Brief Title
A Study of APG-115 in Combination With Pembrolizumab in Patients With Metastatic Melanomas or Advanced Solid Tumors
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
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.
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. 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. 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. Part 2 includes patients with programmed cell death
protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) refractory/relapsed melanoma and MPNST.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Maximum Tolerated Dose
Condition
Unresectable or Metastatic Melanoma or Advanced Solid Tumors
Intervention
APG-115+Pembrolizumab
Study Arms / Comparison Groups
APG-115+Pembrolizumab open label, two-part phase Ib/II
Description: single arm dose escalation and dose expansion
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
224
Start Date
August 29, 2018
Completion Date
March 30, 2024
Primary Completion Date
December 30, 2023
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 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 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 an 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 or serum 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.
Gender
All
Ages
12 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Yifan Zhai, MD, PhD, 301-509-0357, [email protected]
Location Countries
Australia
Location Countries
Australia
Administrative Informations
NCT ID
NCT03611868
Organization ID
APG-115-US-002
Secondary IDs
Keynote MK-3475-B66
Responsible Party
Sponsor
Study Sponsor
Ascentage Pharma Group Inc.
Collaborators
Merck Sharp & Dohme LLC
Study Sponsor
Yifan Zhai, MD, PhD, Study Chair, Ascentage Pharma Group Inc.
Verification Date
January 2023