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
      pembrolizumab in patients with programmed cell death protein 1 (PD-1)/programmed death-ligand
      1 (PD-L1) refractory/relapsed melanoma or NSCLC, lung adenocarcinoma with STK11 mutation,
      solid tumors with P53 WT and ATM mutation, P53 WT and MDM2 amplification liposarcomas,
      PD-1/PD-L1 refractory/relapsed urothelial carcinoma without FGFR translocation mutation, and
      MPNST.
    

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. Four dose
      levels of APG-115 will be administered: 50 mg, 100 mg, 150 mg, and 200 mg. 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, includes cohort A-F six arms. 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.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Maximum Tolerated Dose


Condition

Unresectable or Metastatic Melanoma or Advanced Solid Tumors

Intervention

APG-115+Pembrolizumab

Study Arms / Comparison Groups

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

Publications

* 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

Drug

Estimated Enrollment

203

Start Date

August 29, 2018

Completion Date

January 31, 2023

Primary Completion Date

October 30, 2022

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 1:

               1. Histologically confirmed, unresectable or metastatic melanoma, or advanced solid
                  tumor patients who failed standard of care therapy and no further effective
                  therapy is available

               2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Part 2:

               1. 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)

               2. Cohort B: Histologically confirmed, unresectable or metastatic NSCLC, and
                  refractory or relapse after PD-1/PD-L1 antibody treatment and ineligible for
                  other standard of care therapy per NCCN guideline or Histologically confirmed,
                  unresectable or metastatic lung adenocarcinoma with STK-11 mutation, and with or
                  without previous anti-PD-1/PD-L1 antibody treatment and ineligible for other
                  standard of care therapy per NCCN guideline

               3. Cohort C: Histologically confirmed, unresectable or metastatic solid tumors with
                  P53WT and ATM mutation (including germline ATM mutation)

               4. Cohort D: Histologically confirmed, locally advanced or metastatic
                  well-differentiated or dedifferentiated liposarcomas who have or haven't received
                  prior systemic therapy (either ineligible or declining chemotherapy), and with
                  P53 WT and MDM2 amplification

               5. Cohort E: Histologically confirmed, unresectable or metastatic urothelial
                  carcinoma, and refractory or relapse after PD-1/PD-L1 antibody treatment and
                  ineligible for other standard of care therapy per NCCN guideline

               6. Cohort F: Histologically confirmed, metastatic or unresectable MPNST

               7. 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

               8. ECOG performance status 0-2

          -  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 two 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 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 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.
      

Gender

All

Ages

12 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Yifan Zhai, MD, PhD, 301-802-3414, [email protected]

Location Countries

Australia

Location Countries

Australia

Administrative Informations


NCT ID

NCT03611868

Organization ID

APG-115-US-002

Secondary IDs

Keynote MK-3475-B66

Responsible Party

Sponsor

Study Sponsor

Ascentage Pharma Group Inc.

Collaborators

 Merck Sharp & Dohme Corp.

Study Sponsor

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


Verification Date

July 2021