Combination of Chemoradiation With Immunotherapy in Inoperable œsophageal Cancer

NCT ID: NCT03437200

Last Updated: 2023-02-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-01-17
• Study Completion Date: 2022-10-07

Brief 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).

Conditions

Inoperable œsophageal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Nivolumab

Intervention Type: DRUG

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.

Chemoradiation

Intervention Type: OTHER

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.

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

Group Type: EXPERIMENTAL

Nivolumab

Intervention Type: DRUG

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.

Ipilimumab

Intervention Type: DRUG

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.

Chemoradiation

Intervention Type: OTHER

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.

Interventions

Nivolumab

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.

Intervention Type: DRUG

Ipilimumab

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.

Intervention Type: DRUG

Chemoradiation

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.

Intervention Type: OTHER

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eric Deutsch

Role: PRINCIPAL_INVESTIGATOR

INSTITUT GUSTAVE ROUSSY, Paris, France

Markus Moehler

Role: PRINCIPAL_INVESTIGATOR

UNIVERSITY MEDICAL CENTER MAINZ, Germany

Locations

Assistance Publique - Hopitaux de Paris - La Pitie Salpetriere

Paris, , France

Institut Gustave Roussy

Villejuif, , France

Hospital Del Mar

Barcelona, , Spain

Institut Catala d'Oncologia - ICO Badalona - Hospital De Mataro

Barcelona, , Spain

Institut Catala d'Oncologia - ICO L'Hospitalet - Hospital Duran i Reynals (Institut Catala D'Oncologia)

Barcelona, , Spain

Hospital Universitario de Gran Canaria Doctor Negrin

Las Palmas de Gran Canaria, , Spain

Hospital Universitario 12 De Octubre

Madrid, , Spain

Countries

France; Spain

Other Identifiers

2018-000053-53

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EORTC-1714

Identifier Type: -

Identifier Source: org_study_id