Clinical trial NCT03255434: LEAn Body Mass Normalization of OXaliplatin Based Chemotherapy
Official title: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Stage III Colon Cancer
Lead sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
Sponsor class: OTHER
First posted: 2017-08-21
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Evaluation of neurotoxicity associated with Oxaliplatin
timeFrame: through study completion, an average of 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Marseille
country: France
facility: Hôpital Européen
state: Bouches Du Rhône
city: Montpellier
country: France
facility: Centre hospitalier régional et universitaire de Montpellier
state: Hérault
city: Vandœuvre-lès-Nancy
country: France
facility: CHU de Nancy
state: Lorraine
city: Vandœuvre-lès-Nancy
country: France
facility: Insitut de Cancérologie de Lorraine
state: Meurthe-et-Moselle,
city: Perpignan
country: France
facility: Hôpital Saint-Jean
state: Pyrénées-orientales
city: Caen
country: France
facility: Centre François Baclesse
city: Marseille
country: France
facility: CHU La TIMONE
city: Montpellier
country: France
facility: Institut regional du Cancer - Val d Aurelle
city: Paris
country: France
facility: AP-HP Hôpital Saint-Louis
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Strasbourg
country: France
facility: Centre Paul Strauss
Study officials:
affiliation: Institut régional du Cancer de Montpellier
name: marc YCHOU
role: STUDY_DIRECTOR
References: