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

Official title

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

Overview

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

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.

Interventions

• Drug APG-115
  APG-115 orally once daily from Days 1 to 7 every 28 days.
• Drug Azacitidine
  75 mg/m\^2 SC QD on Days 1- 7 (28-day cycle)
• Drug Cytarabine
  1g/m\^2 IV QD on Days 3-7 (28-day cycle)

Primary outcome measures

• Dose Limiting Toxicities (DLT) [Time frame: From day 1 to the end of cycle 1 (each cycle is 28 days).]

Secondary outcome measures (2)

• Overall Response Rate (ORR) [Time frame: 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) [Time frame: Measured up to 6 months after the last subject has received treatment.]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 14 centers

• The First Hospital of Peking University — Beijing
• Guangzhou panyu central hospital — Guangzhou
• Nanfang Hospital of Southern Medical University — Guangzhou
• Henan Provincial Oncology Hospital — Zhengzhou
• Union Hospital medical college Huazhong University of Science and Technology — Wuhan
• Zhongnan Hospital of Wuhan University — Wuhan
• Xiangya Hospital Central South University — Changsha
• The First Affilated Hospital of Ganzhou Medical University — Suzhou
• … and 6 more centers

Identifiers

NCT: NCT04275518 · APG115AC101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗