Immune Modulation by Abemaciclib in HNSCC. (AIM Trial)

Inclusion Criteria:

1. Cytologic or histologic diagnosis of squamous cell carcinoma of the oral cavity,p16-negative oropharynx, hypopharynx, or larynx.

2. Tumors must be HPV-negative. For eligibility, tumors of the oral cavity,hypopharynx, or larynx will be considered HPV-negative without specialized testing.Tumors of the oropharynx must be HPV-negative as determined by p16immunohistochemistry and/or HPV-DNA per local standard.

3. Clinical stage I-IVa based upon the American Joint Committee on Cancer (AJCC)staging manual, 8th edition.

4. Appropriate and planned for oncologic resection of the primary tumor and/or neckdissection.

5. Clinically or radiologically measurable disease; the primary tumor and/or cervicalnodes may be measurable according to RECIST 1.1 (tumor diameter ≥ 1 cm; short-axislymph node diameter ≥ 1.5 cm) OR by caliper/ruler measurement (tumor diameter ≥ 1cm).

6. No prior treatment for the index (study-qualifying) HNSCC.

7. Patients with two simultaneous primary tumors or bilateral tumors are included.

8. The index HNSCC may be a second primary HNSCC, provided the following criteria aremet: a. The previously treated HNSCC was treated with curative intent. b. The index HNSCCis at least 1 cm from the previously treated HNSCC. c. At least 2 years have elapsedsince curative treatment of the previous HNSCC without evidence for recurrence.

9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. (See Appendix 1.)

10. Adequate hematologic function, as defined by: a. Absolute neutrophil count (ANC) ≥ 1,500/µl b. Platelets ≥ 100,000/µl c.Hemoglobin ≥ 8 g/dL

11. Adequate liver function, as defined by: a. Bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). Patients withGilbert's syndrome with a total bilirubin ≤ 2.0 x ULN and direct bilirubin withinnormal limits are permitted. b. aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN

12. Adequate renal function, as defined by creatinine ≤ 1.5 x ULN.

13. Able to swallow oral medications.

14. Have signed written informed consent.

15. Consent to biomarker collection requirements, including mandatory baseline andintra-operative research biopsies of the index tumor.

Exclusion Criteria:

1. Prior treatment with any cyclin-dependent kinase (CDK) 4/6 inhibitor oranti-programmed death (PD)-1/L1 inhibitor is not allowed.

2. Current or prior use of immunosuppressive medication within 14 days before the firstdose of their assigned protocol treatment. The following are exceptions to thiscriterion unless otherwise indicated:

3. Intranasal, inhaled, or topical steroids, or local steroid injections (eg,intra articular injection)

4. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

5. Steroids as premedication for hypersensitivity reactions (eg, CT premedication)and/or as anti-emetics

6. Active or previously documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis [with theexception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome,Wegener syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoidarthritis, hypophysitis, uveitis, etc.). The following are exceptions to thiscriterion:

7. Patients with vitiligo or alopecia

8. Patients with hypothyroidism (eg, following Hashimoto syndrome) stable onhormone replacement. Subclinical hypothyroidism (eg. Elevatedthyroid-stimulating hormone (TSH), low or normal free T4, and asymptomatic)observed on screening labs is not an exclusion.

9. Any chronic skin condition that does not require systemic therapy

10. Patients without active disease in the last 5 years may be included but onlyafter consultation with the study PI

11. Patients with celiac disease controlled by diet alone

12. Patient has a personal history of any of the following cardiac or pulmonaryabnormalities:

13. Syncope of cardiovascular etiology

14. Ventricular arrhythmia of pathologic origin (including, but limited to,ventricular tachycardia and ventricular fibrillation)

15. Sudden cardiac arrest

16. Documented history of New York Heart Association functional classificationIII-IV congestive heart failure

17. Myocardial infarction ≤ 6 months prior to enrollment

18. Current unstable angina pectoris

19. Interstitial lung disease

20. Severe dyspnea at rest or requiring oxygen therapy

21. Patient with impaired gastrointestinal (GI) function or GI disease that maysignificantly alter the absorption of oral abemaciclib (e.g. history of majorsurgical resection involving the stomach or small bowel, malabsorption syndrome,preexisting Crohn's disease or ulcerative colitis, preexisting chronic conditionresulting in baseline Grade 2 or higher diarrhea).

22. Patients who require the chronic administration of drugs that are strong andmoderate inducers of Cytochrome P450, family 3, subfamily A, (CYP3A) and/or stronginhibitors of CYP3A, and no acceptable substitute can be identified, are noteligible for study (See Appendix 2). Such drugs should be discontinued at least 7days before the start of study treatment.

23. The patient has active bacterial infection (requiring intravenous [IV] antibioticsat time of initiating study treatment), fungal infection, or detectable viralinfection (such as known human immunodeficiency virus positivity or known activehepatitis B or C [e.g. hepatitis B surface antigen positive or hepatitis C antibodypositive with detectable viral load]). Screening for HIV or hepatitis is notrequired for enrollment.

24. Patient with any other condition that would, in the Investigator's judgment,preclude patient's participation in the clinical study due to safety concerns orcompliance with clinical study procedures, e.g. social/psychological complications.

25. Pregnant or nursing (lactating) women.

26. Patient who does not apply highly effective contraception during the study andthrough the duration as defined below after the final dose of study treatment:

27. Sexually active males should use a condom during intercourse while takingabemaciclib and for 4 weeks after the final dose of abemaciclib.

28. Males who are sexually active with a woman of child-bearing potential shouldapply highly effective contraception during the study as defined below, inorder not to father a child in this period.

29. Women of child-bearing potential (WOCBP), defined as all women physiologicallycapable of becoming pregnant, must use highly effective contraception duringthe study and through at least 3 weeks after the final dose of abemaciclib.Highly effective contraception is defined as: i. Total abstinence: When this is in line with the preferred and usual lifestyle ofthe subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal,postovulation methods) and withdrawal are not acceptable methods of contraception].

ii. Female sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment.

iii. Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). [For female study subjects, the vasectomized male partner should be the sole partner for that patient.] iv. Use a combination of the following (both 1+2):

1. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 2. Barriermethods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps)with spermicidal foam/gel/film/cream/vaginal suppository.

v. Note: Hormonal contraception methods (e.g. oral, injected, and implanted) are not allowed as abemaciclib may decrease the effectiveness of hormonal contraceptives.

vi. Note: Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago.

11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) fortreatment of either a psychiatric or physical (e.g., infectious) illness.