A Study of APG-115 in as a Monotherapy or Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors

NCT03611868 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: APG-115-US-002Keynote B66MK3475-B66
• Study Type: interventional
• Target: 230
• Locations: 2 countries
• Sites: 21

Brief Summary

This study aims to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of APG-115, an MDM2 inhibitor, either alone or in combination with pembrolizumab, a programmed cell death protein-1 (PD-1) inhibitor, in patients with metastatic melanomas or advanced solid tumors. Our hypothesis is that restoration of the immune response concomitant to inhibition of the MDM2 pathway (which restores p53 functions) may promote cancer cell death, leading to effective anticancer therapy.

Conditions

Unresectable or Metastatic Melanoma or Advanced Solid Tumors; Melanoma; Uveal Melanoma; P53 Mutation; MDM2 Gene Mutation; Cutaneous Melanoma; Mucosal Melanoma; Malignant Peripheral Nerve Sheath Tumors (MPNST)

Keywords

Metastatic melanoma, MPNST and Advanced Solid Tumors

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose

  Part I is to assess the safety and tolerability of APG-115 by assessing the dose-limiting toxicity (DLT) of APG-115 in combination with pembrolizumab. End points included: Incidence of DLTs during the first 3 weeks of treatment of each dose cohort; Severity and frequency of any adverse event(s) (AE) and serious adverse event(s) (SAE) based on NCI CTCAE 5.0

  21 days

• Recommended Phase II Dose

  Part I is aimed to generate data to select the recommended Phase II dose

  21 days

• Overall Response Rate

  Phase II is to assess overall response rate of APG-115 as monotherapy and in combination with pembrolizumab defined as the percentage of subjects with a best overall confirmed complete response (CR) or a partial response (PR) at any time as per RECIST 1.1

  up to 12 months

Study Arms (1)

APG-115+pembrolizumab open label, two-part phase Ib/II

EXPERIMENTAL

single arm dose escalation and dose expansion

Drug: Phase 1b: APG-115+pembrolizumab

Interventions

Phase 1b: APG-115+pembrolizumab DRUG

dose escalation of APG-115 in combination with label dose of pembrolizumab, Four dose levels of APG-115 will be tested: 50, 100, 150, and 200 mg. APG-115 will be administrateddose escalation of APG-115 in combination with label dose of pembrolizumab, Fourfour dose levels of APG-115 will be tested: 50, 100, 150, and 200 mg. APG-115 will be administrated orally every other day (QOD) for consecutive 2 weeks (ie. dosed at Day 1, 3, 5, 7, 9, 11, and 13), with one week dosing off as there are cycles every 3-weeks a cycle. Pembrolizumab is administrated following FDA approved label dose, i.e., 200 mg intravenous infusion at Day 1 of every 3 weeks as a cycle. Phase II: Combination of APG-115 at 150 mg (RP2D) and pembrolizumab or APG-115 monotherapy alone.

Also known as: KEYTRUDA®

APG-115+pembrolizumab open label, two-part phase Ib/II

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or non-pregnant, non-lactating female patients age ≥18 years, an exception for MPNST cohort: adolescents ≥12 years old (who weigh at least 40 kg) is allowed
• Part 2:
• Measurable disease according to RECIST 1.1. Lesions situated in a previously irradiated area, or an area subject to other loco-regional therapy (e.g., intralesional injections) should be considered non-measurable
• ECOG performance status 0-2
• Cohort A: Histologically confirmed, unresectable or metastatic melanoma, and refractory or relapse after PD-1 antibody treatment and ineligible for other standard of care therapy per NCCN guideline (previous PD-1/PD-L1 antibody treatment not required for uveal melanoma)
• Cohort F: Histologically confirmed, metastatic or unresectable MPNST
• Life expectancy ≥ 3 months
• Continuance of treatment related toxicities (except alopecia) due to prior radiotherapy or chemotherapy agents or biological therapy (including PD-1/PD-L1 antibodies) must be ≤ grade 1 at the time of dosing
• Adequate bone marrow and organ function without continuous supportive treatment
• QTcF interval (mean of 3, 1-3 minutes between tests) ≤450 ms in males and ≤470 ms in females
• Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
• Tumor tissue must be provided for all subjects for biomarker analysis before treatment with investigational product
• Willingness to use contraception by a method that is deemed effective by both male and female patients of childbearing potential and their partners throughout the treatment period and for at least three months following the last dose of study drug
• Ability to understand and willingness to sign a written informed consent form.

You may not qualify if:

• Any prior systemic MDM2-p53 inhibitor treatment
• Received chemotherapy within 21 days (42 days for nitrosoureas or mitomycin C) prior to first dose
• Part 2 Cohort A: Prior loco-regional treatment with intralesional therapy (e.g., talimogene laherparepvec) for unresectable or metastatic melanoma in the last 6 weeks prior to start of study treatment
• Part 2 Cohort B: Has received radiation therapy to the lung that is \>30Gy within 6 months of the first dose of trial treatment
• Part 2 Cohort E: Known FGFR translocation mutation
• Received hormonal and biologic, small molecule targeted therapies or other anti-cancer therapy within 21 days prior to first dose
• Radiation or surgery within 14 days prior to first dose, thoracic radiation within 28 days prior to first dose
• Has known active central nervous (CNS) metastases and/or carcinomatous meningitis. Or has neurologic instability per clinical evaluation due to tumor involvement of the CNS.
• Requirement for corticosteroid treatment (with the exception of megestrol and local use of steroid: i.e., topical corticosteroids, inhaled corticosteroids for reactive airway disease, ophthalmic, intraarticular, and intranasal steroids
• Concurrent treatment with an investigational agent or device within 21 days prior to the first dose of therapy
• Failure to recover adequately, as judged by the investigator, from prior surgical procedures. Patients with active wound healing, patients who have had major surgery within 28 days from 1st dose of study treatment, and patients who have had minor surgery within 14 days from 1st dose of study treatment.
• Unstable angina, myocardial infarction, or a coronary revascularization procedure within 180 days of study entry
• 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, and known clinically active viral infection such as hepatitis B or C, HIV infection, or active COVID-19
• Has received a live vaccine within 30 days prior to first dose.

Sponsors & Collaborators

• Ascentage Pharma Group Inc.: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (21)

University of Arizona Cancer Center

Tucson, Arizona, 85724, United States

Location

Highlands Oncology

Rogers, Arkansas, 72758, United States

Location

UCLA Hematology & Oncology Clinic

Los Angeles, California, 90095, United States

Location

Sarcoma Oncology Research Center

Santa Monica, California, 90403, United States

Location

Children's National Research Institute

Washington D.C., District of Columbia, 20010, United States

Location

Sarah Cannon/FCSRI

Fort Myers, Florida, 33908, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Memorial Sloan Kettering

New York, New York, 10065, United States

Location

Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Penn State Hershey Medical Center Cancer Institute

Hershey, Pennsylvania, 17033, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

Sarah Cannon Cancer Center

Nashville, Tennessee, 37203, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Next Oncology

San Antonio, Texas, 78229, United States

Location

Virginia Cancer Specialists

Fairfax, Virginia, 22031, United States

Location

Metro South Hospital and Health Services via Princess Alexandra Hospital

Brisbane, Queensland, Australia

Location

Queensland Children's Hospital

South Brisbane, Queensland, 4101, Australia

Location

Flinders Medical Centre

Bedford Park, South Australia, 5042, Australia

Location

Austin Health

Heidelberg, Victoria, Australia

Location

MeSH Terms

Conditions

Melanoma; Uveal Melanoma; Neurofibrosarcoma

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Uveal Neoplasms; Eye Neoplasms; Eye Diseases; Uveal Diseases; Fibrosarcoma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Neurofibroma; Nerve Sheath Neoplasms; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases

Study Officials

• Yifan Zhai, MD, PhD

  Ascentage Pharma

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2018
• First Posted: August 2, 2018
• Study Start: August 29, 2018
• Primary Completion: December 30, 2025
• Study Completion: December 30, 2025
• Last Updated: August 7, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (17); AU (4)