Evaluation, in Humans, of the Correlation Between Hepatotoxicity, Neurotoxicity Induced by Oxaliplatin, and Blood Levels of HMGB1 (HEPATOXALI)

October 17, 2024 updated by: University Hospital, Clermont-Ferrand

Oesogastric and pancreatic adenocarcinomas are poor-prognosis cancers. Incidence of pancreatic cancer drastically increases to such an extent that it will become the second cause of cancer's mortality by 2030. A major challenge is to optimize the therapies for localized setting, when oxaliplatin-based chemotherapy is the standard, before and after surgical excision. Because in 50% of cases oxaliplatin triggers a grade 2-3 sinusoidal obstruction syndrome (SOS) which increases post-operative morbidity, decreases histological response to chemotherapy, increases tumor recurrence, and aggravates the risk of chemotherapy-induced peripheral neuropathy (CIPN).

There is an urgent need to better understand the biological processes involved in SOS, in order to prevent and treat it without stopping or reducing oxaliplatin administration.

The biological link between oxaliplatin and SOS has not been described, but recent murine experiments argue for HMGB1 to be the mediator released after exposure to oxaliplatin and inducing SOS, and thereafter CIPN. To date, no biomarker is established between murine and patient analyses, and the release of HMGB1 after oxaliplatin treatment and its effect on hepatic parenchyma is not described in patients. Investigators hypothesized is that HMGB1 would also been increased in patients after oxaliplatin treatment, and correlated to the development of SOS and CIPN. If confirmed, personalized treatment will be possible to target this pathway.

Therefore, investigators propose to dynamically explore this hypothesis in localized oesogastric and pancreatic cancer patients who will be routinely managed by an initial laparoscopy and post-oxaliplatin surgical excision.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

100

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • ECOG WHO Performance status = 0 or 1
  • Signed and dated informed consent
  • Patients with histological diagnosis of oesogastric or pancreatic adenocarcinoma
  • Resectable tumors
  • Patients able to have a laparoscopy
  • In case of absence of peritoneal invasion on the laparoscopy, patient candidate to a chemotherapy schedule by FLOT or FOLFOX in perioperative setting for oesogastric adenocarcinoma, or FOLFIRINOX in perioperative setting for pancreatic adenocarcinoma
  • Registration in a national health care system (CMU included)
  • Patient speak and understand the french

Exclusion Criteria:

  • Histology other than adenocarcinoma
  • Metastatic disease
  • History of previous treatment with oxaliplatine
  • History of systemic chemotherapy administration within 5 years prior to inclusion,
  • Patient with an non balanced progressive condition/disease (liver failure, renal failure (creatinine clearance <30mL/min), respiratory failure, congestive heart failure, myocardial infarction in the last 6 months, etc.),
  • Patient on curative dose anticoagulant,
  • Patient with complete dihydropyrimidine dehydrogenase deficiency (Uracilemia ≥ 150 ng/ml),
  • Patient not operable for the pathology concerned,
  • Pregnant or breastfeeding woman, woman of childbearing age who has not performed a pregnancy test before the procedure,
  • Patient with legal incapacity (person deprived of liberty or under curatorship, stutorship, safeguard of justice),
  • Patient who, for psychiatric, social, family or geographical reasons, cannot be followed and/or comply with the requirements of the study,,
  • Discovery of peritoneal invasion during the peritoneal exploratory of the laparoscopy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: comparate the Serum HMGB1 concentrations between patients with grade <2 SOS and those with grade 2,3
Biological: assess the serum HMGB1 concentrations before and after an oxaliplatin-based chemotherapy
assess the serum HMGB1 concentrations

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum HMGB1 concentrations
Time Frame: At exploratory laparoscopy and at the surgery
Assess Serum HMGB1 concentrations in two groups of patients : with grade 0 or 1 SOS and with grade ≥2 SOS, at two timepoints: before exploratory laparoscopy and before surgical excision to determinate the effect of HMGB1 on SOS development
At exploratory laparoscopy and at the surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
variation of serum HMGBI concentration (ng/ml)
Time Frame: at the exploratory laparoscopy, at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days) and at the surgery
mesurated the serum HMGB1 concentration (ng/ml) at several time of treatment of the patient then comparated these assess the dynamic variation of serum HMGB1 concentrations after oxaliplatin-based chemotherapy in oesogastric and pancreatic cancer patients with grade 0 or 1 SOS and with grade ≥2 SOS
at the exploratory laparoscopy, at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days) and at the surgery
variation of serum RAGE (receptor of HMGBI) concentration
Time Frame: at the exploratory laparoscopy, at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days) and at the surgery
mesurated the serum RAGE concentration (ng/ml) at several time of treatment of the patient then comparated these assess the dynamic variation of serum HMGB1 concentrations after oxaliplatin-based chemotherapy in oesogastric and pancreatic cancer patients with grade 0 or 1 SOS and with grade ≥2 SOS
at the exploratory laparoscopy, at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days) and at the surgery
sinusoidal obstruction syndrome (SOS) diagnosis
Time Frame: before to began chemotherapy and from 15 to 21 days after the last cycle of chemotherapy before surgery
compare SOS histology diagnosis (absent, mild, moderate, severe) with no invasive biological scores "APRI and FIB4"which use ASAT (U/L), ALAT(U/L), plaquettes (G/L) and the age (years) of the patient
before to began chemotherapy and from 15 to 21 days after the last cycle of chemotherapy before surgery
sinusoidal obstruction syndrome (SOS) diagnosis
Time Frame: before to began chemotherapy and from 15 to 21 days after the last cycle of chemotherapy before surgery
compare SOS histology diagnosis (absent, mild, moderate, severe)) with splenic's volumetric measured by radiological's assessment
before to began chemotherapy and from 15 to 21 days after the last cycle of chemotherapy before surgery
Evaluated the chemotherapy-induced peripheral neuropathy (CIPN)
Time Frame: at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days); at the surgery and at the first cycle (D1) then last cycle (assessed up to 75 days) after surgery
the CIPN will be evaluate by the investigator who used the CTCAEv5 classification.
at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days); at the surgery and at the first cycle (D1) then last cycle (assessed up to 75 days) after surgery
Evaluated the chemotherapy-induced peripheral neuropathy (CIPN)
Time Frame: at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days); at the surgery and at the first cycle (D1) then last cycle (assessed up to 75 days) after surgery
the CIPN will be evaluate by each patient who completed the CIPN20 questionnary
at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days); at the surgery and at the first cycle (D1) then last cycle (assessed up to 75 days) after surgery
Evaluated the chemotherapy-induced peripheral neuropathy (CIPN)
Time Frame: at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days); at the surgery and at the first cycle (D1) then last cycle (assessed up to 75 days) after surgery
the CIPN will be evaluate by each patient who completed the visual analog score for pain
at the first (Day1) and last cycle (assessed up to 75 days) of chemotherapy before surgery (each cycle=14 days); at the surgery and at the first cycle (D1) then last cycle (assessed up to 75 days) after surgery
Predictive value of HMGB1 for the development of SOS and CIPN
Time Frame: from exploratory laparoscopy to last cycle of chemotherapy after surgery assessed up to 10 month
Correlate CIPN, neuropathic pain with SOS, HMGB1, and RAGE measurements
from exploratory laparoscopy to last cycle of chemotherapy after surgery assessed up to 10 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Clermont-Ferrand

Investigators

  • Principal Investigator: Marine JARY, MD, CHU Estaing de Clermont Ferrand/FRANCE

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 6, 2024

Primary Completion (Estimated)

June 30, 2028

Study Completion (Estimated)

June 30, 2028

Study Registration Dates

First Submitted

September 5, 2024

First Submitted That Met QC Criteria

October 17, 2024

First Posted (Actual)

October 18, 2024

Study Record Updates

Last Update Posted (Actual)

October 18, 2024

Last Update Submitted That Met QC Criteria

October 17, 2024

Last Verified

October 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RBHP 2023 JARY
  • 2023-A02427-38 (Other Identifier: registration number with the French drug agency)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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