Clinical trial NCT03386526: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors or Hematologic Malignancies
Keywords: IAP inhibitor
Lead sponsor: Ascentage Pharma Group Inc.
Sponsor class: INDUSTRY
First posted: 2017-12-29
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: 18-24 months
Secondary outcomes:
measure: Anti-tumor effects of APG-1387 as a single agent
timeFrame: 18-24 months
measure: Pharmacokinetic evaluation
timeFrame: 18-24 months
measure: Anti-tumor effects of APG-1387 in combination with pembrolizumab or combination with paclitaxel and carboplatin in patients with advanced solid tumors
timeFrame: 18-24 months
measure: Preliminary biomarker assessment
timeFrame: 18-24 months
measure: Pharmacokinetic evaluation
timeFrame: 18-24 months
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: START Midwest
state: Michigan
city: San Antonio
country: United States
facility: The START Center for Cancer Care
state: Texas
Study officials:
affiliation: Ascentage Pharma Group Inc.
name: Yifan Zhai, MD, PhD
role: STUDY_CHAIR
References: