Clinical trial NCT03611868: A Study of APG-115 in as a Monotherapy or Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors
Official title: A Phase Ib/II Study of APG-115 as a Monotherapy or in Combination With Pembrolizumab in Patients With Unresectable or Metastatic Melanomas or Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Unresectable or Metastatic Melanoma or Advanced Solid Tumors
Melanoma
Uveal Melanoma
P53 Mutation
MDM2 Gene Mutation
Cutaneous Melanoma
Mucosal Melanoma
Malignant Peripheral Nerve Sheath Tumors (MPNST)
Keywords: Metastatic melanoma, MPNST and Advanced Solid Tumors
Lead sponsor: Ascentage Pharma Group Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2018-08-02
Enrollment: 230
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This study aims to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of APG-115, an MDM2 inhibitor, either alone or in combination with pembrolizumab, a programmed cell death protein-1 (PD-1) inhibitor, in patients with metastatic melanomas or advanced solid tumors. Our hypothesis is that restoration of the immune response concomitant to inhibition of the MDM2 pathway (which restores p53 functions) may promote cancer cell death, leading to effective anticancer therapy.

Detailed description: This is a phase I/II study to assess the safety and tolerability of APG-115 alone or in combination with pembrolizumab in patients with unresectable or metastatic melanoma, NSCLC, solid tumors with ATM mutation, liposarcoma, urothelial carcinomas, and malignant peripheral nerve sheath tumors (MPNST)The hypothesis is that the current therapy may improve ORR, progression-free survival, and synergistic effect of APG-115 alone or in combination with pembrolizumab in these patients. (n=230, ID: NCT03611868).

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 without continuous supportive treatment
* QTcF interval (mean of 3, 1-3 minutes between 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 both male and female patients of 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.

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
* 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 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.

Primary outcomes:
measure: Maximum Tolerated Dose
timeFrame: 21 days
measure: Recommended Phase II Dose
timeFrame: 21 days
measure: Overall Response Rate
timeFrame: up to 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Rogers
country: United States
facility: Highlands Oncology
state: Arkansas
city: Los Angeles
country: United States
facility: UCLA Hematology & Oncology Clinic
state: California
city: Santa Monica
country: United States
facility: Sarcoma Oncology Research Center
state: California
city: Washington
country: United States
facility: Children's National Research Institute
state: District of Columbia
city: Fort Myers
country: United States
facility: Sarah Cannon/FCSRI
state: Florida
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Hershey
country: United States
facility: Penn State Hershey Medical Center Cancer Institute
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Cancer Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Next Oncology
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Brisbane
country: Australia
facility: Metro South Hospital and Health Services via Princess Alexandra Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
Study officials:
affiliation: Ascentage Pharma
name: Yifan Zhai, MD, PhD
role: STUDY_CHAIR
References: