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A Phase I Trial Evaluating mFOLFOX6 and Avastin With Nexavar as First-Line Treatment for Metastatic Colorectal Cancer

Phase 1
18 Years
Not Enrolling
Metastatic Colorectal Cancer

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Trial Information

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

Inclusion Criteria:

- No prior chemotherapy for metastatic disease.

- Histologically proven colorectal carcinoma.

- Measurable disease by RECIST criteria.

- Age: at least 18 years.

- ECOG performance status of 0 or 1 at study entry.

- Adequate bone marrow, liver and renal function at study entry as assessed by the

- Hemoglobin >9.0 g/dL.

- ANC ≥1500/mm3.

- Platelet count ≥100,000/mm3.

- Total bilirubin ≤1.5 times x ULN.

- ALT and AST ≤2.5 × ULN (≤5 × ULN for patients with liver involvement).

- Creatinine ≤1.5 × ULN.

- INR <1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation
treatment with an agent such as warfarin or heparin may be allowed to participate
after discussion with ACORN. For patients on warfarin, the INR should be measured
prior to initiation of sorafenib and monitored at least weekly, or as defined by the
local standard of care, until INR is stable.

- Women of childbearing potential must have a negative serum or urine pregnancy test
performed within 7 days prior to the start of treatment.

- Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry and for the duration of study
participation. Patients should use adequate birth control for at least 3 months after
the last administration of sorafenib.

- Ability to understand and the willingness to sign a written informed consent. A
signed informed consent must be obtained prior to any study specific procedures.

Exclusion Criteria:

- Prior use of bevacizumab.

- Neuropathy ≥ Grade 2 per CTCAE v3.0.

- Diarrhea ≥ Grade 2 per CTCAE v3.0 within 4 weeks of study treatment start.

- ECOG performance status ≥ 2.

- Proteinuria at baseline: patients discovered to have > 2+ proteinuria at baseline
should undergo a 24 hour urine collection and must demonstrate < 1 gram of protein in
24 hours to be eligible.

- Active malignancy other than mCRC (except non-melanoma skin cancer; in situ carcinoma
of the cervix; in situ carcinoma of the breast) within the last 5 years.

- Treatment with radiotherapy within 2 weeks of enrollment.

- Cardiac disease: Congestive heart failure > Class II NYHA. Patients must not have
unstable angina (anginal symptoms at rest) or new onset angina (began within the last
3 months) or myocardial infarction within the past 6 months.

- Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/
MRI of the brain to exclude brain metastasis.

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

- Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic
pressure > 90 mm Hg, despite optimal medical management.

- Known human immunodeficiency virus infection or chronic Hepatitis B or C.

- Active clinically serious infection > Grade 2 per CTCAE v3.0.

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months.

- Pulmonary hemorrhage/bleeding event ≥ Grade 2 per CTCAE v3.0 within 4 weeks of study
treatment start.

- Any other hemorrhage/bleeding event ≥ Grade 3 per CTCAE v3.0 within 4 weeks of study
treatment start.

- Serious non-healing wound, ulcer, or bone fracture.

- Evidence or history of bleeding diathesis or coagulopathy.

- Major surgery, open biopsy or significant traumatic injury within 4 weeks of study
treatment start; fine needle aspiration or central venous line placement for
chemotherapy administration within 7 days of study treatment start.

- Use of daily corticosteroids, St. John's Wort, rifampin (rifampicin), phenytoin,
carbamazepine, phenobarbital, ketoconazole. Dexamethasone may only be used as an
antiemetic or as a premedication for a bevacizumab hypersensitivity reaction during
participation in this study.

- Known or suspected allergy to sorafenib or any other agent given in the course of
this trial.

- Any condition that impairs patient's ability to swallow whole pills.

- Any malabsorption problem.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determination of the Maximum Tolerated Dose (MTD) of Sorafenib When Given in Combination With mFOLFOX6 and Bevacizumab

Outcome Description:

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.

Outcome Time Frame:

MTD was assessed during the first 2 cycles of treatment (i.e., the first 4 weeks of treatment since cycle length is 2 weeks)

Safety Issue:


Principal Investigator

Fred Schnell, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Central Georgia Cancer Care


United States: Institutional Review Board

Study ID:




Start Date:

October 2008

Completion Date:

March 2011

Related Keywords:

  • Metastatic Colorectal Cancer
  • Metastatic Colorectal Cancer
  • Colorectal Neoplasms



Hematology Oncology Centers of the Northern RockiesBillings, Montana  59101
The West ClinicMemphis, Tennessee  38120
Central Georgia Cancer CareMacon, Georgia  31201