LEAn Body Mass Normalization of OXaliplatin Based Chemotherapy (LEANOX)

LEAn Body Mass Normalization of OXaliplatin Based Chemotherapy for Stage III Colon Cancer Patients Treated in Adjuvant Setting: Impact on Oxaliplatin-induced Sensitive Neurotoxicity. A Multicenter Phase II Randomized Trial (LEANOX)

Cytotoxic chemotherapy is usually scaled to the body surface area (BSA), and is currently not adjusted to the body proportions of lean and fat (i.e. body composition) of individual patients. Patients with low muscle mass behave like patients "overdosed" with chemotherapy resulted in dose-limiting toxicities (e.g. dose reductions, treatment delays or permanent treatment discontinuation), independently of the patient's weight.

Study Overview

• Status: Active, not recruiting
• Conditions: Stage III Colon Cancer
• Intervention / Treatment: Drug: Oxaliplatin; Drug: Oxaliplatin LBM

Detailed Description

Adjuvant chemotherapy with fluoropyrimidines and Oxaliplatin is the current worldwide standard of care for stage III colorectal cancer (CRC). This regimen leads to significant cost, toxicity, and patient inconvenience. Oxaliplatin induces two distinct forms of neuropathy: a common acute syndrome that is transient (dysesthesia, contractures and numbness) and a dose-limiting chronic sensory neurotoxicity that is cumulative. Neurotoxicity is common; it affects 80% of patients and becomes chronic in 15-20% of cases, sometimes irreversibly. Chronic neurotoxicity can severely affect everyday life activities. To date, neuromodulators agents have failed to prevent neurotoxicity and Stop & Go strategies, intended to decrease the cumulative dose of Oxaliplatin administrated, are more appropriate for palliative treatment of advanced CRC. Recent data support the plausibility of a shorter duration of adjuvant treatment without loss of efficacy. This hypothesis is tested in several international trials.

Cytotoxic chemotherapy is usually scaled to the body surface area (BSA), and is currently not adjusted to the body proportions of lean and fat (i.e. body composition) of individual patients. The impact of body composition on drug metabolism is however well known: i.e. anesthetics accumulate in adipose tissue and specific precautions are essential to avoid overdose. Concerning chemotherapies, the lean body mass (LBM) may be the salient feature defining drug metabolism. A theme is emerging from recent studies: in patients with breast cancer and treated with 5-FU (whose dosage was calculated from the body surface), severe depletion of the LBM is a powerful predictor of excessive toxicity. Indeed, depletion of the LBM, as precisely defined by computed tomography, is a unique predictor of clinically unacceptable toxicity. Low LBM was shown to be a significant predictor of dose-limiting toxicity (DLT) in CRC patients administered 5-FU using a conventional BSA-based dosing and DLT was concentrated in patients receiving >20 mg 5FU/kg LBM. Two cohorts of CRC patients treated with Oxaliplatin showed that overall DLTs, and specifically Oxaliplatin-due neuropathy, occurred mostly in patients who receive > 3.09 mg/Oxaliplatin/kg LBM. Although, preliminary findings are available in hepatocellular carcinoma, the area under the concentration time curve (AUC) of Sorafenib cancer therapy was doubled in patients with depleted LBM (102.4 vs. 53.7ng/mL.h), which seem of interest. Patients with low muscle mass behave like patients "overdosed" with chemotherapy resulted in dose-limiting toxicities (e.g. dose reductions, treatment delays or permanent treatment discontinuation), independently of the patient's weight.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Caen, France, 14076
    • Centre Francois Baclesse
  • Marseille, France, 13
    • CHU La Timone
  • Montpellier, France, 34298
    • Institut regional du Cancer - Val d Aurelle
  • Paris, France
    • AP-HP Hopital Saint-Louis
  • Rennes, France, 35042
    • Centre Eugène Marquis
  • Strasbourg, France
    • Centre Paul Strauss
  • Bouches Du Rhône
    • Marseille, Bouches Du Rhône, France, 13003
      • Hôpital Européen
  • Hérault
    • Montpellier, Hérault, France, 34000
      • Centre hospitalier régional et universitaire de Montpellier
  • Lorraine
    • Vandœuvre-lès-Nancy, Lorraine, France, 54511
      • Chu de Nancy
  • Meurthe-et-Moselle,
    • Vandœuvre-lès-Nancy, Meurthe-et-Moselle,, France, 54519
      • Insitut de Cancérologie de Lorraine
  • Pyrénées-orientales
    • Perpignan, Pyrénées-orientales, France, 66000
      • Hôpital Saint-Jean

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age: more than 18 years old up to 75 years old including. Histologically confirmed adenocarcinoma of the colon.
• Has undergone a curative resection for stage III colon cancer.
• Scheduled to receive 6 months of Oxaliplatin-based adjuvant chemotherapy at a dose of 85 mg/m² of Oxaliplatin every 2 weeks (simplified FOLFOX 4 regimen).
• The following laboratory values obtained ≤ 28 days prior to inclusion:

WBC ≥ 3000/mm3; ANC ≥1500/mm3; PLT ≥100,000/mm3; HgB ≥10.0g/dl; Total bilirubin ≤1.5 x upper normal limit (UNL); Serum creatinine ≤1.5 x UNL; Serum calcium ≤ 1.2 x UNL; Serum magnesium ≤ 1.2 x UNL.

• Central venous access line present or patient scheduled to have a central line placed prior to starting chemotherapy or the treatment protocol.
• Negative pregnancy test (serum or urine) done ≤ 7 days prior to registration, for women of childbearing potential only.
• Ability to complete questionnaire(s) by themselves or with assistance.
• ECOG Performance Status (PS) of 0, 1 for patients until 70 years old included and ECOG PS of 0 for patients between 70 to 75 years old included.
• Has provided informed written consent.
• Patient willing to provide blood sample for research purposes
• Patient affiliated to a French social security system

Exclusion Criteria:

• Pregnant or breastfeeding women
• Men or women of childbearing potential who are unwilling to employ adequate contraception since this study involves agents that have known genotoxic, mutagenic and teratogenic effects
• Pre-existing peripheral neuropathy of any grade.
• Prior treatment with neurotoxic chemotherapy such as Oxaliplatin, cisplatin, taxanes, or vinca alkaloids.
• Treatment with 1) the anticonvulsants carbamazepine (e.g., Tegretol®), phenytoin (e.g., Dilantin®), valproic acid (e.g. Depakine®), gabapentin (Neurontin®); pregabalin (Lyrica®); 2) the following neurotropic agents: venlafaxine (Effexor®), desvenlafaxine (Pristiq®), milnacipran (Savella®) or duloxetine (Cymbalta®); 3) Tricyclic antidepressants (such as amitryptilline) or 4) any other agent specifically given to prevent or treat neuropathy.
• Family history of a genetic/familial neuropathy.
• Participation in another medication trial within 30 days prior to study entry
• Legal incapacity or physical, psychological social or geographical status interfering with the patient's ability to sign the informed consent or to terminate the study
• History of other solid tumor in 3 years before the inclusion, excepted of cancer in situ of the cervix and skin cancer (basal or squamous cell) treated and controlled.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Folfox 4; Standard FOLFOX4: Oxaliplatin and simplified LV5FU2 Dose of oxaliplatin 85mg/m²	Drug: Oxaliplatin; Simplified FOLFOX 4 regimen: Association of Oxaliplatin (85 mg/m² ) + simplified LV5FU2 Length of a cycle : 2 days Interval between 2 cycles : 2 weeks (D1=D15) Expected number of cycles: 12
Experimental: Folfox 4 LBM; Adapted FOLFOX4: Oxaliplatin and simplified LV5FU2 Dose of oxaliplatin allocated according to lean body mass (LBM)	Drug: Oxaliplatin LBM; Simplified FOLFOX 4 regimen: Association of Oxaliplatin (LBM) + simplified LV5FU2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of neurotoxicity associated with Oxaliplatin	Neurotoxicity assessment	through study completion, an average of 5 years

Collaborators and Investigators

• Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
• Investigators: Study Director: marc YCHOU, Institut Régional du Cancer de Montpellier

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Actual): July 28, 2022
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: August 11, 2017
• First Submitted That Met QC Criteria: August 18, 2017
• First Posted (Actual): August 21, 2017

Study Record Updates

• Last Update Posted (Estimated): June 16, 2023
• Last Update Submitted That Met QC Criteria: June 15, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Antineoplastic Agents; Oxaliplatin
• Other Study ID Numbers: ICM-URC2016/27

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No