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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 : April 26, 2021
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ascentage Pharma Group Inc.

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 the patients with programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) refractory/relapse melanoma or NSCLC, 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.


Condition or disease Intervention/treatment Phase
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 Drug: APG-115+Pembrolizumab Phase 1 Phase 2

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: 50mg, 100mg, 150mg, and 200mg. 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 five 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 143 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 29, 2018
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : December 31, 2022


Arm Intervention/treatment
Experimental: APG-115+Pembrolizumab open label, two-part phase Ib/II
single arm dose escalation and dose expansion
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 200mg. 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.: 200mg intravenous infusion at Day 1 of every 3 weeks as a cycle.
Other Name: Keytruda




Primary Outcome Measures :
  1. 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

  2. Recommended Phase II Dose [ Time Frame: 21 days ]
    Part I is aimed to generate data to select the recommended Phase II dose

  3. 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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or non-pregnant, non-lactating female patients age ≥18 years
  • 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. 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
    2. 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. Histologically confirmed, unresectable or metastatic solid tumors with P53WT and ATM mutation (including germline ATM mutation)
    4. Histologically confirmed, locally advanced or metastatic liposarcomas who have received at least one prior systemic therapy, and with P53 WT and MDM2 amplification
    5. 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. Histologically confirmed, metastatic or unresectable MPNST
    7. Measurable disease according to irRECIST and 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) ≤450ms in males and ≤470ms 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 males 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
  • 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
  • Has received radiation therapy to the lung that is >30Gy within 6 months of the first dose of trial treatment
  • Received hormonal and biologic (<1 half-lives), small molecule targeted therapies or other anti-cancer therapy within 21 days prior to first dose
  • 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, known clinically active hepatitis B or C, or HIV infection
  • 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
  • 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 (e.g., 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03611868


Contacts
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Contact: Kathryn Shantz 301-802-3414 kate.shantz@ascentage.com

Locations
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United States, Arizona
University of Arizona Cancer Center Recruiting
Tucson, Arizona, United States, 85724
Contact: Jose Vasquez       jrv3@email.arizona.edu   
Principal Investigator: Montaser Shaheen, MD         
United States, Arkansas
Highlands Oncology Recruiting
Rogers, Arkansas, United States, 72703
Contact: Thad Beck, MD    479-936-9900      
Principal Investigator: Thad Beck, MD         
United States, California
UCLA Hematology & Oncology Clinic Recruiting
Los Angeles, California, United States, 90095
Principal Investigator: Bartosz Chemielowski, MD         
United States, District of Columbia
Children's National Research Institute Recruiting
Washington, District of Columbia, United States, 20010
Principal Investigator: AeRang Kim, MD, PhD         
United States, Florida
Sarah Cannon/FCSRI Recruiting
Fort Myers, Florida, United States, 33908
Contact: Patrice Cowan       pcowan@flcancer.com   
Principal Investigator: James Reeves, MD         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Principal Investigator: Brian Van Tine, MD, PhD         
United States, New York
Memorial Sloan Kettering Recruiting
New York, New York, United States, 10065
Principal Investigator: Sujana Movva, MD         
United States, Pennsylvania
Penn State Hershey Medical Center Cancer Institute Recruiting
Hershey, Pennsylvania, United States, 17033
Principal Investigator: Joseph Drabick, MD         
Thomas Jefferson University Hospital Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Joshua Zigmont       Joshua.zigmont@jefferson.edu   
Principal Investigator: Melissa Wilson, MD         
United States, Tennessee
Sarah Cannon Cancer Center Recruiting
Nashville, Tennessee, United States, 37203
Principal Investigator: Meredith McKean, MD         
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Gracy Zacharian       gzachari@mdanderson.org   
Principal Investigator: Neeta Somaiah, MD         
Next Oncology Recruiting
San Antonio, Texas, United States, 78229
Principal Investigator: Anthony Tolcher, MD         
United States, Virginia
Virginia Cancer Specialists Recruiting
Fairfax, Virginia, United States, 22031
Contact: Spira         
Principal Investigator: Alexander Spira, MD         
Australia, Queensland
Metro South Hospital and Health Services via Princess Alexandra Hospital Recruiting
Brisbane, Queensland, Australia
Principal Investigator: Kenneth O'Byrne         
Sponsors and Collaborators
Ascentage Pharma Group Inc.
Merck Sharp & Dohme Corp.
Investigators
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Study Chair: Yifan Zhai, MD, PhD Ascentage Pharma Group Inc.
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Responsible Party: Ascentage Pharma Group Inc.
ClinicalTrials.gov Identifier: NCT03611868    
Other Study ID Numbers: APG-115-US-002
Keynote MK-3475-B66 ( Other Identifier: Merck and Co. )
First Posted: August 2, 2018    Key Record Dates
Last Update Posted: April 26, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ascentage Pharma Group Inc.:
pembrolizumab
Additional relevant MeSH terms:
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Neoplasms
Melanoma
Liposarcoma
Nerve Sheath Neoplasms
Neurofibrosarcoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms, Adipose Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Fibrosarcoma
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neurofibroma
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents