Regorafenib+FOLFIRI Versus Placebo+FOLFIRI as 2nd Line Tx in Metastatic Colorectal Cancer
Condition: Colorectal Cancer Metastatic
MeSH terms: Colorectal Neoplasms
Intervention: Regorafenib (BAY 73-4506); FOLFIRI; Placebo; FOLFIRI
Intervention description: Regorafenib, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle; 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.; Placebo, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle; 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.
Intervention MeSH terms: Leucovorin; Fluorouracil; Irinotecan; Levoleucovorin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 181.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: 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

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria

        Subject must meet all of the inclusion criteria to participate in this study:

          1. Age ≥18 years of age (no upper age limit)

          2. Histological or cytological documentation of adenocarcinoma of the colon or rectum

          3. Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic
             studies required

          4. Metastatic disease not amenable to surgical resection with curative intent

          5. 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

          6. Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT
             scan as defined by RECIST 1.1.

          7. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix C)

          8. Life expectancy of at least 3 months

          9. 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.

         10. 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.

         11. The subject is capable of understanding and complying with parameters as outlined in
             the protocol

         12. 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:

          1. Prior treatment with regorafenib

          2. 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.

          3. Known history of or concomitant malignancy likely to affect life expectancy in the
             judgment of the investigator

          4. 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.

          5. History of Gilbert's syndrome

          6. Known Dihydropyrimidine dehydrogenase (DPD) deficiency

          7. Pernicious anemia or other anemias due to vitamin B12 deficiency (due to potential
             masking of deficiency with leucovorin)

          8. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             before start of Day 1 of treatment with FOLFIRI

          9. Radiotherapy within 4 weeks prior to first dose of FOLFIRI

         10. 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)

         11. Patients with pheochromocytoma

         12. Arterial thrombotic or embolic events such as cerebrovascular accident (including
             transient ischemic attacks), or pulmonary embolism within the 6 months before start of
             FOLFIRI

         13. Ongoing infection >Grade 2 according to NCI Common Terminology Criteria for Adverse
             Events version 4.0 (CTCAE v. 4.0)

         14. Known history of human immunodeficiency virus (HIV) infection

         15. Known history of chronic hepatitis B or C

         16. Patients with seizure disorder requiring medication

         17. 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)

         18. History of organ allograft

         19. Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event > Grade 4
             within 4 weeks of start of FOLFIRI

         20. Non-healing wound, ulcer, or bone fracture

         21. Renal failure requiring hemo- or peritoneal dialysis

         22. Dehydration according to NCI-CTC v 4.0 Grade >1

         23. Substance abuse, medical, psychological, or social conditions that may interfere with
             the patient's participation in the study or evaluation of the study results

         24. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in
             the formulation

         25. Interstitial lung disease with ongoing signs and symptoms at the time of informed
             consent

         26. Inability to swallow oral medications

         27. Any malabsorption condition

         28. 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)

         29. 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)

         30. Unwilling to provide consent for genetic studies of tumor, whole blood, or plasma
             specimens