APG-1387 Plus Chemotherapy in Advanced Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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This study is a two stage study consisting of a dose escalation phase Ib and a phase II study which include subjects with previously-treated, advanced pancreatic adenocarcinoma. Dose Limiting Toxicities (DLTs) and maximum tolerated dose (MTD) of APG1387 in combination with nab-paclitaxel and gemcitabine will be evaluated in the dose escalation phase Ib. Safety and efficacy of APG1387 plus gemcitabine and nab-paclitaxel will be evaluated in phase II.

Detailed Description
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The ability of tumor cells to evade apoptosis is currently a major problem in anti-tumor therapy. IAPs are an important class of apoptosis-regulating proteins. APG-1387, a potent bivalent SMAC mimetic, small molecule of IAP inhibitor, which could inhibit pancreatic cancer proliferation as monotherapy and in combination with chemotherapy through apoptosis pathway. It's an open label, multiple centers phase Ib/II Study. Safety and tolerability of APG1387 combined with nab-paclitaxel and gemcitabine will be evaluated in phase Ib in previously-treated, advanced pancreatic adenocarcinoma patients. Efficacy and tolerability will be evaluated in phase II study in first line standard treatment failed metastatic pancreatic adenocarcinoma patients.

Official Title
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An Open Label, Multiple Centers Phase Ib/II Study of APG-1387 Plus Chemotherapy in Advanced Pancreatic Adenocarcinoma

Conditions
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Advanced Pancreatic Cancer

Intervention / Treatment
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* Drug: APG-1387 for Injection
* Drug: Gemcitabine
* Drug: Nab paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be ≥18 years of age at time of informed consent Able to comply with the study protocol, in the investigator's judgment Expected survival ≥ 3 months Histology or cytology confirmed as advanced pancreatic adenocarcinoma, and: Standard treatment failed or intolerant to standard treatment(Phase Ib); First line standard treatment failed (Phase II). ECOG 0-1; Adequate organ function. Subjects must have at least one measurable lesion evaluated by Computed Tomography (CT) scan on RECIST ver.1.1 at pre-treatment Exclusion Criteria: Has had chemotherapy, radiation, target or other antitumor therapy within 14 days prior to the first dose of study drug. Has received an investigational agent or used an investigational device within 28 days of the first dose of study drug. Has received a therapy with TNFα within 28 days of the first dose of study drug. Known active central nervous system involvement. Has received IAP-inhibitor before. Has had major surgery within 28 days of dosing of investigational agent, or minor surgery within 14 days. Patients with clinically evident Hepatitis B surface antigen (HBs) positive, Hepatitis C virus (HCV) antibody positive, Human Immunodeficiency Virus (HIV) antibody positive. Pregnant or breastfeeding (lactating) women. Other situations that investigator think not suit for study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APG1387 in combination with Gemcitabine and Nab-Paclitaxel<br> | Drug: APG-1387 for Injection<br>* APG1387 will be administered IV days 1， 8, 15 and 22 of a 28 day cycle.<br>Drug: Gemcitabine<br>* Gemcitabine 1000 mg/m^2 will be administered IV days 1, 8, and 15 of a 28 day cycle.<br>Drug: Nab paclitaxel<br>* Nab-Paclitaxel 125mg/m^2 will be administered IV days 1, 8, and 15 of a 28 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLT) of combination therapy (Applicable for: phase Ib stage ). | DLT will be graded according to NCI CTCAE Version 5.0. DLT will be defined as clinically significant drug-related adverse events during the cycle one. | 28 days. | 
| Overall Response Rate (Applicable for: phase II stage) . | Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. | Up to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | From date of treatment start until the date of progression or the date of death due to any cause. | Up to 2 years. | 
| Duration of Response (DOR) | From date of response until the date of progression. | Up to 2 years. | 
| Overall Survival (OS) | From date of treatment start until the date of death due to any cause. | Up to 2 years. | 
| Maximum plasma concentration (Cmax) | Cmax of APG-1387 and Nab-Paclitaxel will be assessed in the patients in this study. | 28 days. | 
| Area under the plasma concentration versus time curve (AUC) | AUC of APG-1387 and Nab-Paclitaxel will be assessed in the patients in this study. | 28 days. | 
| Adverse events | Adverse events (AE) and serious adverse events (SAE) will be graded according to NCI CTCAE Version 5.0. | Up to 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IAP inhibitor, APG-1387, Pancreatic cancer, Inhibitor of apoptosis