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

NCT ID: NCT03386526

Last Updated: 2023-02-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-21
• Study Completion Date: 2022-11-30

Brief Summary

APG-1387 is a potent, bivalent small-molecule Inhibitor of Apoptosis Protein (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 two 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.

Conditions

Advanced Solid Tumors or Hematologic Malignancies

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

APG-1387 for Injection

APG-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.

Group Type: EXPERIMENTAL

APG-1387 for Injection

Intervention Type: DRUG

Multiple dose cohorts, 30 minute IV infusion, once weekly for 3 weeks of a 21-day cycle

Interventions

APG-1387 for Injection

Multiple dose cohorts, 30 minute IV infusion, once weekly for 3 weeks of a 21-day cycle

Intervention Type: DRUG

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. Corrected QT interval (QTc) ≤ 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 upper limit of normal (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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ascentage Pharma Group Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Yifan Zhai, MD, PhD

Role: STUDY_CHAIR

Ascentage Pharma Group Inc.

Locations

University of Michigan

Ann Arbor, Michigan, United States

START Midwest

Grand Rapids, Michigan, United States

The START Center for Cancer Care

San Antonio, Texas, United States

Countries

United States

References

Pan W, Luo Q, Liang E, Shi M, Sun J, Shen H, Lu Z, Zhang L, Yan X, Yuan L, Zhou S, Yi H, Zhai Y, Qiu MZ, Yang D. Synergistic effects of Smac mimetic APG-1387 with anti-PD-1 antibody are attributed to increased CD3 + NK1.1 + cell recruitment secondary to induction of cytokines from tumor cells. Cancer Cell Int. 2024 May 24;24(1):181. doi: 10.1186/s12935-024-03373-7.

Reference Type: DERIVED

PMID: 38790057 (View on PubMed)

Other Identifiers

APG-1387-US-001

Identifier Type: -

Identifier Source: org_study_id