Study of Zanzalintinib (XL092) + Pembrolizumab vs Pembrolizumab in Subjects With PD-L1 Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, controlled Phase 2/3 trial of zanzalintinib in combination with pembrolizumab versus zanzalintinib-matched placebo in combination with pembrolizumab in subjects with PD-L1 positive recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) incurable by local therapies who have not received prior systemic therapy for recurrent or metastatic disease.

Official Title
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A Phase 2/3, Randomized, Double-Blind, Controlled Study of Zanzalintinib (XL092) in Combination With Pembrolizumab vs Pembrolizumab in First-Line Treatment of Subjects With PD-L1 Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Zanzalintinib
* Drug: Zanzalintinib-matched Placebo
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically-confirmed R/M HNSCC that is considered incurable by local therapy. Subjects should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to randomization if given as part of multimodal treatment for locally advanced disease is allowed. The eligible primary tumor locations are the oropharynx, oral cavity, hypopharynx, and larynx. PD-L1 expression level Combined Positive Score (CPS) ≥ 1 by immunohistochemistry (IHC) testing. Have human papilloma virus (HPV) testing result for oropharyngeal cancer defined as p16 IHC testing. Measurable disease according to RECIST 1.1 determined by the Investigator. Tumor samples (archival or fresh tumor biopsy) are required. If archival tissue is unavailable, must provide fresh tumor tissue biopsy prior to randomization. Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from adverse events (AEs) related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. Age 18 years or older on the day of consent. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Adequate organ and marrow function. Exclusion Criteria: Nasopharynx, salivary gland or occult primary site (regardless of p16 status). Has disease that is suitable for local therapy administered with curative intent. Has received prior therapy with zanzalintinib, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). Life expectancy < 3 months. Had progressive disease within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC. Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks prior to randomization. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to randomization. Positive hepatitis B surface antigen (HBsAg) test. Positive hepatitis C virus (HCV) antibody test. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to randomization. Complete wound healing from major or minor surgery must have occurred at least prior to randomization. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 28 days before randomization. Pregnant or lactating females. Administration of a live, attenuated vaccine within 30 days before randomization.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zanzalintinib + Pembrolizumab<br>Subjects with R/M HNSCC will receive zanzalintinib + pembrolizumab | Drug: Zanzalintinib<br>* Specified doses on specified days<br>* Other names: XL092;Biological: Pembrolizumab<br>* Specified doses on specified days<br>* Other names: Keytruda®;|
| Placebo Comparator: Zanzalintinib-Matched Placebo + Pembrolizumab<br>Subjects with R/M HNSCC will receive zanzalintinib-matched placebo + pembrolizumab | Drug: Zanzalintinib-matched Placebo<br>* Specified doses on specified days<br>* Other names: XL092-matched Placebo;Biological: Pembrolizumab<br>* Specified doses on specified days<br>* Other names: Keytruda®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by Blinded Independent Radiology Committee (BIRC) | Defined as the time from randomization to the earlier of either radiographic progressive disease (PD) per RECIST 1.1 as determined by the BIRC or death from any cause | Approximately 28 months after the first subject is randomized | 
| Overall Survival (OS) | Defined as the time from randomization to death due to any cause | Approximately 40 months after the first subject is randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS per RECIST 1.1 by Investigator | Defined as the time from randomization to the earlier of either radiographic PD per RECIST 1.1 as determined by the Investigator or death from any cause | Approximately 28 months after the first subject is randomized | 
| Objective Response Rate (ORR) per RECIST 1.1 by BIRC and Investigator | Defined as the proportion of subjects with the best overall response of complete response (CR) or partial response (PR) per RECIST 1.1 as determined by the BIRC and Investigator | Approximately 28 months after the first subject is randomized | 
| Duration of Response (DOR) Per RECIST 1.1 by BIRC and Investigator | Defined as the time from the first documentation of objective response (subsequently confirmed at a visit ≥ 28 days later) to disease progression or death due to any cause | Approximately 28 months after the first subject is randomized |