A Phase I Trial Evaluating mFOLFOX6 and Avastin With Nexavar as First-Line Treatment for Metastatic Colorectal Cancer
This is an investigator-initiated, multicenter, network, Phase 1, open-label, dose-ranging
study. The maximum sample size will be 45 patients (up to 30 patients for determining MTD at
Phase I, and an additional 15 patients to provide for estimate of progression free
survival). All eligible patients will receive the mFOLFOX6 regimen at full dose followed by
IV bevacizumab 5mg/kg on Day 1 of each treatment cycle. Treatment cycle length is 2 weeks
(Q2W). Sorafenib will be administered daily throughout treatment beginning on day 1.
Dose limiting toxicity will be defined as any grade 4 hematologic event or any grade 3 or 4
non-hematologic event occurring during cycle 1 or 2 that is attributable to sorafenib or the
combination. The following events are excluded from this definition: grade 3 nausea and/or
vomiting responsive to antiemetics; grade 3 fever or infection; grade 3 diarrhea responsive
to antidiarrheal therapy.
Three patients will be enrolled at a dose level and observed for dose-limiting toxicities
(DLTs) for 2 cycles of treatment. Dose escalation for sorafenib will depend on the number of
patients experiencing DLT(s) as follows:
- If 0/3 patients experience DLT(s), then 3 more patients are treated at the next higher
- If 1/3 patients experiences DLT(s), then 3 more patients are enrolled at that dose. If
1/6 of the patients treated at that dose experiences DLT(s), then the next cohort is
treated at the next higher dose. However, if ≥2/6 patients experience DLT(s) at that
dose, then the MTD is considered to have been exceeded. At that point, 3 more patients
are treated at the next lower dose, unless 6 have already been treated at that lower
- If ≥2/3 patients experience DLT(s) at a dose, then 3 more patients are enrolled at the
next lower dose unless 6 patients have already been treated at that dose.
Dose escalation will continue until the MTD is determined or until all dose levels have been
completed. The MTD is defined as the dose at which ≤1 of 6 patients experience DLT(s), and
above which ≥2 of 6 patients experience DLT(s). If the MTD is at Dose Level 2 (or lower),
then the study will be terminated and no further patients will be enrolled.
Once the MTD for sorafenib combined with mFOLFOX6 and bevacizumab has been determined, an
additional 15 patients with mCRC will be enrolled into an extension of the Phase 1 study.
These patients will be treated at the MTD for sorafenib with the combination therapy to
assess PFS and safety of the regimen as first-line therapy in mCRC. All patients will be
eligible for indefinite treatment in the absence of disease progression or unacceptable
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determination of the Maximum Tolerated Dose (MTD) of Sorafenib When Given in Combination With mFOLFOX6 and Bevacizumab
The MTD of sorafenib was determined using a standard 3 + 3 dose escalation cohort design. The total sample and the number of patients who receive each dose depends on the frequency of dose limiting toxicities (DLT) at each dosage. If 0 out of 3 patients experience a DLT at a given dosage level, 3 patients will be enrolled at the next dosage level. If greater than or equal to 2 patients experience a DLT at a given dosage level, dosage escalation will be stopped. If 1 out of 3 patients experience a DLT at a given dosage level, 3 patients are enrolled at the same dosage level.
MTD was assessed during the first 2 cycles of treatment (i.e., the first 4 weeks of treatment since cycle length is 2 weeks)
Fred Schnell, MD
Central Georgia Cancer Care
United States: Institutional Review Board
|Hematology Oncology Centers of the Northern Rockies||Billings, Montana 59101|
|The West Clinic||Memphis, Tennessee 38120|
|Central Georgia Cancer Care||Macon, Georgia 31201|