Patient case: 64-year-old male with head and neck squamous cell carcinoma; genetic feature: CDKN2A

Clinical trial: Preoperative Administration of Olaparib With or Without Cisplatin in Patients Who Are Candidates for Surgery of Carcinoma of Head and Neck

Summary: OPHELIA (OlaParib in patients with HEad and neck squamous-celL carcInomA) trial is a Greek, investigator-initiated, randomized open-label window-of-opportunity phase II study. Patients with operable histologically documented squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx will be randomized between combination with cisplatin and olaparib, monotherapy with olaparib or no treatment, before standard treatment.

Detailed description: OPHELIA is a window-of-opportunity phase II study randomized between combination with cisplatin and olaparib, monotherapy with olaparib or no treatment, before standard treatment.
  Although patients will be randomized between the 3 arms, no formal comparison between the 3 arms will be performed. Patients allocated to the olaparib monotherapy arm will serve as a proof-of-concept to interpret the mechanism of action of olaparib. Patients allocated in the "no treatment" group will be used as control.
  Primary endpoint will be the change in tumour Ki67 (ΔKi67) that is caused by the investigational treatment. Secondary endpoints will be early tumour response by RECIST criteria, pathologic complete response rate, tolerability to treatment and surgical complications rate, and optionally, metabolic response assessed by FDG-PET/CT scan. Translational correlates will be tested in tumour tissue, plasma and germline DNA.
  All the endpoints will be analyzed by an "as treated analysis" since the trial does not include a formal comparison of the treatment arms.
  Administration of olaparib monotherapy has been associated with reports of the following laboratory findings and/or clinical diagnoses, generally of mild or moderate severity (CTCAE Grade 1 or 2) and generally not requiring treatment discontinuation.

Eligibility: Inclusion Criteria:
  -  Provision of signed written informed consent prior to any study specific procedures
  -  Female and/or male patients aged 18 years and over
  -  Newly diagnosed histologically proven squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx
  -  Provision of biological material (tumor tissue and blood), provision of signed informed consent for translational research
  -  Patients selected for a primary surgical treatment
  -  No prior anti-cancer treatment for head and neck cancer
  -  Performance status ECOG 0-1
  -  Adequate hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L; haemoglobin ≥10g/dL
  -  Adequate renal function: serum creatinine level 1.5 mg/dl and Glomelular Filtration Rate50 ml/min by Cockroft/Gault formula
  -  Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline phosphatase, AST, ALT 5xULN
  -  No active rheumatoid arthritis, active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation.
  -  Ability to swallow tablets.
  -  Regular follow-up feasible
  -  Baseline evaluations performed before registration: clinical and blood evaluations no more than 1 week (7 days) prior to registration, tumour assessment (CT or MRI scan of the head and neck, chest, abdomen and pelvis at the discretion of the investigator) no more than 30 days prior to registration
  -  Treatment initiation planned less than 1 week (7 days) after registration
  -  For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior of starting study treatment
  -  Women of childbearing potential and their partners, who are sexually active, must agree to the use of TWO highly effective forms of contraception in combination, throughout the period of taking study treatment and for at least 1-6 month (according to the treatment group) after last dose of study drug(s) (where applicable). Male patients and their partners, who are sexually active and of childbearing potential, must agree to the use of TWO highly effective forms of contraception in combination, throughout the period of taking study treatment and for 3-6 months (according tot he treatment group) after last dose of study drug(s) (where applicable).
  Exclusion Criteria:
  -  Metastatic or locally advanced unresectable disease Uncontrolled hypercalcemia
  -  Concomitant unplanned antitumour therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy)
  -  Treatment with any other investigational medicinal product within 28 days prior to study entry
  -  Other serious and uncontrolled non-malignant chronic disease
  -  Treatment with CYP3A4 inhibitors as well as inducers, unless discontinued 7 days prior to randomization
  -  Any of the following within 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding, treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, or diverticulitis
  -  Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for 5 years
  -  Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days
  -  Pregnant or breastfeeding women
  -  Patients with known allergy to any excipients to study drugs,
  -  History of myocardial infarction and/or stroke or other arterial thrombotic events or pulmonary embolism or unstable angina pectoris within 6 months prior to registration
  -  No features suggestive of MDS/ AML
  -  Poorly controlled cardiac arrhythmias
  -  Bowel obstruction
  -  History of severe tumour bleeding or bleeding disorders
  -  No blood transfusion within the 28 days prior to study
  -  Poorly controlled anti-coagulation therapy (INR3.0 on coumadin or heparin compounds)
  -  Palliative radiation therapy within 4 weeks prior to registration
  -  Pregnancy or men or women of reproductive age not agreeing to use contraceptive measures

Relevance to patient case: not relevant