A Study of Oral IRAK-4 Inhibitor CA-4948 in Combination With Pembrolizumab and Stereotactic Radiosurgery in Patients With Melanoma Brain Metastases

NCT05669352 | Suspended Phase 1 DMC FDA Drug

• 1 other identifier: UF-CUT-002
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Melanoma Metastatic in the Brain

Keywords

melanoma; stereotactic radiosurgery; brain metastases

Outcome Measures

Primary Outcomes (1)

• Reduction in need for repeated intercranial intervention 1 year after initial stereotactic radiosurgery (SRS)

  Determine if the combination of CA-4948 and pembrolizumab reduces the need for repeated intercranial intervention 1 year after initial SRS, as measured by remaining free from need for repeated intracranial intervention 1 year after initial SRS (surgery, SRS, laser interstitial thermal therapy, or whole brain radio-therapy).

  1 year

Secondary Outcomes (4)

• Intracranial objective response rate

  2 years

• Systemic objective response rate

  2 years

• Radiation necrosis-free survival at 1 year

  1 year

• Overall survival

  2 years

Study Arms (1)

CA-4948 and Pembrolizumab

EXPERIMENTAL

Drug: CA-4948; Drug: Pembrolizumab

Interventions

CA-4948 DRUG

Subjects on both the phase I and phase II portions will take 200 mg CA-4948 orally two times daily.

CA-4948 and Pembrolizumab

Pembrolizumab DRUG

Subjects on both the phase I and phase II portions will receive 400 mg pembrolizumab intravenously once every six weeks.

CA-4948 and Pembrolizumab

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have radiographic or histologically confirmed melanoma brain metastases (MBM) and be planning to undergo or have undergone SRS for treatment
• Patients must have measurable disease
• Patients may be treatment-naïve or currently on therapy for systemic disease control at time of MBM development. If MBM diagnosis coincides with initial diagnosis, patients may be treatment-naïve with systemic disease.
• In patient who develop MBM while previously having received treatment for metastatic melanoma at other systemic locations, previous treatment with dual checkpoint inhibitor therapy (CTLA-4/aPD1 or LAG-3/aPD-1) or single agent immunotherapy therapy will be allowed, as long as at the time of SRS to these MBM lesions the patient is planned to receive aPD1 therapy as long as the above criteria are met and the patients systemic disease is displaying at least SD on last surveillance imaging performed.
• SD is determined by clinician judgement at time of study enrollment. In patients on systemic single agent aPD1 there is no washout necessary in this case and patients can start pembrolizumab and study drug at next scheduled cycle of treatment following completion of SRS as long as all other rules have been met for enrollment.
• Previous oral BRAFi/MEKi treatment will also be allowed, as long as at the time of MBM treatment with SRS the patient is planned to initiate aPD1 therapy and not continue on BRAFi/MEKi. A washout period of 14 days from last dose of BRAFi/MEKi to initiation of study drug is required.
• Treatment of symptomatic MBM with corticosteroids is allowed while receiving CA- 4948, but in order to start aPD1 therapy, patient must be on ≤ 10mg of oral prednisone daily or equivalent.
• Patients must be tolerant of receiving MRI and cannot have intolerance to gadolinium contrast.
• Age ≥18 years at time of informed consent.
• ECOG performance status ≤1
• 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

You may not qualify if:

• Subject of child-bearing potential who has a positive urine pregnancy test within 72 hours prior to treatment
• Subject has received prior systemic anti-cancer therapy including investigational agents or devices within 4 weeks prior to screening
• If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
• Prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids over ≤ 10mg of oral prednisone daily or equivalent, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. mRNA COVID-1 vaccines are allowed.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab, CA-4948, or any of their excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• Has a history of non-infectious pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy, is patient is receiving oral antibiotics for localized infection with planned end date they may enroll on study as soon as duration is complete.
• 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.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the trial's requirements.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
• Has had an allogenic tissue/solid organ transplant.

Sponsors & Collaborators

• University of Florida: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32608, United States

Location

MeSH Terms

Conditions

Melanoma; Brain Neoplasms

Interventions

CA-4948; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Bently Doonan, MD, MS

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2022
• First Posted: December 30, 2022
• Study Start: April 1, 2025
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2027
• Last Updated: April 4, 2025

Record last verified: 2025-03

Locations

US (1)