LEAn Body Mass Normalization of OXaliplatin Based Chemotherapy

NCT ID: NCT03255434

Last Updated: 2025-02-13

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 160 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-01
• Study Completion Date: 2025-07-31

Brief Summary

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.

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.

Conditions

Stage III Colon Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Folfox 4

Standard FOLFOX4: Oxaliplatin and simplified LV5FU2 Dose of oxaliplatin 85mg/m²

Group Type: ACTIVE_COMPARATOR

Oxaliplatin

Intervention Type: DRUG

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

Folfox 4 LBM

Adapted FOLFOX4: Oxaliplatin and simplified LV5FU2 Dose of oxaliplatin allocated according to lean body mass (LBM)

Group Type: EXPERIMENTAL

Oxaliplatin LBM

Intervention Type: DRUG

Simplified FOLFOX 4 regimen: Association of Oxaliplatin (LBM) + simplified LV5FU2

Interventions

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

Intervention Type: DRUG

Oxaliplatin LBM

Simplified FOLFOX 4 regimen: Association of Oxaliplatin (LBM) + simplified LV5FU2

Intervention Type: DRUG

Other Intervention Names

Oxaliplatin

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institut du Cancer de Montpellier - Val d'Aurelle

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

marc YCHOU

Role: STUDY_DIRECTOR

Institut régional du Cancer de Montpellier

Locations

Hôpital Européen

Marseille, Bouches Du Rhône, France

Centre hospitalier régional et universitaire de Montpellier

Montpellier, Hérault, France

CHU de Nancy

Vandœuvre-lès-Nancy, Lorraine, France

Insitut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, Meurthe-et-Moselle,, France

Hôpital Saint-Jean

Perpignan, Pyrénées-orientales, France

Centre François Baclesse

Caen, , France

CHU La TIMONE

Marseille, , France

Institut regional du Cancer - Val d Aurelle

Montpellier, , France

AP-HP Hôpital Saint-Louis

Paris, , France

Centre Eugène Marquis

Rennes, , France

Centre Paul Strauss

Strasbourg, , France

Countries

France

References

Assenat E, Ben Abdelghani M, Gourgou S, Perrier H, Akouz FK, Desgrippes R, Galais MP, Janiszewski C, Mazard T, Rinaldi Y, Lepage C, Tetreau R, Senesse P. Impact of Lean Body Mass-Based Oxaliplatin Dose Calculation on Neurotoxicity in Adjuvant Treatment of Stage III Colon Cancer: Results of the Phase II Randomized LEANOX Trial. J Clin Oncol. 2025 Aug 10;43(23):2616-2627. doi: 10.1200/JCO-24-02754. Epub 2025 Jun 20.

Reference Type: DERIVED

PMID: 40540704 (View on PubMed)

Other Identifiers

ICM-URC2016/27

Identifier Type: -

Identifier Source: org_study_id