Clinical Trials /

Combination of Chemoradiation With Immunotherapy in Inoperable œsophageal Cancer

NCT03437200

Description:

The main objective of the trial is to assess the feasibility and the safety of the addition of immunotherapy with PD-1 antibody nivolumab +/- CTLA-4 antibody ipilimumab to concomitant chemoradiation therapy (CRT) in inoperable patients with early or locally advanced oesophageal cancer and to select the more promising experimental arm among the two possible combinations in terms of activity (based on progression free survival (PFS) at 12 months according to RECIST 1.1) for further evaluation in a phase III trial. The secondary objectives will aim to evaluate progression-free survival, failure-free survival and overall survival and pattern of progression (including incidence of distance metastasis).

Related Conditions:
  • Esophageal Adenocarcinoma
  • Esophageal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination of Chemoradiation With Immunotherapy in Inoperable œsophageal Cancer
  • Official Title: Phase II Trial in Inoperable œsophageal Cancer Evaluating the Feasibility of the Combination of Definitive Chemoradiation With the Immune Checkpoint Blockers Nivolumab +/- Ipilimumab

Clinical Trial IDs

  • ORG STUDY ID: EORTC-1714
  • SECONDARY ID: 2018‐000053‐53
  • NCT ID: NCT03437200

Conditions

  • Inoperable œsophageal Cancer

Interventions

DrugSynonymsArms
NivolumabArm A: Chemoradiation + Nivolumab
IpilimumabArm B: Chemoradiation + Nivolumab + Ipilimumab

Purpose

The main objective of the trial is to assess the feasibility and the safety of the addition of immunotherapy with PD-1 antibody nivolumab +/- CTLA-4 antibody ipilimumab to concomitant chemoradiation therapy (CRT) in inoperable patients with early or locally advanced oesophageal cancer and to select the more promising experimental arm among the two possible combinations in terms of activity (based on progression free survival (PFS) at 12 months according to RECIST 1.1) for further evaluation in a phase III trial. The secondary objectives will aim to evaluate progression-free survival, failure-free survival and overall survival and pattern of progression (including incidence of distance metastasis).

Trial Arms

NameTypeDescriptionInterventions
Arm A: Chemoradiation + NivolumabExperimentalAll patients will receive standard fractionation radiation therapy (RT) scheme: 50Gy in 25 fractions over 5 weeks (i.e. 2Gy per fraction), concurrently with 3 cycles of 2 weeks of FOLFOX followed by 3 cycles of 2 weeks of FOLFOX without RT. Induction phase: Nivolumab IV 240 mg on days 1, 15 and 29 followed by a maintenance phase (to start on day 43) of Nivolumab IV 240 mg q2 weekly for up to 1 year.
  • Nivolumab
Arm B: Chemoradiation + Nivolumab + IpilimumabExperimentalSame as arm A + induction phase: Ipilimumab IV 1 mg/kg on day 1 followed by a maintenance phase (to start on day 43) of Ipilimumab IV 1 mg/kg q6 weekly for up to 1 year
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically proven oesophageal squamous cell carcinoma or adenocarcinoma

          -  Both early stage and locally advanced tumor patients (according to TNM staging version
             8):

          -  T1, N1-3, M0 after complete work-up

          -  T2, N0-3, M0 after complete work-up

          -  T3, N0-3, M0

          -  Patient eligible for definitive chemoradiation and not considered for primary surgery
             after multidisciplinary meeting decision or patient refuses to undergo surgery

          -  Subject must be previously untreated with systemic treatment given as primary therapy
             for advanced or metastatic disease

          -  At least one measurable lesion by CT scan or MRI based on RECIST version 1.1 with
             radiographic tumor assessment performed within 28 days prior to randomization

          -  Availability of adequate tissue in terms of quality and quantity for
             immunohistochemical staining for PDL-1

          -  WHO performance status 0 or 1

          -  Adequate organ function within 14 days prior to randomization

        Exclusion Criteria:

          -  Cancer of cervical oesophagus (15 to 19 cm from dental ridge)

          -  Known Her2 positive adenocarcinoma

          -  Weight loss > 15 % over the last 3 months without improvement after nutritional
             support

          -  Patient with cardiac dysfunction e.g. symptomatic congestive heart failure,
             uncontrolled hypertension

          -  Known history of positive test for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS), hepatitis B or hepatitis C.

          -  Any prior treatment for advanced disease including treatment with an anti-Programmed
             Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2,
             anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody or any other
             antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.

          -  Live vaccines within 30 days prior to the first dose of study therapy. Examples of
             live vaccines include, but are not limited to the following: measles, mumps, rubella,
             chicken pox, yellow fever, H1N1 flu, rabies, BCG, and typhoid vaccine

          -  History of hypersensitivity to study drugs or any excipient (refer to SmPCs for
             ipilimumab, nivolumab, 5-FU and oxaliplatin)

          -  Current participation or treatment with an investigational agent or use of an
             investigational agent within 4 weeks of the first dose of study treatment

          -  Serious comorbidity or life expectancy less than one year

          -  Contraindication to chemoradiation therapy

          -  Treatment history of radiotherapy

          -  Child-Pugh B/C and patients with history of acute or chronic pancreatitis

          -  Patient with Type I diabetes mellitus, or skin disorders

          -  Known severe systemic autoimmune disease affecting the lungs or the bowel

          -  Known contraindication to CT scans with IV contrast

          -  Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in
             the last 15 days prior to enrollment

          -  Active autoimmune disease that has required systemic treatment in past 2 years

          -  Autoimmune paraneoplastic syndrome requiring immunosuppressive or dedicated treatment

          -  History of any other hematologic or primary solid tumor malignancy, unless in
             remission for at least 5 years.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:12-Month Progression-free survival using RECIST 1.1
Time Frame:3.8 years from first patient in
Safety Issue:
Description:The analysis of the 12-Month Progression-free survival rate (PFS-12) will be done when all patients achieved at least 15 months follow-up (12 months for the primary endpoint plus 100 days after the end of the protocol treatment).

Secondary Outcome Measures

Measure:Best overall response according to RECIST 1.1
Time Frame:3.8 years from first patient in
Safety Issue:
Description:
Measure:Pattern of first cause of progression (either local relapse/progression,either regional relapse/progression, either distant metastasis)
Time Frame:3.8 years from first patient in
Safety Issue:
Description:
Measure:Progression-free survival using RECIST 1.1
Time Frame:3.8 years from first patient in
Safety Issue:
Description:
Measure:Failure-free survival
Time Frame:3.8 years from first patient in
Safety Issue:
Description:
Measure:Overall survival
Time Frame:3.8 years from first patient in
Safety Issue:
Description:
Measure:Percentage of patients receiving the planned chemoradiation
Time Frame:3.8 years from first patient in
Safety Issue:
Description:
Measure:Relative dose intensity of oxaliplatinum
Time Frame:3.8 years from first patient in
Safety Issue:
Description:The dose intensity and relative dose intensity of treatments will be presented by drug and by treatment arm using median, range and interquartile range.
Measure:Relative dose intensity of 5FU
Time Frame:3.8 years from first patient in
Safety Issue:
Description:The dose intensity and relative dose intensity of treatments will be presented by drug and by treatment arm using median, range and interquartile range.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:European Organisation for Research and Treatment of Cancer - EORTC

Trial Keywords

  • œsophageal cancer nivolumab ipilimumab

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