Alisertib and Pembrolizumab for the Treatment of Patients With Rb-deficient Head and Neck Squamous Cell Cancer

Inclusion Criteria - phase II only

• Histologically or cytological confirmed diagnosis of Rb-deficient HNSCC for which no standard curative therapy is available.
• Rb deficient HNSCC includes CLIA-certified testing confirming one of the following:

A. HPV positive as determined by any one of the following: p16 immunohistochemistry (IHC), HPV RNA in situ hybridization (ISH), RNAscope (mRNA ISH), DNA ISH, DNA PCR, or qRT PCR.

B. No Rb protein expression in the tumor as determined by IHC.41, 48 3. Progression on prior treatment with an anti-PD-1 antibody or an anti-PD-L1 antibody.

A. Has received at least 2 doses of a PD-1/PD-L1 checkpoint blockade therapy. B. Clinical or radiographical progression has been documented within 12 weeks from the last dose of PD-1/PD-L1 checkpoint blockade therapy.

Inclusion Criteria - phase I only

• Histologically or cytological confirmed diagnosis of an invasive solid tumor malignancy, for which no standard curative or life prolonging therapy is available.

Inclusion Criteria - both phase I and phase II

• Male or female patients ≥ 18 years of age.
• ECOG performance status of ≤ 2 (see section 7.4).
• Clinical laboratory values as specified below within 22 days before the first dose of study drug
• Absolute neutrophil count (ANC) > 1500/mm³
• Platelets > 100,000/mm³
• Hgb > 9 g/dL. Values must be obtained without need for myeloid growth factor or platelet transfusion support within 14 days, however, erythrocyte growth factor is allowed as per published ASCO guidelines.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• SGOT (AST) and SGPT (ALT) 2 weeks before treatment is started or whole brain radiation was performed > 4 weeks before treatment is started, and are clinically stable (not requiring steroids or anti-epileptic drugs).
• Known hypersensitivity to any of the excipients of alisertib enteric coated tablets or severe reaction to any human monoclonal antibody.
• Patients with a prior history of clinically significant metabolic acidosis (exclusion only for patients receiving alisertib oral solution).
• Major surgery within 28 days prior to first dose of alisertib or persisting side effects that have not improved to NCI-CTCAE grade 1 or better.
• Patients who are on (or will require) prolonged systemic corticosteroid treatment during the study except for replacement dosing for adrenal insufficiency.
• Concurrent severe and/or uncontrolled medical conditions that would, in the investigator's judgment, contraindicate patient participation in the clinical study or require concomitant anti-cancer drugs (e.g. active or uncontrolled severe infection, chronic active hepatitis, immuno-compromised, acute or chronic pancreatitis, uncontrolled high blood pressure, interstitial lung disease).
• Patients with active, known, diagnosed or suspected autoimmune disease. Patients suffering from vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring thyroid hormone replacement therapy, or psoriasis not requiring systemic treatment can be enrolled.
• Patients diagnosed with active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis or another condition requiring immunosuppressive doses of systemic medication such as systemic corticosteroids or absorbed topical corticosteroids (doses ≥ 10 mg/day prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical corticosteroids, adrenal replacement doses, or < 10 mg daily prednisone or equivalent are permitted.
• Administration of any live vaccine within 30 days before first dose of study drug.
• Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus or hepatitis C virus, except for: Patients with HIV who have controlled infection (undetectable viral load and CD4 count above 350 cells/mm3 either spontaneously or on a stable antiviral regimen) are permitted; Patients with