A Study to Investigate APL-4098 Alone and/or in Combination With Azacitidine in R/R AML and High-Risk MDS

A Phase 1/2 Study to Assess the Safety and Antitumor Activity of APL-4098 Alone and/or in Combination With Azacitidine in Adults With Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome/AML (MDS/AML) or Myelodysplastic Syndrome With Excess Blasts (MDS-EB)

This is an open-label, Phase 1/2 study to determine the safety, tolerability, and efficacy of APL-4098 alone and/or in combination with azacitidine for the treatment of relapsed or refractory (R/R) acute myeloid leukemia (AML), myelodysplastic syndrome (MDS)/AML and MDS-excess blasts (EB). Participants with the MDS-EB subtype will be eligible for the Phase 1 part of the study only.

Study Overview

• Status: Not yet recruiting
• Conditions: Myelodysplastic Syndrome With Excess Blasts; Acute Myeloid Leukemia, in Relapse; Acute Myeloid Leukemia Refractory; Myelodysplastic Syndrome Acute Myeloid Leukemia
• Intervention / Treatment: Drug: APL-4098; Drug: Azacitidine and APL-4098

• Study Type: Interventional
• Enrollment (Estimated): 112
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Apollo Therapeutics; Phone Number: 781-479-2267; Email: AP30@apollotx.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 years or older
• Confirmed diagnosis of relapsed refractory acute myeloid leukemia (R/R AML), myelodysplastic syndrome (MDS)/ AML, or MDS-excess blasts (MDS-EB) with the following characteristics: - R/R AML (primary or secondary, including treatment-related), participant is intolerant to, or considered ineligible for available therapies known to provide clinical benefit.
• WBC count ≤ 25,000/microliter
• ECOG Performance Status of ≤ 2
• Weight ≥ 40kg
• Female participants of childbearing potential must have negative serum pregnancy test at screening; must not plan to become pregnant or have ova harvested or breastfeed while on study; must we willing to use specific contraception or avoid intercourse
• Male participants must be willing to use specific contraception and not plan to impregnant a female partner or donate sperm while on study
• Participant must be willing and able to provide written informed consent and to comply with the requirements of the trial

Exclusion Criteria:

• Certain prior therapies such as: received an allogeneic stem cell transplant within 6 months of screening, received an autologous stem cell transplant within 3 months of screening, received any anti-cancer treatments within 2 weeks of Cycle 1 Day 1, prior radiation therapy within 4 weeks of screening
• Certain medical conditions such as: other malignancies, myocardial infarction within 6 months of screening, symptomatic congestive heart failure, uncontrolled active infection, history of arterial thrombosis within 6 months of screening
• Diagnostic assessments: Left ventricular ejection fraction < 45%, Fridericia's corrected QT interval > 470msec, Aspartate aminotransferase and/or alanine aminotransferase > 3 x upper limit of normal (ULN), total bilirubin > 1.5 x ULN, calculated or measured creatinine clearance < 45 mL/minute (multiply by 0.85 if female)
• Infectious disease: HIV positive, active hepatitis B and/or C

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation Phase: APL-4098 monotherapy; Dose escalation with different dosing levels of APL-4098.	Drug: APL-4098; APL-4098 is administered orally in 28-day cycles
Experimental: Dose Escalation Phase: APL-4098 and azacitidine; Dose escalation with different dosing levels of APL-4098 in combination with azacitidine (75 mg/m2).	Drug: Azacitidine and APL-4098; Azacitidine is administered at the standard dose of 75mg/m2 on Day 1 - Day 7 of each 28-day cycle; APL-4098 is administered orally.
Experimental: Phase 2 Dose Expansion: APL-4098 monotherapy	Drug: APL-4098; APL-4098 is administered orally in 28-day cycles
Experimental: Phase 2 Dose Expansion: APL-4098 and azacitidine	Drug: Azacitidine and APL-4098; Azacitidine is administered at the standard dose of 75mg/m2 on Day 1 - Day 7 of each 28-day cycle; APL-4098 is administered orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment Emergent Adverse Events [Safety] (Phase 1)	Evaluation of safety parameters including treatment emergent adverse events as detected by hematology, chemistry, coagulation safety labs, physical exams, vital signs, Electrocardiogram results	Through study completion, approximately one year
Incidence of Dose Limiting Toxicities [Tolerability] (Phase 1)	Evaluation of tolerability parameters including dose limiting toxicities as detected by hematology, chemistry, coagulation safety labs, physical exams, vital signs, and Electrocardiogram results	Cycle 1 Day 1 to Cycle 2 Day 1 (a cycle is 28 days)
Estimate the Maximum Tolerated Dose (MTD) of APL-4098 alone and/or in combination with azacitidine (Phase 1)		Cycle 1 Day 1 to Cycle 2 Day 1 (a cycle is 28 days)
Determine Recommended Phase 2 Dose (RP2D) levels of APL-4098 alone and/or in combination with azacitidine (Phase 1)		Approximately one year
Assess the Pharmacokinetics of APL-4098 alone and/or in combination with azacitidine (Phase 1)	Evaluate PK parameters: Maximum plasma concentration (Cmax)	On Days 1, 2, 4, 8, and 15 of Cycle 1, and on Day 1 of Cycle 2 (each cycle is 28 days)
Assess the Pharmacokinetics of APL-4098 alone and/or in combination with azacitidine (Phase 1)	Evaluate PK parameters: area under the curve (AUC)	On Days 1, 2, 4, 8, and 15 of Cycle 1, and on Day 1 of Cycle 2 (each cycle is 28 days)
Assess the Pharmacokinetics of APL-4098 alone and/or in combination with azacitidine (Phase 1)	Evaluate PK parameters: Time to peak concentration (Tmax)	On Days 1, 2, 4, 8, and 15 of Cycle 1, and on Day 1 of Cycle 2 (each cycle is 28 days)
Assess efficacy of APL-4098 alone and/or in combination with azacitidine (Phase 2)	Response is assessed per European LeukemiaNet 2022 criteria	Response is assessed at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 7 Day 1 (each cycle is 28 days long), then every three cycles thereafter (assessed for up to 2 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess response to disease with APL-4098 alone and/or in combination with azacitidine (Phase 1)	R/R AML and MDS/AML participants: response is assessed per European LeukemiaNet (ELN) 2022 criteria MDS-EB participants: response is assessed per revised International Working Group 2023 response criteria	Response is assessed at Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 7 Day 1 (each cycle is 28 days long), then every three cycles thereafter (assessed for up to 2 years)
Duration of response with APL-4098 alone and/or in combination with azacitidine [Further efficacy] (Phase 2)		From Cycle 1 Day 1 (a cycle is 28 days long) through end of study (approximately 2 years)
Time to response with APL-4098 alone and/or in combination with azacitidine [Further efficacy] (Phase 2)		From Cycle 1 Day 1 (a cycle is 28 days long) through end of study (approximately 2 years)
Event Free Survival with APL-4098 alone and/or in combination with azacitidine [Further efficacy] (Phase 2)		From Cycle 1 Day 1 (a cycle is 28 days long) through end of study (approximately 2 years)
Overall Survival with APL-4098 alone and/or in combination with azacitidine [Further efficacy] (Phase 2)		From Cycle 1 Day 1 (a cycle is 28 days long) through end of study (approximately 2 years)
Incidence of Treatment Emergent Adverse Events [Further Safety] (Phase 2)	Evaluation of safety parameters including treatment emergent adverse events as detected by hematology, chemistry, coagulation safety labs, physical exams, vital signs, Electrocardiogram results	Through study completion (approximately 2 years)
Incidence of Adverse Events leading to discontinuation of APL-4098 [Further Tolerability] (Phase 2)		Through study completion (approximately 2 years)
Further assess the PK of APL-4098 alone and/or in combination with azacitidine (Phase 2)	Evaluate PK parameters: Maximum plasma concentration (Cmax)	At Cycle 1 Day 1 and at Cycle 2 Day 1 (each cycle is 28 days)
Further assess the PK of APL-4098 alone and/or in combination with azacitidine (Phase 2)	Evaluate PK parameters: area under the curve (AUC)	At Cycle 1 Day 1 and at Cycle 2 Day 1 (each cycle is 28 days)
Further assess the PK of APL-4098 alone and/or in combination with azacitidine (Phase 2)	Evaluate PK parameters: Time to peak concentration (Tmax)	At Cycle 1 Day 1 and at Cycle 2 Day 1 (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: Apollo Therapeutics Ltd
• Investigators: Study Chair: Daniela Pignataro, MD, Apollo Therapeutics

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: March 11, 2024
• First Submitted That Met QC Criteria: April 15, 2024
• First Posted (Actual): April 18, 2024

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Precancerous Conditions; Anemia, Refractory; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Anemia, Refractory, with Excess of Blasts; GATA2 Deficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: AP30CP01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No