Clinical trial NCT01298570: Regorafenib+FOLFIRI Versus Placebo+FOLFIRI as 2nd Line Tx in Metastatic Colorectal Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer Metastatic
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
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2011-02-17
Enrollment: 181
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 5.5 years
Secondary outcomes:
measure: Overall Response(OR)Rate
timeFrame: 3 years
measure: Disease Control (DC) Rate
timeFrame: 3 years
measure: Overall Survival (OS)
timeFrame: 5.5 years
measure: Drug Metabolism
timeFrame: 28 days
measure: Percentage of Patients With Severe Adverse Events
timeFrame: 3 years
Other outcomes:
Locations:
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Miami
country: United States
facility: Mount Sinai Medical Center-Miami
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Georgia Cancer Specialists
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University Simon Cancer Center
state: Indiana
city: Louisville
country: United States
facility: University of Louisville James Brown Cancer Center
state: Kentucky
city: Manhasset
country: United States
facility: North Shore Long Island Jewish Health System
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: Boone
country: United States
facility: Seby B. Jones Cancer Center
state: North Carolina
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas HealthCare System
state: North Carolina
city: Goldsboro
country: United States
facility: Southeast Medical Oncology Center
state: North Carolina
city: Greensboro
country: United States
facility: The Moses Cone Regional Cancer Center
state: North Carolina
city: Greenville
country: United States
facility: Leo W. Jenkins Cancer Center at ECU Medical School
state: North Carolina
city: Pinehurst
country: United States
facility: First Health of the Carolinas, Moore Regional Hospital
state: North Carolina
city: Raleigh
country: United States
facility: Rex Cancer Center at Rex Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Portsmouth
country: United States
facility: Portsmouth Naval Medical Center
state: Virginia
city: Tacoma
country: United States
facility: Multicare Regional Cancer Center
state: Washington
city: Dublin
country: Ireland
facility: Ireland Cooperative Clinical Research Group
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Hanna Sanoff, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Quintanilha JCF, Geyer S, Etheridge AS, Racioppi A, Hammond K, Crona DJ, Pena CE, Jacobson SB, Marmorino F, Rossini D, Cremolini C, Sanoff HK, Abou-Alfa GK, Innocenti F. KDR genetic predictor of toxicities induced by sorafenib and regorafenib. Pharmacogenomics J. 2022 Dec;22(5-6):251-257. doi: 10.1038/s41397-022-00279-3. Epub 2022 Apr 28.
citation: Schultheis B, Folprecht G, Kuhlmann J, Ehrenberg R, Hacker UT, Kohne CH, Kornacker M, Boix O, Lettieri J, Krauss J, Fischer R, Hamann S, Strumberg D, Mross KB. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol. 2013 Jun;24(6):1560-7. doi: 10.1093/annonc/mdt056. Epub 2013 Mar 13.