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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03611868
Recruitment Status : Recruiting
First Posted : August 2, 2018
Last Update Posted : August 7, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Ascentage Pharma Group Inc.

Brief Summary:

Part 1 is a phase Ib standard "3 + 3" design will be employed to determine the MTD of APG-115 by assessing the DLT of APG-115 in combination with pembrolizumab.

Part 2 is a Simon two-stage phase II study design. At RP2D of APG-115 in combination with pembrolizumab, approximately 43 patients will be treated with the combination until disease progression, unacceptable toxicity, or another discontinuation criterion is met.


Condition or disease Intervention/treatment Phase
Unresectable or Metastatic Melanoma or Advanced Solid 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 an MTD/RP2D of APG-115 in combination with pembrolizumab. Dose levels/schedule of APG115 will be tested: 50mg, 100mg, 150mg, and 200mg, QOD with 2 weeks on 1 week off as a cycle of 21 days (3 weeks), pembrolizumab will administrated with label dose.

Part 2 is the phase II portion of the study to evaluate the clinical efficacy and safety of the RP2D of APG-115 in combination with label dose of pembrolizumab in patient with unresectable or metastatic melanoma who is refractory or relapse of PD1 therapy. In this part, Simon's two-stage design (Simon R (1989). Controlled Clinical Trials 10: 1-10.) will be used. The null hypothesis that the true response rate is 10% or lower will be tested against a one-sided alternative. In the first stage, 18 patients will be accrued. If there are 2 or fewer responses in these patients, the study will be stopped. Otherwise, 25 additional patients will be accrued for a total of 43. The null hypothesis will be rejected if 8 or more responses are observed in 43 patients. This design yields a type I error rate of 0.10 and power of 80% when the true response rate is 25% or higher.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 67 participants
Intervention Model: Sequential Assignment
Intervention Model Description: phase Ib portion of the study is to establish an MTD/RP2D of APG-115 in combination with pembrolizumab. Dose levels/schedule of APG115 will be tested: 50mg, 100mg, 150mg, and 200mg, QOD with 2 weeks on 1 week off as a cycle of 21 days (3 weeks), pembrolizumab will administrated with label dose. phase II portion of the study will evaluate the clinical efficacy and safety of the RP2D of APG-115 in combination with label dose of pembrolizumab in patient with unresectable or metastatic melanoma who is refractory or relapse of PD1 therapy.
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 : September 18, 2018
Estimated Primary Completion Date : September 15, 2020
Estimated Study Completion Date : May 15, 2021

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

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.




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 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 CR or a PR at any time as per RECIST 1.1



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 on day of signing the informed consent

Part 1:

  1. Histologically confirmed, unresectable or metastatic melanoma or advanced solid tumor patients who failed standard of care therapy;
  2. ECOG PS 0-2
  3. No CNS metastases

Part 2:

  1. Histologically confirmed, unresectable or metastatic melanoma, and refractory or relapse after PD1 antibody treatment and ineligible for other standard of care therapy;
  2. ECOG PS 0-2;
  3. 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 Life expectancy ≥ 3 months Continuance of treatment related toxicities (except alopecia) due to prior radiotherapy or chemotherapy agents or biological therapy (including PD1/PDL1 antibodies) must ≤ 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 QTc interval (mean of 3) ≤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

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 months prior to start of study treatment.

Received hormonal and biologic (<1 half-lives), small molecule targeted therapies or other anti-cancer therapy within 21 days prior to first dose Radiation or surgery within 14 days of study entry, 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, 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 28 days prior to the first dose of therapy


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: Yifan Zhai, MD 1-240-505-6608 yzhai@ascentagepharma.com
Contact: Yuefen Tang, MD (301)520-4013 yftang@ascentagepharma.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   
United States, Arkansas
Highlands Oncology Recruiting
Rogers, Arkansas, United States, 72758
Contact: Thad Beck, MD    479-936-9900      
Principal Investigator: Thad Beck, MD         
United States, California
UCLA Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Bartosz Chemielowski, MD         
United States, Connecticut
Yale Hospital Not yet recruiting
New Haven, Connecticut, United States, 06510
Contact: Daniel Petrylak, MK         
United States, District of Columbia
Childrens National Research Institute Not yet recruiting
Washington, District of Columbia, United States, 20012
Contact: Aereng Kim, MD         
United States, Florida
Sarah Cannon/FCSRI Recruiting
Fort Myers, Florida, United States, 33901
Contact: Patrice Cowan       pcowan@flcancer.com   
United States, New York
Memorial Sloan Kettering Not yet recruiting
New York, New York, United States, 10065
Contact: Moova Sujanni, MD         
United States, Pennsylvania
Thomas Jefferson University Hospital Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Joshua Zigmont       Joshua.zigmont@jefferson.edu   
United States, Tennessee
Sarah Cannon Cancer Center Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
University of Texas MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Gracy Zacharian       gzachari@mdanderson.org   
Next Oncology Recruiting
San Antonio, Texas, United States, 78240
Principal Investigator: Anthony Tolcher, MD         
United States, Virginia
Virginia Cancer Specialists Recruiting
Fairfax, Virginia, United States, 22031
Contact: Alexander Spira, MD         
Sponsors and Collaborators
Ascentage Pharma Group Inc.
Merck Sharp & Dohme Corp.
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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: August 7, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Melanoma
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents