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

Advanced Solid Tumors or Hematologic Malignancies Clinical Trial

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 Details — Status: Completed

Administrative data

• NCT number: NCT03386526
• Other study ID #: APG-1387-US-001
• Status: Completed
• Phase: Phase 1
• Start date: November 21, 2017
• Est. completion date: November 30, 2022

Study information

• Verified date: January 2023
• Source: Ascentage Pharma Group Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: November 30, 2022
• Est. primary completion date: October 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Solid Tumors or Hematologic Malignancies
• Hematologic Neoplasms
• Neoplasms

Intervention

Drug:
• APG-1387 for Injection
Multiple dose cohorts, 30 minute IV infusion, once weekly for 3 weeks of a 21-day cycle

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	START Midwest	Grand Rapids	Michigan
United States	The START Center for Cancer Care	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Ascentage Pharma Group Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (MTD)	Patients with APG-1387 treatment related adverse events (AE), serious adverse events (SAE) will be assessed according NCI CTCAE Version 4.03	18-24 months
Secondary	Anti-tumor effects of APG-1387 as a single agent	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	18-24 months
Secondary	Pharmacokinetic evaluation	Maximum plasma concentration (Cmax) will be assessed in the patients treated with APG-1387	18-24 months
Secondary	Anti-tumor effects of APG-1387 in combination with pembrolizumab or combination with paclitaxel and carboplatin in patients with advanced solid tumors	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	18-24 months
Secondary	Preliminary biomarker assessment	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	18-24 months
Secondary	Pharmacokinetic evaluation	Area under the plasma concentration versus time curve (AUC) of APG-1387 will be assessed on patients treated with APG-1387	18-24 months