Advanced Gastric and Gastro-oesophageal cancer MedDRA version: 18.0 Level: PT Classification code 10017758 Term: Gastric cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 18.0 Level: PT Classification code 10062878 Term: Gastrooesophageal cancer System Organ Class:
Conditions
Interventions
Product Name: Olaparib (Lynparza)
Product Code: AZD2281
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: olaparib
CAS Number
Sponsors
The Royal Marsden NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Advanced gastric or gastro-oesophageal junction cancer (HER2 positive or negative) which has progressed following first line treatment 2. Male and female patients must be aged 18 or above* 3. Availability of a tissue sample (resection or biopsy) confirming gastric or gastro-oesophageal junction adenocarcinoma* 4. At least one lesion, not previously irradiated, that can be accurately measured at baseline as = 10 mm in the longest diameter (except lymph nodes which must have short axis = 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) 5. Provision of fully informed consent* 6. Adequate organ and bone marrow function measured within 28 days prior to starting treatment as detailed below: - Haemoglobin = 10.0 g/dL and no blood transfusions in the 28 days prior to study entry - Absolute neutrophil count (ANC) = 1.5 x 109/L - White blood cells (WBC) > 3 x 109/L - Platelet count = 100 x 109/L - Total bilirubin = 1.5 x institutional upper limit of normal (ULN) - AST/ ALT = 2.5 x institutional ULN (unless liver metastases are present in which case it must be = 5x ULN) - Serum creatinine = 1.5 x institutional upper limit of normal (ULN) 7. ECOG performance status of 2 or less 8. Life Expectancy of 16 weeks or more 9. Evidence of non-childbearing status for women of childbearing potential (ie negative urine or serum pregnancy test within 7 days of study treatment) or postmenopausal status. Postmenopausal status is defined as: - Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments, - 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, - or surgical sterilisation (bilateral oophorectomy or hysterectomy). 10. Patient is willing and able to comply with the protocol for the duration of the study including having examinations, undergoing treatment and attending scheduled visits (including follow up). 11. Patients of child bearing potential and their partners, who are sexually active, must agree to the use of two highly effective forms of contraception throughout their participation in the study and for 3 months after last dose of study drug(s). For example condom with spermicide and oral contraceptive/hormonal therapy or condom with spermicide and placement of an intra-uterine device. * Starred inclusion criteria must be met for enrolment to the pre-screening part of the study Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 64 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 90
Exclusion criteria
Exclusion criteria: 1. More than 1 prior chemotherapy regimen used for the treatment of advanced gastric cancer (except for adjuvant/neoadjuvant chemotherapy which is permitted except with a taxane- see below) 2. Any previous treatment with a PARP inhibitor, including olaparib* 3. Any second primary cancer (except adequately treated non-melanoma skin cancer, curatively treated cervical carcinoma-in-situ and curatively treated other solid tumours with no evidence of disease for 5 years or more) 4. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons) or investigational product within 2 weeks from the last dose prior to starting treatment (or a longer period depending on the defined characteristics of the agents used). A stable dose of bisphosphonates is permitted for bone metastases before and during the study as long as they were started at least 4 weeks prior to starting treatment 5. Clinically significant heart disease or myocardial infarction within the previous 12 months 6. Interstitial pneumonia or symptomatic fibrosis of the lungs 7. Active brain or leptomeningeal metastases. A scan to confirm the absence of brain metastases is not required. Patients with known brain metastases are eligible if they have been treated and there is no evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. Patients can take a stable dose of corticosteroids before and during the study as long as these were started 4 or more weeks prior to treatment 8. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any previous major surgery 9. Pregnant and breastfeeding women 10. 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, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent. 11. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with study medication absorption 12. Persistent toxicities (of CTCAE grade 2 or above) with the exception of alopecia, caused by previous cancer therapy. 13. Immunocompromised patients e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy. 14. Patients with known active hepatic disease (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids. 15. Patients with intestinal obstruction or patients with CTCAE grade = 3 upper GI bleeding within 4 weeks of study entry 16. Any previous treatment with a taxane in the metastatic or recurrent setting. (A taxane may have been used in the neoadjuvant or adjuvant setting, as long as progression occurred more than 6 months following completion of treatment)* 17. Patients receivi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Principal research question/Objective: To assess if adding olaparib to paclitaxel in the second line treatment of Western patients with advanced gastric cancer or oesophagi-gastric (OG) cancer improves overall survival, compared to treating patients with paclitaxel alone. Here overall survival is defined as the length of time from when a patient enters the study (and is assigned a treatment) to their death from any cause. ; Secondary Objective: Secondary Research Question/Objectives: • To investigate the safety and tolerability of the combination of olaparib and paclitaxel (i.e. which side effects are experienced by patients and the severity of these side effects) • To investigate the efficacy of olaparib in combination with paclitaxel compared with paclitaxel alone as defined by progression free survival (how long patients survive before their disease gets worse, progresses) and response rate (the proportion of patients who have a response to treatment with disease shrinkage on their CT scans) • To investigate the effect of treatment with olaparib in combination with paclitaxel compared with paclitaxel alone on patients' quality of life and symptoms, measured using questionnaires. • To investigate how commonly low levels of ATM protein are seen in advanced OG cancer in a Western population • To investigate the association of ATM levels with response to olaparib in a Western population • To investigate the efficacy o ;Primary end point(s): Overall Survival (OS) defined as time from randomisation to date of death, patients alive at time of analysis will be censored at date of last follow-up; Timepoint(s) of evaluation of this end point: OS will be calculated from the time of randomisation to the date of death from any cause, patients alive at time of analysis will be | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •Progression free survival (PFS) defined as time from randomization to date of radiological progression or death from any cause. PFS will be be evaluated according to RECIST 1.1 criteria. Progression events will be determined by local investigator assessment. Patients alive and progression free at time of analysis will be censored at date of last follow-up. •Overall Survival (OS) in ATM negative patients. •Objective response rate (ORR) defined as the proportion of patients with a reduction in tumour burden (CR or PR according to RECIST 1.1 criteria). Response will be determined by local investigator assessment. Additional scans specifically to confirm responses will not be required in this study. Patients with no scan available will be excluded from the analysis unless they are known to have progressed or died prior to the scan (included as having disease progression). •Patient reported outcome (PRO). Health related quality of life (HRQoL) will be assessed using EORTC QLQ-C30 and STO22 questionnaires. Subscales will be defined as per the standard guidelines. •Adverse event (AE) assessment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. •Time to response (TTR) defined as time from randomisation to objective tumour response (CR or PR according to RECIST 1.1 criteria). •Duration of response (DoR) defined as time from 1st documented tumour response to disease progression (CR or PR to PD according to RECIST 1.1 criteria). Patients alive and progression free at time of analysis will be censored at date of last follow-up. Exploratory and subgroup analyses •Biomarker analyses- including but not limited to the measurement of HRD factors such as ATM, BRCA-1, MDC-1 and PARP to correlate outcome with study therapy •There will also be a number of pre- | — |
Countries
United Kingdom
Contacts
Public ContactMs Ye mong To
The Royal Marsden NHS Foundation Trust
Outcome results
None listed