A Phase Ib Study of APG-115 Single Agent or in Combination With Azacitidine or Cytarabine in Patients With AML and MDS.
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: APG-115/APG-115+Cytarabine in Relapse/Refractory AML
|
Drug: APG-115
APG-115 orally once daily from Days 1 to 7 every 28 days.
Drug: Cytarabine
1g/m^2 IV QD on Days 3-7 (28-day cycle)
|
| Experimental: APG-115/APG-115+Aza in relapsed/progressed high risk MDS
|
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)
|
Outcome Measures
Primary Outcome Measures
- Dose Limiting Toxicities (DLT) [From day 1 to the end of cycle 1 (each cycle is 28 days).]
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.
Secondary Outcome Measures
- Overall Response Rate (ORR) [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).]
ORR is defined by CR + CRi+ PR (according to IWG AML（2003）and IWG MDS（2006）criteria)
- Overall survival (OS) [Measured up to 6 months after the last subject has received treatment.]
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.
Eligibility Criteria
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
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Age >/= 18 years.
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Adequate organ function
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Subject must have a projected life expectancy of at least 12 weeks.
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ECOG performance status of 0-1.
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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.
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Subject has a white blood cell count< 50 × 109/L. Note: Hydroxyurea is permitted to meet this criterion.
Exclusion Criteria:
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Subject has acute promyelocytic leukemia.
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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)
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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.
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Active infection requiring systemic antibiotic/antifungal medication, known clinically active hepatitis B or C, or HIV infection.
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Participants who have received allogeneic HSCT, or autologous HSCT within 12 months.
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Patients with active, uncontrolled CNS leukemia will not be eligible.
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Any prior systemic MDM2-p53 inhibitor treatment
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Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study.
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Subject has a history of other malignancies within 2 years prior to study entry, with the exception of:
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Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;
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Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
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Previous malignancy confined and surgically resected (or treated with other modalities) with curative intention: requires discussion with sponsor.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The First Hospital of Peking University | Beijing | Beijing | China | 100034 |
| 2 | Guangzhou panyu central hospital | Guangzhou | Guangdong | China | |
| 3 | Nanfang Hospital of Southern Medical University | Guangzhou | Guangdong | China | |
| 4 | Henan Provincial Oncology Hospital | Zhengzhou | Henan | China | |
| 5 | Union Hospital medical college Huazhong University of Science and Technology | Wuhan | Hubei | China | |
| 6 | Zhongnan Hospital of Wuhan University | Wuhan | Hubei | China | |
| 7 | Xiangya Hospital Central South University | Changsha | Hunan | China | |
| 8 | The First Affilated Hospital of Ganzhou Medical University | Suzhou | Jiangsu | China | 215636 |
| 9 | The First affiliated hospital of Soochow University | Suzhou | Jiangsu | China | |
| 10 | The First Affiliated Hospital of Nanchang University | Nanchang | Jiangxi | China | 330006 |
| 11 | First Hospital of Jilin University | Changchun | Jilin | China | |
| 12 | Shanghai Jiao Tong University school of medicine Ruijing Hospital | Shanghai | Shanghai | China | |
| 13 | Shanghai Sixth people's Hospital | Shanghai | Shanghai | China | |
| 14 | Blood Diseases Hospital Chinese Academy of Medical Sciences | Tianjin | Tianjin | China | 300020 |
Sponsors and Collaborators
- Ascentage Pharma Group Inc.
- Suzhou Yasheng Pharmaceutical Co., Ltd.
Investigators
- Principal Investigator: Jianxiang Wang, M.D., Blood Diseases Hospital Chinese Academy of Medical Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- APG115AC101