Neoadjuvant XL-092 and Pembrolizumab for the Treatment of Locally Advanced Resectable Oral Cavity Squamous Cell Cancer, H&N NEO-COMBAT XL Trial

Inclusion Criteria

• Written informed consent obtained to participate in the study and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
• Subject is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee
• Age >= 18 years at the time of consent
• Tumors must have PD-L1 combined positive score (CPS) >= 1
• Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance status of 0-1
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 30 days prior to treatment
• Histological or cytological evidence/confirmation of locally advanced oral cavity squamous cell carcinoma clinical stage III-IVb (American Joint Committee on Cancer [AJCC], 8th Edition). Subjects must have stage III-IVb disease and being willing to undergo definitive resection (AJCC 8th edition): * Stage III defined as T3N0M0 or T1-3N1M0 * Stage IVA defined as T4aN0-1M0 or T1-4aN2M0 * Stage IVB defined as TxN3M0 or T4bNxM0
• Willing to provide biopsy tissue from tumor lesion if unable to provide archived biopsy tissue
• Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods of contraception from the time of informed consent until 6 months after last dose of XL092. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label. In addition, women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods
• Females of childbearing potential must have a negative serum pregnancy test within 3 days prior to study treatment * NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other biological or physiological causes. In addition, females < 55 years-of-age must have a serum follicle stimulating hormone [FSH] level > 40 mIU/mL to confirm menopause). Documentation of postmenopausal status must be provided ** Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff
• Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 96 days after the last dose of study therapy
• Hemoglobin (Hgb) >= 9.0 g/dL without transfusion within 2 weeks prior to screening laboratory sample collection (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• 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 (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Platelets >= 100 x 10^9/L (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• International normalized ratio (INR) =< 1.5 (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Activated partial thromboplastin time (aPTT) =< 1.2 x upper limit of normal (ULN) (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Creatinine =< 1.5 x ULN or creatinine clearance >= 30 mL/min (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Urine protein-to-creatinine ratio =< 1 mg/mg (=< 113.2 mg/mmol) creatinine (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Bilirubin =< 1.5 x ULN (obtained within 30 days prior to initiating study treatment) * Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin < 3.0 mg/dL * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Albumin >= 2.5 mg/dL (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Alanine aminotransferase (ALT) =< 2.5 x ULN (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Aspartate aminotransferase (AST) =< 2.5 x ULN (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
• Alkaline phosphatase (ALP) =< 2.5 x ULN (obtained within 30 days prior to initiating study treatment) * Note: Hematology and other lab parameters that are >= grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy

Exclusion Criteria

• Known human papillomavirus (HPV)-positive cancer
• Active infection requiring systemic therapy
• Prior treatment with XL-092
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
• Treatment with any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or cytotoxic, biologic or other systemic anticancer therapy (including investigational) (or 5.5 1/2 lives) within 4 weeks prior to study treatment. The subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to =< grade 1 or baseline prior to initiating study treatment
• Prior therapy within < 1 week prior to study day 1 or patients who have not recovered (i.e., =< grade 2) from adverse events due to a previously administered agent. Patients should not have prior exposure to any immuno- modulating agents to the index tumor
• Has active autoimmune disease that has required systemic treatment in the past 6 months (i.e., with use of disease modifying agents, corticosteroids [> 10 mg of prednisone or equivalent] or immunosuppressive drugs). 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
• Has a history of receiving chronic systemic steroid therapy which exceeds prednisone 10mg (or equivalent) or any form of immunosuppressive one week prior to first dose of study treatment * Note: Transient short-term use of higher doses of systemic corticosteroids for allergic conditions (eg, contrast allergy) is also allowed
• Recent radiation therapy including: (a) treatment of bone metastases within 2 weeks; (b) any other radiation therapy within 4 weeks, or (c) systemic treatment with radionuclides within 6 weeks before first dose of study treatment * Note: ongoing clinically relevant complications from prior radiation therapy are not eligible
• Have clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months prior to study treatment, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication). Subjects are required to have a normal left ventricular ejection fraction as determined by echocardiography. Subjects must have a Fridericia’s formula-corrected QT interval (QTcF) =< 470 msec 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) * Note: Uncontrolled hypertension (HTN) is defined as (> 140 mm Hg systolic or > 90 mmHg diastolic)
• Primary tumors originating in the nasopharynx or sinonasal cavity
• Metastatic disease determined by chest CT and/or PET/CT. Metastatic disease to neck nodes is considered locally advanced and therefore allowable
• Lesions involving major blood vessels
• A subject with prior brain metastasis if related to HNSCC
• 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
• Uncontrolled, significant intercurrent or recent illness including, but not limited to: pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before first dose of study treatment
• 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 do not require prior anticoagulation therapy may be eligible but must be discussed and approved by the principal investigator
• Prior history of myocarditis
• History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent
• 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 investigator, would compromise the safety of the patient or the patient’s ability to complete the study
• 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 before first dose 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 * Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks
• 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)
• 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.uL; 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 (eg, 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 * Note: Fine needle aspiration and core biopsies are allowed on study drug without drug hold. Complete wound healing from major or minor surgery must have occurred at least prior to first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible
• 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
• Known positive test for tuberculosis infection if supported by clinical or radiographic evidence of disease
• Free thyroxine (FT4) outside the laboratory normal reference range. Asymptomatic subjects with FT4 abnormalities can be eligible after principal investigator approval
• Administration of a live, attenuated vaccine within 30 days before first dose of study treatment
• Subject is receiving prohibited medications or treatments that cannot be discontinued/replaced by an alternative therapy within 7 of initiating treatment