CA-4948 + Pembrolizumab for Melanoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: University of Florida
Must not be taking: Immunosuppressants, Steroids
Disqualifiers: Pregnancy, Active infection, Autoimmune, others
No Placebo Group
Breakthrough Therapy
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 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.
12345What 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.
23678What 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.
124910Eligibility 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
I am 18 years old or older.
You must have a disease that can be measured.
I am fully active and can carry on all my pre-disease activities without restriction.
+5 more
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
+14 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: CA-4948 and PembrolizumabExperimental Treatment2 Interventions
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of FloridaGainesville, FL
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Who Is Running the Clinical Trial?
University of FloridaLead Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
References
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.
Pembrolizumab: first global approval. [2021]Pembrolizumab [Keytruda(®) (US)], a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein, has been developed by Merck & Co for the treatment of cancer. Pembrolizumab has received its first global approval for the treatment of advanced, unresectable or metastatic malignant melanoma in the US, for use in patients with disease progression after prior treatment with ipilimumab and, for BRAF V600 mutation-positive patients, a BRAF inhibitor. It is the first anti-PD-1 therapy to receive regulatory approval in the US, and is currently under regulatory review in the EU. This article summarizes the milestones in the development of pembrolizumab leading to this first approval for the treatment of malignant melanoma.
Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. [2023]Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.
Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. [2022]Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized.
Pembrolizumab superior to ipilimumab in melanoma. [2017]In the first randomized trial to compare FDA-approved immune checkpoint inhibitors as first-line therapy for patients with advanced melanoma, pembrolizumab yielded significantly better treatment outcomes than ipilimumab.
FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.
FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigator's choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.47-0.83; P < 0.001; every-3-week arm: HR = 0.69; 95% CI, 0.52-0.90; P = 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response-based endpoints using RECIST or immune-related RECIST. Clin Cancer Res; 23(19); 5661-5. ©2017 AACR.
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.
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.
Comparison of three-weekly and six-weekly pembrolizumab United Kingdom prescribing practice for advanced and resected melanoma. [2023]Pembrolizumab is approved for the treatment of advanced and resected melanoma and was originally licensed as a three-weekly infusion (Q3W). In April 2019, a six-weekly infusion schedule (Q6W) was also approved. We retrospectively reviewed pembrolizumab prescribing for patients with melanoma across multiple United Kingdom (UK) centres to compare the safety and efficacy of Q6W with Q3W in real-world clinical practice.