Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors

Intervention / Treatment
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* Drug: Sorafenib and irinotecan combination
* Drug: Sorafenib monotherapy
* Drug: Irinotecan monotherapy


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Irinotecan monotherapy<br>Intravenous infusion irinotecan 180 mg/m2 over 90 minutes (D1=D15) with cross over to irinotecan and sorafenib combination at progression. | Drug: Irinotecan monotherapy<br> <br> |
| Active Comparator: Sorafenib monotherapy<br>Oral sorafenib 400 mg twice daily (total dose 800 mg/day) with cross over to irinotecan and sorafenib combination at progression | Drug: Sorafenib monotherapy<br> <br> |
| Experimental: Sorafenib and irinotecan combination<br>Intravenous infusion irinotecan 120 mg/m2 over 90 minutes (D1=D15) at Cycle 1, 150 mg/m² at C2 if no diarrhea > grade 1 and no other toxicity > grade 2, and 180 mg/m² at C3 in the same conditions Oral sorafenib 400 mg twice daily (total dose 800 mg/day) from C1. 1 cycle = 15 days and 1 course = 4 weeks. | Drug: Sorafenib and irinotecan combination<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-progression rate | To evaluate the non-progression rate at 2 months according to RECIST criteria (Version 1.1) | At 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate | According to RECIST criteria (Version 1.1) | At 2 months | 
| Treatment-related toxicity | According to NCI CTC V4.0 | At 6 months | 
| Overall survival | Overall survival is defined as the time from the date of inclusion to the date of death from any cause. | At 6 months | 
| Quality of life questionnaire | Using the EORTC QLQ-C30 questionnaire | 6 months | 
| Progression Free Survival | Progression Free Survival is defined as the time from the date of inclusion to first documentation of objective tumor progression or to death due to progression. | At 6 months | 
| Response rate | According to RECIST criteria (Version 1.1) | At 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic colorectal cancer patients, KRAS mutation, Sorafenib