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

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ClinicalTrials.gov Identifier: NCT03611868
Recruitment Status : Recruiting
First Posted : August 2, 2018
Last Update Posted : August 31, 2021
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ascentage Pharma Group Inc.

Tracking Information
First Submitted Date  ICMJE July 27, 2018
First Posted Date  ICMJE August 2, 2018
Last Update Posted Date August 31, 2021
Actual Study Start Date  ICMJE August 29, 2018
Estimated Primary Completion Date October 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 25, 2021)
  • Maximum Tolerated Dose [ Time Frame: 21 days ]
    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
  • Recommended Phase II Dose [ Time Frame: 21 days ]
    Part I is aimed to generate data to select the recommended Phase II dose
  • Overall Response Rate [ Time Frame: up to 12 months ]
    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
Original Primary Outcome Measures  ICMJE
 (submitted: July 27, 2018)
  • Maximum Tolerated Dose [ Time Frame: 21 days ]
    Part I is to assess the safety and tolerability of APG-115 by assessing the Dose Limiting Toxicity 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
  • Recommended Phase II Dose [ Time Frame: 21 days ]
    Part I is aimed to generate data to select the recommended Phase II dose
  • Overall Response Rate [ Time Frame: up to 12 months ]
    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 CR or a PR at any time as per RECIST 1.1
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of APG-115 in Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors
Official Title  ICMJE 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Unresectable or Metastatic Melanoma or Advanced Solid Tumors
  • Melanoma
  • Uveal Melanoma
  • Non Small Cell Lung Cancer
  • ATM Gene Mutation
  • P53 Mutation
  • MDM2 Gene Mutation
  • Liposarcoma
  • Urothelial Carcinoma
  • MPNST
  • Cutaneous Melanoma
  • Mucosal Melanoma
  • Malignant Peripheral Nerve Sheath Tumors
  • STK11 Gene Mutation
Intervention  ICMJE Drug: APG-115+Pembrolizumab
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.
Other Name: Keytruda
Study Arms  ICMJE Experimental: APG-115+Pembrolizumab open label, two-part phase Ib/II
single arm dose escalation and dose expansion
Intervention: Drug: APG-115+Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 27, 2021)
203
Original Estimated Enrollment  ICMJE
 (submitted: July 27, 2018)
67
Estimated Study Completion Date  ICMJE January 31, 2023
Estimated Primary Completion Date October 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kathryn Shantz 301-802-3414 kate.shantz@ascentage.com
Listed Location Countries  ICMJE Australia,   United States
Removed Location Countries China
 
Administrative Information
NCT Number  ICMJE NCT03611868
Other Study ID Numbers  ICMJE APG-115-US-002
Keynote MK-3475-B66 ( Other Identifier: Merck and Co. )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ascentage Pharma Group Inc.
Study Sponsor  ICMJE Ascentage Pharma Group Inc.
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Study Chair: Yifan Zhai, MD, PhD Ascentage Pharma Group Inc.
PRS Account Ascentage Pharma Group Inc.
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP