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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03611868




Registration number
NCT03611868
Ethics application status
Date submitted
27/07/2018
Date registered
2/08/2018
Date last updated
19/07/2024

Titles & IDs
Public title
A Study of APG-115 in as a Monotherapy or Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors
Scientific 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
Secondary ID [1] 0 0
Keynote B66
Secondary ID [2] 0 0
APG-115-US-002
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Unresectable or Metastatic Melanoma or Advanced Solid Tumors 0 0
Melanoma 0 0
Uveal Melanoma 0 0
P53 Mutation 0 0
MDM2 Gene Mutation 0 0
Cutaneous Melanoma 0 0
Mucosal Melanoma 0 0
Malignant Peripheral Nerve Sheath Tumors (MPNST) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma
Cancer 0 0 0 0
Neuroendocrine tumour (NET)
Cancer 0 0 0 0
Sarcoma (also see 'Bone') - soft tissue
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Phase 1b: APG-115+pembrolizumab

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


Treatment: Drugs: Phase 1b: 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 administrateddose escalation of APG-115 in combination with label dose of pembrolizumab, Fourfour 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 there are cycles every 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.

Phase II: Combination of APG-115 at 150 mg (RP2D) and pembrolizumab or APG-115 monotherapy alone.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Maximum Tolerated Dose
Timepoint [1] 0 0
21 days
Primary outcome [2] 0 0
Recommended Phase II Dose
Timepoint [2] 0 0
21 days
Primary outcome [3] 0 0
Overall Response Rate
Timepoint [3] 0 0
up to 12 months

Eligibility
Key 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.
Minimum age
12 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
29/08/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/03/2025
Actual
Sample size
Target
230
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC
Recruitment hospital [1] 0 0
Metro South Hospital and Health Services via Princess Alexandra Hospital - Brisbane
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [4] 0 0
Austin Health - Heidelberg
Recruitment postcode(s) [1] 0 0
- Brisbane
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
5042 - Bedford Park
Recruitment postcode(s) [4] 0 0
- Heidelberg
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Arkansas
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
District of Columbia
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Missouri
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
North Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Pennsylvania
Country [11] 0 0
United States of America
State/province [11] 0 0
Tennessee
Country [12] 0 0
United States of America
State/province [12] 0 0
Texas
Country [13] 0 0
United States of America
State/province [13] 0 0
Virginia

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Ascentage Pharma Group Inc.
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Merck Sharp & Dohme LLC
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT03611868
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Yifan Zhai, MD, PhD
Address 0 0
Ascentage Pharma
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Kat Richardson
Address 0 0
Country 0 0
Phone 0 0
202-590-8039
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03611868