Regorafenib+FOLFIRI Versus Placebo+FOLFIRI as 2nd Line Tx in Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This randomized (2:1), multi-center, placebo-controlled, phase II efficacy study is designed to compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients with mCRC previously treated with a FOLFOX regimen.

Detailed Description
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This randomized (2:1 ratio), multi-center, placebo-controlled, phase II efficacy study is designed to compare progression-free survival (PFS) between regorafenib + FOLFIRI (5-fluorouracil + leucovorin + irinotecan [ARM A] versus placebo + FOLFIRI [ARM B]) in patients with metastatic colorectal carcinoma (mCRC) previously treated with a FOLFOX (5-fluorouracil + leucovorin + oxaliplatin) regimen. Secondary objectives include objective response (OR) rates, disease control (DC) rates, and overall survival (OS). A pharmacokinetic (PK) evaluation of irinotecan will be conducted in a subset of patients at selected sites. This trial also incorporates a number of exploratory analyses designed to evaluate potential correlations between blood and tissue biomarkers and clinical benefit.

Official Title
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Multi-Center, Randomized, Placebo-Controlled Phase II Study of Regorafenib in Combination With FOLFIRI Versus Placebo With FOLFIRI as Second-Line Therapy in Patients With Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: Regorafenib (BAY 73-4506)
* Drug: FOLFIRI
* Drug: Placebo
* Drug: FOLFIRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subject must meet all of the inclusion criteria to participate in this study: Age ≥18 years of age (no upper age limit) Histological or cytological documentation of adenocarcinoma of the colon or rectum Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies required Metastatic disease not amenable to surgical resection with curative intent Progression during or within 6 months following administration of a standard regimen[2] for treatment of metastatic disease that included oxaliplatin with any of the following agents with or without bevacizumab: 5-fluorouracil (F-FU) with or without leucovorin or levoleucovorin Capecitabine Note: In patients receiving FOLFOX, oxaliplatin is sometimes discontinued due to toxicity or as part of maintenance therapy strategy. If such patients progress while on 5-FU alone, they are eligible for this trial. As an example, a patient who is begun on FOLFOX or CapeOx (capecitabine with oxaliplatin, with or without bevacizumab), whose oxaliplatin is held for neurotoxicity and who is switched to capecitabine monotherapy or capecitabine with bevacizumab, would be considered to have had one prior therapy. OR Patients who develop metastatic disease within 9 months of adjuvant FOLFOX for stage II or III colon cancer Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix C) Life expectancy of at least 3 months Adequate bone marrow, renal, and hepatic function, as evidenced by the following: absolute neutrophil count (ANC) ≥1,500/mm3 platelets ≥100,000/mm3 hemoglobin ≥9.0 g/dL serum creatinine ≤1.5 x upper limit of normal (ULN) Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 (see Appendix A) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer Bilirubin ≤1.5 X ULN Alkaline phosphatase ≤3 x ULN (≤5 x ULN with liver involvement of their cancer) Amylase and lipase ≤1.5 x ULN Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urine analysis.If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours International normalized ratio (INR)/Partial thromboplastin time (PTT) ≤1.5 x ULN Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care. Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care. The subject is capable of understanding and complying with parameters as outlined in the protocol Signed, Institutional Review Board (IRB)-approved written informed consent Exclusion Criteria Any subject meeting any of the following exclusion criteria at baseline will be ineligible for study participation: Prior treatment with regorafenib More than 1 prior chemotherapy regimen for mCRC (see section 3.1.5) Previous adjuvant FOLFOX based chemotherapy is allowed. Prior FOLFIRI or single agent irinotecan is prohibited. Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator Pregnant or breastfeeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of FOLFIRI treatment, and a negative result must be documented before start of treatment. History of Gilbert's syndrome Known Dihydropyrimidine dehydrogenase (DPD) deficiency Pernicious anemia or other anemias due to vitamin B12 deficiency (due to potential masking of deficiency with leucovorin) Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of Day 1 of treatment with FOLFIRI Radiotherapy within 4 weeks prior to first dose of FOLFIRI Active cardiac disease including any of the following: Congestive heart failure (New York Heart Association (NYHA)) ≥Class 2 (see Appendix D) Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of Day 1 of FOLFIRI Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) Uncontrolled hypertension. (Systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management) Patients with pheochromocytoma Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of FOLFIRI Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0) Known history of human immunodeficiency virus (HIV) infection Known history of chronic hepatitis B or C Patients with seizure disorder requiring medication Symptomatic metastatic brain or meningeal tumors unless the patient is >6 months from definitive therapy, has a negative imaging study within 4 weeks of FOLFIRI initiation, and is clinically stable with respect to the tumor at the time of study entry. Also, the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies) History of organ allograft Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 4 within 4 weeks of start of FOLFIRI Non-healing wound, ulcer, or bone fracture Renal failure requiring hemo- or peritoneal dialysis Dehydration according to NCI-CTC v 4.0 Grade >1 Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation Interstitial lung disease with ongoing signs and symptoms at the time of informed consent Inability to swallow oral medications Any malabsorption condition Unresolved toxicity higher than CTCAE v. 4.0 Grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin-induced neurotoxicity (which must be ≤Grade 2) Patients unable or unwilling to discontinue (and substitute if necessary) use of prohibited drugs for at least 30 days prior to Day 1 of FOLFIRI initiation (see Appendix B for list of prohibited drugs) Unwilling to provide consent for genetic studies of tumor, whole blood, or plasma specimens

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Regorafenib + FOLFIRI<br>regorafenib 160 mg + FOLFIRI | Drug: Regorafenib (BAY 73-4506)<br>* Regorafenib, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle<br>Drug: FOLFIRI<br>* FOLFIRI (Irinotecan,180 mg/m2 IV over 90 minutes; 5-Fluorouracil l400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours; Leucovorin 200-400c mg/m2 IV over 2 hours) Day 1 and Day 15 of each 28 day cycle.<br>* Other names: FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin);|
| Placebo Comparator: Placebo + FOLFIRI<br>Placebo + FOLFIRI | Drug: Placebo<br>* Placebo, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle<br>Drug: FOLFIRI<br>* FOLFIRI (Irinotecan,180 mg/m2 IV over 90 minutes; 5-Fluorouracil l400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours; Leucovorin 200-400c mg/m2 IV over 2 hours) Day 1 and Day 15 of each 28 day cycle.<br>* Other names: FOLFIRI (Irinotecan + 5-Fluorouracil + Leucovorin);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | To compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients failing one prior oxaliplatin-containing regimen for metastatic colorectal cancer. PFS is defined as the time from randomization until metastatic colorectal cancer (mCRC) progression or death as a result of any cause. Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 5.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response(OR)Rate | To compare overall response (OR) rates (OR= CR + PR) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 3 years | 
| Disease Control (DC) Rate | To compare Disease Control (DC) Rate (DC= CR + PR + SD) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions and Stable Disease (SD) ), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 3 years | 
| Overall Survival (OS) | To compare overall survival (OS) between ARM A and ARM B. OS is defined as the time from randomization until death as a result of any cause. | 5.5 years | 
| Drug Metabolism | To compare the pharmacokinetic (PK) profile of FOLFIRI between a subset of patients receiving regorafenib (ARM A) and patients receiving placebo (Arm B). The Area Under the Curve (AUC) levels of the irinotecan metabolite SN-38 were compared. | 28 days | 
| Percentage of Patients With Severe Adverse Events | Toxicity Assessments were made according to NCI CTCAE v. 4.0 . Severe events (grades 3-4) that occurred in a higher percentage of regorafenib treated participants as compared to placebo are reported below. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Colorectal Cancer, K-RAS mutation, BRAF mutation, Regorafenib, BAY 73-4506, FOLFIRI, Irinotecan, 5-FU, Leucovorin, Placebo, Phase II, Multi-Center, Randomized, Lineberger, North Carolina Cancer Hospital, UNC