Olaparib and Radiotherapy in Head and Neck Cancer

• ≥18 years of age
• Histologically confirmed squamous cell carcinoma of the larynx stage II-III (T2N0M0 or T1-2N1M0 or T3N0-1M0) or histologically confirmed squamous cell carcinoma of the oropharynx stage II-III (T1-2N1M0 or T3N0-1M0)
• In case of oropharyngeal carcinoma: tumor HPV status negative
• WHO performance 0-1
• Life expectancy of at least 6 months

• Adequate hematological, renal and hepatic functions

  • Hemoglobin ≥ 6.2 mmol/l
  • Leucocytes 3.0 x 10E9/l
  • Absolute neutrophil count 1.5x10E9/l
  • Platelet count 100 x 10E9/l
  • Total bilirubin ≤ 1.5 x UNL
  • ASAT/ALAT ≤ 2.5 x UNL
  • Creatinine clearance 50 ml/min; measured using a 24-hours urine sample or calculated using the Cockcroft-Gault formula

• Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 21 days of study treatment. Non-childbearing potential or postmenopausal is defined as:

  • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
  • LH and FSH levels in post menopausal range for women under 50 years of age
  • Radiation-induced oophorectomy with last menses > 1 year ago
  • Chemotherapy-induced menopause with > 1 year interval since last menses
  • Surgical sterilisation (bilateral oophorectomy or hysterectomy)
• Patients of reproductive potential must agree to practice two effective medically approved contraceptive method during the trial and 3 months afterwards
• Signed written informed consent.

Exclusion Criteria:

• Patients eligible for concurrent chemoradiotherapy rather than radiotherapy alone
• Concurrent active malignancy other than localized, non-melanoma skin cancer or carcinoma-in-situ of the cervix (unless definitive treatment was completed 3 years or more before study entry and the patient has remained disease free)
• Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the 3 weeks prior to start of therapy (or a longer period depending on the defined characteristics of the agents used e.g. 6 weeks for mitomycin or nitrosourea). Patients may continue the use of LHRH agonists for cancer; bisphosphonates for bone disease and corticosteroids.
• Major surgery within two weeks of starting study treatment.
• Participation in other trial with investigational drug or treatment modality
• Gastrointestinal disorders that may interfere with absorption of the study drug or patients who are not able to take oral medication.
• Tube feeding before the start of treatment.
• Prior radiotherapy to head \& neck region.
• Blood transfusion in the four weeks prior to study entry
• Persistent toxicities (CTC ≥ grade 2) with the exception of alopecia, caused by previous cancer therapy
• QT-interval >470 msec

• Significant cardiovascular disease as defined by:

  • History of congestive heart failure defined as NYHA class III
  • History of unstable angina pectoris or myocardial infarction up to 3 months prior to trial entry;
  • Presence of severe valvular heart disease
  • Presence of a ventricular arrhythmia requiring treatment;
  • Uncontrolled hypertension

• Patients considered a poor medical risk due to:

  • non-malignant systemic disease
  • active, uncontrolled infection requiring parenteral antibiotics

  • a serious, uncontrolled medical disorder; examples include, but are not limited to:

    • uncontrolled major seizure disorder
    • unstable spinal cord compression
    • superior vena cava syndrome
    • extensive bilateral lung disease on HRCT scan
    • any psychiatric disorder that prohibits obtaining informed consent.
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy.
• Patients with known active hepatic disease (i.e. Hepatitis B or C)
• Patients with myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on peripheral blood smear.

• Concomitant medications:

  • Any previous treatment with a PARP inhibitor, including olaparib

  • Patients receiving the following classes of inhibitors of CYP3A4 (see paragraph 6.4.2 for guidelines and wash out periods)

    • Azole antifungals
    • Macrolide antibiotics
    • Protease inhibitors
• Breast-feeding women