Clinical trial NCT01715441: Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors
Official title: A Randomized Phase II Trial Assessing Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors After Failure of All Drugs Known to be Effective
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors
Keywords: Metastatic colorectal cancer patients
KRAS mutation
Sorafenib
Lead sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
Sponsor class: OTHER
First posted: 2012-10-29
Enrollment: 173
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.


Eligibility criteria: Inclusion Criteria:

* Male or female ≥ 18 years old
* Histologically confirmed diagnosis of colorectal cancer
* Asymptomatic or resected primary tumor
* Metastatic colorectal cancer patient not eligible for curative surgery
* At least one target lesion:

  * Unidimensionally measurable on cross-sectional imaging
  * In an area not previously irradiated
* Disease progression after failure of active drugs (5-Fu or 5-Fu prodrugs, irinotecan, oxaliplatin, bevacizumab)
* Patients with bone metastases are eligible if they have other measurable lesions
* WHO performance status ≤ 2
* Confirmation of KRAS mutation in codons 12 or 13 in the primary tumor or metastases
* Total bilirubin ≤ 1.5 ULN, ALT or AST ≤ 2.5 ULN (or \< 5 in case of liver impairment)
* Haemoglobin ≥ 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3
* Serum creatinine ≤ 1.5 ULN
* Negative pregnancy test in women of childbearing potential
* Use of an effective contraceptive method during the whole treatment and up to 3 months after the completion of treatment in males and females
* Life expectancy of at least 3 months
* Informed consent signed prior any study specific procedures
* Tumor evaluation should be performed within 3 weeks prior to starting treatment

Exclusion Criteria:

* History of Gilbert's syndrome
* Symptomatic brain metastases or carcinomatous meningitis
* Bone-only metastases
* History or presence of other cancers within the past 5 years (except curatively treated non-melanoma skin cancer and in situ cervical cancer)
* Prior surgery or radiotherapy within 4 weeks before entering the study
* Cardiac arrhythmia requiring treatment (except for beta-blockers and digoxin), unstable cardiac disease, myocardial infarction within the previous 6 months, \> grade II NYHA heart failure, uncontrolled hypertension
* Kalemia lower than normal serum potassium value
* From ECG, QTc interval \> 470 ms
* History of acute or chronic pancreatitis
* History of epileptic seizures requiring long-term anticonvulsant therapy
* History of organ transplantation with use of immunosuppression therapy
* Severe bacterial or fungal infection (Grade \> 2 NCI-CTCAE v.4.0)
* Known HIV infection
* Long-term use of CYP 3A4 enzyme-inducing agents such as rifampicin, St. John's Wort (hypericum perforatum), phenytoin, carbamazepine, phenobarbital, dexamethasone, and ketoconazole
* Pregnant or breastfeeding women
* Bowel malabsorption or extended bowel resection that could affect the absorption of sorafenib, occlusive syndrome, inability to take oral medications
* Inflammatory bowel disease with chronic diarrhea (NCI-CTCAE v.4.0)
* Participation in another clinical trial 30 days prior to study entry
* Concurrent treatment with any other investigational product or anticancer therapy (except for irinotecan or sorafenib)
* Psychological, social, geographical disorders or any other condition that would preclude study compliance (treatment administration and study follow-up).

Primary outcomes:
measure: Non-progression rate
timeFrame: At 2 months
Secondary outcomes:
measure: Disease control rate
timeFrame: At 2 months
measure: Treatment-related toxicity
timeFrame: At 6 months
measure: Overall survival
timeFrame: At 6 months
measure: Quality of life questionnaire
timeFrame: 6 months
measure: Progression Free Survival
timeFrame: At 6 months
measure: Response rate
timeFrame: At 2 months
Other outcomes:
measure: Cmax and Tmax of sorafenib and irinotecan
timeFrame: Up to 3 months
Locations:
city: Bobigny
country: France
facility: Hôpital AVICENNE
city: Caen
country: France
facility: Centre François Baclesse
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hôpital LA TIMONE
city: Montpellier
country: France
facility: CRLC Val d'Aurelle-Paul Lamarque
city: Reims
country: France
facility: C.H.U. de REIMS
city: Rouen
country: France
facility: CHU Charles Nicolle
city: St. Herblain
country: France
facility: Institut de Cancérologie de l'Ouest - René Gauducheau
Study officials:
affiliation: CRLC Val d'Aurelle-Paul Lamarque
name: Emmanuelle SAMALIN, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CRLC Val d'Aurelle
name: Marc YCHOU, MD,
role: STUDY_CHAIR
References:
citation: Samalin E, Fouchardiere C, Thezenas S, Boige V, Senellart H, Guimbaud R, Taieb J, Francois E, Galais MP, Lievre A, Seitz JF, Metges JP, Bouche O, Boissiere-Michot F, Lopez-Crapez E, Bibeau F, Ho-Pun-Cheung A, Ychou M, Adenis A, Di Fiore F, Mazard T. Sorafenib Plus Irinotecan Combination in Patients With RAS-mutated Metastatic Colorectal Cancer Refractory To Standard Combined Chemotherapies: A Multicenter, Randomized Phase 2 Trial (NEXIRI-2/PRODIGE 27). Clin Colorectal Cancer. 2020 Dec;19(4):301-310.e1. doi: 10.1016/j.clcc.2020.04.008. Epub 2020 May 15.