A Phase Ib Study of APG-115 Single Agent or in Combination With Azacitidine or Cytarabine in Patients With AML and MDS.

Study Overview
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Brief Summary
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Acute myeloid leukemia is a malignant disorder characterized by the rapid, uncontrolled proliferation of malignant clonal hematopoietic stem cells that accumulate as immature, undifferentiated cells (blasts) in the bone marrow and circulation. APG-115 is a potent and orally active small-molecule MDM2 inhibitor, it binds to MDM2 protein and shows potent cell growth inhibitory activity in vitro with low nanomolar potencies in a subset of human cancer cell lines. APG-115 has demonstrated its strong antitumor activities with either daily or less frequent dosing-schedules in the acute leukemia xenograft models. This is a phase 1b, open-label, three-stages study that will initially evaluate the safety and PK/PD profile of APG-115 as a single agent, followed by a combination of APG-115 + azacytidine or cytarabine in R/R AML or MDS subjects. Patients will continue treatment for maximally 6 cycles or until progression of disease or unacceptable toxicity is observed or administrative discontinuation whichever occurs first. Patients who continue to be benefit after 6 cycles' treatment will receive additional cycles of treatment until progression of disease, unacceptable toxicity is observed or administrative discontinuation. (As long as it is proven safe).

Detailed Description
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Stage 1: This will be a 3+3 dose escalation to determine the DLTs and MTD/RP2D of APG-115 given according to the different dose levels once daily from Days 1 to 7 every 28 days. Stage 2: After stage 1 of APG-115 single agent dose escalation first cycle is completed, stage 2 can be initiated with the combination regimen. This will be a 3+3 dose escalation to determine the MTD/RP2D and DLTs of APG-115 + AZA(arm A)/Cytarabine (arm B)combination. Stage 3: dose expansion of the combination regimes.

Official Title
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A Phase Ib Study to Investigate the Safety, Pharmacokinetics and Pharmacodynamics of APG-115 as a Single Agent or in Combination With Azacitidine or Cytarabine in Patients With Relapse/Refractory AML and Relapsed/Progressed High/Very High Risk MDS

Conditions
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Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes (MDS)

Intervention / Treatment
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* Drug: APG-115
* Drug: Azacitidine
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a diagnosis of histologically confirmed relapsed or refractory (R/R) acute myeloid leukemia by WHO classification or relapsed/progressed high/very high risk MDS (score≥4.5) according to IPSS-R risk stratification Age >/= 18 years. Adequate organ function Subject must have a projected life expectancy of at least 12 weeks. ECOG performance status of 0-1. Patient must have the ability to understand the requirements of the study and signed informed consent. A signed informed consent by the patient or his legally authorized representative is required prior to their enrollment on the protocol. Subject has a white blood cell count< 50 × 109/L. Note: Hydroxyurea is permitted to meet this criterion. Exclusion Criteria: Subject has acute promyelocytic leukemia. Patients must not have had leukemia biotherapy 4 weeks prior to starting investigational drug, or less than 5 half-lives small molecular targeted drug therapy, or 28 days any anti-cancer therapy (whichever is longer) Uncontrolled intercurrent illness including, but not limited to active uncontrolled infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV infection. Participants who have received allogeneic HSCT, or autologous HSCT within 12 months. Patients with active, uncontrolled CNS leukemia will not be eligible. Any prior systemic MDM2-p53 inhibitor treatment Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study. Subject has a history of other malignancies within 2 years prior to study entry, with the exception of: Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; Previous malignancy confined and surgically resected (or treated with other modalities) with curative intention: requires discussion with sponsor.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APG-115/APG-115+Cytarabine in Relapse/Refractory AML<br> | Drug: APG-115<br>* APG-115 orally once daily from Days 1 to 7 every 28 days.<br>Drug: Cytarabine<br>* 1g/m^2 IV QD on Days 3-7 (28-day cycle)<br>|
| Experimental: APG-115/APG-115+Aza in relapsed/progressed high risk MDS<br> | Drug: APG-115<br>* APG-115 orally once daily from Days 1 to 7 every 28 days.<br>Drug: Azacitidine<br>* 75 mg/m^2 SC QD on Days 1- 7 (28-day cycle)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLT) | DLT will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 5) by organ system. DLT will be defined as clinically significant drug-related adverse events during the Cycle one. | From day 1 to the end of cycle 1 (each cycle is 28 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined by CR + CRi+ PR (according to IWG AML（2003）and IWG MDS（2006）criteria) | Evaluated for response by the end of cycle 1 and cycle 2, and then 2 months thereafter till complete 6 cycles treatment or 1 month after last dose (each cycle is 28 days). | 
| Overall survival (OS) | From date of treatment start until the date of death due to any cause or date of termination of the study, whichever came first. Termination of the Study: The last subject has completed at least 6 cycle's treatment or the subject discontinues treatment for any reason. | Measured up to 6 months after the last subject has received treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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APG-115, MDS, AML