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.
- 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
Clinical Trial IDs
- ORG STUDY ID:
- SECONDARY ID:
- NCT ID:
- Unresectable or Metastatic Melanoma or Advanced Solid Tumors
|APG-115+Pembrolizumab||APG-115+Pembrolizumab open label, two-part phase Ib/II|
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.
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.
|APG-115+Pembrolizumab open label, two-part phase Ib/II||Experimental||single arm dose escalation and dose expansion|
Male or non-pregnant, non-lactating female patients age ≥18 years on day of signing the
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
1. Histologically confirmed, unresectable or metastatic melanoma, and refractory or
relapse after PD1 antibody treatment and ineligible for other standard of care
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
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
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
|Maximum Eligible Age:||N/A|
|Minimum Eligible Age:||18 Years|
Primary Outcome Measures
|Measure:||Maximum Tolerated Dose|
|Time Frame:||21 days|
|Description:||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|
|Phase:||Phase 1/Phase 2|
|Lead Sponsor:||Ascentage Pharma Group Inc.|
August 7, 2020