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TerminatedNCT03437200CRUCIALUpdated Feb 21, 2023

Combination of Chemoradiation With Immunotherapy in Inoperable œsophageal Cancer

A Phase 2 interventional study of Nivolumab and Ipilimumab in Inoperable œsophageal Cancer, sponsored by European Organisation for Research and Treatment of Cancer - EORTC. Terminated at 7 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-02-21.

Sponsored by European Organisation for Research and Treatment of Cancer - EORTC · Phase 2, Interventional, and Treatment

Why this study was terminated
Poor accrual
Phase
Phase 2
Study type
Interventional
Enrollment
8
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study summary

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).

02

Conditions studied

  • Inoperable œsophageal Cancer

Keywords

  • œsophageal cancer nivolumab ipilimumab
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
04

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
8 participants (actual)

Study arms

  • Experimental
    Arm A: Chemoradiation + Nivolumab

    All 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.

    Drug: Nivolumab · Other: Chemoradiation

  • Experimental
    Arm B: Chemoradiation + Nivolumab + Ipilimumab

    Same 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

    Drug: Nivolumab · Drug: Ipilimumab · Other: Chemoradiation

Interventions

  • DrugNivolumab

    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.

  • DrugIpilimumab

    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.

  • OtherChemoradiation

    All 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 (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, bolus fluorouracil 400 mg/m2, and infusional fluorouracil 1600 mg/m2 over 48 h), followed by 3 cycles of 2 weeks of FOLFOX without RT.

05

What researchers measure

Primary outcomes

  1. 12-Month Progression-free survival using RECIST 1.1

    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).

    Time frame: 3.8 years from first patient in

Secondary outcomes

  1. Best overall response according to RECIST 1.1

    Time frame: 3.8 years from first patient in

  2. 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

  3. Progression-free survival using RECIST 1.1

    Time frame: 3.8 years from first patient in

  4. Failure-free survival

    Time frame: 3.8 years from first patient in

  5. Overall survival

    Time frame: 3.8 years from first patient in

  6. Percentage of patients receiving the planned chemoradiation

    Time frame: 3.8 years from first patient in

  7. Relative dose intensity of oxaliplatinum

    The dose intensity and relative dose intensity of treatments will be presented by drug and by treatment arm using median, range and interquartile range.

    Time frame: 3.8 years from first patient in

  8. Relative dose intensity of 5FU

    The dose intensity and relative dose intensity of treatments will be presented by drug and by treatment arm using median, range and interquartile range.

    Time frame: 3.8 years from first patient in

06

Study locations

7 sites
  • Assistance Publique - Hopitaux de Paris - La Pitie Salpetriere
    Paris, 75651, France
  • Institut Gustave Roussy
    Villejuif, 94805, France
  • Hospital Del Mar
    Barcelona, 08003, Spain
  • Institut Catala d'Oncologia - ICO Badalona - Hospital De Mataro
    Barcelona, 08304, Spain
  • Institut Catala d'Oncologia - ICO L'Hospitalet - Hospital Duran i Reynals (Institut Catala D'Oncologia)
    Barcelona, 08908, Spain
  • Hospital Universitario de Gran Canaria Doctor Negrin
    Las Palmas De Gran Canaria, 35019, Spain
  • Hospital Universitario 12 De Octubre
    Madrid, 28041, Spain
07

Registry details

Key details

Study ID
NCT03437200
Lead sponsor
European Organisation for Research and Treatment of Cancer - EORTC
Responsible party
Sponsor
First posted
Feb 19, 2018
Start date
Jan 17, 2019
Primary completion
Oct 7, 2022
Completion
Oct 7, 2022
Last update
Feb 21, 2023

Study contacts

Eric Deutsch
principal investigator · INSTITUT GUSTAVE ROUSSY, Paris, France
Markus Moehler
principal investigator · UNIVERSITY MEDICAL CENTER MAINZ, Germany

Oversight

FDA-regulated drug
No
FDA-regulated device
No
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