure date, death date] - first dose date + 1). | Up to 2 years | 
| Duration of overall survival (OS) | OS is defined as the time from the date of first dose until the date of death from any cause (death date - first dose date + 1). | Up to 2 years | 
| CR rates for participants with R/R AML | CR rate is defined as the number of participants who achieve CR at any of the postbaseline visits divided by the number of participants in the analysis population. | Up to 2 years | 
| Best response (CRc + PR) rates for participants with R/R AML | Best response rate is defined as the number of subjects who achieve CRc or PR at any of the postbaseline visits divided by the number of subjects in the analysis population. | Up to 2 years | 
| CRh rates for participants with R/R AML | CRh rate is defined as the number of participants who achieve CRh at any of the postbaseline visits divided by the number of participants in the analysis population. | Up to 2 years | 
| CR rates for participants with R/R higher risk MDS | CR rate is defined as the number of participants who achieve CR at any of the postbaseline visits divided by the number of participants in the analysis population. | Up to 2 years | 
| Hematologic improvement (HI) rates for participants with R/R higher risk MDS | HI requires 1 measurement of erythroid or platelets or neutrophils maintained at a specified level for at least 8 weeks without ongoing cytotoxic therapy | Up to 2 years | 
| Objective response (CR + BM CR + PR + HI) rates (ORR) for participants with R/R higher risk MDS | Objective response (CR + BM CR + PR + HI) rates (ORR) for participants with R/R higher risk MDS [Time Frame: Up to 2 years] ORR is defined as the number of participants who achieve CR or BM CR or PR or HI at any of the postbaseline visits divided by the number of participants in the analysis population. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASP7517, Safety, Efficacy, Tolerability