APG-115 + Pembrolizumab for Skin Cancer
Recruiting in Palo Alto (17 mi)
+20 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Ascentage Pharma Group Inc.
Must not be taking: Corticosteroids, Antibiotics, Antifungals, others
Disqualifiers: CNS metastases, Chronic infections, Organ transplant, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received chemotherapy, hormonal, biologic, or other anti-cancer therapies within 21 days before the first dose, and certain other treatments have specific time restrictions.
What data supports the effectiveness of the drug pembrolizumab for skin cancer?
Research shows that pembrolizumab has been effective in treating various types of skin cancer, including melanoma and cutaneous squamous cell carcinoma, by helping the immune system attack cancer cells. It has shown durable antitumor activity and manageable safety in these conditions.
12345Is the combination of APG-115 and Pembrolizumab safe for humans?
Pembrolizumab, also known as Keytruda, has been studied in various cancers and generally shows a manageable safety profile, meaning that side effects are present but can be controlled. In studies with nonhuman primates, pembrolizumab did not show significant toxic effects, suggesting it is generally safe. However, specific safety data for the combination with APG-115 is not provided in the available research.
12456What makes the drug APG-115 + Pembrolizumab unique for treating skin cancer?
The combination of APG-115 and Pembrolizumab is unique because it pairs a novel agent, APG-115, with Pembrolizumab, a well-established drug that helps the immune system attack cancer cells by blocking a protein called PD-1. This combination may enhance the immune response against skin cancer compared to using Pembrolizumab alone.
34789Eligibility Criteria
This trial is for adults with metastatic melanomas or advanced solid tumors who have specific heart health measures, can provide tumor tissue samples, and are willing to use effective contraception. It's not for those with active brain metastases, certain recent treatments, uncontrolled illnesses, autoimmune diseases requiring steroids, live vaccines recently taken, or women who are pregnant.Inclusion Criteria
I can provide a sample of my tumor for testing before starting the trial treatment.
My melanoma cannot be surgically removed, has returned or didn't respond to PD-1 treatment, and I can't receive other standard treatments.
Ability to understand and willingness to sign a written informed consent form. Willingness and ability to comply with study procedures and follow-up examination
+10 more
Exclusion Criteria
I have never been treated with MDM2-p53 inhibitors.
I haven't used any experimental drugs or devices recently.
I haven't had a heart attack or heart surgery recently.
+20 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive APG-115 alone or in combination with pembrolizumab to assess safety, tolerability, and efficacy
21 days
Dose escalation and expansion visits
Follow-up
Participants are monitored for safety and effectiveness after treatment
up to 12 months
Participant Groups
The study tests APG-115 combined with pembrolizumab. Part 1 finds the safe dose level; Part 2 uses this dose in a larger group to see how well it works against different types of cancer like melanoma and nerve sheath tumors.
1Treatment groups
Experimental Treatment
Group I: APG-115+pembrolizumab open label, two-part phase Ib/IIExperimental Treatment1 Intervention
single arm dose escalation and dose expansion
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Cincinnati Children's Hospital Medical CenterCincinnati, OH
UCLA Hematology & Oncology ClinicLos Angeles, CA
Highlands OncologyRogers, AR
University of Texas MD Anderson Cancer CenterHouston, TX
More Trial Locations
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Who Is Running the Clinical Trial?
Ascentage Pharma Group Inc.Lead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
References
Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.
Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial. [2022]Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC).
Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]Pembrolizumab (MK-3475) is a monoclonal antibody that binds to the PD-1 receptor on T cells and prevents binding to its ligands PD-L1 and PD-L2. Blocking this receptor frees T cells from the inhibitory effects of PD-L1 and allows them to mediate antitumor effects against cancer cells. In a large Phase I study of 411 patients with melanoma, high durable response rates over a range of doses and schedules have been shown with very little toxicity. A Phase III study of pembrolizumab comparing two schedules of administration with the current standard treatment with the anti-CTLA-4 monoclonal antibody is in progress. Combinations with other checkpoint inhibitors as well as other anticancer agents are also being evaluated. Approval of pembrolizumab for the treatment of melanoma is expected.
Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled.
Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. [2021]Safety and efficacy of pembrolizumab, a humanized programmed death 1 monoclonal antibody, was assessed in KEYNOTE-028, a multicohort, phase Ib trial for patients with programmed death ligand 1 (PD-L1)-positive advanced solid tumors. We report results for the cohort of patients with advanced anal carcinoma.
Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances the functional activity of T cells to facilitate tumor regression and ultimately immune rejection. Pembrolizumab binds to human and cynomolgus monkey PD-1 with picomolar affinity and blocks the binding of human and cynomolgus monkey PD-1 to PD-L1 and PD-L2 with comparable potency. Pembrolizumab binds both the C'D and FG loops of PD-1. Pembrolizumab overcomes human and cynomolgus monkey PD-L1-mediated immune suppression in T-cell cultures by enhancing IL2 production following staphylococcal enterotoxin B stimulation of healthy donor and cancer patient cells, and IFNγ production in human primary tumor histoculture. Ex vivo and in vitro studies with human and primate T cells show that pembrolizumab enhances antigen-specific T-cell IFNγ and IL2 production. Pembrolizumab does not mediate FcR or complement-driven effector function against PD-1-expressing cells. Pembrolizumab displays dose-dependent clearance and half-life in cynomolgus monkey pharmacokinetic and toxicokinetic studies typical for human IgG4 antibodies. In nonhuman primate toxicology studies, no findings of toxicologic significance were observed. The preclinical data for pembrolizumab are consistent with the clinical anticancer activity and safety that has been demonstrated in human clinical trials.
Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. [2022]The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma.
Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. [2022]Pembrolizumab is an anti- Programmed Death 1 (PD-1) antibody approved in melanoma, non-small cell lung cancer and investigated in malignant pleural mesothelioma. The most frequent immunotherapy related autoimmune reactions include dermatitis, pneumonitis, colitis, hypophysitis, uveitis, hypothyreodism, hepatitis and interstitial nephritis.
Safety and efficacy of pembrolizumab in a patient with advanced melanoma on haemodialysis. [2019]Patients with end-stage renal disease present with a distinct challenge in oncology. Many anticancer drugs and their metabolites are excreted by the kidney, but data to guide dose and schedule adjustments in renal dialysis are scant. Pembrolizumab is an anti-programmed cell death protein 1 monoclonal antibody proven to be effective in patients with metastatic melanoma. It has demonstrated promising results and was granted US Food and Drug Administration (FDA) approval in September, 2014 for metastatic melanoma. It was additionally approved for patients with metastatic non-small cell lung cancer by the FDA in October, 2015. We present the first case, to the best of our knowledge, of a patient with metastatic melanoma successfully treated with pembrolizumab while on haemodialysis.