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

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

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

    NCT ID: NCT02678182

    ORG ID: 3804

    Trial Conditions

    Adenocarcinoma of the Oesophagus

    Adenocarcinoma of the Gastro-oesophageal Junction

    Adenocarcinoma of the Stomach

    Trial Interventions

    Drug Synonyms Arms
    Capecitabine Arm A2: Capecitabine Maintenance
    MEDI4736 Arm A3: MEDI4736
    Trastuzumab Arm B1: Trastuzumab Maintenance

    Trial 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) 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

    Name Type Description Interventions
    A1: Surveillance No Intervention Patients in this Arm will follow current UK standard of care for this setting and will be reviewed every 4 weeks
    Arm A2: Capecitabine Maintenance Experimental 1250 mg/M2/DAY on days 1-21 Capecitabine
    Arm A3: MEDI4736 Experimental IV treatment on day 1 +15, on a 28 day cycle. MEDI4736
    Arm B1: Trastuzumab Maintenance Active Comparator 6mg/kg on day 1 every 21 days Trastuzumab

    Eligibility Criteria

    Inclusion Criteria - All Patients

    - Histologically verified inoperable locally advanced or metastatic adenocarcinoma of
    the oesophagus, oesophago-gastric junction, or stomach.

    - Completion of at least 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.

    - 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.

    - Uni-dimensionally measurable disease (CT or MRI as per RECIST).

    - 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.

    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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Progression Free Survival (PFS)

    Secondary Outcome Measures

    Progression - free rate (PFR)

    Overall survival (OS)

    Objective response rate (ORR) by RECIST 1.1

    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.

    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.

    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.

    Trial Keywords