First Line Treatment of Metastatic Colorectal Cancer With mFOLFOX6 in Combination With Regorafenib

Study Overview
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Brief Summary
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This is a study to evaluate the efficacy (effectiveness) and the safety of regorafenib when given in combination with chemotherapy mFOLFOX6 as first line therapy in patients with metastatic colorectal cancer (CRC). mFOLFOX6 is an approved chemotherapy. Regorafenib is an oral (i.e. taken by mouth) multi-targeted kinase inhibitor. A kinase inhibitor targets certain key proteins that are essential for the survival of the cancer cell. By specifically targeting these proteins, regorafenib may stop cancer growth. The growth of the tumor may be decreased by preventing these specific proteins from functioning. The primary endpoint (the most meaningful result to be tracked) of this study is based on the rate of response, i.e. the disease getting smaller. The aim is to show that the therapy of colorectal cancer with mFOLFOX6 in combination with regorafenib improves the response rate observed for the standard therapy only.

Official Title
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An Uncontrolled, Open-label, Phase II Study in Subjects With Metastatic Adenocarcinoma of the Colon or Rectum Who Are Receiving First Line Chemotherapy With mFOLFOX6 (Oxaliplatin/ Folinic Acid/5-fluorouracil [5-FU]) in Combination With Regorafenib

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: Regorafenib (Stivarga, BAY73-4506)
* Drug: Oxaliplatin
* Drug: Folinic acid
* Drug: 5-FU (mFOLFOX6)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged ≥ 18 years Histological or cytological documentation of adenocarcinoma of the colon or rectum Suitable to receive mFOLFOX6 regimen as first line metastatic treatment At least 1 measurable lesion as per RECIST version 1.1 Unresectable or unlikely becoming resectable metastatic disease Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Life expectancy of at least 3 months Adequate bone marrow, liver, and renal function Exclusion Criteria: Prior systemic anticancer therapy for metastatic colorectal cancer (CRC). Adjuvant chemotherapy for CRC (Stage I, II, III) is permitted, if the adjuvant therapy ended > 6 months before screening and recurrent disease was documented. Prior treatment with antivascular endothelial growth factor (anti-VEGF) agents and any signal transduction inhibitors (STIs) Uncontrolled hypertension Subjects with symptoms, signs, or history of brain metastases Any hemorrhage or bleeding event ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 within 4 weeks of start of study treatment Sensory neuropathy (> CTCAE Grade 1), unresolved toxicity > CTCAE Grade 1 attributed to any prior therapy/procedure excluding alopecia

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regorafenib + oxaliplatin/folinic acid/5-FU (mFOLFOX6)<br>On Day 1, participants received 85 mg/m^2 oxaliplatin as a 2-hour intravenous (IV) infusion and folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2-hour IV infusion. Once the initial infusion was completed, participants received 5-FU 400 mg/m^2 IV bolus injection immediately followed by a 5-FU 2400 mg/m^2 IV infusion for 46 hours. The next cycle of mFOLFOX6 was administered on Day 15 to 17. Participants received Regorafenib (Stivarga, BAY73-4506) 160 mg orally (po) once daily (qd) on Days 4 to 10 and Days 18 to 24. One cycle comprised 28 days. | Drug: Regorafenib (Stivarga, BAY73-4506)<br>* Subjects will receive regorafenib 160 mg od on days 4 to 10 and days 18 to 24 as four 40 mg coprecipitate tablets. In case of administration as a single agent during the study, regorafenib will be administered 160 mg od for 3 weeks on/1 week off. Each cycle consists of 28 days.<br>Drug: Oxaliplatin<br>* On day 1 and day 15 of each cycle, participants will receive 85 mg/m^2 oxaliplatin as a 2 hour i.v. infusion.<br>Drug: Folinic acid<br>* On day 1 and day 15 of each cycle, participants will receive folinic acid (either 400 mg/m^2 D/L-folinic acid or 200 mg/m^2 L-folinic acid) as a 2 hour i.v. infusion.<br>Drug: 5-FU (mFOLFOX6)<br>* Participants will receive a 400 mg/m^2 5 FU i.v. bolus injection immediately followed by a 2400 mg/m^2 5 FU 46 hour i.v. infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (OR) | OR was defined as the best tumor response (confirmed complete response [CR] or partial response [PR]) observed by MRI or CT scan assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. CR and PR were confirmed not earlier than 4 weeks following the initial detection of response. CR = Disappearance of all clinical and radiological evidence of tumor (both target and no-target). Any pathological lymph nodes (whether target or non target) must have a reduction in short axis to < 10 mm. PR = At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing nontarget lesions and no appearance of new lesions. | From start of treatment until 30 days after termination of study medication, an average of 47 weeks. Assessed every 8 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was calculated as the time from first date of receiving study treatment to date of death due to any cause. Participants alive at the time of analysis were censored at their last date of follow-up. | From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks | 
| Progression-free Survival (PFS) | PFS was defined as time from the date of start of study treatment to the date of first observed disease progression (radiological according to central assessment or clinical), or death due to any cause, if death occurred before progression was documented. PFS for participants without disease progression or death at the date of database cutoff were right-censored at the last date of tumor assessment. Participants who had no tumor evaluation after baseline and no clinical progression post baseline and who did not die were censored at Day 1 in the analysis. PD = At least a 20% increase in the sum of diameters of target lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non target lesions or the appearance of one or more new lesions will also constitute PD. | From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks | 
| Disease Control (DC) | DC was defined as the proportion of participants who had a best response rating of CR, PR, or stable disease (SD) according to RECIST criteria that was achieved during treatment or within 30 days after termination of study treatment. CR and PR were confirmed not earlier than 4 weeks following the initial detection of response. A minimum of 8 weeks (allowing a minus 7-day time window) between start of study treatment and the first follow-up tumor assessment with SD as response was required to assign SD as best overall response. | From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks | 
| Duration of Response (DOR) | DOR was defined as the time from the date of first documented objective response of PR or CR, whichever was noted earlier, to first subsequent disease progression or death (if death occurred before progression was documented). DOR was defined for responders only (that is, subjects with CR or PR). DOR for subjects without disease progression or death before progression was right censored at the date of their last tumor assessment. | From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks | 
| Duration of Stable Disease (DOSD) | DOSD was only evaluated in participants failing to achieve a best response of CR or PR, but who achieved SD. DOSR was defined as the time (in days) from date of start of study treatment to the date at which disease progression or death (if death occurred before progression was first documented). The date the tumor scan was performed was used for this calculation. DOSD for participants without disease progression or death before progression at the time of analysis were censored at the date of their last tumor assessment. | From start of treatment until 30 days after the last dose of study treatment, assessed by every 8 weeks |