Radiotherapy & Olaparib in COmbination for Carcinoma of the Oesophagus (ROCOCO)

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

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.

Study Overview

• Status: Unknown
• Conditions: Carcinoma of the Oesophagus
• Intervention / Treatment: Drug: Olaparib; Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ian Emerson, Mr; Phone Number: +44 (0)161 918 7443; Email: ian.emerson@christie.nhs.uk

Study Locations

• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • Not yet recruiting
    • The Christie NHS Foundation Trust
    • Principal Investigator: Hamid Shiekh, Dr
  • Southampton, United Kingdom, SO16 6YD
    • Recruiting
    • Southampton General Hospital
    • Contact: Andrew Jackson, MD; Phone Number: +44(0)2380795386; Email: Andrew.Jackson@uhs.nhs.uk
    • Principal Investigator: Andrew Jackson, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

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 chemoradiation therapy but suitable for radiotherapy
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. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see ECOG criteria appendix 1)
8. Provision of fully informed consent, signed, written and dated, prior to any study specific procedures.
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
    • 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)
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 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).
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.

Exclusion Criteria:

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 poly adenosine diphosphate-ribose polymerase (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 cytochrome P450 3A4 (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 chronic obstructive pulmonary disease (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 medication.
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 product.
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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: OLA-0 (de-escalation dose); 25mg olaparib twice daily + radiotherapy (50Gy in 25 fractions)	Drug: Olaparib; 25mg tablets, oral. Commenced 3 days prior to radiotherapy and continuing until the last day of radiotherapy (36 days in total).; Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions; 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.
Experimental: OLA-1; 50mg olaparib twice daily + radiotherapy (50Gy in 25 fractions)	Drug: Olaparib; 25mg tablets, oral. Commenced 3 days prior to radiotherapy and continuing until the last day of radiotherapy (36 days in total).; Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions; 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.
Experimental: OLA-2; 100mg olaparib twice daily + radiotherapy (50Gy in 25 fractions)	Drug: Olaparib; 25mg tablets, oral. Commenced 3 days prior to radiotherapy and continuing until the last day of radiotherapy (36 days in total).; Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions; 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.
Experimental: OLA-3; 200mg olaparib twice daily + radiotherapy (50Gy in 25 fractions)	Drug: Olaparib; 25mg tablets, oral. Commenced 3 days prior to radiotherapy and continuing until the last day of radiotherapy (36 days in total).; Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions; 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.
Active Comparator: RT alone	Radiation: Radical external beam radiotherapy, 50Gy in 25 fractions; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The Christie NHS Foundation Trust
• Collaborators: AstraZeneca; Cancer Research UK
• Investigators: Principal Investigator: Andrew Jackson, Dr, University Hospital Southampton NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Anticipated): July 1, 2015
• Study Completion (Anticipated): August 1, 2018

Study Registration Dates

• First Submitted: October 25, 2011
• First Submitted That Met QC Criteria: October 26, 2011
• First Posted (Estimate): October 27, 2011

Study Record Updates

• Last Update Posted (Estimate): August 19, 2013
• Last Update Submitted That Met QC Criteria: August 16, 2013
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Carcinoma; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib
• Other Study ID Numbers: 10_DOG03_194