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

Study Overview
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Brief Summary
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Part 1 is the dose escalation of APG-115 in combination with label dose of pembrolizumab. Part 2 is phase II design of APG-115 at recommended phase 2 dose (RP2D) in combination with pembrolizumab.

Detailed Description
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Part 1 is the open label, dose-escalation phase Ib portion of the study to establish the maximum tolerated dose (MTD)/RP2D of APG-115 in combination with pembrolizumab. APG-115 will be administered orally every other day (QOD) for consecutive 2 weeks and 1 week off dosing as a cycle of 21 days (3 weeks), pembrolizumab will administrated with label dose. Part 2 is a phase II study design. The patients will be treated with APG-115 at 150 mg QOD (RP2D) in combination with pembrolizumab until disease progression, unacceptable toxicity, or another discontinuation criterion is met. Part 2 includes patients with programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) refractory/relapsed melanoma and MPNST.

Official Title
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A Phase Ib/II Study of APG-115 in Combination With Pembrolizumab in Patients With Unresectable or Metastatic Melanomas or Advanced Solid Tumors

Conditions
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Unresectable or Metastatic Melanoma or Advanced Solid Tumors, Melanoma, Uveal Melanoma, P53 Mutation, MDM2 Gene Mutation, MPNST, Cutaneous Melanoma, Mucosal Melanoma, Malignant Peripheral Nerve Sheath Tumors

Intervention / Treatment
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* Drug: APG-115+Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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: 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 as indicated by the following laboratory values without continuous supportive treatment (such as blood transfusion, coagulation factors and/or platelet infusion, red/white blood cell growth factor administration, or albumin infusion) as assessed by laboratory for eligibility 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 the investigator by both male and female patients of child bearing potential (postmenopausal women must have been amenorrhea for at least 12 months to be considered of non-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 (the consent form must be signed by the patient prior to any screening procedures). Willingness and ability to comply with study procedures and follow-up examination. 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 Uncontrolled concurrent illness including, but not limited to: symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with the study requirements Has an active autoimmune disease, or a documented history of autoimmune disease, or a syndrome, that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement are not excluded from the study. Has received a live vaccine within 30 days prior to first dose. Note that killed vaccines, mRNA vaccines, and non-live attenuated vaccines (i.e., for the SARS-Cov-2 virus or COVID-19) are allowed for patients on study. Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis 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. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

Ages Eligible for Study
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Minimum Age: 12 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APG-115+Pembrolizumab open label, two-part phase Ib/II<br>single arm dose escalation and dose expansion | Drug: APG-115+Pembrolizumab<br>* 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 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 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.<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pembrolizumab