Clinical Trials /

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

NCT02678182

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Carcinoma
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Planning Treatment for Oesophago-gastric Cancer: a Maintenance Therapy Trial
  • Official Title: Planning Treatment for Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial

Clinical Trial IDs

  • ORG STUDY ID: 3804
  • NCT ID: NCT02678182

Conditions

  • Adenocarcinoma of the Oesophagus
  • Adenocarcinoma of the Gastro-oesophageal Junction
  • Adenocarcinoma of the Stomach

Interventions

DrugSynonymsArms
CapecitabineArm A2: Capecitabine Maintenance
MEDI4736Arm A3: MEDI4736 (Durvalumab)
TrastuzumabArm B1: Trastuzumab Maintenance
RucaparibArm A4: Rucaparib
RamucirumabArm A5: Capecitabine and Ramucirumab

Purpose

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
A1: SurveillanceNo InterventionPatients in this Arm will follow current UK standard of care for this setting and will be reviewed every 4 weeks
    Arm A2: Capecitabine MaintenanceExperimental1250 mg/M2/DAY on days 1-21
    • Capecitabine
    Arm A3: MEDI4736 (Durvalumab)ExperimentalIV treatment on day 1 +15, on a 28 day cycle.
    • MEDI4736
    Arm B1: Trastuzumab MaintenanceActive Comparator6mg/kg on day 1 every 21 days
    • Trastuzumab
    Arm A4: RucaparibExperimental600mg PO twice daily
    • Rucaparib
    Arm A5: Capecitabine and RamucirumabExperimentalcapecitabine 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
    • Capecitabine
    • Ramucirumab

    Eligibility Criteria

            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.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Progression Free Survival (PFS)
    Time Frame:5 years
    Safety Issue:
    Description: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

    Measure:Progression - free rate (PFR)
    Time Frame:5 years
    Safety Issue:
    Description: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.
    Measure:Overall survival (OS)
    Time Frame:5 years
    Safety Issue:
    Description: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.
    Measure:Objective response rate (ORR) by RECIST 1.1
    Time Frame:5 years
    Safety Issue:
    Description:This will be evaluated according to RECIST 1.1.
    Measure:The number of participants with treatment related adverse events as assessed by CTCAE v 4.0
    Time Frame:5 years
    Safety Issue:
    Description:The number of participants with treatment related adverse events as assessed by CTCAE v 4.0
    Measure: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.
    Time Frame:5 years
    Safety Issue:
    Description: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.
    Measure: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.
    Time Frame:5 years
    Safety Issue:
    Description: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.
    Measure: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.
    Time Frame:5 years
    Safety Issue:
    Description: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.
    Measure: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.
    Time Frame:5 years
    Safety Issue:
    Description: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.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Royal Marsden NHS Foundation Trust

    Last Updated

    February 19, 2020