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PReoperative Chemoradiation (Paclitaxel-carboplatin or FOLFOX) for Resectable Esophageal and Junctional Cancer (PROTECT)

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ClinicalTrials.gov Identifier: NCT02359968
Recruitment Status : Recruiting
First Posted : February 10, 2015
Last Update Posted : May 15, 2019
Sponsor:
Collaborator:
National Cancer Institute, France
Information provided by (Responsible Party):
Centre Oscar Lambret

Tracking Information
First Submitted Date  ICMJE January 12, 2015
First Posted Date  ICMJE February 10, 2015
Last Update Posted Date May 15, 2019
Actual Study Start Date  ICMJE February 26, 2015
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 9, 2015)
Short-term benefit of 2 preoperative regimen: complete resection rate AND severe (grade ≥ 3) postoperative morbidity/mortality according to the Clavien-Dindo classification [ Time Frame: up to 30 days after surgery ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 9, 2015)
  • Rate of completion of full treatment without modification [ Time Frame: up to 58 days ]
  • Recurrence rate [ Time Frame: From date of inclusion until the date of first documented progression whichever came first, assessed up to 5 years ]
  • disease-free survival [ Time Frame: From date of inclusion until the date of death from any cause assessed up to 5 years ]
  • Tolerance according to NCI-CTCAE v4.0 and Clavien-Dindo [ Time Frame: up to 30 days after surgery ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 9, 2015)
DVH (CoDose-Volume-Histogram (DVH) and postoperative respiratory morbidity [ Time Frame: up to 30 days after the beginning of radiotherapy ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE PReoperative Chemoradiation (Paclitaxel-carboplatin or FOLFOX) for Resectable Esophageal and Junctional Cancer
Official Title  ICMJE PReoperative Chemoradiation With Paclitaxel-carboplatin or With Fluorouracil-oxaliplatine-acide Folinique (FOLFOX) for Resectable Esophageal and Junctional Cancer - A Randomized Phase II Trial
Brief Summary

Resectable esophageal or junctional cancer requires medical treatment by radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy treatment is the FOLFOX. It is a combination of three drugs administered intravenously: fluorouracil, oxaliplatin and folinic acid. This is the standard treatment.

Another protocol of chemotherapy is widely used by certain European and American teams, due to promising results : a combination of two drugs administered intravenously: Paclitaxel and Carboplatin (CarboP-pacliT). At present, no clinical study has shown the superiority of one treatment over the other.

The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments.

Detailed Description

There is no standard preoperative (neoadjuvant) chemoradiation (NCRT) regimen for resectable esophageal cancer, because most if all trials failed to show any survival advantage favoring pCRT when compared to surgery only. This failure had been related to the lack of power of some trials, as well as the ability of chemoradiation to potentiate post-operative morbidity (including mortality), and therefore hampering the accrual of its own survival benefit. Hopefully, meta-analyses showed that NCRT increases survival when compared to surgery only. However, in the clinical practice, this does not make easier the choice of the best NCRT treatment. It appeared that the radiation regimen that were used in each randomized trials were heterogeneous with respect with dose, fraction, length of treatment, fields, dosimetry planning, and quality control. This applies also to chemotherapy with respect with the kind of cytotoxics that were used (including number of drugs), as well as dosage, and the number of cycles, although most of the time cytotoxics were fluorouracil and cisplatin.

Dutch colleagues recently showed that NCRT with weekly carboplatin and paclitaxel increase survival, without increasing postoperative mortality. Of note, most tumors in this trial arose from the lower third of the esophagus and esogastric junction and these habitually correlate with less postoperative morbidity compared to upper third tumors. Moreover, the lung volume spared from radiation was greater in junctional tumors than in upper third cancers - a critical point in the development of radiation-induced pneumonitis and subsequent postoperative mortality. It is difficult to understand how this taxane-based chemotherapy is active, as it did not make better that fluorouracil-based regimen in non-operable patients, and as NCRT with taxanes makes radiation-induced pneumonitis more likely. The favorable impact of this NCRT may lie on its radiation regimen. A moderate total dose of radiation, smaller radial margins than in other trials and modern dosimetry with 3D-planning all improve the safety of treatment and of subsequent surgery. Finally, the favorable impact of the Dutch NCRT regimen may lies on the fact that it does not include cisplatin, a compound which has been found related to the occurrence of more sudden deaths than a non cisplatin-based regimen such as the FOLFOX combination (fluorouracil, oxaliplatin, folinic acid) in the setting of definitive chemoradiotherapy.

Our aim is to evaluate the short-term benefit (complete resection rate) and safety (severe postoperative rate) of 2 preoperative regimen, (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid), combined to the Dutch radiation backbone, in operable esophageal and junctional (Siewert I-II) cancer. The present trial offers the unique opportunity to compare two therapeutic strategies that have already been shown to be efficient in large randomized controlled trials offering level-1 evidence.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Esophageal Neoplasms
Intervention  ICMJE
  • Drug: FOLFOX
    radiochemotherapy before surgery
    Other Names:
    • Fluorouracil
    • Oxaliplatin
    • Folinic acid
    • Elvorine
  • Drug: CarboP-pacliT
    radiochemotherapy before surgery
    Other Names:
    • Carboplatine
    • paclitaxel
Study Arms  ICMJE
  • Active Comparator: FOLFOX
    • Fluorouracil 400 mg/m², IV bolus dose on day 1, followed by continuous IV infusion of fluorouracil 1600 mg/m² over 2 days
    • Oxaliplatin 85 mg/m², 2-hr IV infusion on day 1
    • Folinic acid 200 mg/m² 2-hr IV infusion on day 1
    • 3 cycles, q14
    Intervention: Drug: FOLFOX
  • Experimental: CarboP-pacliT
    • Carboplatin (carboP) AUC=2, given by intravenous infusion
    • Paclitaxel (pacliT) 50 mg/m², given by intravenous infusion
    • on days 1, 8, 15, 22 and 29
    Intervention: Drug: CarboP-pacliT
Publications * Messager M, Mirabel X, Tresch E, Paumier A, Vendrely V, Dahan L, Glehen O, Vasseur F, Lacornerie T, Piessen G, El Hajbi F, Robb WB, Clisant S, Kramar A, Mariette C, Adenis A. Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin-folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial. BMC Cancer. 2016 May 18;16:318. doi: 10.1186/s12885-016-2335-9.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 9, 2015)
106
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2023
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Resectable and operable esophageal cancer located under the carena (beyond 25 cm from the incisors) or junctional cancer (Siewert I or II)
  • Invasive adenocarcinoma or squamous cell type (to stick to the population included in the CROSS trial)
  • Patient who present with:

    • stage IIB (T1 N1 M0 or T2 N1 M0),
    • stage III (T3 N1 M0 or T4 N0 N1 M0) tumors (appendix 5)
  • ECOG performance status 0, 1 or 2 (appendix 7)
  • Patient eligible for preoperative chemoradiation with either fluorouracil- oxaliplatin-folinic acid, or Paclitaxel-carboplatin
  • Age ≥ 18 and ≤ 75 years
  • Peripheral neuropathy ≤ NCI-CTC grade 1 (appendix 3)
  • Adequate bone marrow reserve, normal renal and liver functions:

    • Neutrophil count ≥ 1500/mm3
    • Platelet count ≥ 100 000/mm3
    • Hemoglobin ≥ 10 g/dl (after transfusion, if necessary)
    • Creatinin < 15mg/L
    • Clearance of creatinin (Cockcroft formulae) ≥ 60 ml/mn (appendix 6)
    • Prothrombin time ≥ 60%
    • ASAT-ALAT ≤2.5 x ULN
    • Total bilirubin < 1.5 x ULN
    • Albumin greater the lower limit of normal
  • Start of treatment within 28 days of inclusion
  • Negative pregnancy test (serum beta-HCG) performed within 1 week prior to start of study treatment in females with reproductive potential

Exclusion Criteria:

  • Patient who present with stage I or stage IIA (including T3 N0) or stage IV
  • Patient who present with common contraindications for surgery related to patient status
  • Patient who present with common contraindications for surgery related to disease extension
  • Patient who present with common contraindication to radiochemotherapy with either fluorouracile-cisplatin or with paclitaxel-carboplatin:
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Antoine ADENIS, MD +33 3 20 29 59 18 a-adenis@o-lambret.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02359968
Other Study ID Numbers  ICMJE PROTECT-1402
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Centre Oscar Lambret
Study Sponsor  ICMJE Centre Oscar Lambret
Collaborators  ICMJE National Cancer Institute, France
Investigators  ICMJE
Principal Investigator: Antoine ADENIS, MD Centre Oscar Lambret
Principal Investigator: Christophe MARIETTE, MD University Hospital of Lille
PRS Account Centre Oscar Lambret
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP