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

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Brief Title

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

Official Title

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

Brief Summary

      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

Detailed Description

      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.

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Maximum Tolerated Dose


Unresectable or Metastatic Melanoma or Advanced Solid Tumors



Study Arms / Comparison Groups

 APG-115+Pembrolizumab open label, two-part phase Ib/II
Description:  single arm dose escalation and dose expansion


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

August 29, 2018

Completion Date

March 30, 2024

Primary Completion Date

December 30, 2023

Eligibility Criteria

        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 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

          -  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

          -  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

          -  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

          -  Has a history of (non-infectious) pneumonitis that required steroids or current

          -  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.




12 Years - N/A

Accepts Healthy Volunteers



Yifan Zhai, MD, PhD, 301-509-0357, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Secondary IDs

Keynote MK-3475-B66

Responsible Party


Study Sponsor

Ascentage Pharma Group Inc.


 Merck Sharp & Dohme LLC

Study Sponsor

Yifan Zhai, MD, PhD, Study Chair, Ascentage Pharma Group Inc.

Verification Date

January 2023