APG-115 + Pembrolizumab for Skin Cancer

Recruiting at 20 trial locations

Overseen By Jocelyn Budzynski

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ascentage Pharma Group Inc.

Must not be taking: Corticosteroids, Antibiotics, Antifungals, others

Disqualifiers: CNS metastases, Chronic infections, Organ transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days

230 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 4 5 6}

What 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. ^{3 4 7 8 9}

Research Team

Yifan Zhai, MD, PhD

Principal Investigator

Ascentage Pharma

Eligibility 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

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.

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

Treatment Details

Interventions

• APG-115
• Pembrolizumab

Trial Overview 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.

Participant Groups

Group I: APG-115+pembrolizumab open label, two-part phase Ib/II Experimental Treatment 1 Intervention

single arm dose escalation and dose expansion

Who Is Running the Clinical Trial?

Ascentage Pharma Group Inc.

Lead Sponsor

Trials

54

Recruited

5,700+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase II trial involving 159 patients with locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma, pembrolizumab showed significant antitumor activity, with an objective response rate of 50.0% in the locally advanced cohort and 35.2% in the recurrent/metastatic cohort.

The treatment demonstrated a manageable safety profile, with only 11.9% of patients experiencing grade 3-5 treatment-related adverse events, indicating that pembrolizumab is a promising and durable treatment option for cSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial. Hughes, BGM., Munoz-Couselo, E., Mortier, L., et al.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a phase Ib trial (KEYNOTE-028) involving 43 patients with advanced anal carcinoma, pembrolizumab showed a manageable safety profile, with 64% experiencing treatment-related adverse events, but no treatment-related deaths or discontinuations.

Among patients with PD-L1-positive tumors, pembrolizumab achieved a 17% overall response rate and a 58% disease control rate, indicating promising antitumor activity and supporting further research in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ott, PA., Piha-Paul, SA., Munster, P., et al.[2021]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

In a study involving 173 patients with advanced melanoma who had not responded to previous treatments, pembrolizumab showed an overall response rate of 26% at both 2 mg/kg and 10 mg/kg doses, indicating its potential effectiveness in this challenging patient population.

The treatment was well tolerated with no drug-related deaths, and the safety profiles were similar across both doses, with fatigue, pruritus, and rash being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Robert, C., Ribas, A., Wolchok, JD., et al.[2022]

Pembrolizumab, an anti-PD-1 antibody used for treating malignant pleural mesothelioma, can cause serious side effects such as minimal change disease (MCD), which was identified in a 62-year-old patient who developed nephrotic syndrome and acute renal failure after treatment.

The patient's symptoms improved significantly after discontinuing pembrolizumab and starting steroid treatment, highlighting the importance of monitoring renal function and recognizing potential autoimmune reactions in patients receiving this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. Bickel, A., Koneth, I., Enzler-Tschudy, A., et al.[2022]

This study presents the first known case of a patient with metastatic melanoma who was successfully treated with pembrolizumab while undergoing hemodialysis, highlighting its potential efficacy in patients with end-stage renal disease.

Pembrolizumab, an FDA-approved monoclonal antibody for metastatic melanoma and non-small cell lung cancer, shows promise for use in patients with renal complications, although specific dosing guidelines for such patients are still lacking.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab in a patient with advanced melanoma on haemodialysis. Chang, R., Shirai, K.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

4. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab in a patient with advanced melanoma on haemodialysis. [2019]