APG-115 + Pembrolizumab for Skin Cancer

Not currently recruiting at 22 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for individuals with certain types of advanced skin cancer, such as melanoma, that have not responded to previous treatments. The study examines the safety and effectiveness of a new drug, APG-115 (also known as Alrizomadlin), used alone or with pembrolizumab, a drug that aids the immune system in fighting cancer. The goal is to determine if these drugs can work together to help the body kill cancer cells more effectively. Suitable participants have melanoma that cannot be surgically removed or has spread after other treatments failed. Participants should not have received similar treatments before or have certain medical conditions, such as active infections. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of APG-115 and pembrolizumab is generally easy for patients to tolerate. In earlier studies, patients did not experience overlapping harmful effects when these treatments were used together. Reports from these studies indicate that patients managed the combination well without serious side effects. These findings suggest that the treatment is relatively safe for people, based on data from these earlier trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of APG-115 and pembrolizumab for skin cancer because this duo could offer a fresh approach to treatment. APG-115 is a novel drug that targets the MDM2 protein, a strategy that could enhance the effectiveness of pembrolizumab, an established immunotherapy. Unlike traditional options like surgery, chemotherapy, or radiation, this combination aims to boost the immune system's ability to fight cancer cells more effectively. By potentially overcoming resistance to current immunotherapies, this treatment could provide new hope for patients who have limited options.

What evidence suggests that this treatment might be an effective treatment for skin cancer?

Research has shown that using APG-115 with pembrolizumab may help treat advanced skin cancers, such as metastatic melanoma. In this trial, participants will receive a combination of APG-115, which blocks a pathway to restore the function of p53—a protein that helps destroy cancer cells—and pembrolizumab, which boosts the immune system. This treatment has shown early signs of reducing tumors in some patients. Recent studies found that this combination was generally well tolerated, with some patients experiencing smaller tumors. These findings suggest that the combination may help the immune system fight cancer more effectively. ^{1 4 6 7 8}

Who Is on the Research Team?

Yifan Zhai, MD, PhD

Principal Investigator

Ascentage Pharma

Are You a Good Fit for This Trial?

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 have a condition like RA or IBD that causes long-term inflammation.

I haven't used any experimental drugs or devices recently.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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]

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]

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 (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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.9559

A phase 2 study of alrizomadlin (APG-115) in combination ... Results: As of December 12, 2022, preliminary and interim results are reported for 31 patients with cutaneous melanoma, of whom 21 were male and ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03611868

NCT03611868 | A Study of APG-115 in as a Monotherapy ... This study aims to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of APG-115, an MDM2 inhibitor, either alone or in combination ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.9517

Newly updated activity results of alrizomadlin (APG-115), a ... Alrizomadlin, combined with pembrolizumab, is well tolerated and demonstrates preliminary antitumor activity in multiple tumor types.

4. ascentage.com ascentage.com/live-from-asco-2023-for-the-third-consecutive-year-ascentage-pharma-releases-promising-results-of-alrizomadlin-plus-pembrolizumab-in-patients-with-cutaneous-melanoma-that-failed-immuno-oncologic-i/

Live from ASCO 2023 | For the Third Consecutive Year ... A phase 2 study of alrizomadlin (APG-115) in combination with pembrolizumab in patients with unresectable or metastatic cutaneous melanoma that ...

5. clinicaltrial.be clinicaltrial.be/en/details/67835?per_page=20&only_recruiting=0&only_eligible=0&only_active=0

A Study of APG-115 in as a Monotherapy or Combination ... This is a phase I/II study to assess the safety and tolerability of APG-115 alone or in combination with pembrolizumab in patients with ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.2506

Preliminary results of a phase II study of alrizomadlin (APG- ... Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and may restore antitumor effects in pts with cancer resistant to or ...

7. onclive.com onclive.com/view/alrizomadlin-pembrolizumab-demonstrate-promising-preliminary-responses-in-unresectable-or-metastatic-melanoma-or-advanced-solid-tumors

Alrizomadlin/Pembrolizumab Induces Early Efficacy in ... In the melanoma group, treatment with alrizomadlin plus pembrolizumab achieved an ORR of 24.1%, which included 1 complete response (CR), 5 ...

8. ascentage.com ascentage.com/live-from-asco-2021-ascentage-pharma-presents-updated-results-of-mdm2-p53-inhibitor-alrizomadlin-apg-115-demonstrating-an-orr-of-24-1-including-complete-response-in-combination-with-pembrolizumab/

Live from ASCO 2021 In conclusion, alrizomadlin combined with pembrolizumab is well tolerated, and did not exhibit any overlapping toxicity. These preliminary ...