Clinical trial NCT04275518: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Acute Myeloid Leukemia (AML)
Myelodysplastic Syndromes (MDS)
Keywords: APG-115
AML
MDS
Lead sponsor: Ascentage Pharma Group Inc.
Sponsor class: INDUSTRY
Collaborators: name: Suzhou Yasheng Pharmaceutical Co., Ltd.
First posted: 2020-02-19
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Eligibility criteria: Inclusion Criteria:

1. 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
2. Age \>/= 18 years.
3. Adequate organ function
4. Subject must have a projected life expectancy of at least 12 weeks.
5. ECOG performance status of 0-1.
6. 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.
7. Subject has a white blood cell count\< 50 × 109/L. Note: Hydroxyurea is permitted to meet this criterion.

Exclusion Criteria:

1. Subject has acute promyelocytic leukemia.
2. 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)
3. 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.
4. Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV infection.
5. Participants who have received allogeneic HSCT, or autologous HSCT within 12 months.
6. Patients with active, uncontrolled CNS leukemia will not be eligible.
7. Any prior systemic MDM2-p53 inhibitor treatment
8. Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.
9. 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.

Primary outcomes:
measure: Dose Limiting Toxicities (DLT)
timeFrame: From day 1 to the end of cycle 1 (each cycle is 28 days).
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 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).
measure: Overall survival (OS)
timeFrame: Measured up to 6 months after the last subject has received treatment.
Other outcomes:
Locations:
city: Beijing
country: China
facility: The First Hospital of Peking University
state: Beijing
city: Guangzhou
country: China
facility: Guangzhou panyu central hospital
state: Guangdong
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Zhengzhou
country: China
facility: Henan Provincial Oncology Hospital
state: Henan
city: Wuhan
country: China
facility: Union Hospital medical college Huazhong University of Science and Technology
state: Hubei
city: Wuhan
country: China
facility: Zhongnan Hospital of Wuhan University
state: Hubei
city: Changsha
country: China
facility: Xiangya Hospital Central South University
state: Hunan
city: Suzhou
country: China
facility: The First Affilated Hospital of Ganzhou Medical University
state: Jiangsu
city: Suzhou
country: China
facility: The First affiliated hospital of Soochow University
state: Jiangsu
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University
state: Jiangxi
city: Changchun
country: China
facility: First Hospital of Jilin University
state: Jilin
city: Shanghai
country: China
facility: Shanghai Jiao Tong University school of medicine Ruijing Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Sixth people's Hospital
state: Shanghai
city: Tianjin
country: China
facility: Blood Diseases Hospital Chinese Academy of Medical Sciences
state: Tianjin
Study officials:
affiliation: Blood Diseases Hospital Chinese Academy of Medical Sciences
name: Jianxiang Wang, M.D.
role: PRINCIPAL_INVESTIGATOR
References: