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TerminatedNCT00779311Updated Nov 2, 2011Results posted

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

A Phase 1 interventional study of sorafenib and bevacizumab in Metastatic Colorectal Cancer, sponsored by Accelerated Community Oncology Research Network. Terminated at 3 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2011-11-02.

Sponsored by Accelerated Community Oncology Research Network · Phase 1, Interventional, and Treatment

Why this study was terminated
Dose limiting toxicity at the lowest planned dose level.
Phase
Phase 1
Study type
Interventional
Enrollment
8
Allocation
Not applicable
Ages
18 Years and older
Sex
All
01

Study summary

This research study is being performed at approximately 3 sites associated with Accelerated Community Oncology Research Network, Inc. (ACORN). Approximately 45 subjects will take part in this study.

In this study, everyone will receive the same dose of mFOLFOX6 and Avastin. There will be five groups of subjects. Each group of subjects will receive a higher dose of Nexavar than the previous group. This will continue until a subject group has a major side effects from the dose they are given. This is so that the sponsor can determine the highest dose of Nexavar that can be used with mFOLFOX6 and AVastin (this is called the maximum tolerated dose or MTD).

Read the detailed description

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 dose.
  • 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 dose.
  • 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 toxicity.

02

Conditions studied

  • Metastatic Colorectal Cancer

Keywords

  • Metastatic Colorectal Cancer
03

In context

Colorectal Neoplasms

5,734 studies on the registry are indexed under Colorectal Neoplasms; 1,481 are open to participants now.

This study's enrollment of 8 is below the median of 77 across 4,222 interventional studies indexed under Colorectal Neoplasms.

Browse Colorectal Neoplasms studies →

Lead sponsor

Accelerated Community Oncology Research Network is the lead sponsor of 17 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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 following:

    • 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

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.
05

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
8 participants (actual)

Study arms

  • Experimental
    Experimenal

    All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle. Sorafenib will be administered daily throughout treatment beginning on day 1

    Drug: sorafenib · Drug: bevacizumab · Drug: mFOLFOX6 regimen

Interventions

  • Drugsorafenib

    Sorafenib will be administered daily starting day 1 at 200mg QOD at Dose Level 1; 200mg/day at Dose Level 2; 200mg BID (5 days on/ 2 days off) at Dose Level 3; 200mg BID at Dose Level 4; and 400mg BID at Dose Level 5.

    Also known as: Nexavar

  • Drugbevacizumab

    Bevacizumab will be administered as 5mg/kg IV on Day 1 of each treatment cycle.

    Also known as: Avastin

  • DrugmFOLFOX6 regimen

    The mFOLFOX6 regimen will be administered on Day 1 of each treatment cycle. This regimen consists of oxaliplatin 85 mg/m2 IV given over 2 hours, leucovorin 400 mg/m2 IV given over 2 hours, and fluorouracil 400 mg/m2 IV bolus, followed by fluorouracil 1200 mg/m2 per day for 2 days continuous infusion.

06

What researchers measure

Primary outcomes

  1. 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.

    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)

Secondary outcomes

  1. Determination of Progression Free Survival (PFS) Among Patients on This Regimen

    PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first.

    Time frame: PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first.

  2. Determination of Quality of Life (QoL) as Indicated by Patient Care Monitor (PCM) Data Among Patients on This Regimen

    The subject answers questions from the following 6 categories: general physical symptoms, treatment side effects, distress, despair, impaired performance, and impaired ambulation. Each question has a scale from 0 through 10, where 0 is not a problem and 10 is as bad as possible. The frequency of patient reported severe (rated as \>=7) symptoms reported from the set of symptoms assessed by the PCM.

    Time frame: The PCM questionnaire was administered on day 1 of each cycle (approximately every 2 weeks) during study treatment.

07

Results

Posted Oct 26, 2011
Limitations and caveats
Early termination due to the MTD determined to be Dose Level 1, leading to a small number of subjects analyzed.

Participant flow

Three community oncology research sites across the US within the ACORN Network participated in this study. Enrollment started in October 2008 and was closed early in April 2010 due to two subjects experiencing DLT at the lowest dose level.

Participant flow — Overall Study
MilestoneDose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD Determination
Started80000
Dose limiting toxicity (dlt) evaluation60000
Completed80000
Not completed00000

Outcome measures

PrimaryDetermination 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.

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)
Reported as:
Number · mg every other day
Determination of the Maximum Tolerated Dose (MTD) of Sorafenib When Given in Combination With mFOLFOX6 and Bevacizumab
mg every other dayDose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD Determination
Determination of the Maximum Tolerated Dose (MTD) of Sorafenib When Given in Combination With mFOLFOX6 and Bevacizumab200————
SecondaryDetermination of Progression Free Survival (PFS) Among Patients on This Regimen

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first.

Time frame:
PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first.
Reported as:
Median · Months
Determination of Progression Free Survival (PFS) Among Patients on This Regimen
MonthsDose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD Determination
Determination of Progression Free Survival (PFS) Among Patients on This Regimen10.61 (3.61 to 13.40)————
SecondaryDetermination of Quality of Life (QoL) as Indicated by Patient Care Monitor (PCM) Data Among Patients on This Regimen

The subject answers questions from the following 6 categories: general physical symptoms, treatment side effects, distress, despair, impaired performance, and impaired ambulation. Each question has a scale from 0 through 10, where 0 is not a problem and 10 is as bad as possible. The frequency of patient reported severe (rated as \>=7) symptoms reported from the set of symptoms assessed by the PCM.

Time frame:
The PCM questionnaire was administered on day 1 of each cycle (approximately every 2 weeks) during study treatment.
Reported as:
Number · Participants
Determination of Quality of Life (QoL) as Indicated by Patient Care Monitor (PCM) Data Among Patients on This Regimen
ParticipantsDose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD Determination
Fatigue3————
Change in taste2————
Mouth sores/ulcers1————
Sore throat1————
Trouble swallowing1————
Day sweat1————
Night sweat1————
Reduced sexual enjoyment, interest, or performance2————
Heartburn1————
Nausea2————
Problem with urination1————
Bruising1————
New lump/mass1————
Hair loss1————
Nails change1————
Joint pain2————
Muscle aches2————
Weakness of body parts2————
Burning sensation in hands or feet2————
Numbness/tingling2————
Trouble sleeping at night2————
Pain1————
Attend paid job2————
Attend social activity1————
Hard work or activity2————
Household work1————
Light work or activity1————
Run2————
Walk1————
Crying/feeling like crying1————
Feeling helpless1————
Feeling hopeless1————
Lost interest in people1————
Nervous, tense, anxious2————
Worry2————

Adverse events

Collected over Adverse events were collected beginning on day 1 of study treatment until one month after the end of study treatment.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Dose Level (DL) 1 for MTD Determination—5/8 (62.5%)8/8 (100%)
Dose Level (DL) 2 for MTD Determination———
Dose Level (DL) 3 for MTD Determination———
Dose Level (DL) 4 for MTD Determination———
Dose Level (DL) 5 for MTD Determination———
Most frequent serious events
Most frequent serious events
EventDose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD Determination
DiarrheaGastrointestinal disorders1/8————
Chest painGeneral disorders1/8————
GastroenteritisInfections and infestations1/8————
PneumoniaInfections and infestations1/8————
DysgeusiaNervous system disorders1/8————
LethargyNervous system disorders1/8————
Renal failure acuteRenal and urinary disorders1/8————
DyspneaRespiratory, thoracic and mediastinal disorders1/8————
Pulmonary embolismRespiratory, thoracic and mediastinal disorders1/8————
Most frequent other events
Showing 10 of 68
Most frequent other events
EventDose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD Determination
NeutropeniaBlood and lymphatic system disorders5/8————
ConstipationGastrointestinal disorders5/8————
NauseaGastrointestinal disorders5/8————
FatigueGeneral disorders5/8————
DiarrheaGastrointestinal disorders4/8————
DysgeusiaNervous system disorders4/8————
EpistaxisRespiratory, thoracic and mediastinal disorders4/8————
Peripheral coldnessVascular disorders4/8————
AnemiaBlood and lymphatic system disorders3/8————
StomatitisGastrointestinal disorders3/8————

Baseline characteristics

Age Categorical
Age Categorical(participants)Dose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD DeterminationTotal
<=18 years0————0
Between 18 and 65 years3————3
>=65 years5————5
Age Continuous
Age Continuous(years)Dose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD DeterminationTotal
Mean62.0 ± 11.40————62.0 ± 11.40
Gender
Gender(participants)Dose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD DeterminationTotal
Female3————3
Male5————5
Region of Enrollment
Region of Enrollment(participants)Dose Level (DL) 1 for MTD DeterminationDose Level (DL) 2 for MTD DeterminationDose Level (DL) 3 for MTD DeterminationDose Level (DL) 4 for MTD DeterminationDose Level (DL) 5 for MTD DeterminationTotal
United States8————8
08

Study locations

3 sites
  • Central Georgia Cancer Care
    Macon, Georgia 31201, United States
  • Hematology Oncology Centers of the Northern Rockies
    Billings, Montana 59101, United States
  • The West Clinic
    Memphis, Tennessee 38120, United States
09

Timeline

Tracking since Sep 25, 2026
Not marked actual or estimatedDates not marked actual or estimated

The record gives a start of Oct 2008, a primary completion of Mar 2011 and a completion of Mar 2011. It does not say whether these dates are actual or estimated.

Results were first posted in Oct 2011, 7 months after primary completion.

How these figures are worked out, and which studies are left out of them.

Registered
Oct 23, 2008
First posted
Oct 24, 2008
Start
Oct 2008
Primary completionActual
Mar 2011
CompletionActual
Mar 2011
Results first posted
Oct 26, 2011
Last update
Nov 2, 2011
What these dates mean
Start.
When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.
When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.
When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.
Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.
No changes since tracking began. The registry record was last updated on Nov 2, 2011, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT00779311
Lead sponsor
Accelerated Community Oncology Research Network
Collaborators
Bayer
Responsible party
Sponsor
First posted
Oct 24, 2008
Start date
Oct 2008
Primary completion
Mar 2011
Completion
Mar 2011
Results posted
Oct 26, 2011
Last update
Nov 2, 2011

Study contacts

Fred Schnell, MD
principal investigator · Central Georgia Cancer Care

Oversight

Data monitoring committee
No
View the source record on ClinicalTrials.gov ↗

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