Clinical Trials /

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

NCT04275518

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: APG115AC101
  • NCT ID: NCT04275518

Conditions

  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndromes (MDS)

Interventions

DrugSynonymsArms
APG-115APG-115/APG-115+Aza in relapsed/progressed high risk MDS
AzacitidineAPG-115/APG-115+Aza in relapsed/progressed high risk MDS
CytarabineAPG-115/APG-115+Cytarabine in Relapse/Refractory AML

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
APG-115/APG-115+Cytarabine in Relapse/Refractory AMLExperimentalStage 1: APG-115 orally once daily from Days 1 to 7 every 28 days, starting from 100 mg and will be increased in subsequent cohorts to 150 mg , 200 mg , 250 mg. Stage 2: APG-115 orally once daily from Days 1 to 7 every 28 days, starting from 100 mg and will be increased in subsequent cohorts to 150 mg , 200 mg; Cytarabine V QD on Days 3-7 (28-day cycle). Stage 3: APG-115 MTD/RP2D combined with Cytarabine
  • APG-115
  • Cytarabine
APG-115/APG-115+Aza in relapsed/progressed high risk MDSExperimentalStage 1: APG-115 orally once daily from Days 1 to 7 every 28 days, starting from 100 mg and will be increased in subsequent cohorts to 150 mg , 200 mg , 250 mg. Stage 2: APG-115 orally once daily from Days 1 to 7 every 28 days, starting from 100 mg and will be increased in subsequent cohorts to 150 mg , 200 mg; Azacitidine 75 mg/m^2 SC QD on Days 1- 7 (28-day cycle). Stage 3: APG-115 MTD/RP2D combined with Azacitidine.
  • APG-115
  • Azacitidine

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 12 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 5 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicities (DLT)
Time Frame:From day 1 to the end of cycle 1 (each cycle is 28 days).
Safety Issue:
Description: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

Measure: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).
Safety Issue:
Description:ORR is defined by CR + CRi+ PR (according to IWG AML(2003)and IWG MDS(2006)criteria)
Measure:Overall survival (OS)
Time Frame:Measured up to 6 months after the last subject has received treatment.
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Ascentage Pharma Group Inc.

Trial Keywords

  • APG-115
  • AML
  • MDS

Last Updated

February 23, 2020