Clinical Trials /

APG-1387 in Patients With Advanced Solid Tumors or Hematologic Malignancies

NCT03386526

Description:

APG-1387 is a potent, bivalent small-molecule IAP antagonist. APG-1387 has shown strong dose- and schedule-dependent antitumor activities in multiple human cancer xenograft models, APG-1387 also demonstrates its synergistic effect in combination with immune checkpoint inhibitor anti-PD-1 antibody, and such a combinatory effect was further enhanced by chemotherapeutic agent. A total of 35 patients with advanced solid tumors or lymphomas have been treated with APG-1387 in two Phase I dose-escalation studies in Australia and in China Ten dose levels have been tested ranging from 0.3 mg to 45 mg in these 2 studies. Based on the preliminary results, APG-1387 is well-tolerated at the dose levels evaluated to date. APG-1387 is intended for the treatment of patients with advanced solid tumors and hematologic malignancies. After establishing the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and/or recommended phase 2 dose (RP2D), several Ib /II studies will be implemented accordingly to further access the antitumor effects of APG-1387 in combination with either pembrolizumab or the chemotherapeutic agents.

Related Conditions:
  • Hematopoietic and Lymphoid Malignancy
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: APG-1387 in Patients With Advanced Solid Tumors or Hematologic Malignancies
  • Official Title: A Phase I Study of the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of APG-1387 as A Single Agent or in Combination With Systemic Anti-Cancer Agents in Patients With Advanced Solid Tumors or Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: APG-1387-US-001
  • NCT ID: NCT03386526

Conditions

  • Advanced Solid Tumors or Hematologic Malignancies

Interventions

DrugSynonymsArms
APG-1387 for InjectionAPG-1387 for Injection

Purpose

APG-1387 is a potent, bivalent small-molecule IAP antagonist. APG-1387 has shown strong dose- and schedule-dependent antitumor activities in multiple human cancer xenograft models, APG-1387 also demonstrates its synergistic effect in combination with immune checkpoint inhibitor anti-PD-1 antibody, and such a combinatory effect was further enhanced by chemotherapeutic agent. A total of 35 patients with advanced solid tumors or lymphomas have been treated with APG-1387 in two Phase I dose-escalation studies in Australia and in China Ten dose levels have been tested ranging from 0.3 mg to 45 mg in these 2 studies. Based on the preliminary results, APG-1387 is well-tolerated at the dose levels evaluated to date. APG-1387 is intended for the treatment of patients with advanced solid tumors and hematologic malignancies. After establishing the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and/or recommended phase 2 dose (RP2D), several Ib /II studies will be implemented accordingly to further access the antitumor effects of APG-1387 in combination with either pembrolizumab or the chemotherapeutic agents.

Trial Arms

NameTypeDescriptionInterventions
APG-1387 for InjectionExperimentalAPG-1387 will be explored sequentially using a standard 3+3 escalation scheme at the dose escalation phase and up to 20 patient per group at the dose expansion phase.
  • APG-1387 for Injection

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically confirmed solid tumor or hematological malignancies

          2. Life expectancy ≥ 3 months

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2

          4. QTc interval ≤ 450 ms in males, and ≤ 470 ms in females

          5. Adequate hematologic function

          6. International normalized Ratio (INR), Prothrombin Time (PT) or Activated Partial
             Thromboplastin time (aPTT) ≤1.5 X ULN

          7. Adequate renal and liver function

          8. Willingness to use contraception

          9. Ability to understand and willingness to sign a written informed consent form

         10. Willingness and ability to comply with study procedures and follow-up examination

         11. Have provided tissue for biomarker analysis from a newly or recently-obtained biopsy
             of a tumor lesion not previously irradiated

        Exclusion Criteria:

        Patients who meet any of the following exclusion criteria are not to be enrolled in this
        study.

          1. Received chemotherapy within 21 days (42 days for nitrosoureas or mitomycin C) prior
             to entering the study

          2. Received hormonal, biologic (< 2 half-lives), small molecule targeted therapies or
             other anti-cancer therapy within 21 days of study entry

          3. Radiation or surgery within 14 days of study entry, thoracic radiation within 28 days
             of study entry.

          4. Has known active central nervous (CNS) metastases and/or carcinomatous meningitis.
             Patients who have received prior radiotherapy for previous brain metastasis must have
             discontinued steroids for 14 days prior to study entry and be clinically stable.

          5. Continuance of toxicities due to prior radiotherapy or chemotherapy agents that do not
             recover to ≤ Grade 1 except alopecia

          6. Requirement for corticosteroid treatment, with the exception of megestrol, local use
             of steroid.

          7. Use of therapeutic anticoagulants

          8. International normalized ratio (INR) or activated partial thromboplastin time (APTT) ≥
             1.5 x ULN

          9. Concurrent treatment with an investigational agent or device within 28 days prior to
             the first dose of therapy

         10. Unstable angina, myocardial infarction, or a coronary revascularization procedure
             within 180 days of study entry

         11. Neurologic instability per clinical evaluation due to tumor involvement of the central
             nervous system (CNS).

         12. History of Bell's palsy

         13. Active rheumatoid arthritis (RA), active inflammatory bowel disease, chronic
             infections, or any other disease or condition associated with chronic inflammation

         14. Active infection requiring systemic antibiotic/ antifungal medication,

         15. Known or suspected Wilson's Disease.

         16. Prior treatment with IAP inhibitors

         17. History of hypersensitivity to paclitaxel, or any therapeutic antibody

         18. Has an active autoimmune disease, or a documented history of autoimmune disease, or a
             syndrome that requires systemic steroids or immunosuppressive agents.

         19. Is on chronic systemic steroid therapy

         20. Has received a live vaccine within 30 days prior to first dose.

         21. Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow
             transplant
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:18-24 months
Safety Issue:
Description:Patients with APG-1387 treatment related adverse events (AE), serious adverse events (SAE) will be assessed according NCI CTCAE Version 4.0

Secondary Outcome Measures

Measure:Anti-tumor effects of APG-1387 as a single agent
Time Frame:18-24 months
Safety Issue:
Description:Response will be evaluated every 2 cycles (8 weeks), according to the revised RECIST Guideline, Version 1.1 or the Revised Response Criteria for Malignant Lymphoma (Cheson, 2007).
Measure:Pharmacokinetic evaluation
Time Frame:18-24 months
Safety Issue:
Description:Maximum plasma concentration (Cmax) will be assessed in the patients treated with APH-1387
Measure:Anti-tumor effects of APG-1387 in combination with pembrolizumab , or combination with paclitaxel and carboplatin in patients with advanced solid tumors
Time Frame:18-24 months
Safety Issue:
Description:Response will be evaluated every 2 cycles (8 weeks), according to the revised RECIST Guideline, Version 1.1 or the Revised Response Criteria for Malignant Lymphoma (Cheson, 2007).
Measure:Preliminary biomarker assessment
Time Frame:18-24 months
Safety Issue:
Description:Tumor biopsy and peripheral blood sample) at baseline and 15-21 days after administration of APG-1387 alone or in combination with systemic anti-cancer therapy
Measure:Pharmacokinetic evaluation
Time Frame:18-24 months
Safety Issue:
Description:Area under the plasma concentration versus time curve (AUC) of APG-1387 will be assessed on patients treated with APG-1387

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ascentage Pharma Group Inc.

Trial Keywords

  • IAP inhibitor

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