Testing APG-115 Alone or With Pembrolizumab for Advanced Melanoma and Other Cancers
A Phase Ib/II Study of APG-115 as a Monotherapy or in Combination With Pembrolizumab in Patients With Unresectable or Metastatic Melanomas or Advanced Solid Tumors
In Plain English
This trial is testing a new drug called APG-115, either by itself or combined with pembrolizumab (a well-known immunotherapy drug). The goal is to see if APG-115 can help your body's immune system fight cancer more effectively. Here's how it works: Cancer cells have a trick—they produce something called MDM2 that shuts down a protective protein in your body called p53 (think of p53 as your body's natural "cancer fighter"). APG-115 blocks MDM2, which wakes up p53 again. When combined with pembrolizumab (which removes the brakes on your immune system), the two drugs work together to help your immune cells recognize and destroy cancer cells. The trial has two phases: Phase 1b tests different doses of APG-115 combined with pembrolizumab to find the safest dose. Phase 2 uses that safe dose and tests whether APG-115 alone or combined with pembrolizumab actually shrinks tumors. You'll take APG-115 as a pill every other day for 2 weeks, then have a week off. Pembrolizumab is given as an IV infusion every 3 weeks. The trial includes about 230 patients with various advanced cancers, including uveal melanoma (eye cancer).
What This Trial Does
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 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.
How It Works
This is a phase I/II study to assess the safety and tolerability of APG-115 alone or in combination with pembrolizumab in patients with or melanoma, NSCLC, solid tumors with ATM mutation, liposarcoma, urothelial carcinomas, and malignant peripheral nerve sheath tumors (MPNST)The hypothesis is that the current therapy may improve ORR, progression-free survival, and synergistic effect of APG-115 alone or in combination with pembrolizumab in these patients. (n=230, ID: NCT03611868).
Who Can Join
Inclusion Criteria
- 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:
- 1. 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
- 2. ECOG performance status 0-2
- 3. 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)
- 4. 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.
Exclusion Criteria
- 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.
- Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant
- Has previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
- Any other condition or circumstance that would, in the opinion of the investigator, make the patient unsuitable for participation in the study
- History of organ transplant requiring use of immunosuppressive medication
- A woman of childbearing potential who has a positive urine or serum pregnancy test (within 72 hours) prior to treatment.
Treatments
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.
Trial Sites (21)
University of Arizona Cancer Center
Tucson, Arizona, United States
Highlands Oncology
Rogers, Arkansas, United States
UCLA Hematology & Oncology Clinic
Los Angeles, California, United States
Sarcoma Oncology Research Center
Santa Monica, California, United States
Children's National Research Institute
Washington D.C., District of Columbia, United States
Sarah Cannon/FCSRI
Fort Myers, Florida, United States
Washington University School of Medicine
St Louis, Missouri, United States
Memorial Sloan Kettering
New York, New York, United States
Duke Cancer Institute
Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Cleveland Clinic
Cleveland, Ohio, United States
Penn State Hershey Medical Center Cancer Institute
Hershey, Pennsylvania, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, United States
Sarah Cannon Cancer Center
Nashville, Tennessee, United States
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Next Oncology
San Antonio, Texas, United States
Virginia Cancer Specialists
Fairfax, Virginia, United States
Metro South Hospital and Health Services via Princess Alexandra Hospital
Brisbane, Queensland, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Flinders Medical Centre
Bedford Park, South Australia, Australia
Austin Health
Heidelberg, Victoria, Australia