Adenocarcinoma of the Oesophagus, Adenocarcinoma of the Gastro-oesophageal Junction, Adenocarcinoma of the Stomach
Conditions
Brief summary
To evaluate the efficacy of maintenance therapies following completion of standard first-line chemotherapy in patients with locally advanced or metastatic HER-2 positive or HER-2 negative oesophago-gastric adenocarcinomas.
Detailed description
This is a prospective, open label, multicentre, randomised phase II clinical trial. An adaptive trial design is proposed to allow ineffective treatments to be discontinued early, and to potentially add novel treatment arms as the trial progresses. Patients will initially receive standard chemotherapy for their locally advanced or metastatic oesophago-gastric adenocarcinoma, according to local practice based upon their HER-2 status (tested locally). In order to be eligible for trial entry, HER-2 negative patients should have received a platinum-fluoropyrimidine based chemotherapy doublet of either cisplatin + capecitaine (CX), oxaliplatin + capecitabine (CAPOX), or 5FU + oxaliplatin (FOLFOX) (Arm A), whilst HER-2 positive patients (IHC 3+ or IHC 2+ and FISH positive) should have received cisplatin in combination with either capecitabine or 5-FU (CX or CF) plus trastuzumab chemotherapy (Arm B). Potentially eligible patients will be registered with the trials office whilst undergoing first line chemotherapy. Patients will become eligible for trial recruitment and randomisation after 18 weeks standard chemotherapy with stable disease (SD) or better on the end-of-treatment CT scan. Please note: if your patient has been receiving a regimen delivered every three weeks (e.g. CX) they should have completed 6 cycles. If your patient has been receiving a regimen delivered every 2 weeks (e.g. FOLFOX) they should have received 9 cycles of treatment. Eligible patients will then be randomised according to HER-2 status as follows: * HER-2 positive patients (\ 20%) will be assigned maintenance single-agent trastuzumab (current UK standard) * HER-2 negative patients (\ 80%) will be randomised 1:1 between surveillance (current UK standard) and maintenance capecitabine. Patients will be stratified according to: centre region, disease extent and performance status (0 versus 1 versus 2). Review of patients will occur every 4 weeks in the surveillance arm. In maintenance therapy arms, patients will be reviewed every 3 or every 4 weeks depending upon the treatment strategy. CT assessments of response will occur every 12 weeks (3 months) in all arms of the trial. Treatment will be continued until disease progression, unacceptable toxicity, or patient withdrawal for another reason. The trial is being run from the RM GI and Lymphoma CTU with Professor David Cunningham as the Chief Investigator (CI). Effective arms in the phase II portion of the trial may be taken forward into a phase III maintenance trial powered for overall survival. It is also hoped that, as more robust data becomes available for other biomarker-selected populations (e.g. MET-positive, FGFR-amplified), it may be possible to amend the overall trial design to incorporate these biomarker-targeted maintenance therapies in the HER-2 negative population.
Interventions
DRUGCapecitabine
1250 mg/m2/day, 21 day cycle
IV treatment on days 1&15 of 28 day cycle
DRUGTrastuzumab
6mg/kg on day 1 cycle every 21 days
DRUGRucaparib
600mg PO twice daily
DRUGRamucirumab
ramucirumab 8mg/kg IV day 1 and day 8
Sponsors
MedImmune LLC
Clovis Oncology, Inc.
Eli Lilly and Company
AstraZeneca
Royal Marsden NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- All Patients * Histologically verified inoperable locally advanced or metastatic adenocarcinoma of the oesophagus, oesophago-gastric junction, or stomach. * Completion of 18 weeks of first-line chemotherapy with either CX/ CAPOX or FOLFOX (HER2 negative) or CX/ CF + trastuzumab (HER2 positive) for locally advanced / metastatic disease with \> stable disease on the end of treatment CT scan (HER2 positive patients must have received at least one cycle of trastuzumab alongside first line chemotherapy; patients receiving chemotherapy delivered on a 3-weekly basis eg CX/ CAPOX should have received 6 cycles and on a two weekly basis e.g. FOLFOX should have received 9 cycles). * Disease which, following first-line chemotherapy, remains inoperable and unsuitable for definitive chemoradiotherapy. * Able to proceed with maintenance treatment within 28 days of the last day of the last cycle of chemotherapy. * Formalin fixed paraffin embedded (FFPE) blocks of diagnostic tissue available for biomarker analysis. * Any prior chemotherapy or radiotherapy in the adjuvant setting must have been completed at least 6 months prior to the first occurrence of metastatic disease. * No prior radiotherapy in the advanced disease setting. Patients receiving palliative radiotherapy to sites of disease that are not measurable may be eligible and should be discussed with the Chief Investigator. * Male/female patients aged ≥18 years. * WHO Performance status 0, 1 or 2. * Patients should have a projected life expectancy of at least 3 months. * Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5x109/l; white blood cell count ≥ 3x109/l; platelets ≥ 100x109/l; haemoglobin (Hb) ≥ 9g/dl (can be post-transfusion). * Adequate renal function: calculated creatinine clearance ≥50ml/minute. * Adequate liver function: serum bilirubin ≤1.5x ULN; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤2.5 x ULN (5 × ULN is acceptable for ALT, AST and ALP if liver metastases are present). * Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 7 months following the last dose of assigned study drug(s). * Written informed consent must be obtained from the patient before any study-specific procedures are performed.
Exclusion criteria
- All Patients * Concurrent enrolment in another clinical trial unless it is an observational (non-interventional) clinical study. * Tumours of squamous histology. * Documented brain metastases, central nervous system metastases or leptomeningeal disease. * Patients who have not recovered from clinically significant effects of any prior surgery, radiotherapy or any other anti-neoplastic therapies. All toxicities must have resolved to grade 1 or less, with the exception of peripheral neuropathy which must be less than or equal to grade 2 according to NCI CTCAE version 4.0. * Any major surgery within 4 weeks prior to the start of study treatment. * Uncontrolled hypertension (systolic blood pressure \>180 mm Hg or diastolic blood pressure \>100 mm Hg). * Clinically significant (i.e. active) cardiac disease e.g. symptomatic coronary artery disease, symptomatic congestive heart failure, uncontrolled cardiac dysrhythmia, or myocardial infarction within the last 12 months. Patients with any prior history of clinically significant cardiac failure are excluded from study entry. * History of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan. * Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication. * Patients who are pregnant or lactating. * Known positive tests for human immunodeficiency virus (HIV) infection, hepatitis A or C virus, acute or chronic active hepatitis B infection. * Other clinically significant disease or co-morbidity which may adversely affect the safe delivery of treatment within this trial. * Any other malignancies within the last 3 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix). * Treatment with another investigational agent within 30 days of commencing study treatment. Additional Inclusion /
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 5 years | The progression free survival will be calculated from the date of randomisation to the date of disease progression according to RECIST 1.1 criteria or death from any cause, whichever comes first. In HER 2 negative patients the PFS will be compared between the standard Arm (A1) and capecitabine (A2) and then separately between standard arm (A1) and MEDI 4736 (A3), or standard arm (A1) and Rucaparib (A4), or standard arm (A1) and Ramucirumab (A5). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | 5 years | Will be calculated from the date of randomisation until the date of death from any cause. Patients remaining alive at the time of the analysis will be censored a the date of last follow up. |
| Objective response rate (ORR) by RECIST 1.1 | 5 years | This will be evaluated according to RECIST 1.1. |
| The number of participants with treatment related adverse events as assessed by CTCAE v 4.0 | 5 years | The number of participants with treatment related adverse events as assessed by CTCAE v 4.0 |
| Progression - free rate (PFR) | 5 years | Progression-free rate (defined as stable disease, partial or complete response) at 12 weeks (3 months) , 24 weeks (6 months) and 52 weeks (1 year) will be evaluated using RECIST 1.1 criteria. Progression events will be determined by local investigator assessment, and will be collected for up to a 5 year period. |
| Analysis of PFR may also be conducted according to biomarker status in relevant arms. For example in HER2 negative patients outcomes in Arm A1 and A3 will be compared according to PDL1 expression status assessed by immunohistochemistry on tissue. | 5 years | Analysis of PFR may also be conducted according to biomarker status in relevant arms. For example in HER2 negative patients outcomes in Arm A1 and A3 will be compared according to PDL1 expression status assessed by immunohistochemistry on tissue. |
| Analysis of OS may also be conducted according to biomarker status in relevant arms. For example in HER2 negative patients outcomes in Arm A1 and A3 will be compared according to PDL1 expression status assessed by immunohistochemistry on tissue. | 5 years | Analysis of OS may also be conducted according to biomarker status in relevant arms. For example in HER2 negative patients outcomes in Arm A1 and A3 will be compared according to PDL1 expression status assessed by immunohistochemistry on tissue. |
| Analysis of ORR may also be conducted according to biomarker status in relevant arms. For example in HER2 negative patients outcomes in Arm A1 and A3 will be compared according to PDL1 expression status assessed by immunohistochemistry on tissue. | 5 years | Analysis of ORR may also be conducted according to biomarker status in relevant arms. For example in HER2 negative patients outcomes in Arm A1 and A3 will be compared according to PDL1 expression status assessed by immunohistochemistry on tissue. |
| Analysis of PFS may also be conducted according to biomarker status in relevant arms. For example in HER2 negative patients outcomes in Arm A1 and A3 may be compared according to PDL1 expression status assessed by immunohistochemistry on tissue. | 5 years | Analysis of PFS may also be conducted according to biomarker status in relevant arms. For example in HER2 negative patients outcomes in Arm A1 and A3 may be compared according to PDL1 expression status assessed by immunohistochemistry on tissue. |
Countries
United Kingdom
Outcome results
None listed