Summary

This phase II trial studies how well pembrolizumab and cabozantinib work in treating patients with head and neck squamous cell cancer that has come back (recurrent) or spread to other places in the body (metastatic) and cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozntinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and cabozantinib may work better in treating patients with head and neck squamous cell cancer.

Objectives

PRIMARY OBJECTIVE:
I. To estimate the overall response rate (ORR) of patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN) who receive the combination of pembrolizumab and cabozantinib S-malate (cabozantinib).

SECONDARY OBJECTIVES:
I. To estimate the progression-free survival (PFS) of patients treated with the combination of pembrolizumab and cabozantinib.
II. To further define the toxicities associated with these regimens in patients with SCCHN.

EXPLORATORY OBJECTIVES:
I. To identify potential biomarkers related to response to the combination of pembrolizumab and cabozantinib in patients with RM SCCHN.
II. To evaluate whether markers of angiogenesis, hypoxia, Met or pMet expression or inflammatory activation can predict response to the combination or PFS.
III. To gather exploratory clinical data on a potentially predictive set of biomarkers (potential biomarkers include MET expression by fluorescence in situ hybridization [FISH], next generation sequencing [NGS] and immunohistochemistry [IHC]/immunofluorescence [IHF] of cMET, pMET, HGF, HER2, HER3 and heregulin messenger ribonucleic acid [mRNA] level).
IV. To evaluate circulating cell-free deoxyribonucleic acid (cfDNA) in plasma and its association with response to the combination or PFS.
V. To evaluate potential neoantigens in the tumor deoxyribonucleic acid (DNA), their expression, and their association with response to the combination or PFS.
VI. To evaluate peripheral blood mononuclear cells (PBMC) for immune monitoring and their association with response to the combination or PFS.
VII. To determine a quantitative radiomics based on computed tomography (CT) and/or positron emission tomography (PET) images as a prognostic biomarker in recurrent or metastatic HNSCC.
VIII. To determine a computational pathology (or pathomics) based prognostic marker from standard digitized hematoxylin and eosin (H&E) images of the tumor in recurrent or metastatic HNSCC.

OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day and cabozantinib S-malate orally (PO) once daily (QD) on days 1-21. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI) or positron emission tomography (PET) scan and blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30-37 days and 1 and 2 years.

Eligibility

1. The subject has a histologic or cytologic diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, paranasal sinuses, hypopharynx, nasopharynx or larynx; squamous cell carcinoma of unknown primary in cervical lymph node can be included only if human papillomavirus (HPV) status is positive
2. Patients must have refractory, recurrent or metastatic disease, which is deemed to be inoperable
3. In case patients received prior systemic therapy within the definitive or metastatic setting, disease progression must be documented following prior therapy; this can be in the recurrent or metastatic setting or in the concurrent setting
4. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator
5. A maximum of one prior radiotherapy regimen, curative or palliative, to the head and neck is allowed; if the radiation is combined with chemotherapy, a minimum of 4 months must elapse between the end of radiotherapy and registration; if the radiation is given alone, a minimum of 8 weeks must elapse between the end of radiotherapy and registration; a minimum of 3 weeks must elapse between prior radiation to other areas and registration; treatment areas should be healed with no sequelae from radiation therapy (RT) that would predispose to fistula formation
6. The subject has had an assessment of all known disease sites e.g., by computerized tomography (CT) scan, magnetic resonance imaging (MRI), bone scan or positron emission tomography (PET)/CT as appropriate, within 28 days before the first dose of cabozantinib
7. The subject is >= 18 years old on the day of consent
8. Life expectancy of greater than 3 months
9. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
10. Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v.)4.0 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy
11. The absolute neutrophil count (ANC) >= 1000/mm^3 without colony stimulating factor support (within 7 days before the first dose of cabozantinib)
12. Platelets >= 100,000/mm^3 (within 7 days before the first dose of cabozantinib)
13. Hemoglobin >= 9 g/dL (within 7 days before the first dose of cabozantinib)
14. Bilirubin =< 1.5 x the upper limit of normal (ULN); for subjects with known Gilbert’s disease, bilirubin =< 3.0 mg/dL (within 7 days before the first dose of cabozantinib)
15. Serum albumin >= 2.8 g/dl (within 7 days before the first dose of cabozantinib)
16. Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min (within 7 days before the first dose of cabozantinib); for creatinine clearance estimation, the Cockcroft and Gault equation should be used
17. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 x ULN (within 7 days before the first dose of cabozantinib)
18. Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis (within 7 days before the first dose of cabozantinib)
19. Urine protein/creatinine ratio (UPCR) =< 1 (within 7 days before the first dose of cabozantinib)
20. Serum phosphorus, calcium, magnesium and potassium >= lower limit of normal (LLN) (within 7 days before the first dose of cabozantinib)
21. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
22. Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s)
23. Female subjects of childbearing potential must not be pregnant at screening; females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy); however, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons
24. A male participant must agree to use a contraception as detailed in this protocol during the treatment period and for at least during the active treatment plus an additional 90 days (a spermatogenesis cycle) for study treatments with evidence of genotoxicity at any dose] after the last dose of study treatment and refrain from donating sperm during this period

Treatment Sites in Georgia