CA-4948 + Pembrolizumab for Melanoma

Overseen By Priya Gurjar

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Florida

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Pregnancy, Active infection, Autoimmune, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

29 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial will investigate the use of the novel oral IRAK-4 inhibitor CA-4948 in combination with pembrolizumab therapy following stereotactic radiosurgery (SRS) in patients with melanoma brain metastases (MBM). The investigators hypothesize that the addition of CA-4948 will reduce the rate of distant intracranial failure and reduce the need for subsequent radiation therapy. The investigators also propose that it will have a significant reduction in radiation necrosis and improve patient-reported symptoms and quality of life. This trial represents the first time an oral IRAK-4 inhibitor has been used in combination with aPD1 therapy in MBM and will yield valuable insight into its synergistic potential both in MBM and additional sites of metastases.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that you cannot continue medications that are contraindicated (not recommended) with CA-4948 or pembrolizumab. It's best to discuss your current medications with the trial team to see if any changes are needed.

What data supports the effectiveness of the drug CA-4948 + Pembrolizumab for melanoma?

Pembrolizumab, a part of the treatment, has shown strong antitumor activity and safety in patients with advanced melanoma, with high response rates and better outcomes compared to other treatments like ipilimumab. ^{1 2 3 4 5}

What safety data exists for Pembrolizumab (KEYTRUDA) in humans?

Pembrolizumab has been shown to be generally safe in humans, with common side effects including fatigue, cough, nausea, itching, rash, decreased appetite, constipation, joint pain, and diarrhea. Some patients may experience immune-related side effects like lung inflammation, colon inflammation, liver inflammation, and thyroid issues. ^{2 3 6 7 8}

What makes the drug CA-4948 + Pembrolizumab unique for treating melanoma?

This drug combination is unique because it combines CA-4948, a novel treatment, with Pembrolizumab, a well-established anti-PD-1 therapy that helps the immune system attack cancer cells. Pembrolizumab has shown high response rates in melanoma, and combining it with CA-4948 may enhance its effectiveness. ^{1 2 4 9 10}

Research Team

Bently Doonan, MD, MS

Principal Investigator

University of Florida

Eligibility Criteria

Adults with melanoma brain metastases planning to undergo stereotactic radiosurgery, who have good organ function and performance status. They must be able to tolerate MRIs, not be pregnant or breastfeeding, agree to use contraception, and can't have had certain treatments or vaccines recently. Those with controlled HIV or hepatitis are eligible.

Inclusion Criteria

You must have a disease that can be measured.

I am fully active and can carry on all my pre-disease activities without restriction.

Patients must have adequate organ and marrow function as defined below: absolute neutrophil count ≥ 1,500/mcL, platelets ≥ 100,000/mcL, hemoglobin ≥ 9.0 g/dL or ≥5.6 mmol/L, coagulation PT/INR and aPTT ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic ranged of intended use for anticoagulants, total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) OR direct bilirubin no lower than the ULN if total bilirubin > 1.5 × ULN, AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN (with confirmed liver metastases: AST and ALT ≤ 5 x ULN), creatinine clearance (CrCl)≤ 1.5 × ULN measured or calculated OR glomerular filtration rate (GFR)≥ 30 mL/min based on modified Cockcroft and Gault formula for participants with creatinine levels > 1.5 × institutional upper limit of normal (ULN), HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial, for patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated, patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load, subjects of childbearing potential must have a negative serum pregnancy test at screening and agree to use of highly effective methods of contraception throughout the study and for at least four months following the last dose of study treatment, subjects with partners of childbearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation and 4 months after completion of CA-4948 administration, patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial, participants must have recovered from all adverse events due to previous therapies to ≤Grade 1 or baseline with the exception of alopecia, archival tumor tissue sample or newly obtained biopsy of a tumor lesion not previously irradiated has been provided, ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

I haven't needed systemic treatment for an autoimmune disease in the last 2 years.

I have received an organ or tissue transplant from another person.

Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stereotactic Radiosurgery

Participants undergo stereotactic radiosurgery as part of the initial treatment

1 week

Treatment

Participants receive oral IRAK-4 inhibitor CA-4948 in combination with pembrolizumab

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• CA-4948
• Pembrolizumab

Trial Overview The trial is testing a new oral drug called CA-4948 combined with Pembrolizumab after targeted brain radiation therapy in patients with melanoma that has spread to the brain. It aims to see if this combination reduces further brain tumors and improves quality of life.

Participant Groups

Group I: CA-4948 and Pembrolizumab Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

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 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]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

In a study of 655 patients with advanced melanoma, pembrolizumab showed a 5-year overall survival rate of 34%, with even better outcomes (41%) for treatment-naive patients, indicating its long-term efficacy.

The treatment was generally well-tolerated, with 86% of patients experiencing treatment-related adverse events, but only 7.8% discontinued due to these effects, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Hamid, O., Robert, C., Daud, A., et al.[2023]

In a post hoc analysis of the KEYNOTE-006 study involving 555 patients with advanced melanoma, both ipilimumab and BRAF ± MEK inhibitors showed antitumor activity as subsequent therapies after pembrolizumab, with overall response rates (ORR) of 17.5% for ipilimumab and 30.5% for BRAF ± MEK inhibitors.

Patients who had not previously received BRAF ± MEK inhibitors showed a significantly higher ORR of 43.2% when treated with these agents after pembrolizumab, indicating that prior treatment status may influence the effectiveness of subsequent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. Long, GV., Arance, A., Mortier, L., et al.[2022]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

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 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]

In a study of 277 melanoma patients treated with pembrolizumab, the six-weekly (Q6W) infusion schedule showed similar safety profiles to the three-weekly (Q3W) schedule, with comparable rates of severe adverse events (14.9% for Q6W vs. 15.5% for Q3W).

The estimated 12-month recurrence-free survival was slightly higher for the Q6W group (78.9%) compared to the Q3W group (74.2%), suggesting that Q6W is an effective alternative that can help reduce healthcare resource use without compromising patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of three-weekly and six-weekly pembrolizumab United Kingdom prescribing practice for advanced and resected melanoma. Mehta, I., Dayimu, A., Kumar, S., et al.[2023]

References

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

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

2. New Zealand pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. [2021]

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

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. [2022]

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

8. 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]

9. 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]

10. England pubmed.ncbi.nlm.nih.gov

Comparison of three-weekly and six-weekly pembrolizumab United Kingdom prescribing practice for advanced and resected melanoma. [2023]