Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

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 and KRAS or BRAF mutant disease previously treated with a FOLFOX regimen.

Further Study Information

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 KRAS or BRAF mutant 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.

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 3 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 (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)

• AST and 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

• INR/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, 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 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

Trial Contact Information

Trial Lead Organizations/Sponsors

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Bert H. O'Neil

Principal Investigator

Maureen Tynan, RN		Ph: (919) 843-7039
		Email: maureen_tynan@med.unc.edu

U.S.A.
Colorado
	Denver
	Rocky Mountain Cancer Centers - Denver Midtown
		Allen L. Cohn	Principal Investigator
Florida
	Miami
	Mount Sinai Comprehensive Cancer Center at Mount Sinai Medical Center
		Joseph Pizzolato, MD	Principal Investigator
	Tampa
	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
		Richard Kim, MD	Principal Investigator
Georgia
	Atlanta
	Georgia Cancer Specialists - Northside Office
		Mansoor Noorali Saleh	Principal Investigator
	Winship Cancer Institute of Emory University
		Basil El-Rayes	Principal Investigator
Illinois
	Evanston
	Palliative CareCenter and Hospice of the North Shore
		Robert Marsh, MD	Principal Investigator
Kentucky
	Louisville
	CBC/Baptist Hospital East
		Wangjian Zhong, MD, PhD	Principal Investigator
	University of Louisville James Brown Cancer Center
		Rebecca Redman, MD	Principal Investigator
New York
	Manhasset
	Long Island Jewish Medical Center
		Bhoomi Mehrotra	Principal Investigator
	New York
	NYU Cancer Institute at New York University Medical Center
		Theresa Ryan, MD	Principal Investigator
North Carolina
	Boone
	Seby B. Jones Cancer Center
		Anna Sobol, MD	Principal Investigator
	Chapel Hill
	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
		Bert H. O'Neil	Principal Investigator
	Goldsboro
	Southeast Medical Oncology Center
		Samer Kasbari, MD	Principal Investigator
	Greensboro
	The Moses Cone Regional Cancer Center
		Gary Sherrill, MD	Principal Investigator
	Greenville
	Leo W. Jenkins Cancer Center at ECU Medical School
		Prashanti Atluri, MD	Principal Investigator
	Pinehurst,
	FirstHealth Moore Regional Community Hospital Comprehensive Cancer Center
		Todd Moore, MD	Principal Investigator
	Raleigh
	Rex Cancer Center at Rex Hospital
		Lola Olajide, MD	Principal Investigator
	Rocky Mount
	Nash Health Care Systems
		Xiang Sean Wang, MD	Principal Investigator
	Washington
	Marion L. Shepard Cancer Center at Beaufort County Hospital
		John Inzerillo, MD	Principal Investigator
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		George Yacoub, MD	Principal Investigator
Ohio
	Cincinnati
	Charles M. Barrett Cancer Center at University Hospital
		Olugbenga Olowokure, MD	Principal Investigator
	Columbus
	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
		Tanios Be Bekaii-Saab, MD	Principal Investigator
Virginia
	Charlottesville
	University of Virginia
		Geoffrey Weiss, MD	Principal Investigator
	Portsmouth
	Naval Medical Center - Portsmouth
		Karen Russell, MD	Principal Investigator
Washington
	Tacoma
	Multicare Regional Cancer Center
		Yoshio Inoue, MD	Principal Investigator
Ireland
	Dublin
	Ireland Cooperative Clinical Research Group
		Robert Byrne	Ph: +353 (0)1 6677211

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01298570
Information obtained from ClinicalTrials.gov on April 29, 2013

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