Radiotherapy & Olaparib in COmbination for Carcinoma of the Oesophagus

Study Overview
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Brief Summary
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The purpose of this study is to determine the Maximum Tolerated Dose (MTD) of olaparib in combination with radical radiotherapy in patients with oesophageal cancer who are unsuitable for platinum containing chemotherapy.

Official Title
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Radiotherapy & Olaparib in COmbination for Carcinoma of the Oesophagus. A Phase I Trial.

Conditions
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Carcinoma of the Oesophagus

Intervention / Treatment
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* Drug: Olaparib
* Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus including Siewert type 1 or 2 tumours with ≤2cm gastric mucosal extension Unsuitable for radical chemoradiation therapy but suitable for radiotherapy Total length of tumour and involved lymph nodes ≤10cm No oesophageal stent in situ No previous chemotherapy or radiotherapy for oesophagus cancer Disease which can be encompassed within a radical radiotherapy treatment volume Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see ECOG criteria appendix 1) Provision of fully informed consent, signed, written and dated, prior to any study specific procedures. > 18 years of age. 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 Aspartate aminotransferase (AST(SGOT)/Alanine transaminase (ALT)SGPT) ≤ 2.5 x institutional upper limit of normal Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) Adequate lung function: no history of interstitial lung disease and FEV1 > 1litre and >30% predicted. 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, surgical sterilisation (bilateral oophorectomy or hysterectomy). Patient willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. Fit to receive all study treatments Swallowing sufficiently good to tolerate oral medication Life expectancy ≥ 4 months. Exclusion Criteria: Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) Previous enrolment in the present study Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used) Any previous treatment with a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, including olaparib. 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. Patients receiving the following classes of inhibitors of cytochrome P450 3A4 (CYP3A4) Azole antifungals Macrolide antibiotics Protease inhibitors Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. 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. Patients with a history of interstitial lung disease, inflammatory lung conditions, or severe chronic obstructive pulmonary disease (COPD) (FEV1<1litre or < 30% predicted). Patients with pneumonia within the previous 3 months. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. Patients with oesophageal stent in-situ Patients with myelodysplastic syndrome/acute myeloid leukaemia Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV). Patients with known active hepatic disease (i.e., Hepatitis B or C). Patients with a known hypersensitivity to olaparib or any of the excipients of the product. Patients with uncontrolled seizures. Concurrent uncontrolled medical illness, or other previous or current malignant disease likely to interfere with protocol treatments / comparisons Age < 18 Any pregnant, lactating women or potentially childbearing patients not using adequate contraception (see section 3.4 for details of required contraception). Previous chemotherapy or radiotherapy for oesophageal cancer 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) ECOG performance status >2

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OLA-0 (de-escalation dose)<br>25mg olaparib twice daily + radiotherapy (50Gy in 25 fractions) | Drug: Olaparib<br>* 25mg tablets, oral. Commenced 3 days prior to radiotherapy and continuing until the last day of radiotherapy (36 days in total).<br>Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions<br>* Radiotherapy to the oesophageal carcinoma. For patients receiving olaparib this is delivered as 50Gy in 25 daily fractions for 5 weeks (Monday-Friday only). For patients in the comparator arm (RT only) other total doses/ fractionation are permitted, according to local policy/ best standard care.<br>|
| Experimental: OLA-1<br>50mg olaparib twice daily + radiotherapy (50Gy in 25 fractions) | Drug: Olaparib<br>* 25mg tablets, oral. Commenced 3 days prior to radiotherapy and continuing until the last day of radiotherapy (36 days in total).<br>Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions<br>* Radiotherapy to the oesophageal carcinoma. For patients receiving olaparib this is delivered as 50Gy in 25 daily fractions for 5 weeks (Monday-Friday only). For patients in the comparator arm (RT only) other total doses/ fractionation are permitted, according to local policy/ best standard care.<br>|
| Experimental: OLA-2<br>100mg olaparib twice daily + radiotherapy (50Gy in 25 fractions) | Drug: Olaparib<br>* 25mg tablets, oral. Commenced 3 days prior to radiotherapy and continuing until the last day of radiotherapy (36 days in total).<br>Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions<br>* Radiotherapy to the oesophageal carcinoma. For patients receiving olaparib this is delivered as 50Gy in 25 daily fractions for 5 weeks (Monday-Friday only). For patients in the comparator arm (RT only) other total doses/ fractionation are permitted, according to local policy/ best standard care.<br>|
| Experimental: OLA-3<br>200mg olaparib twice daily + radiotherapy (50Gy in 25 fractions) | Drug: Olaparib<br>* 25mg tablets, oral. Commenced 3 days prior to radiotherapy and continuing until the last day of radiotherapy (36 days in total).<br>Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions<br>* Radiotherapy to the oesophageal carcinoma. For patients receiving olaparib this is delivered as 50Gy in 25 daily fractions for 5 weeks (Monday-Friday only). For patients in the comparator arm (RT only) other total doses/ fractionation are permitted, according to local policy/ best standard care.<br>|
| Active Comparator: RT alone<br> | Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions<br>* Radiotherapy to the oesophageal carcinoma. For patients receiving olaparib this is delivered as 50Gy in 25 daily fractions for 5 weeks (Monday-Friday only). For patients in the comparator arm (RT only) other total doses/ fractionation are permitted, according to local policy/ best standard care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of olaparib in combination with radical radiotherapy in patients with oesophageal cancer | MTD will be determined by the number of patients experiencing dose limiting toxicities (DLTs) in each treatment cohort, using a 3+3 dose escalation schedule. A DLT is determined as grade 4 oesophagitis or dysphagia, or any other grade 3 toxicity. DLTs will be assessed weekly during treatment (day -3 to week 5), 10-14 days after completing treatment, weekly for a further 3 weeks and 3 months after completing treatment. | 3 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall toxicity profile of treatment (NCRI Common Toxicity Criteria for Adverse Effects V3) | Toxicity of treatment will be assessed via collection of adverse events, categorised by the NCRI Common Toxicity Criteria for Adverse Effects (CTCAE) V3. Adverse event data will be collected continuously from screening, with patients seen weekly during their treatment, 10-14 days after treatment completion, weekly for 3 further weeks, 3 monthly until 1 year then 6 monthly until 3 years. | Assessed at all study visits, up to 3 years post treatment. | 
| Olaparib compliance |  | At completion of olaparib treatment (end of week 5) | 
| Radiotherapy (RT) compliance |  | At completion of RT treatment (end of week 5) | 
| Local and overall treatment failure rate | This is defined as residual disease pathologically on endoscopic assessment & biopsy or progressive disease on CT scan of thorax and abdomen. | 3 months | 
| Exploration of blood and tissue borne pharmacodynamic markers to establish the biological efficacy of the addition of Olaparib to radiotherapy. | Endoscopic biopsy sample taken for analysis at screening & 3 months post treatment Translational research blood samples taken at screening, weekly during treatment, at end of treatment visit & 3 months after treatment Skin biopsy samples taken from within & outside irradiated field at week 4 | Up to 3 months post treatment |