XL092 and Cemiplimab in BRAF WT Thyroid Cancer (NEO-COMBATXL)

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).

Study Overview

• Status: Recruiting
• Conditions: Thyroid Cancer; Anaplastic Thyroid Cancer; BRAF Mutation-Related Tumors
• Intervention / Treatment: Biological: Cemiplimab; Drug: XL092

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Rose Hall; Phone Number: 1-(919) 966-0808; Email: rose_hall@med.unc.edu
• Study Contact Backup: Name: Lori Stravers; Phone Number: 1-(919) 966-4432; Email: lori_stravers@med.unc.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Not yet recruiting
      • Dana Farber/Harvard Cancer Center
      • Contact: Veronica Bedard; Phone Number: 617-582-7323
      • Contact: Theodora Pappa, MD, PhD; Phone Number: 617-732-5666; Email: theodora_pappa@dfci.harvard.edu
      • Principal Investigator: Theodora Pappa, MD, PhD
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Recruiting
      • University of North Carolina At Chapel Hill
      • Contact: Siddharth Sheth, MD; Email: siddharth.sheth@unchealth.unc.edu
      • Contact: Melissa B Flores; Phone Number: (919)-966-4432; Email: melissa_flores@med.unc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: neoadjuvant XL092 and cemiplimab; Subjects with BRAFV600E wild type (WT) anaplastic thyroid cancer (ATC) who are scheduled to undergo surgical resection as part of their standard of care will receive neoadjuvant XL092 and cemiplimab. Adjuvant therapy may be indicated based on surgical pathology.	Biological: Cemiplimab; Cemiplimab will be administered at a dose of 350mg intravenous over 30 minutes every 3 weeks for 3 cycles (cycle length is 21 days) at weeks 1, 4, and 7.; Drug: XL092; XL092 will be administered at a dose of 60mg PO daily for 8 weeks (weeks 1-8)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete gross resection	Complete gross resection (CGR) is defined as the proportion of patients who undergo successful thyroidectomy with negative (R0) or microscopically positive (R1) surgical margins.	12 weeks
Non-hematologic treatment related adverse events (TRAEs)	Non-hematologic treatment related adverse events (TRAEs) with neoadjuvant and maintenance XL092 and cemiplimab will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI- CTCAE) v5.0.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Objective response rate (ORR) following neoadjuvant therapy prior to surgery as defined as a partial or complete response per Radiographic response will be measured by RECIST, 1.1 criteria. Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	10 weeks
Time to surgery	Time to surgery following completion of neoadjuvant XL092 and cemiplimab will be defined as the time from completion of neoadjuvant therapy to date of surgery. Participants who do not receive surgery due to progressive disease or non-treatment-related adverse events death will not be counted.	12 weeks
The rate of pathologic response	The rate of pathologic response will be defined as either a pathological complete response (pCR), which is the absence of a residual viable tumor or a major pathological response (MPR), which is < 10% residual tumor following neoadjuvant therapy and surgery.	12 weeks
Conversion rate from unresectable to resectable disease	Conversion rate from unresectable to resectable disease will be defined as the number of subjects with unresectable disease at the time of screening who are deemed to have resectable disease at the completion of neoadjuvant therapy.	12 weeks
Event free survival (EFS)	Event free survival (EFS) will be defined as the time of first treatment to an event which may include disease progression, discontinuation of the treatment for any reason, or death from any cause, where disease progression will be determined based on RECIST 1.1 criteria. If a patient has no events, they will be censored at the last known alive date. Complete Response (CR), the disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	Up to 5 years
Overall survival (OS)	Overall survival (OS) of participants receiving neoadjuvant XL092 and cemiplimab will be defined as the time from the date of first treatment to death.	Up to 5 years

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: Regeneron Pharmaceuticals; Exelixis
• Investigators: Principal Investigator: Siddharth Sheth, DO MPH, UNC Lineberger Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• UNC Lineberger Comprehensive Cancer Center Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2025
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): August 31, 2028

Study Registration Dates

• First Submitted: March 18, 2025
• First Submitted That Met QC Criteria: March 18, 2025
• First Posted (Actual): March 30, 2025

Study Record Updates

• Last Update Posted (Estimated): November 5, 2025
• Last Update Submitted That Met QC Criteria: November 3, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: neoadjuvant chemotherapy; receptor tyrosine kinase inhibitor; standard of care; neoadjuvant immunotherapy; cemiplimab; XL092; BRAF V600E-WT ATC
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Thyroid Diseases; Thyroid Neoplasms; Thyroid Carcinoma, Anaplastic; Antineoplastic Agents, Immunological; Antineoplastic Agents; cemiplimab
• Other Study ID Numbers: LCCC2255

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No