Overview
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.
Principal investigator
Eligibility criteria
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.
* 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.
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