XL092 and Cemiplimab in BRAF WT Thyroid Cancer

NEO-COMBAT XL: Neoadjuvant and Maintenance XL092 and Cemiplimab in BRAF V600E-wildtype Anaplastic Thyroid Cancer: a Phase 1B Study

This multicenter study examines the safety and feasibility of the combination of neoadjuvant XL092 and cemiplimab prior to surgical resection in participants with wild-type (WT) anaplastic thyroid cancer (ATC) that has a BRAF mutation (BRAF V600E).

This study includes subjects with BRAFV600E wild type (WT) anaplastic thyroid cancer (ATC) who are scheduled to undergo surgical resection as part of their standard of care. The study hypothesizes that the combination of neoadjuvant XL092 and cemiplimab will be safe and feasible prior to surgical resection in participants with BRAF V600E-WT ATC.

Anaplastic thyroid cancer (ATC) is a highly aggressive and fatal malignancy. For patients with BRAF V600E-wildtype ATC, chemotherapy, whether as a single agent or in combination, remains the standard treatment despite its low response rates. Studies have shown that while immunotherapy (IO) and receptor tyrosine kinase inhibitor (TKI) monotherapy are safe for these patients, their efficacy as single agents is limited.

This study addresses a significant unmet need and is based on the strong synergy observed between IO and TKI in clinical studies of other cancers. It includes subjects with BRAF V600E-wildtype ATC who are scheduled for surgical resection as part of their standard care. The study hypothesizes that the combination of neoadjuvant XL092 and cemiplimab will be safe and feasible before surgical resection in these patients.

Inclusion Criteria:

• Written informed consent was obtained to participate in the study and HIPAA authorization for the release of personal health information.
• Subjects are willing and able to comply with study procedures based on the judgment of the investigator.
• Age ≥ 18 years at the time of consent.
• the Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
• Pathologic findings supporting the clinical impression of anaplastic thyroid cancer. Terminology consistent or suggestive of diagnosis may include the following: anaplastic thyroid carcinoma, undifferentiated carcinoma, squamous carcinoma; carcinoma with spindled, giant cell, or epithelial features; poorly differentiated carcinoma with pleomorphism, extensive necrosis with tumor cells present.
• Subject is willing to have a fresh biopsy at least 3 days prior to neoadjuvant therapy if archival tissue is unavailable. Also willing to have a biopsy at the time of SOC surgery, if applicable.
• Must have BRAF V600E mutation-negative tumor, as determined by BRAF V600E immunohistochemistry on tumor tissue or genetic/molecular testing of the tumor.

Exclusion Criteria:

• Pregnant or breastfeeding (Note: breast milk cannot be stored for future use while the mother is being treated on the study). Females should not breastfeed while receiving study treatment and for 1 month from the last dose of XL092.
• Patients who have had prior exposure to any immune modulating agents or any type of small molecule kinase inhibitor (including investigational agents) and have documented disease progression on these agents will not be eligible.
• Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments (i.e., with use of disease modifying agents, corticosteroids (>10 mg of prednisone or equivalent) or immunosuppressive drugs) which may suggest risk of immune-mediated Adverse Events.
• 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. The following are not exclusionary: vitiligo, childhood asthma that has resolved, type 1 diabetes, residual hypothyroidism that required only hormone replacement, or psoriasis that does not require systemic treatment.
• Subject history of documented allergic reactions or acute hypersensitivity reactions attributed to antibody treatments.
• Subject is receiving prohibited medications or treatments as listed in the protocol that cannot be discontinued/replaced by an alternative therapy within 7 days of initiating treatment.
• Participation in another clinical study with an investigational product during the last 3 weeks.