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

Prior treatment

• 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.
• Administration of a live, attenuated vaccine within 30 days before randomization.
• Has received prior systemic immunotherapy 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), except for anti-PD-1 or anti-PD-L1 agents in the peri-operative setting if progression/recurrence occurred ≥12 months after its completion.
• Life expectancy < 3 months and/or a rapidly progressing disease (eg, uncontrolled tumor pain), which should be reviewed in the context of prior systemic therapy in the curative setting and must be discussed with the Sponsor.
• Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks prior randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy, such as radiation pneumonitis or fistulation, are not eligible
• 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

Other illness

• Has disease that is suitable for local therapy administered with curative intent
• Had documented progressive disease within less than 6 months of completion of either curatively or palliatively intended systemic treatment (ie, chemotherapy) for HNSCC, in locally advanced HNSCC or peri-operative setting. Note: radiographic confirmation of progressive disease is required. If both histologic and radiographic confirmations are available, the earliest date should be considered for documentation purposes. Subjects who progressed within 6 months of systemic treatment in non-curative setting are also excluded.
• Positive hepatitis B surface antigen (HBsAg) test.
• Positive hepatitis C virus (HCV) antibody test

Lab values

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 28 days before randomization.

Other

• Nasopharynx, salivary gland or occult primary site (regardless of p16 status)
• Pregnant or lactating females.

• Histologically or cytologically-confirmed R/M HNSCC that is considered incurable by local therapy Note: 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. Note: The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
• PD-L1 expression level Combined Positive Score (CPS) ≥ 1
• Subjects with oropharynx cancer must have assessment of HPV status from tumor tissue, per p16 testing.
• Measurable disease according to RECIST 1.1 determined by the Investigator.
• Recovery to baseline or ≤ Grade 1 severity(CTCAE v5) from adverse events (AEs) related to any prior treatments, unless AE(s) is clinically nonsignificant and/or stable on supportive therapy.
• Age 18 years (or the legal age of consent in your country, if higher than 18) or older on the day of consent.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 ; with documented assessment of independent activities of daily living (ADLs) and physical activity, as appropriate and according to subject’s age.
• Adequate organ and marrow function