Pembrolizumab in Combination with Olaparib before and after Standard Chemoradiation for the Treatment of Stage III-IVB Head and Neck Squamous Cell Carcinoma

Inclusion Criteria

• Age >= 18 year on day of signing consent
• 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
• Subject must be willing to consent to a mandatory pre-study biopsy, unless sufficient archival tissue is available
• Biopsy confirmed American Joint Committee on Cancer (AJCC) 8th Edition stage III-IVB oral cavity squamous cell carcinoma (SCC), p16-negative oropharyngeal SCC, stage III-IVB hypopharyngeal SCC, stage III-IVB laryngeal SCC -OR- HPV-associated oropharyngeal SCC (p16 positive or HPV-associated) ** Note: Patients with a primary tumor spanning both the nasopharynx and oropharynx who have HPV associated disease may be eligible following discussion with the study principal investigator (PI). • T4 or N3 • T1-3N2 or • T3N0-1 with > 10 pack year tobacco history
• At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by imaging (CT/ PET) and is suitable for repeated assessment
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• No prior curative attempts for this cancer (i.e., surgery, radiation, systemic therapy) and not currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. No evidence of metastatic disease (M0)
• A female participant is eligible to participate if she is not pregnant by a negative urine pregnancy test within 72 hours prior to induction. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP/postmenopausal). Postmenopausal is defined as: ** Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments ** Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50 ** Radiation-induced oophorectomy with last menses > 1 year ago ** Chemotherapy-induced menopause with > 1-year interval since last menses ** Surgical sterilization (bilateral oophorectomy or hysterectomy) OR * A WOCBP who agrees to follow the contraceptive guidance starting from the signing of the informed consent and continue throughout the period of taking study treatment and for at least 4 month after last dose of pembrolizumab or the olaparib/pembrolizumab combination, 1 month after the last dose of olaparib; or they must totally/truly abstain from any form of sexual intercourse for the same amounts of time; whichever time is longer
• Females of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to induction. * 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 for at least 12 consecutive months. Documentation of postmenopausal status must be provided
• A male participant must agree to use a contraception. Acceptable Birth Control Methods of this protocol during the treatment period and for 4 months after the last dose of pembrolizumab or the pembrolizumab/olaparib combination, or 3 months after the last dose of olaparib (whichever is longest) when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Male subjects should not donate sperm throughout the period of taking olaparib and for 3 months following the last dose of olaparib or 4 months after the last dose of pembrolizumab alone or in combination with olaparib
• Absolute neutrophil count (ANC) >= 1500/uL (within 28 days prior to administration of study treatment)
• Platelets >= 75, 000/uL (within 28 days prior to administration of study treatment)
• Hemoglobin >= 9.0 g/dL or if < 9 transfusions are acceptable to increase hemoglobin above 9 (within 28 days prior to administration of study treatment)
• Creatinine =< 1.5 x upper limit or normal (ULN) OR creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (within 28 days prior to administration of study treatment)
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (within 28 days prior to administration of study treatment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 2.5 x ULN unless liver metastases are present in which case, they must be =< 5 x ULN (within 28 days prior to administration of study treatment)
• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (within 28 days prior to administration of study treatment)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (within 28 days prior to administration of study treatment)
• Must be willing and able to perform the requested study activities

Exclusion Criteria

• Subjects with prior and concurrent malignancies of different tumor types whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the study drug are eligible with the following exception: * Subjects with prior history of HNSCC treated < 3 years to date of consent
• Cisplatin-ineligible
• Severe, active medical comorbidity. Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
• Subjects unable to swallow orally administered medication prior to initiation of study treatment
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed
• Concomitant use of prohibited substances
• Major surgery within 2 weeks of starting study treatment
• Previous allogenic bone marrow transplant, allogenic solid organ transplant or double umbilical cord blood transplantation (dUCBT)
• Subjects with a known hypersensitivity to olaparib or any of the excipients of the product
• Has severe hypersensitivity (>= grade 3) to any excipients of pembrolizumab
• Presence of uncontrolled, potentially reversible cardiac conditions, as judged by the Investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure) or congenital long QC syndrome.). Electrocardiogram (ECG) will be done at screening to confirm
• Has active autoimmune disease that has required systemic treatment in the past 1 years (i.e. with use of disease modifying agents, corticosteroids 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 and is allowed
• Subjects must not receive any other concurrent anti-cancer therapy, including study agents, while on study treatment. Subjects may continue the use of bisphosphonates or denosumab for bone disease (i.e. osteoporosis but not bony metastases)
• Subjects must not receive systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology
• If a female participant is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 4 months after the last dose of trial treatment
• If a male participant is expecting to father children within the projected duration of the study, starting with the screening visit through 4 months after the last dose of trial treatment
• Has a known history of active TB (Bacillus Tuberculosis)
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy. Subject must not have received any antibiotics < 7 days prior to 1st dose of pembrolizumab. If the subject receives either IV antibiotics or > 5-day treatment course (oral or IV), then the 1st pembrolizumab dose should not be given until 14 days of last antibiotic dose. During eligibility screening, subjects who receive any antibiotics within 30 days prior to the proposed initial infusion of pembrolizumab should be flagged and reviewed by the site’s principal investigator to determine if the subject is a good candidate to receive pembrolizumab
• Immunocompromised subjects, e.g., subjects who are known to be serologically positive for human immunodeficiency virus (HIV)
• Subjects with known active hepatitis (i.e. Hepatitis B or C): * Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator