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

Study Overview
=================
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.

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

Conditions
-----------------
Advanced Solid Tumors or Hematologic Malignancies

Intervention / Treatment
-----------------
* Drug: APG-1387 for Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed solid tumor or hematological malignancies Life expectancy ≥ 3 months Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2 Corrected QT interval (QTc) ≤ 450 ms in males, and ≤ 470 ms in females Adequate hematologic function International normalized ratio (INR), prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤1.5 x upper limit of normal (ULN) Adequate renal and liver function Willingness to use contraception Ability to understand and willingness to sign a written informed consent form Willingness and ability to comply with study procedures and follow-up examination Have provided tissue for biomarker analysis from a newly or recently-obtained biopsy of a tumor lesion not previously irradiated Exclusion Criteria: Received chemotherapy within 21 days (42 days for nitrosoureas or mitomycin C) prior to entering the study Received hormonal, biologic (< 2 half-lives), small molecule targeted therapies or other anti-cancer therapy within 21 days of study entry Radiation or surgery within 14 days of study entry, thoracic radiation within 28 days of study entry 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 Continuance of toxicities due to prior radiotherapy or chemotherapy agents that do not recover to ≤ Grade 1 except alopecia Requirement for corticosteroid treatment, with the exception of megestrol, local use of steroid Use of therapeutic anticoagulants International normalized ratio (INR) or activated partial thromboplastin time (APTT) ≥ 1.5 x ULN Concurrent treatment with an investigational agent or device within 28 days prior to the first dose of therapy Unstable angina, myocardial infarction, or a coronary revascularization procedure within 180 days of study entry Neurologic instability per clinical evaluation due to tumor involvement of the central nervous system (CNS) History of Bell's palsy Active rheumatoid arthritis (RA), active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation Active infection requiring systemic antibiotic/ antifungal medication Known or suspected Wilson's Disease Prior treatment with IAP inhibitors History of hypersensitivity to paclitaxel, or any therapeutic antibody Has an active autoimmune disease, or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents Is on chronic systemic steroid therapy Has received a live vaccine within 30 days prior to first dose Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APG-1387 for Injection<br>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. | Drug: APG-1387 for Injection<br>* Multiple dose cohorts, 30 minute IV infusion, once weekly for 3 weeks of a 21-day cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Pharmacokinetic evaluation | Maximum plasma concentration (Cmax) will be assessed in the patients treated with APG-1387 | 18-24 months | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
IAP inhibitor