Neoplasms

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Digestive System Diseases

Adenocarcinoma

Neoplasm Metastasis

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Oxaliplatin

Leucovorin

Fluorouracil

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Antineoplastic Agents, Immunological

CT-011 (3 mg/kg) administered intravenously every 4 weeks for 4 weeks and every 12 weeks thereafter until disease progression or maximum tolerance.

FOLFOX (FOLFOX4 or mFOLFOX6) administered 7 days after the first administration of CT-011 and repeated every 14 days for up to 24 cycles. At the end of FOLFOX therapy, patients who have not progressed will be eligible for maintenance chemotherapy with 5-FU/leucovorin at the same dose and schedule until disease progression or study drug discontinuation.

FOLFOX (FOLFOX-4 or mFOLFOX6) administered every 14 days for up to 24 cycles. At the end of FOLFOX therapy, patients who have not progressed will be eligible for maintenance chemotherapy with 5-FU/leucovorin at the same dose and schedule until disease progression or study drug discontinuation.

CT-011

FOLFOX-4: each cycle consists of the following: oxaliplatin 85 mg/m2 on Day 1, leucovorin 200 mg/m2/day on Day 1 and Day 2 followed by 5-FU 400 mg/m2 bolus and a 22 hour infusion of 5-FU 600 mg/m2 for two consecutive days.

mFOLFOX-6: each cycle consists of the following: oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 on Day 1, followed by 5-FU 400 mg/m2 bolus, followed by 5-FU 1200 mg/m2/day for two consecutive days (total 2,400 mg/m2 over 46-48 hours).

FOLFOX

Leonard B Saltz, MD

This clinical trial will be performed in previously untreated patients with metastatic colorectal cancer. The study will evaluate the safety, tolerability and efficacy of the study drug, CT-011, in combination with FOLFOX chemotherapy (FOLFOX4 or mFOLFOX6) compared with treatment by FOLFOX alone.

The proposed clinical trial will be a multi-center, randomized, open label, active control study in previously untreated patients with metastatic colorectal cancer aimed to evaluate the safety, tolerability and efficacy of the monoclonal antibody, CT-011, administered at 3mg/kg in combination with FOLFOX chemotherapy (FOLFOX4 or mFOLFOX6) compared with treatment by FOLFOX alone. Approximately 168 patients are planned to be enrolled to this study.

Study to Evaluate the Safety, Tolerability and Efficacy of FOLFOX + CT-011 Versus FOLFOX Alone

Phase II Study to Evaluate the Safety, Tolerability and Efficacy of FOLFOX + CT-011 Versus FOLFOX Alone Administered Intravenously to Patients With Colorectal Adenocarcinoma Previously Untreated for Metastatic Disease

Medivation, Inc.

Hematinics

Vitamins

Amino Acids

Cetuximab

Levoleucovorin

Folic Acid

Dasatinib

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antidotes

Protective Agents

Vitamin B Complex

Trace Elements

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Folinic Acid

Folate

Vitamin B9

Tyrosine

5-FU 2400 mg/m\^2 by vein over 46 Hours On Days 1 \& 2. Cetuximab initial dose = 400 mg/m\^2 by vein, then 250 mg/m\^2 Weekly On Days 1 \& 8. Dasatinib 100 mg by mouth daily on days 1-14. Leucovorin 400 mg/m\^2 by vein on day 1. Oxaliplatin 85 mg/m\^2 by vein on day 1.

2400 mg/m\^2 by vein over 46 Hours On Days 1 \& 2.

5-FU

Initial Dose = 400 mg/m\^2 by vein, then 250 mg/m\^2 Weekly On Days 1 \& 8

Starting dose level: 100 mg by mouth daily on days 1-14.

Scott Kopetz, MD

The goal of the Phase I part of this clinical research study is to find the highest tolerable dose of a combination of dasatinib, cetuximab, and FOLFOX (5-fluorouracil \[5-FU\], leucovorin \[LV\], and Eloxatin \[oxaliplatin\]) that can be given to patients with metastatic colorectal cancer. The safety of these drugs in combination will also be studied.

The goal of the Phase II part of this clinical research study is to learn if dasatinib given in combination with FOLFOX with or without cetuximab can help to control metastatic colorectal cancer.

Cetuximab is a drug designed to block the activity of EGFR, a protein on the surface of some tumor cells that may cause the cells to grow. Blocking EGFR may stop or slow the growth of tumor cells. Dasatinib is a drug that inhibits a protein called c-Src. High levels of c-Src may make it harder for chemotherapy to work against the cancer. If dasatinib can inhibit c-Src, the chemotherapy may be more effective against the cancer. FOLFOX is a drug combination frequently used to treat colon or rectal cancer that has spread to other parts of the body. FOLFOX is designed to kill rapidly dividing cells by preventing DNA (the genetic material of cells) from duplicating.

Kirsten Rat Sarcoma (KRAS) Testing:

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 KRAS gene mutation.

If you take part in the Phase I part of this study, your tumor tissue from a previous biopsy or surgery will be used to test for KRAS mutation. If you have the KRAS gene mutation, you will not take part in this study.

If you take part in the Phase II part of this study, your tumor tissue from a previous biopsy or surgery will be used to test for KRAS mutation. If you have the KRAS gene mutation, you may take part in the study but you will not receive cetuximab.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group (Phase I or Phase II) based on when you join this study.

If you are enrolled in the Phase I portion, the dose of dasatinib you will receive will depend on when you joined the study. Three (3) to 6 participants will be entered at each dose level. Each new group of participants will receive a higher dose, until the highest tolerable dose is found. Once the highest tolerable dose is found, 12 participants will be enrolled at that dose level. Your doctor will tell you what dose level you will be receiving and how this dose compares to the doses other participants have received. The starting dose of cetuximab and FOLFOX will be the same for all participants. The dose of dasatinib will be increased with the next group of 3-6 participants. Every 14 days is considered 1 study "cycle".

If you are enrolled in the Phase II portion, you will receive the dose of dasatinib found to be best tolerated in the Phase I portion. You will also receive FOLFOX. If you do not have the KRAS gene mutation, you will also receive cetuximab. Every 14 days is considered 1 study "cycle".

Central Venous Catheter (CVC) Placement:

Before receiving the study drugs, you will have a CVC placed. A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

Study Drug Administration:

You will take dasatinib by mouth once a day, every day during this study. Your study doctor and research nurse will tell you how many pills you will take. Dasatinib should be taken at the same time each day, with or without meals. If you miss a dose of dasatinib, you should not double the next dose. It is important to take dasatinib with water, and not fruit juices. You should not drink grapefruit juice or eat grapefruit while you are on this study. Dasatinib should not be touched by children, pregnant women, or women who are breastfeeding. If a caregiver must handle the drug, a protective glove should be worn.

While you are taking dasatinib, you will be given a drug diary. In this diary, you will write down the date, the time, and the number of dasatinib tablets taken. Certain drugs and herbal supplements may not be taken while you are receiving dasatinib. These drugs could affect how your body breaks down dasatinib, which could have a bad effect on you. Your doctor will give you a list of drugs and herbal supplements that you must not take while on this study. You must tell your doctor before taking any new drugs while on this study.

On Day 1 of every cycle, you will receive oxaliplatin and LV through the CVC over about 2 hours. On Day 1, you will receive 5-FU through a portable pump for the next 46 hours. If you are receiving cetuximab in the Phase I portion of the study, you will receive it on Days 1 and 8 through the CVC over about 2 hours. If you are receiving cetuximab in the Phase II portion of the study, you will receive it on Day 1 through the CVC over about 2 hours.

Study Visits for Phase I:

If you are enrolled at the highest tolerable dose level, you will have 2 core liver biopsies. The liver tissue will be studied to learn the effect of the study drugs on stopping the protein c-Src. You will have 2 liver biopsies collected. The first liver biopsy will be collected before you start the study drugs, and the second will be performed in either Cycle 2 or 3. Before the liver biopsy, you will receive fluids and drugs for relaxation and/or pain through an needle in your arm or hand. You will be awake during the biopsy. A radiologist will find the tumor in the liver with the help of radiographic imaging procedures such as an ultrasound or CT scan. Your skin around this area will be cleansed, and a local anesthetic will be given. A long, hollow needle will be inserted through the skin into the liver tumor, and a tissue sample(s) will be taken.

On Day 8, blood (about 1-2 tablespoons) will be drawn for routine tests.

You will have extra blood samples drawn (1 tablespoon each time) before receiving the study drugs and on Day 8 of Cycles 2 and 4. This blood will be drawn at the same time as your routine blood tests are drawn. These blood samples will be used to develop tests that may help doctors be able to predict who will best benefit from dasatinib.

If you are enrolled in the group that receives the highest tolerable dose level, the Day 8 blood draw during cycle 2 will not be performed. Instead, blood will be collected at the time of the liver biopsy that is to be performed between Days 8-14 of cycle 2 or 3 about 2 to 6 hours after taking the daily dose of dasatinib.

Study Visits for Phase II:

You will have extra blood samples drawn (1 tablespoon each time) before receiving the study drugs and at the end of every 4 cycles. This blood will be drawn at the same time as your routine blood tests are drawn. These blood samples will be used to develop tests that may help doctors be able to predict who will best benefit from dasatinib.

Before the start of each new cycle and when you stop study treatment, you will be asked to complete a questionnaire about any symptoms you may be experiencing. The questionnaire will take up to 5 minutes to complete.

Once you stop receiving study drugs, the study team will contact you by telephone every 3 months to check how you are doing. Each phone call will take about 5 minutes.

Phase I and Phase II:

Before each new cycle, you will be asked questions about any side effects you may have had. At each visit, it is important to tell the study staff about any drugs you are currently taking. You will have a physical exam, including measurement of your vital signs and weight. You will have a performance status evaluation. Blood (about 1-2 tablespoons) will be drawn for routine tests.

Women who are able to become pregnant will have a blood or urine pregnancy test every month.

If you experience severe side effects, the study drugs may be delayed, stopped, or you may receive smaller doses of the drugs.

You may remain on this study for as long as you are benefiting. You will be taken off this study if the disease gets worse or intolerable side effects occur.

Once you are off-study, you will have an end-of-study visit. At this visit, blood (about 3 tablespoons) will be collected for routine tests. You will be asked questions about any side effects you may have had and about any drugs you are currently taking. You will have a physical exam, including measurement of your vital signs and weight. You will have a performance status evaluation. If not performed recently, you will have a CT scan or MRI scan of your chest, abdomen and pelvis to check the status of the disease. If you are having side effects after you stop receiving the study drugs, you will be contacted by phone to check how you are feeling, or you will have follow-up visits until the side effects have gone away.

This is an investigational study. Dasatinib is FDA approved for the treatment of leukemia. Its use in this study, for this disease, is considered to be investigational. Cetuximab, 5-FU, LV, and oxaliplatin are all FDA approved and commercially available for the treatment of colorectal cancer. Up to 83 patients will take part in this study. All patients will be enrolled at MD Anderson.

FOLFOX Chemotherapy Regimen (5-FU, Leucovorin, Oxaliplatin) in Metastatic Colorectal Cancer

Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined With FOLFOX Chemotherapy in Metastatic Colorectal Cancer (CA180048)

If 2 or more out of the 6 patients in the cohort have dose limiting toxicity (DLT) then the prior dose level is the MTD.

Response and progression evaluated using a modification of the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee \[JNCI 92(3):205-216, 2000\]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST criteria. Duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.

Bristol-Myers Squibb

M.D. Anderson Cancer Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Evaluate the Safety, Tolerability and Efficacy of FOLFOX + CT-011 Versus FOLFOX Alone	NCT00890305	Metastatic Colo...	CT-011 FOLFOX	18 Years -	Medivation, Inc.
Study to Evaluate the Safety, Tolerability and Efficacy of FOLFOX + CT-011 Versus FOLFOX Alone	NCT00890305	Metastatic Colo...	CT-011 FOLFOX	18 Years -	Medivation, Inc.
FOLFOX Chemotherapy Regimen (5-FU, Leucovorin, Oxaliplatin) in Metastatic Colorectal Cancer	NCT00501410	Colorectal Canc...	5-FU Cetuximab Dasatinib Leucovorin Oxaliplatin	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for folfox chemotherapy