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Hepatic Arterial Infusion of Oxaliplatin in Combination With Systemic Fluorouracil, Leucovorin and Bevacizumab With/Without Cetuximab by K-RAS Mutational Status and Liver Function for Advanced Cancers Metastatic to the Liver


Phase 1
N/A
N/A
Open (Enrolling)
Both
Advanced Cancers

Thank you

Trial Information

Hepatic Arterial Infusion of Oxaliplatin in Combination With Systemic Fluorouracil, Leucovorin and Bevacizumab With/Without Cetuximab by K-RAS Mutational Status and Liver Function for Advanced Cancers Metastatic to the Liver


The Study Drugs:

Oxaliplatin is designed to keep new cancer cells from growing.

5-fluorouracil is designed to block the way cancer cells grow and divide, which may slow or
stop their growth and keep them from spreading throughout the body. This may cause the
cancer cells to die.

Leucovorin is designed to strengthen the effect of 5-fluorouracil by reducing tumor cell
resistance to 5-fluorouracil. BECAUSE OF A PHARMACY SHORTAGE OF IV LEUCOVORIN, PATIENTS WILL
CONTINUE TREATMENT WITHOUT LEUCOVORIN UNTIL IT BECOMES AVAILABLE.

Bevacizumab is designed to block the growth of blood vessels that supply nutrients necessary
for tumor growth. This may prevent or slow down the growth of cancer cells. Bevacizumab is
no longer FDA approved to treat breast cancer.

Cetuximab is designed to prevent or slow down the growth of cancer cells by blocking
proteins inside the cancer cell, called the epidermal growth factor receptor (EGFR).

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study
"arm" (group) based on the results of your screening tests. All patients will receive
oxaliplatin and bevacizumab. If your doctor thinks it is in your best interest, you will
also receive cetuximab. However, recent studies have found that cetuximab, when given alone
or in combination with other chemotherapy drugs, was not effective when given to patients
with colorectal cancer that had a K-RAS mutation. If you have colorectal cancer and you are
tested for and do not have the K-RAS gene, you will also receive cetuximab. Patients with
normal liver function will also receive 5-FU.

- If you are in Arm A, you will receive oxaliplatin, 5-FU, and bevacizumab.

- If you are in Arm B, you will receive oxaliplatin, 5-FU, leucovorin, bevacizumab, and
cetuximab.

- If you are in Arm C, you will receive oxaliplatin and bevacizumab.

- If you are in Arm D, you will receive oxaliplatin, bevacizumab, and cetuximab.

Arm A:

All participants will receive the same dose levels of oxaliplatin and bevacizumab.

You will be assigned to a dose level of 5-FU based on when you joined this study. Up to 4
dose levels of 5-FU will be tested. Up to 6 participants will be enrolled at each dose
level. The first group of participants will receive the lowest dose level. Each new group
will receive a higher dose than the group before it, if no intolerable side effects were
seen.

Arm B:

All participants will receive the same dose levels of oxaliplatin, bevacizumab, and
leucovorin.

You will be assigned to a combination dose level of 5-FU and cetuximab based on when you
joined this study. Up to 4 combination dose levels of 5-FU and cetuximab will be tested.
Up to 6 participants will be enrolled at each dose level. The first group of participants
will receive the lowest dose level. Each new group will receive a higher dose than the
group before it, if no intolerable side effects were seen.

Arm C:

All participants will receive the same dose levels of oxaliplatin.

You will be assigned to a dose level of bevacizumab based on when you joined this study. Up
to 4 dose levels of bevacizumab will be tested. Up to 6 participants will be enrolled at
each dose level. The first group of participants will receive the lowest dose level. Each
new group will receive a higher dose than the group before it, if no intolerable side
effects were seen.

Arm D:

All participants will receive the same dose levels of oxaliplatin.

You will be assigned to a combination dose level of bevacizumab and cetuximab based on when
you joined this study. Up to 4 combination dose levels of bevacizumab and cetuximab will be
tested. Up to 6 participants will be enrolled at each dose level. The first group of
participants will receive the lowest dose level. Each new group will receive a higher dose
than the group before it, if no intolerable side effects were seen.

In each group, after the highest tolerable dose of the study drug combination is found, up
to 12 additional patients will receive that dose level.

Additionally, for Arm A and Arm B, after the highest tolerable dose of the study drug
combination is found, up to 20 additional participants with colorectal cancer will be added
to Arm A and Arm B.

Catheter Placement for Study Drug Administration:

You will be hospitalized to receive the study drug combination. On the day of your
admission to the hospital, you will have a catheter (a sterile flexible tube that will be
placed in the hepatic artery [a blood vessel in the liver] while you are under local
anesthesia) through which you will receive the study drugs. The catheter will be placed and
removed during each cycle. Your doctor will explain this procedure to you in more detail,
and you will be required to sign a separate consent form.

You must lay in bed for the entire time that the catheter is in place. In some cases, the
catheter will be removed right after your chemotherapy is complete. In some cases, the
catheter may remain in overnight. Therefore, you must remain in bed until the catheter is
removed.

Study Drug Administration:

Arm A:

On day 1 of each 21 day cycle you will receive oxaliplatin through the hepatic arterial
catheter over 2 hours. You will then receive 5-FU over 24 hours through the hepatic
arterial catheter. You will then receive bevacizumab by vein over 1 1/2 hours.

Arm B:

On day 1 of each 21 day cycle you will receive oxaliplatin through the hepatic arterial
catheter over 2 hours and 5-FU and leucovorin by vein over 24 hours on Days 1 and 2 of each
cycle (a total of 48 hours). You will then receive bevacizumab by vein over about 1 1/2
hours, followed by cetuximab by vein over 1-2 hours.

Arm C:

On day 1 of each 21 day cycle you will receive oxaliplatin through the hepatic arterial
catheter over 2 hours and bevacizumab by vein over about 1 1/2 hours.

Arm D:

On day 1 of each 21 day cycle you will receive oxaliplatin through the hepatic arterial
catheter over 2 hours and you will receive bevacizumab by vein over about 1 1/2 hours. You
will also receive cetuximab by vein over about 1-2 hours on Day 1 of each cycle.

Study Visits:

At each study visit, you will be asked about any other drugs you may be receiving and about
any side effects you may be having.

On Day 1 of Cycle 1:

- Your medical history will be recorded.

- You will have a physical exam, including measurement of your weight and vital signs.

- Blood (about 4 teaspoons) will be drawn for routine tests.

- Blood (about 1 teaspoon) will be used to test your blood's ability to clot.

- If your study doctor thinks it is needed, you will have an ECG.

- Women who are able to become pregnant will have a urine pregnancy test.

On Day 2 of Cycle 1:

-You will have a physical exam, including measurement of your weight and vital signs.

On Day 1 of Cycles 2 and beyond:

- You will have a physical exam, including measurement of your weight and vital signs.

- Blood (about 4 teaspoons) will be drawn for routine tests.

- If your study doctor thinks it is needed, you will have an ECG.

- Women who are able to become pregnant will have a urine pregnancy test.

On Day 2 of Cycles 2 and beyond:

-You will have a physical exam, including measurement of your weight and vital signs.

At the end of each cycle, blood (about 1 teaspoon) will be drawn to test your blood's
ability to clot.

At the end of Cycle 2 and then every 2-3 cycles after that, you will have scans to check the
status of the disease. This may include a chest x-ray, CT scan, MRI scan, a PET scan and/or
a PET/CT scan. If the study doctor thinks it is more appropriate for you, other types of
scans may need to be performed. The study doctor will discuss these scans with you, and you
may be asked to sign a separate consent form.

Length of Study:

You may continue to receive the study drug combination for as long as you are benefitting.
You will be taken off study if the disease gets worse or if you experience any intolerable
side effects.

Follow-Up:

About 6 weeks after your last dose of study drugs, the following tests and procedures will
be performed:

- Blood (about 3 teaspoons) will be drawn for routine tests.

- You will have a physical exam, including measurement of your weight and vital signs.

This is an investigational study. All of the study drugs are FDA-approved and commercially
available for use in other types of cancer:

- 5-FU - for cancers of the breast, pancreas, colon/rectum, stomach, and a type of skin
cancer (superficial basal cell carcinoma).

- Oxaliplatin and leucovorin - for colorectal cancer.

- Bevacizumab - for colorectal and lung cancers.

- Cetuximab - for colorectal and head/neck cancers.

It is investigational to give the study drugs together for advanced cancer.

Up to 198 participants will take part in this study. All will be enrolled at M. D.
Anderson.


Inclusion Criteria:



1. Patients must have histologically confirmed cancer with metastatic liver metastases.

2. Patients should be refractory to standard therapy, relapsed after standard therapy,
or have no standard therapy that increases survival by at least 3 months, unless the
drugs in the protocol regimen are part of the standard of care.

3. Performance status Eastern Cooperative Oncology Group (ECOG) 0-2 (Capable of all self
care but unable to carry out any work activities). Pediatric: performance status
Karnovsky (>10) or Lansky (<10).

4. Adequate renal function (Serum Creatinine
5. Patients will be stratified by liver function tests: Normal liver function: Total
Bilirubin reference value. Abnormal liver function: Total bilirubin >3 mg/dL and/or elevated
ALT > 5 x upper limit of normal (ULN). If bilirubin is >/= 5 mg/dL, fluorouracil
(5FU) dose will be omitted. Both of the above groups will be eligible.

6. Adequate bone marrow function (Absolute Neutrophil Count (ANC) >/=1500 cells/uL;
Platelets (PLT) >/= 100,000 cells/uL).

7. At least three weeks from previous cytotoxic chemotherapy before day 1 of hepatic
arterial infusion (HAI) infusion. After targeted or biologic therapy, there should be
5 half-lives or three weeks, whichever is shorter.

8. All females in childbearing age MUST have a negative urine human chorionic
gonadotropin (HCG) test unless prior hysterectomy or menopause (defined as age above
55 and six months without menstrual activity). Patients should not become pregnant or
breast feed while on this study. Sexually active patients should use effective birth
control.

9. Ability to sign informed consent form. Pediatric: age 7-18 would sign assent, (<7
would not assent), parent or guardian would sign consent.

10. Patients with colorectal cancer must agree to K-RAS mutational status screening, if
not available. If tissue is not available, patients can enter on trial, but not on
the cetuximab arms.

Exclusion Criteria:

1. Pregnant females.

2. Inability to complete informed consent process and adhere to protocol treatment plan
and follow-up requirements.

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

4. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 28 days.

5. Uncontrolled systemic vascular hypertension (Systolic blood pressure > 140 mmHg,
Diastolic Blood Pressure > 90 mmHg).

6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring parental antibiotics, or psychiatric illness/social situations
that would limit compliance with study requirements.

7. Patients already in uncompensated liver failure (i.e. Child Pugh Liver Classification
C).

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose and Toxicity

Outcome Time Frame:

Following each treatement cycle (every 3 weeks)

Safety Issue:

Yes

Principal Investigator

Apostolia M. Tsimberidou, MD, PHD

Investigator Role:

Study Chair

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

2009-0023

NCT ID:

NCT00941499

Start Date:

July 2009

Completion Date:

Related Keywords:

  • Advanced Cancers
  • Advanced Cancers
  • Liver
  • Oxaliplatin
  • Eloxatin
  • Bevacizumab
  • Avastin
  • Anit-VEGF monoclonal antibody
  • rhuMAb-VEGF
  • 5-fluorouracil
  • 5-FU
  • Adrucil
  • Efudex
  • Leucovorin
  • Citrovorum
  • Wellcovorin
  • Cetuximab
  • C225
  • Erbitux
  • IMC-C225
  • Neoplasms

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030