A Phase 1/2 Study of Oral IRAK-4 Inhibitor CA-4948 in Combination With Pembrolizumab Following Stereotactic Radiosurgery in Patients With Melanoma Brain Metastases

Sponsor

University of Florida (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05669352

Collaborator

Merck Sharp & Dohme LLC (Industry)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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 in patients with melanoma brain metastases (MBM). We hypothesize that the addition of CA-4948 will reduce the rate of distant intracranial failure and reduce the need for subsequent radiation therapy. We 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.

Condition or Disease	Intervention/Treatment	Phase
Melanoma Metastatic in the Brain	Drug: CA-4948 Drug: Pembrolizumab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

29 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2 Study of Oral IRAK-4 Inhibitor CA-4948 in Combination With Pembrolizumab Following Stereotactic Radiosurgery in Patients With Melanoma Brain Metastases

Anticipated Study Start Date :

Aug 1, 2023

Anticipated Primary Completion Date :

Aug 1, 2026

Anticipated Study Completion Date :

Aug 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CA-4948 and Pembrolizumab	Drug: CA-4948 Subjects on both the phase I and phase II portions will take 200 mg CA-4948 orally two times daily. Drug: Pembrolizumab Subjects on both the phase I and phase II portions will receive 400 mg pembrolizumab intravenously once every six weeks.

Arm

Intervention/Treatment

Experimental: CA-4948 and Pembrolizumab

Drug: CA-4948

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

Drug: Pembrolizumab

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

Outcome Measures

Primary Outcome Measures

Reduction in need for repeated intercranial intervention 1 year after initial sterotactic radiosurgery (SRS) [1 year]
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).

Secondary Outcome Measures

Intracranial objective response rate [2 years]
Determine the intracranial objective response rate, as measured by Response Assessment in Neuro-Oncology (RANO) criteria
Systemic objective response rate [2 years]
Determine the systemic objective response rate, as measured by iRECIST criteria
Radiation necrosis-free survival at 1 year [1 year]
Overall survival [2 years]
Determine the overall survival of patients with melanoma brain metastases treated with CA-4948 and pembrolizumab

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have radiographic or histologically confirmed melanoma brain metastases (MBM) and be planning to undergo 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 currently on therapy, patients must have at least stable disease (SD) systemically per RECIST criteria at the time of MBM diagnosis. If MBM diagnosis coincides with initial diagnosis, patients may be treatment-naïve with systemic disease.
Patients must have peripheral disease amenable to biopsy.
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
hemoglobina ≥ 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)
Human immunodeficiency virus (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. Subjects should also not donate sperm from first dose of therapy until 4 months after the last dose of treatment.
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:

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.
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.
Unable to discontinue medications contraindicated to CA-4948 or pembrolizumab.
Patients with uncontrolled intercurrent illness.