Study of Olaparib With Radiation Therapy and Cetuximab in Advanced Head and Neck Cancer With Heavy Smoking History

Inclusion Criteria: 1. Provision of fully informed consent prior to any study specific procedures. 2. Patients must be \> 18 years of age. 3. Histologically or cytologically confirmed (from the primary lesion and/or regional lymph nodes) squamous cell carcinoma of the oropharynx, hypopharynx, or larynx that has not been previously treated or resected 4. Stage IV A or stage IV B disease prior to induction chemotherapy with no proven hematogenous metastatic disease (includes T4aN0-1M0, T1-4aN2M0, T4b, any N, M0 or any T, N3M0) 5. History of ≥ 10 pack-years of smoking cigarettes. 6. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: * Hemoglobin ≥ 9.0 g/dL * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * White blood cells (WBC) \> 3x109/L * Platelet count ≥ 100 x 109/L * Total bilirubin ≤ 1.5 x institutional upper limit of normal * Aspartate Aminotransferase(AST) (SGOT)/Alanine Aminotransferase (ALT) (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be ≤ 5x ULN * Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) * Creatinine clearance (CCr) ≥ 50 ml/min within 2 weeks prior to registration as determined by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = \[(140 - age) x (wt in kg)\]/ \[(Serum Cr mg/dl) x (72)\] CCr female = 0.85 x (CrCl male) 7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (see Appendix F) 8. Patients must have a life expectancy ≥ 16 weeks. 9. Evidence of non-childbearing status for women of childbearing potential, or postmenopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1 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 post menopausal range for women under 50, * radiation-induced oophorectomy with last menses \>1 year ago, * chemotherapy-induced menopause with \>1 year interval since last menses, * or surgical sterilisation (bilateral oophorectomy or hysterectomy). 10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. 11. At least one lesion prior to induction chemotherapy, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT), magnetic resonance imaging (MRI) or clinical examination (for instance, palpable lymph node in neck) and which is suitable for accurate repeated measurements. Patients with measurable disease prior to induction Docetaxel, Cisplatin and 5-fluorouracil (TPF) chemotherapy who obtain a complete clinical response prior to assignment to protocol therapy (RT + C225 + Olaparib) are still eligible for enrollment. 12. If formalin fixed, paraffin embedded tumor sample from biopsy exists, it should be available for testing. For inclusion in genetic research (analysis of biologic marker expression), patients must fulfill the following criterion: Provision of informed consent for genetic (biomarker) research (If a patient declines to participate in the research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent to that part.) Exclusion Criteria: 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 2. Previous enrollment (or assignment) in the present study 3. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used) 4. Any previous treatment with a PARP inhibitor, including olaparib. 5. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years. 6. Patients receiving any systemic chemotherapy or targeted agents for treatment of the current HNSCC 7. Patients receiving any prior radiation therapy to the head or neck. 8. Patients receiving the following classes of inhibitors of Cytochrome P450 3A4 (see Section 5.4.2 for guidelines and wash out periods). * Azole antifungals * Macrolide antibiotics * Protease inhibitors 9. Toxicities \> Common Toxicity Criteria for Adverse Effects (CTCAE) grade 2 caused by previous cancer therapy. 10. Patients with metastatic disease (only Stage IVA-B patients permitted) 11. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. 12. Patients 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, or any psychiatric disorder that prohibits obtaining informed consent. Evidence of severe or uncontrolled systemic disease or any concurrent condition which, in the investigator's opinion, makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol. 13. Patients unable to swallow orally administered medication at treatment initiation and patients with gastrointestinal disorders likely to interfere with absorption of the study medication 14. Breast feeding women 15. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV). 16. Patients with known active hepatic disease (i.e., Hepatitis B or C). 17. Patients with a known hypersensitivity to olaparib or any of the excipients of the product. Patients with known hypersensitivity to C225 or any of the excipients of the product. 18. Patients with uncontrolled seizures.