PLATFORM: Planning Treatment for Oesophago-gastric Cancer: a Maintenance Therapy Trial

Sponsor

Royal Marsden NHS Foundation Trust (Other)

Overall Status

Recruiting

CT.gov ID

NCT02678182

Collaborator

MedImmune LLC (Industry), Clovis Oncology, Inc. (Industry), Eli Lilly and Company (Industry)

924

Enrollment

Location

Arms

124

Duration (Months)

7.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Oesophagus Adenocarcinoma of the Gastro-oesophageal Junction Adenocarcinoma of the Stomach	Drug: Capecitabine Drug: MEDI4736 Drug: Trastuzumab Drug: Rucaparib Drug: Ramucirumab	Phase 2

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 or triplet (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 then become eligible for trial recruitment and randomization following completion of at least 6 cycles of standard chemotherapy with ≥SD (stable disease) or better on the end-of-treatment CT scan. Eligible patients will then be randomised according to HER-2 status as follows:

HER-2 positive patients (~20%) will be currently not be randomised and will be assigned maintenance single-agent trastuzumab (current UK standard), a comparator arm is in development.
HER-2 negative patients (~80%) will be randomised in a 1:1:1 fashion between surveillance only (current UK standard), maintenance capecitabine, or maintenance immuno-modulatory therapy (anti-PD-L1 antibody)

Patients will be stratified according to: locally advanced disease versus metastatic disease, and performance status (0 versus 1 versus 2).

Review of patients will occur every 4 weeks in the observation only 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 indefinitely until the occurrence of either disease progression, unacceptable toxicity, or patient withdrawal for another reason.

The trial is being run from the RMH GI clinical trials unit with Professor David Cunningham as the over-arching 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

924 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Planning Treatment for Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial

Study Start Date :

Feb 1, 2015

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: A1: Surveillance Patients in this Arm will follow current UK standard of care for this setting and will be reviewed every 4 weeks
Experimental: Arm A2: Capecitabine Maintenance 1250 mg/M2/DAY on days 1-21	Drug: Capecitabine 1250 mg/m2/day, 21 day cycle
Experimental: Arm A3: MEDI4736 (Durvalumab) IV treatment on day 1 +15, on a 28 day cycle.	Drug: MEDI4736 IV treatment on days 1&15 of 28 day cycle
Active Comparator: Arm B1: Trastuzumab Maintenance 6mg/kg on day 1 every 21 days	Drug: Trastuzumab 6mg/kg on day 1 cycle every 21 days
Experimental: Arm A4: Rucaparib 600mg PO twice daily	Drug: Rucaparib 600mg PO twice daily
Experimental: Arm A5: Capecitabine and Ramucirumab capecitabine 1250 mg/m2/day PO in two divided doses continuously from days 1-21 of each 21 day cycle (see section 12) and ramucirumab 8mg/kg IV day 1 and day 8	Drug: Capecitabine 1250 mg/m2/day, 21 day cycle Drug: Ramucirumab ramucirumab 8mg/kg IV day 1 and day 8

Outcome Measures

Primary Outcome Measures

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).

Secondary Outcome Measures

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.
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
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.
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria - All Patients

Histologically verified inoperable locally advanced or metastatic adenocarcinoma of the oesophagus, oesophago-gastric junction, or stomach.
Completion of 6 cycles of first-line chemotherapy for locally advanced / metastatic disease (this must have included a platinum and fluoropyrimidine in all cases; HER-2 positive patients must have received trastuzumab alongside chemotherapy) with > stable disease on the end of treatment CT scan. If your patient has received first line therapy, delivered on a two weekly basis e.g. FOLFOX they should have received 8 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 < 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 / Exclusion Criteria - HER-2 Negative Patients (Arm A)

Patients must have histologically or cytologically confirmed HER-2 negative disease (HER-2 0 or 1 by IHC or HER-2 2+ by IHC and no HER-2 gene amplification by ISH).
Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency or known capecitabine intolerance are excluded. This includes patients with previous coronary artery spasm or chest pain deemed to be capecitabine-related.
Patients with known allergy or reaction to any component of the MEDI4736 formulation are excluded.
Patients with current or prior use of immunosuppressive medication within 4 weeks are excluded, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent.
Patients with active or prior documented autoimmune disease within the past 2 years are excluded. Subjects with vitiligo, Grave's disease, and psoriasis not requiring systemic treatment within the past 2 years are eligible.
Patients with active or prior documented inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis) are excluded.
Patients with a history of primary immunodeficiency are excluded.
Patients with a history of organ transplant requiring use of immunosuppressives are excluded.
Patients with known history of tuberculosis are excluded.
Patients who have received a live attenuated vaccination within 30 days prior to study entry are excluded.
Prior treatment with a PARP inhibitor is excluded.
Any Grade 3 or 4 GI bleeding within 3 months prior to enrollment are excluded
Any significant history of DVT or PE within 3 months of randomisation (catheter associated or superficial venous thrombosis are not considered significant) are excluded.
History of GI perforation within 6 months of randomisation are excluded
History of hepatic encephalopathy or cirrhosis (level Child-Pugh B or worse) are excluded
Patients must have adequate coagulation function as defined by International Normalised Ratio (INR) ≤1.5 and a partial thromboplastin thime (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy. Patients receiving warfarin must be switched to low molecular weight heparin prior to randomisation.
Patients with a serious or non-healing wound, ulcer or bone fracture within 28 days prior to randomisation are excluded.
The patient's urinary protein is ≤1+ on dipstick or routine urinalysis (if urine dipstick is
2+, a 24 hour urine collection for protein must demonstrate < 1000mg of protein in 24 hours.
Patients experiencing thromboembolic events, including but not limited to myocardial infarction, transient ischaemic attack, cerebrovascular accident, unstable angina, within 6 months prior to first dose of protocol therapy are excluded.
Patients who have undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/ subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy are excluded.
Patients receiving chronic anti-platelet therapy or NSAIDS including ibuprofen, naproxen, dipyridamole or clopidogrel, or similar agents are excluded. Once daily aspirin use (up to 325mg/day) is permitted.

Additional Inclusion / Exclusion Criteria - HER-2 Positive Patients (Arm B)

Patients must have histologically or cytologically confirmed HER-2 positive disease (HER-2 3+ by IHC or HER-2 2+ by IHC and HER-2 gene amplified by ISH).
Patients must have left ventricular ejection fraction (LVEF) >50% as measured by echocardiogram or >45% measured by MUGA (must also be greater than lower limit of normal at institution).
Patients with active or prior history of New York Heart Association (NYHA) congestive heart failure are excluded.
Patients with a known history of hypersensitivity to trastuzumab or any of its components are excluded.