Zanzalintinib with Pembrolizumab and Cetuximab for the Treatment of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

Inclusion Criteria

• Have histologically or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma of the head and neck that is considered incurable by local therapies. * Eligible primary tumor locations include oropharynx, oral cavity, hypopharynx, larynx, nasopharynx, and sinonasal. Unknown primary is also eligible
• Patients must be at least 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• Patients with oropharyngeal primary must have results from testing of human papillomavirus (HPV) (p16) status. * p16 immunohistochemistry (IHC) is sufficient (p16 IHC interpretation to follow guidelines by Jordan and Lingen et al). * Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by p16 IHC as by convention these tumor locations are assumed to be HPV negative
• Availability of PD-L1 combined positive score (CPS) score is required. Patients enrolled with previously untreated disease in the recurrent and/or metastatic setting must have PD-L1 combined positive score of 1 or greater to be eligible for the current study. There is no PD-L1 restriction for patients who have previously received anti-PD(L)1 therapy
• Recovery to baseline or ≤ grade 1 severity (CTCAE v 5) from adverse events (AEs), including immune-related adverse events (irAEs), related to any prior treatments, unless AEs are clinically nonsignificant and/or stable on supportive therapy (eg, physiological replacement of mineral corticosteroid). Low-grade or controlled toxicities such as alopecia, ≤ grade 2 hypomagnesemia, ≤ grade 2 neuropathy are permitted)
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (≥ 1.5 GI/L) without granulocyte colony-stimulating factor support within 2 weeks of screening laboratory sample collection (within 14 days before first dose of study treatment)
• Platelets ≥ 100,000/mm^3 (≥ 100 GI/L) without transfusion within 2 weeks of screening laboratory sample collection (within 14 days before first dose of study treatment)
• Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 2 weeks prior to screening laboratory sample collection (within 14 days before first dose of study treatment)
• International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.2 x upper limit of normal (ULN) (within 14 days before first dose of study treatment)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x ULN. For subjects with documented bone metastasis ALP ≤ 5 x ULN. For subjects with castration-resistant prostate carcinoma (CRPC) and bone metastasis ALP ≤ 10 x ULN if predominantly bone-specific ALP (within 14 days before first dose of study treatment)
• Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert’s disease ≤ 3 x ULN) (within 14 days before first dose of study treatment)
• Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 mL/min (≥ 0.67 mL/sec) using the Cockcroft Gault equation (within 14 days before first dose of study treatment)
• Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine (within 14 days before first dose of study treatment)
• Capable of understanding and complying with the protocol requirements and must have signed the informed consent document
• Sexually active fertile subjects and their partners must agree to use highly effective method of contraception during the course of the study and for 2 months after the last dose of cetuximab and 4 months after the last dose of pembrolizumab. An additional contraceptive method, such as a barrier method (eg, condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods, through 186 days after the last dose of zanzalintinib for women of childbearing potential (WOCBP) or through 96 days after the last dose of zanzalintinib for men
• Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-ag15e in the absence of other biological or physiological causes. In addition, females < 55 years-of-age must have a serum follicle stimulating hormone level > 40 mIU/mL to confirm menopause). * Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff

Exclusion Criteria

• Prior treatment with zanzalintinib or other VEGFR-targeted therapy. Prior treatment with cetuximab or other EGFR inhibitors. Patients who received prior pembrolizumab are eligible
• Patients with more than two prior lines of systemic therapy in the recurrent/metastatic setting
• Patients who have relapsed disease within three months of definitive therapy
• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment
• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment
• Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy 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 before first dose of study treatment. * Note: Subjects with an incidental finding of an isolated brain lesion < 1 cm in diameter may be eligible after Principal Investigator approval if the lesion is radiographically stable for 4 weeks before first dose and does not require treatment per Principal Investigator judgement. * Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment
• Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin inhibitors ) and platelet inhibitors (eg, clopidogrel). Allowed anticoagulants are the following: * Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). * Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen. * Note: Subjects must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer
• Any complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders: ** Congestive heart failure New York Heart Association Class 3 or 4, class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (eg, ventricular flutter, ventricular fibrillation, Torsades de pointes). ** Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. ** Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other clinically significant arterial thrombotic and/or ischemic event within 6 months before first dose of study treatment. ** Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous or non-cerebrovascular accident (CVA)/TIA arterial thromboembolic events within 3 months before to first dose of study treatment. *** Note: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen. *** Note: Subjects who don’t require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator. ** Prior history of myocarditis * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: ** Tumors invading the GI-tract from external viscera ** Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis ** Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months unless cause of obstruction is definitively managed and subject is asymptomatic ** Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. *** Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment. ** Known gastric or esophageal varices
• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before first dose of study treatment
• Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed)
• Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks
• Lesions invading major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta. * Note: Subjects with intravascular tumor extension (eg, tumor thrombus in renal vein or inferior vena [V.] cava) may be eligible following Principal Investigator approval
• Other clinically significant disorders that would preclude safe study participation. * Active infection requiring systemic treatment. ** Note: Prophylactic antibiotic treatment is allowed. * Known infection with acute or chronic hepatitis B or C, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness except for subjects meeting all of the following criteria: ** (1) on stable anti-retroviral therapy; ** (2) CD4+ T cell count ≥ 200/µL; and ** (3) an undetectable viral load. *** Note: HIV testing will be performed at screening if and as required by local regulation. *** Note: To be eligible, participants taking CYP inhibitors (eg, zidovudine, ritonavir, cobicistat, didanosine) or CYP3 inducers (efavirenz) must change to a different regimen not including these drugs 7 days prior to initiation of study treatment. Anti-retroviral therapies (ART) must have been received for at least 4 weeks prior to the first dose. *** Note: CD4+ T cell counts, and viral load are monitored per standard of care by the local health care provider. * Serious non-healing wound/ulcer/bone fracture. ** Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions. * Malabsorption syndrome. * Pharmacologically uncompensated, symptomatic hypothyroidism. * Moderate to severe hepatic impairment (Child-Pugh B or C). * Requirement for hemodialysis or peritoneal dialysis. * History of solid organ or allogeneic stem cell transplant.
• Major surgery; e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to first dose of study treatment. Prior laparoscopic surgeries (ie nephrectomy) within 4 weeks prior to first dose of study treatment. Minor surgery (eg, simple excision, tooth extraction) within 5 days before first dose of study treatment. Complete wound healing from major or minor surgery must have occurred at least prior to first dose of study treatment. * Note: Fresh tumor biopsies should be performed at least 5 days before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms within 14 days per electrocardiogram (ECG) before first dose of study treatment. * Note: Triplicate ECG evaluations will be performed and the average of these 3 consecutive results for QTcF will be used to determine eligibility
• History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent
• Pregnant or lactating females. Pregnant women are excluded from this study because pembrolizumab is a class D agent with the potential for teratogenic or abortifacient effects. Cetuximab is a class C agent with potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab, cetuximab, and zanzalintinib, breastfeeding should be discontinued if the mother is treated with pembrolizumab, cetuximab, or zanzalintinib. These potential risks may also apply to other agents used in this study
• Inability to swallow tablets or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube
• Previously identified allergy or hypersensitivity to components of the study treatment formulations
• Another malignancy that requires active therapy and in the opinion of the Investigator would interfere with monitoring of radiologic assessments of response to Investigational Product, within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6
• Other conditions, which in the opinion of the Principal Investigator, would compromise the safety of the patient or the patient’s ability to complete the study
• Any active, known or suspected autoimmune disease. * Note: Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Patients with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome, psoriasis controlled with topical medication, or positive serology, such as antinuclear antibodies (ANA) or anti-thyroid antibodies, are eligible to enroll if they are asymptomatic and do not require systemic therapy
• Known positive test for tuberculosis infection if supported by clinical or radiographic evidence of disease
• History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Patients with symptomatic hypothyroidism or hyperthyroidism. Patients with asymptomatic abnormalities in thyroid function tests are eligible to enroll
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy (> 10 mg daily prednisone equivalent) or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment. Inhaled, intranasal, intraarticular, and topical corticosteroids and mineralocorticoids are allowed. * Note: Adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. Transient short-term use of higher doses of systemic corticosteroids for allergic conditions (eg, contrast allergy) is also allowed
• Administration of a live, attenuated vaccine within 30 days before first dose of study treatment