Clinical trial NCT04079296: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia (AML)
Myelodysplastic Syndrome
Keywords: ASP7517
Safety
Efficacy
Tolerability
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2019-09-06
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Day 1 up to 28 days
measure: Number of Participants With Treatment Emergent Adverse Events (TEAE) & Serious TEAE
timeFrame: From first dose up to 43 months
measure: Phase 2: Composite Complete Remission (CRc) Rate for Participants With R/R AML
timeFrame: From first dose up to 43 months
measure: Phase 2: Complete Remission + Bone Marrow Complete Remission + Partial Remission (CR + BM CR + PR) Rate for Participants With R/R Higher Risk MDS
timeFrame: From first dose up to 43 months
measure: Number of Participants With ECOG Performance Status at Cycle 1(C1) Day2(D2)
timeFrame: C1D2
measure: Number of Participants With ECOG Performance Status at C1D4
timeFrame: C1D4
measure: Number of Participants With ECOG Performance Status at C1D8
timeFrame: C1D8
measure: Number of Participants With ECOG Performance Status at C1D11
timeFrame: C1D11
measure: Number of Participants With ECOG Performance Status at C1D15
timeFrame: C1D15
measure: Number of Participants With ECOG Performance Status at C1D18
timeFrame: C1D18
measure: Number of Participants With ECOG Performance Status at C1D22
timeFrame: C1D22
measure: Number of Participants With ECOG Performance Status at C1D25
timeFrame: C1D25
measure: Number of Participants With ECOG Performance Status at C2D1
timeFrame: C2D1
measure: Number of Participants With ECOG Performance Status at C2D2
timeFrame: C2D2
measure: Number of Participants With ECOG Performance Status at C2D4
timeFrame: C2D4
measure: Number of Participants With ECOG Performance Status at C2D8
timeFrame: C2D8
measure: Number of Participants With ECOG Performance Status at C2D15
timeFrame: C2D15
measure: Number of Participants With ECOG Performance Status at C2D22
timeFrame: C2D22
measure: Number of Participants With ECOG Performance Status at C3D1
timeFrame: C3D1
measure: Number of Participants With ECOG Performance Status at C3D15
timeFrame: C3D15
measure: Number of Participants With ECOG Performance Status at C4D1
timeFrame: C4D1
measure: Number of Participants With ECOG Performance Status at C4D15
timeFrame: C4D15
measure: Number of Participants With ECOG Performance Status at C5D1
timeFrame: C5D1
measure: Number of Participants With ECOG Performance Status at C5D15
timeFrame: C5D15
measure: Number of Participants With ECOG Performance Status at C6D1
timeFrame: C6D1
measure: Number of Participants With ECOG Performance Status at C6D15
timeFrame: C6D15
measure: Number of Participants With ECOG Performance Status at End of Treatment (EOT) (Dose Escalation Phase)
timeFrame: EOT (up to 63 Days)
measure: Number of Participants With ECOG Performance Status at EOT (Dose Expansion Phase)
timeFrame: EOT (up to 175 days)
measure: Number of Participants With ECOG Performance Status at Observation Period (OP) (Week 2)
timeFrame: OP (week 2)
measure: Number of Participants With ECOG Performance Status at OP (Week 4)
timeFrame: OP (week 4)
measure: Number of Participants With ECOG Performance Status at OP (Week 6)
timeFrame: OP (week 6)
measure: Number of Participants With ECOG Performance Status at OP (Week 8)
timeFrame: OP (week 8)
measure: Number of Participants With ECOG Performance Status at OP (Week 10)
timeFrame: OP (week 10)
measure: Number of Participants With ECOG Performance Status at OP (Week 12)
timeFrame: OP (week 12)
Secondary outcomes:
measure: Duration of Remission (DR) for Participants With R/R AML
timeFrame: From first response up to 43 months
measure: Duration of Remission (DR) for Participants With R/R Higher Risk MDS
timeFrame: From first response up to 43 months
measure: Event Free Survival (EFS)
timeFrame: From first dose up to 43 months
measure: Overall Survival (OS)
timeFrame: From first dose up to 43 months
measure: CR for Participants With R/R AML
timeFrame: From first dose up to 43 months
measure: Best Response (CRc + PR) Rates for Participants With R/R AML
timeFrame: From first dose up to 43 months
measure: CRh for Participants With R/R AML
timeFrame: From first dose up to 43 months
measure: CR for Participants With R/R Higher Risk MDS
timeFrame: From first dose up to 43 months
measure: Hematologic Improvement (HI) for Participants With R/R Higher Risk MDS
timeFrame: From first dose up to 43 months
measure: Objective Response (OR) (CR + BM CR + PR + HI) Rates (ORR) for Participants With R/R Higher Risk MDS
timeFrame: From first dose up to 43 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Pembroke Pines
country: United States
facility: Memorial Healthcare System-West
state: Florida
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Nagoya
country: Japan
facility: Site JP81005
state: Aichi
city: Matsuyama
country: Japan
facility: Site JP81016
state: Ehime
city: Yoshida-gun
country: Japan
facility: Site JP81009
state: Fukui
city: Maebashi
country: Japan
facility: Site JP81004
state: Gunma
city: Kobe
country: Japan
facility: Site JP81007
state: Hyogo
city: Isehara
country: Japan
facility: Site JP81013
state: Kanagawa
city: Sendai
country: Japan
facility: Site JP81017
state: Miyagi
city: Shinagawa
country: Japan
facility: Site JP81001
state: Tokyo
city: Fukuoka
country: Japan
facility: Site JP81002
city: Gifu
country: Japan
facility: Site JP81010
city: Okayama
country: Japan
facility: Site JP81008
city: Osaka
country: Japan
facility: Site JP81011
city: Osaka
country: Japan
facility: Site JP81012
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: