Inclusion Criteria:

For inclusion in the study patients should fulfill the following 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. HPV testing is required, although both
HPV-positive and -negative patients are eligible

4. Stage IVA or IVB 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

- Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN)

- Creatinine clearance ≥ 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. 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,

- LH and 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 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 fulfil 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:

Patients should not enter the study if any of the following exclusion criteria are
fulfilled

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 CYP3A4 (see Section 5.4.2
for guidelines and wash out periods).

- Azole antifungals

- Macrolide antibiotics

- Protease inhibitors

9. Toxicities (> 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.