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Association of Radiochemotherapy and Immunotherapy for the Treatment of Unresectable Oesophageal caNcer (ARION)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03777813
Recruitment Status : Suspended (Temporary suspension since March 13 due to COVID-19 pandemic)
First Posted : December 17, 2018
Last Update Posted : April 21, 2020
Sponsor:
Information provided by (Responsible Party):
UNICANCER

Brief Summary:
This study aims to assess the efficacy of durvalumab in combination with radiochemotherapy (FOLFOX and IMRT) and then as maintenance therapy for treating patients with localised unresectable oesophageal cancer. This is a randomized, French national, multicentre, comparative phase II trial

Condition or disease Intervention/treatment Phase
Esophagus Cancer Unresectable Malignant Neoplasm Drug: Durvalumab Combination Product: IMRT 50 Gy + FOLFOX4 simplifIed (oxaliplatin, leucovorin, 5-FU) Phase 2

Detailed Description:

ARION study will randomize 120 patients, in 12 centers in France, according to a ratio 1:1 in the following arm of treatment:

- Standard and experimental arm:

Definitive modulated-intensity radiotherapy will be delivered according to boost integrated technique 5 days a week for 5 weeks at a dose of:

  • 50 Gy delivered in 25 fractions to the macroscopic disease (endoscopic, TDM and fused FDG PET)
  • 45 Gy to the adjacent peri tumoral mucosis and prophylactic lymph node

FOLFOX 4 simplified protocol, 1 infusion every 2 weeks (q2w) during 3 months starting with radiotherapy (+/- 1 day):

  • IV oxaliplatin 85 mg/m² in 2 h on day 1 (D1)
  • IV Leucovorin 200 mg/m² in 2 h on D1, followed by
  • IV 5-FU 400 mg/m² in 10 minutes on D1 followed by
  • IV continuous infusion 5-FU 2400 mg/m² in 46 h
  • Experimental arm: Concomitant administration of durvalumab:

Every 4 weeks during concurrent FOLFOX (dose: 1500 mg) and after FOLFOX completion (total of 12 months of treatment).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Association of Radiochemotherapy and Immunotherapy for the Treatment of Unresectable Oesophageal caNcer: a Comparative Randomized Phase II Trial
Actual Study Start Date : December 5, 2018
Estimated Primary Completion Date : September 1, 2024
Estimated Study Completion Date : September 1, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A

Concomitant administration of durvalumab (dose: 1500 mg):

Every 4 weeks during concurrent FOLFOX and after FOLFOX completion (total of 12 months of treatment)

Definitive modulated-intensity radiotherapy will be delivered according to boost integrated technique 5 days a week for 5 weeks at a dose of:

  • 50 Gy delivered in 25 fractions to the macroscopic disease (endoscopic, TDM and fused FDG PET)
  • 45 Gy to the adjacent peri tumoral mucosis and prophylactic lymph node

FOLFOX 4 simplified protocol, 1 infusion every 2 weeks during 3 months starting with radiotherapy (+/- 1 day):

  • IV oxaliplatin 85 mg/m² in 2 h on D1
  • IV Leucovorin 200 mg/m² in 2 h on D1, followed by
  • IV 5-FU 400 mg/m² in 10 minutes on D1 followed by
  • IV continuous infusion 5-FU 2400 mg/m² in 46 h
Drug: Durvalumab
Radiochemotherapy in standard arm and in experimental arm: 10 weeks (RT 50 Gy and FOLFOX q2w) Immunotherapy in experimental arm only: Patients will received concomitantly a maximum of 12 infusions
Other Name: IMRT 50 Gy + FOLFOX4 simplifIed (oxaliplatin, leucovorin, 5-FU)

Combination Product: IMRT 50 Gy + FOLFOX4 simplifIed (oxaliplatin, leucovorin, 5-FU)
Radiochemotherapy in standard arm and in experimental arm: 10 weeks (RT 50 Gy and FOLFOX q2w)

Active Comparator: Arm B

Definitive modulated-intensity radiotherapy will be delivered according to boost integrated technique 5 days a week for 5 weeks at a dose of:

  • 50 Gy delivered in 25 fractions to the macroscopic disease (endoscopic, TDM and fused FDG PET)
  • 45 Gy to the adjacent peri tumoral mucosis and prophylactic lymph node

FOLFOX 4 simplified protocol, 1 infusion every 2 weeks during 3 months starting with radiotherapy (+/- 1 day):

  • IV oxaliplatin 85 mg/m² in 2 h on D1
  • IV Leucovorin 200 mg/m² in 2 h on D1, followed by
  • IV 5-FU 400 mg/m² in 10 minutes on D1 followed by
  • IV continuous infusion 5-FU 2400 mg/m² in 46 h
Combination Product: IMRT 50 Gy + FOLFOX4 simplifIed (oxaliplatin, leucovorin, 5-FU)
Radiochemotherapy in standard arm and in experimental arm: 10 weeks (RT 50 Gy and FOLFOX q2w)




Primary Outcome Measures :
  1. cPFS (centrally reviewed cPFS) [ Time Frame: 12-months cPFS ]
    defined by a blinded independent centralized revue of progression free survival. cPFS is defined as the time from randomization until progression or death; patients alive and without documented progression at last follow-up news have PFS censored at this date or at initiation of new anticancer treatment (if applicable). Progression will be defined with central external reviewing of TDM per RECIST v1.1


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: For each treatment arms, survival rates (PFS and OS) will be estimated at 12, 18 and 24 months ]
    defined as the time between randomization and death due to any cause.

  2. Adverse Events [ Time Frame: 2 years after randomization ]
    will be assessed on occurrence of Adverse Events (AEs) based on NCI CTCAE v5.0

  3. Quality of Life OES18, used for patients with oesophageal cancer always complemented by the QLQ-C30 measuring 5 functional scales (physical, everyday activity, cognitive, emotional and social) and 3 symptoms scales (fatigue, pain, nausea and vomiting) [ Time Frame: 2 years after randomization ]
    scores EORTC QLQ C30 - OES18



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically proven squamous cell carcinoma or adenocarcinoma of the oesophagus,
  2. Unresectable disease due to anatomical consideration or medical condition,
  3. Presence of at least one measurable lesion >10 mm with spiral CT scan,
  4. Age ≥18 years old,
  5. World Health Organization performance status <2 (i.e., 0 or 1),
  6. Body weight >35 kg,
  7. Life expectancy of at least 12 weeks ,
  8. Adequate haematology laboratory data within the 7 days before randomization

    1. Absolute neutrophils >1.5 x 10⁹/L
    2. Platelets >100 x 10⁹/L
    3. Haemoglobin ≥9 g/dL,
  9. Adequate Biochemistry laboratory data within the 7 days before randomization

    1. Total bilirubin ≤1.5 x upper limit of normal (ULN)
    2. Transaminases ≤2.5 x ULN
    3. Alkaline phosphatases ≤5 x ULN,
    4. Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min by the Cockcroft-Gault formula,
    5. Glycaemia ≤1.5 x ULN
    6. Cholesterolaemia ≤7.30 mmol/L,
    7. Albumin >28 g/L
  10. Adequate haemostasis laboratory data within 7 days prior to randomization: prothrombin time (PT) within the normal range,
  11. Women should be post-menopause or willing to accept the use an effective contraceptive regimen during the treatment period and for at least 6 months after the end of the study. All non-menopausal women should have a negative pregnancy test within 72 h prior to randomization. Men should accept to use an effective contraception during treatment period and at least 3 months after the end of the study.
  12. Patients must have provided consent for the study by signing and dating a written informed consent form prior to any study specific procedures, sampling, or analyses,
  13. Patient affiliated to a social security regimen.

Exclusion Criteria:

  1. Previous treatment with another PD-1, PD-L1 including durvalumab or CTLA-4 inhibitor
  2. Metastatic disease,
  3. No prior therapy for pathology investigated including chemotherapy or radiotherapy prior to the study, except anterior out of field radiotherapy, received for treatment of another primary tumor considered in remission,
  4. Patients should not receive live vaccine 30 days prior to study drug
  5. Female patients who are pregnant or breastfeeding
  6. Uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, pulmonary failure, chronic renal or hepatic diseases, active peptic ulcer disease or gastritis, active bleeding, diatheses... (non-exhaustive list),
  7. Clinically significant cardiac disease or impaired cardiac function, such as:

    1. Congestive heart failure requiring treatment (New York Heart Association (NYHA) grade ≥2), left ventricular ejection fraction (LVEF) <50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO), or uncontrolled arterial hypertension defined by blood pressure >140/100 mmHg at rest (average of 3 consecutive readings),
    2. History or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high- grade/complete auriculoventricular-blockage,
    3. Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting), <3 months prior to screening,
    4. MeanQT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction.
  8. Current or prior use of immunosuppressive medication within 28 days before the first administration of durvalumab (exception: systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or equivalent are allowed as well as steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) - Topical, inhaled, nasal, and ophthalmic steroids are allowed,
  9. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stabilised with hormone replacement therapy
    3. Any chronic skin condition that does not require systemic therapy
    4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    5. Patients with coeliac disease controlled by diet alone
  10. Known primary immunodeficiency or active HIV,
  11. Patient with a dihydropyrimidine dehydrogenase (DPD) deficiency (the test should be done for all patients before 5-FU administration as per the ANSM's recommendations),
  12. Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months indicated by positive HbS antibody (Hepatitis B surface antibody) test for hepatitis B or hepatitis C virus ribonucleic acid (HCV antibody),
  13. History of organ transplantation requiring the use of immunosuppressive medication,
  14. History of active tuberculosis or latent disease capable of reactivation,
  15. Current pneumonitis or interstitial lung disease,
  16. Other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only,
  17. History of severe allergic reactions or hypersensitivity to any unknown allergens or any components of the study drug (refer to Investigator's Brochure of durvalumab section 5.4.2.2).
  18. Any prior corticosteroid-refractory immune-related adverse event (irAE),
  19. Oeso-tracheal or oeso-bronchial fistulae,
  20. Participation in another therapeutic trial within the 30 days prior to study inclusion,
  21. Patients deprived of liberty or under guardianship,
  22. Patients unable to adhere to the protocol for geographical, social, or psychological reasons.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03777813


Locations
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France
Centre Oscar Lambret, CLCC UNICANCER
Lille, France
Hôpital Saint Louis, APHP
Paris, France, 75010
Hôpital Haut-Lévêque
Pessac, France, 33604
Centre Hospitalier Universitaire
Poitiers, France
Centre Paul Strauss, CLCC UNICANCER
Strasbourg, France
Iuct, Clcc Unicancer
Toulouse, France, 31059
CHU Rangueil Larrey
Toulouse, France
Sponsors and Collaborators
UNICANCER
Investigators
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Principal Investigator: Anouchka Modesto, Doctor Institut Claudius Regaud
Principal Investigator: Laurent Quero, Doctor Hôpital Saint Louis / Université Paris Diderot
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Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT03777813    
Other Study ID Numbers: UC-110/1719 -PRODIGE 67-UCGI33
2018-000708-40 ( EudraCT Number )
First Posted: December 17, 2018    Key Record Dates
Last Update Posted: April 21, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Unicancer will share de-identified individual data that underlie the results reported. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan will be examined upon request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: The data shared will be limit to that required for independent mandated verification of the published results, the applicant will need authorization from Unicancer for personal access, and data will only be transferred after signing of a data access agreement.
Access Criteria: Unicancer will consider access to study data upon written detailed request sent to Unicancer, from 6 months until 5 years after publication of summary data.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by UNICANCER:
oesophagus
localised unresectable
adenocarcinoma or squamous cell carcinoma
durvalumab
FOLFOX 4 simplified
Definitive modulated-intensity radiotherapy
Additional relevant MeSH terms:
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Esophageal Neoplasms
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Leucovorin
Oxaliplatin
Durvalumab
Levoleucovorin
Antineoplastic Agents
Antidotes
Protective Agents
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Antineoplastic Agents, Immunological