Radiotherapy & Olaparib in COmbination for Carcinoma of the Oesophagus. A Phase I Trial.
1. Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus
including Siewert type 1 or 2 tumours with ≤2cm gastric mucosal extension
2. Unsuitable for radical CRT but suitable for RT
3. Total length of tumour and involved lymph nodes ≤10cm
4. No oesophageal stent in situ
5. No previous chemotherapy or radiotherapy for oesophagus cancer
6. Disease which can be encompassed within a radical radiotherapy treatment volume
7. ECOG performance status 0-2 (see ECOG criteria appendix 1)
8. Provision of fully informed consent, signed, written and dated, prior to any study
9. > 18 years of age.
10. Adequate organ and bone marrow function measured within 28 days prior to
administration of study treatment as defined below:
- Haemoglobin ≥ 10.0 g/dL
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- White blood cells (WBC) > 3 x 109/L
- Platelet count ≥ 100 x 109/L
- No dysplastic features on peripheral blood smear
- Total bilirubin ≤ 1.5 x institutional upper limit of normal
- AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal
- Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN)
11. Adequate lung function: no history of interstitial lung disease and FEV1 > 1litre
and >30% predicted.
12. 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
- 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,
- surgical sterilisation (bilateral oophorectomy or hysterectomy).
13. Patient willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations.
14. Fit to receive all study treatments
15. Swallowing sufficiently good to tolerate oral medication
16. Life expectancy ≥ 4 months.
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 enrolment 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 tumours
curatively treated with no evidence of disease for ≥ 5 years.
6. Patients receiving the following classes of inhibitors of CYP3A4
- Azole antifungals
- Macrolide antibiotics
- Protease inhibitors
7. Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.
8. 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, or any
psychiatric disorder that prohibits obtaining informed consent.
9. Patients with a history of interstitial lung disease, inflammatory lung conditions,
or severe COPD (FEV1<1litre or < 30% predicted). Patients with pneumonia within the
previous 3 months..
10. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
11. Patients with oesophageal stent in-situ
12. Patients with myelodysplastic syndrome/acute myeloid leukaemia
13. Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV).
14. Patients with known active hepatic disease (i.e., Hepatitis B or C).
15. Patients with a known hypersensitivity to olaparib or any of the excipients of the
16. Patients with uncontrolled seizures.
17. Concurrent uncontrolled medical illness, or other previous or current malignant
disease likely to interfere with protocol treatments / comparisons
18. Age < 18
19. Any pregnant, lactating women or potentially childbearing patients not using adequate
contraception (see section 3.4 for details of required contraception).
20. Previous chemotherapy or radiotherapy for oesophageal cancer
21. Metastatic disease apart from local lymph node disease which can be reasonably
encompassed within the radiotherapy volume (total length of tumour and lymph node
disease should be <10cm)
22. ECOG performance status >2