Combination of Chemoradiation With Immunotherapy in Inoperable œsophageal Cancer

NCT03437200 | Terminated Phase 2

• 2 other identifiers: EORTC-17142018-000053-53
• Study Type: interventional
• Target: 8
• Locations: 2 countries
• Sites: 7

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

Keywords

œsophageal cancer nivolumab ipilimumab

Outcome Measures

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).

  3.8 years from first patient in

Secondary Outcomes (8)

• Best overall response according to RECIST 1.1

  3.8 years from first patient in

• Pattern of first cause of progression (either local relapse/progression,either regional relapse/progression, either distant metastasis)

  3.8 years from first patient in

• Progression-free survival using RECIST 1.1

  3.8 years from first patient in

• Failure-free survival

  3.8 years from first patient in

• Overall survival

  3.8 years from first patient in

Study Arms (2)

Arm A: Chemoradiation + Nivolumab

EXPERIMENTAL

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

Arm B: Chemoradiation + Nivolumab + Ipilimumab

EXPERIMENTAL

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

Nivolumab 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.

Arm A: Chemoradiation + Nivolumab; Arm B: Chemoradiation + Nivolumab + Ipilimumab

Ipilimumab 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.

Arm B: Chemoradiation + Nivolumab + Ipilimumab

Chemoradiation 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 A: Chemoradiation + Nivolumab; Arm B: Chemoradiation + Nivolumab + Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead

Study Sites (7)

Assistance Publique - Hopitaux de Paris - La Pitie Salpetriere

Paris, 75651, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Hospital Del Mar

Barcelona, 08003, Spain

Location

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

Barcelona, 08304, Spain

Location

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

Barcelona, 08908, Spain

Location

Hospital Universitario de Gran Canaria Doctor Negrin

Las Palmas de Gran Canaria, 35019, Spain

Location

Hospital Universitario 12 De Octubre

Madrid, 28041, Spain

Location

MeSH Terms

Interventions

Nivolumab; Ipilimumab; Chemoradiotherapy

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Combined Modality Therapy; Therapeutics; Drug Therapy; Radiotherapy

Study Officials

• Eric Deutsch

  INSTITUT GUSTAVE ROUSSY, Paris, France

  PRINCIPAL INVESTIGATOR

• Markus Moehler

  UNIVERSITY MEDICAL CENTER MAINZ, Germany

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 6, 2018
• First Posted: February 19, 2018
• Study Start: January 17, 2019
• Primary Completion: October 7, 2022
• Study Completion: October 7, 2022
• Last Updated: February 21, 2023

Record last verified: 2023-02

Locations

FR (2); ES (5)