Testing the Addition of an Anti-cancer Drug, Ipatasertib, to the Usual Immunotherapy Treatment (Pembrolizumab) in Patients With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed recurrent or metastaticHNSCC that is considered incurable.

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chestx-ray or as >=10 mm (>= 1 cm) with CT scan, magnetic resonance imaging (MRI), orcalipers by clinical exam.

• Primary tumor locations of oral cavity, oropharynx, hypopharynx, and larynx areallowed. Participants may not have a primary tumor site of nasopharynx.

• Patients with oropharyngeal cancer must have known human papillomavirus (HPV) statusdefined by human papillomavirus type 16 (p16) testing.

• Patients should not have had prior systemic therapy administered in the recurrent ormetastatic setting. Systemic therapy which was given as part of multimodal treatmentfor locally advanced disease is allowed.

• Patients must be able to provide an archival tissue specimen.

• Patients must be willing to undergo a mandatory tumor biopsy on treatment

• Tumor tissue must have a documented combined positive score (CPS) of >= 1 for PD-L1.

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of ipatasertib in combination with pembrolizumab in patients < 18 years ofage, children are excluded from this study.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >= 60%).

• Absolute neutrophil count >= 1,000/mcL.

• Platelets >= 100,000/mcL.

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN.

• Creatinine =< 1.5 x institutional ULN.

• Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 (using the Cockcroft-Gaultformula).

• Human immunodeficiency virus (HIV) infected patients on effective antiretroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better.

• Patients must be able to swallow orally administered medication whole.

• For women of childbearing potential (WOCBP): agreement to remain abstinent (refrainfrom heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period, for 5 months after the last dose ofpembrolizumab and 28 days after the last dose of ipatasertib, and agreement torefrain from donating eggs during this same period.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive measures, agreement to refrain from donating sperm during thetreatment period, and for 5 months after the last dose of pembrolizumab and 28 daysafter the last dose of ipatasertib.

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible.

Exclusion Criteria:

• Prior treatment with a checkpoint inhibitor given for relapsed or metastaticdisease. Prior treatment with a checkpoint inhibitor for locally advanced disease aspart multidisciplinary treatment is allowed.

• History of malabsorption syndrome or other condition that would interfere withenteral absorption or result in the inability or unwillingness to swallow pills.

• Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of trial treatment.The use of physiologic doses of corticosteroids may be approved after consultationwith the study principal investigator (PI).

• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressivedrugs). Replacement therapy (e.g., thyroxine or physiologic corticosteroidreplacement for adrenal or pituitary insufficiency, etc.) is not considered a formof systemic treatment.

• Type 1 or Type 2 diabetes mellitus requiring insulin at study entry are ineligible.

• Patients who are on a stable dose of oral diabetes medication >= 4 weeks priorto initiation of study treatment may be eligible for enrollment. Patients mustmeet the laboratory eligibility criteria for fasting blood glucose andhemoglobin A1c.

• Fasting glucose =< 150 mg/dL (8.3 mmol/L) and hemoglobin A1c =< 7.5% (58mmol/mol).

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study.

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1). Note: Patients with grade =< 2neuropathy or grade =< 2 alopecia are an exception to this criterion and may qualifyfor the study. Note: If patients received major surgery, they must have recoveredadequately from the toxicity and/or complications from the intervention prior tostarting therapy.

• Patients who are receiving any other investigational agents.

• Patients with known active CNS metastases and/or carcinomatous meningitis. Patientswith previously treated brain metastases may participate provided they areradiologically stable, i.e., without evidence of progression for at least 4 weeks byrepeat imaging (note that the repeat imaging should be performed during studyscreening), clinically stable and without requirement of steroid treatment for atleast 14 days prior to first dose of study treatment.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ipatasertib or hypersensitivity (grade >= 3) topembrolizumab and/or any of the components of the solution for injection.

• Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5drug-elimination half-lives, whichever is longer, prior to initiation of study drugis prohibited. Because the lists of these agents are constantly changing, it isimportant to regularly consult a frequently-updated medical reference. As part ofthe enrollment/informed consent procedures, the patient will be counseled on therisk of interactions with other agents, and what to do if new medications need to beprescribed or if the patient is considering a new over-the-counter medicine orherbal product.

• Patients with uncontrolled intercurrent illness (including but not limited tointerstitial lung disease or active, non-infectious pneumonitis) or a history of (non-infectious) pneumonitis that required steroids.

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements.

• Patients who are pregnant or breastfeeding, or are expecting to conceive or fatherchildren within the projected duration of the study, starting with the screeningvisit through 5 months after the last dose of study treatment. A WOCBP who has apositive urine pregnancy test (e.g., within 72 hours) prior to treatment will beexcluded from the study. If the urine test is positive or cannot be confirmed asnegative, a serum pregnancy test will be required. Pregnant women are excluded fromthis study because pembrolizumab is a monoclonal antibody agent and ipatasertib isan oral AKT inhibitor with the potential for teratogenic or abortifacient effects.Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with pembrolizumab and ipatasertib,breastfeeding should be discontinued if the mother is treated with pembrolizumab oripatasertib. Due to the potential risks, WOCBPs and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry, for the duration of study participation, and for 5 months after thelast dose of pembrolizumab and 28 days after the last dose of ipatasertib. Should awoman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physician immediately.

• Patients with grade >= 2 uncontrolled or untreated hypercholesterolemia orhypertriglyceridemia are excluded.

• Patient has a known additional malignancy that is progressing or requires activetreatment. Exceptions include basal cell carcinoma of the skin, squamous cellcarcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervicalcancer) that has undergone potentially curative therapy.

• History of or active inflammatory bowel disease (e.g., Crohn's disease andulcerative colitis) or active bowel inflammation (e.g., diverticulitis).

• Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,cystic fibrosis, aspergillosis, active tuberculosis, or history of opportunisticinfections (pneumocystis pneumonia or cytomegalovirus pneumonia).

• Known clinically significant history of liver disease consistent with Child PughClass B or C, including active viral or other hepatitis (e.g., positive forhepatitis B surface antigen [HbsAg] or hepatitis C virus [HCV] antibody atscreening), current drug or alcohol abuse, or cirrhosis.