Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Colorectal Neoplasms

Neoplasms, Second Primary

Liver Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Liver Diseases

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Oxaliplatin

Fluorouracil

Irinotecan

Cetuximab

Liver Extracts

Antineoplastic Agents, Immunological

Topoisomerase I Inhibitors

Enzyme Inhibitors

Cetuximab is administered every two weeks at the dose of 500 mg/m² over 2h30 (150 minutes).

IV cetuximab

Irinotecan (180 mg/m²) on day 2 as a 6 hour infusion, starting at 2:00, with a peak at 5:00

Oxaliplatin (85 mg/m²) in split daily doses for 3 days, starting on day 2. Daily sinusoidal infusion duration will last from 10:15 to 21:45, with peak delivery rate at 16:00.

5-Fluorouracil (2800 mg/m²) in split daily doses for 3 days, alternating with oxaliplatin infusions, starting on day 2. Daily sinusoidal infusions will last from 22:15 to 9:45 , with peak delivery at 4:00.

Treatments will be repeated every 2 weeks.

HAI chronomodulated chemotherapy

Irinotecan (180 mg/m²) on day 1 as a one hour infusion, then

Oxaliplatin (85 mg/m²) on day 1 as a two hour infusion, then

5-Fluorouracil (2800 mg/m²) as a 48 h infusion starting on day 2, after completion of oxaliplatin delivery.

Treatments will be repeated every 2 weeks.

HAI conventional chemotherapy

Francis A. Lévi, M.D., Ph.D.

The primary objective of the study is to increase by 15% the complete macroscopic resection rate of predominantly liver metastases from metastatic colorectal cancer through combining systemic cetuximab and hepatic artery infusion of three-drug chemotherapy (irinotecan, oxaliplatin and 5-fluorouracil).

Primary end-point: incidence of complete macroscopic resections of liver metastases (R0+R1).

Secondary end-points:

* the rate of histologic complete responses,
* the individual rates of R0 and R1 resections,
* the rate and site(s) of relapse in the resected patients throughout the 3-year span that follows hepatectomy,,
* the relapse-free survival curve and median in the resected patients,
* the progression-free and the overall survival in the patients receiving at least 4 full courses of HAI therapy and in all the patients (intent to treat),
* the objective response rate,
* the rate of adverse events,
* the dose intensities over 3, 6 and 9 courses,
* the per-operative and post-operative complications associated to liver surgery.

The study also includes a pharmacokinetic analysis, a translational research and a rest/activity monitoring investigation.

Open, label, European, non randomized, multicenter, phase II study of intravenous cetuximab (ERBITUX®) and hepatic artery infusion of three-drug chemotherapy (irinotecan, 5-fluorouracil and oxaliplatin) using conventional or chronomodulated delivery (according to institution experience) in patients with liver metastases from colorectal cancer.

Patients undergo partial hepatectomy after 6 ± 3 courses of therapy whenever possible. The minimum of 3 and the maximum of 9 courses before liver surgery depend upon results from iterative onco-surgical evaluations. A minimum of 6 and up to 9 additional courses of therapy will be administered after surgery, depending upon results of liver surgery, pathology report and patient's status. Overall, the patients will receive 9 to 18 courses of protocol therapy.

The interval between the last course of cetuximab-HAI chemotherapy and surgery will be 2 to 4 weeks. Post operative treatment will be initiated 2 to 4 weeks after liver surgery.

TRANSLATIONAL RESEARCH:

1. Pharmacokinetics:

   For a subset of 16 patients (8 on conventional administration and 8 on chronotherapeutic delivery), plasma pharmacokinetics of irinotecan, 5-FU and oxaliplatin and main metabolites will be evaluated after the first course.
2. Rest-Activity monitoring:

   Rest-activity will be monitored with a wrist-worn actigraph (Ambulatory Monitoring, USA) for 1 week prior to treatment onset and during the 2 weeks following treatment onset (3 weeks). This evaluation will be repeated before, during and after the 4th treatment course and before during and after 7th treatment course. Participation of the centers to this investigation will be left optional.

   Time series will be analyzed before, during and after chemotherapy course, with the time courses of the following parameters:
   * Autocorrelation coefficient at 24 h (r24)
   * Dichotomy index I\<O
   * Wavelet-based model function at baseline, and deviation from this model function during and after treatment course delivery.
3. Predictive molecular factors:

In primary tumor and/or in metastases obtained any time prior to inclusion and in resected metastases and non tumoral liver:

* EGFR immunohistochemistry and gene expression or amplification and polymorphism.
* K-ras mutations.
* Clock genes polymorphism or mRNA or protein expression.
* Gene polymorphisms or expression for main pharmacology determinants of irinotecan, 5- FU and oxaliplatin efficacy.
* Inflammatory and immune cell subsets infiltration. Whenever possible, a biopsy of a liver metastasis will also be obtained before treatment onset for documenting these translational endpoints.

In serum, upon inclusion and after 3 courses:

· Determination of serum levels of TGFa, EGF, VEGF, IL-6, IL-8, amphiregulin and epiregulin.

In blood cells upon inclusion:

· Constitutive polymorphisms for ADCC (FCII and FCIII), circadian clock and EGFR.

STATISTICAL METHODS AND SAMPLE SIZE:

The main endpoint will be the incidence of macroscopically complete resections of liver metastases (R0+R1). The confidence intervals (CI) for the response rate will be based on the exact binomial distribution.

For the secondary endpoints, rate of histologic complete responses, rate of R0 resections, rate of R1 resections, rate of relapses, rate of objective responses, the results will be estimated with CI based on the exact binomial distribution. Overall survival time (OS) and progression free survival (PFS) will be analyzed by Kaplan Meier curve. Multivariate analysis will be performed using the Cox proportional hazard model. This analysis will include the following factors: center, performance status, gender, liver disease characteristics, leucocyte count and alkaline phosphatases upon inclusion and treatment delivery schedule, Relapse incidence (RI) is defined as the probability of having had a relapse before time t. Death without experiencing a relapse is a competing event. The method of analysis will be therefore the estimation of Cumulative Incidence curve in a competing risk setting. Multivariate analysis will be performed by the Fine \& Gray model. All patients achieving complete remission will be analyzed.

The goal is to increase the rate of complete resections (R0+R1) by 15%, i.e. from 15% (p0=0.15) to 30% (p1=0.30). According to the exact single-stage phase II design method, the trial for accepting that p1 is to be preferred to p0 (with a=5% and b=20%) requires 48 patients assessable for response. To obtain 48 patients assessable for response, 60 patients will be included in the trial.

A major additional effect expected further from this combined treatment modality is the increase of complete histologic responses, a secondary endpoint in this trial, from 5% (with systemic chemotherapy) to 20% with combined cetuximab and 3-drug HAI. This improvement should further reduce the risk of relapse in the liver or outside the liver by 15 %, i.e. from 80% to 65%.

Therefore, the total number of patients will be 60 patients, including 48 assessable and 12 estimated as unassessable for technical reasons (i.e. HAI catheter dysfunction within the first 2 months).

Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy

Optimal Control of Liver Metastases With Intravenous Cetuximab and Hepatic Artery Infusion of Three-drug Chemotherapy in Patients With Liver-only Metastases From Colorectal Cancer. A European Multicenter Phase II Trial

Gustave Roussy, Cancer Campus, Grand Paris

Merck Serono International SA

Pfizer

CRESGE

Association pour la Recherche sur le Temps Biologique et la Chronothérapie

GVAX, up to 6 vaccinations, administered via injection

GVAX

Cristina Ferrone, MD

This study is a Pilot clinical trial. Pilot clinical trials test the safety of an investigational combination of drugs. Pilot studies provide information on what effects, both good and bad, the Investigational agent might have on your disease. "Investigational" means that the intervention is still being studied and that research doctors are trying to find out more about it. It also means that the FDA has not approved the treatment for your type of cancer.

The main purposes of this study are to determine:

* The amount of vaccine that can be made for your colorectal tumor cells
* If the vaccine can be given safely
* What the effects of the vaccine are, both good and bad
* How the vaccine affects your immune system
* Whether this vaccine might have any effect on the return of your cancer in the liver after surgical removal

This study is being done because there are currently no treatments which have demonstrated to cure diseae which has progressed, or moved beyond the site of the primary site of disease (colon or rectum). These vaccinations will be given after you have completed the standard of care treatment as determined by your doctor.

Laboratory research has made vaccines from cancer cells by inserting genetic material from a protein called granulocyte-macrophage colony stimulating factor (GM-CSF) into the cancer cell. Once complete, the cancer cells are able to produce large amounts of GM-CSF. The vaccine made form these cells has a greater anti-tumor effect than cancer cells without GM-CSF. The purpose of this research study is to determine the safety of an investigational vaccine that will be made using your own colorectal cancer cells in the manner described above.

This vaccine has been used in several other research studies for treatment for other cancers (skin, lung, ovarian, sarcoma and leukemia.) Information from these other research studies suggests that this vaccine may help to reduce the risk of your colorectal cancer returning after you have your colorectal cancer surgery.

Due to these results in melanoma and several other tumors we are encouraged to use this vaccine approach in patients with liver metastases from colorectal cancer, after the cancer in the liver has been removed by surgery.

After you have given your consent to participate in this study, your study doctor will perform some tests to confirm that you are eligible to participate. These tests may take place up to 21 days before the surgery to remove a liver tumor, which will be used to create the vaccines. Many of the following examinations are commonly done to determine diagnosis and/or stage of disease and you may have already had some or all of these evaluations. They may or may not have to be repeated. These tests include a medical history, performance status, blod samples, routine blood tests, tumor assessment and blood pregnancy test (if applicable). If these tests indicate you are eligible for this study and you agree to participate, you will be referred to a surgeon for the surgical removal of tumor tissue from which the vaccine will be made.

The surgery will be performed at Massachusetts General Hospital. You will be asked to sign a separate consent form to give permission to the surgeon to perform this operation. That consent will describe the risks of the operation which involves removing the tumor cells from your liver.

After your surgery, there is a possibility that your physician will recommend other treatment before starting the vaccines if he or she feels it would be beneficial to your care and medically appropriate. This part of the treatment would not be experimental (for example, chemotherapy or radiation therapy).

Then, in this case, the vaccines made from your cancer will not be administered to you until at least 4 weeks after your last chemotherapy or radiation treatment. If the time between your operation and the first scheduled vaccine injection is 8 weeks or longer, we will ask you to undergo another chest, abdomen and pelvic CT scan and clinical blood work to confirm that it is still safe for you to proceed with the vaccines. After this 4 week rest period, vaccine administration will occur as previously outlined.

If these tests indicate you are eligible for this study and you agree to participate, you will be referred to a surgeon for the surgical removal of tumor tissue from which the vaccine will be made.

It is important to know that sometimes we are unable to collect enough cells from the tumor collection. In those cases we can try to grow the tumor cells for a short period of time to get enough cells to make a vaccine, but we can not guarantee that we will always be able to produce vaccine for every participant who undergoes tumor cell collection.

The vaccines created from your colorectal cancer cells are scheduled to be given to you on days 1, 8, 15 and then every two weeks after that until 6 total vaccines have been administered. The amount of vaccines is dependent on the total amount of cells collected when your colorectal cancer liver metastasis is processed and prepared into vaccine in our lab. It is hoped that you will receive at least six vaccines. All scheduled treatment will occur in the outpatient clinic.

The vaccines will be administered in two injections that will be placed underneath your skin. The two injections will be given at the same place on your body. The recommended sites are your arms, thighs or trunk area and the sites will rotate per vaccine.

Day 1 is the first day of treatment on study. The following procedures are planned on this day: update of medical history, physical exam, blood samples for routine labs, required blood sample for immune studies, vaccine administration, and, if enough cells can be grown, you will receive an injection of cancer cells that have been killed but not able to secrete GM-CSF. This is done to measure the amount of reaction of your immune system caused by the vaccine alone.

Punch biopsies will be obtained 2 days after the first and fifth vaccinations. A DTH injection will also be administered at the first and fifth vaccine. Two days after the vaccine and DTH administration punch biopsy will be taken. DTH injections are Delayed-type Hyper-sensitivity Tests. This injection inserts a small amount of the vaccine under your skin to determine if you have any allergic reactions to the vaccine. This will consist of a small piece of skin tissue removed under local anesthesia. A small stitch will be placed after the biopsy. You will sign a separate consent form for this procedure.

The following procedures are planned for Days 8 and 15: update of medical history, weight and vital signs, blood samples for routine labs and immune studies, and vaccine administration.

On day 29 and every two weeks (until no more vaccines are available) you wil undergo an update of medical history, physical exam, weight and vital signs, blood samples for routine labs and immune studies, punch biopsy and vaccine administration. With vaccine #5, you may receive a second DTH injection. Two days after the vaccine and DTH injection, punch biopsies will be taken off both sites to further evaluate your body's response to the treatment.

After the final dose of study drug, your treating physician will determine if you are eligible to receive a second series of vaccinations. In addition, there must be sufficient numbers of cells for vaccine remaining from the original harvest or a new liver metastasis has occurred and been removed to make more vaccine.

If you give consent to participate in the repeat dose phase, you will be required to repeat the screening tests to see if you are still eligible to participate in the study.

It is possible that additional rounds of vaccine therapy may be offered after the second round, as long as it is appropriate in the opinion of your treating physician and additional tumor is available to make vaccine and you continue to meet the eligibility criteria.

Participants will be monitored every 3 months with a blood test for the first 3 years and then every 6-12 months for a total of 5 years. Staging CT scans will be performed 3 months after the last vaccination, then every 6 months for the first three years and then yearly to year 5. After 5 years imaging will be at the discretion of the treating physician. Blood draws for immune research studies will occur every 3 months for 2 years after completing all vaccinations.

Pilot Study of GVAX in Colorectal Cancer Cells

A Pilot Safety Study of Vaccination With Autologous, Lethally Irradiated Colorectal Cancer Cells Engineered by Adenoviral Mediated Gene Transfer to Secrete Human Granulocyte-Macrophage Stimulating Factor

To determine the safety of 6 vaccinations with lethally irradiated, autologous colorectal cancer cells engineered by adenoviral mediated gene transfer to secrete GM-CSF in stage IV colorectal cancer patients who are completely resected. Patient safety will be assured by monitoring the number of patients who fail to receive the first six scheduled vaccinations because of toxicity. If three or more patients experience grade 4 or worse toxicity due to the vaccine before completing six immunizations, the study will be terminated.

To determine the progression free survival of stage IV colorectal cancer patients vaccinated with lethally irradiated, autologous colorectal cancer cells engineered by adenoviral mediated gene transfer to secrete GM-CSF. Progression-Free Survival (PFS) is defined as the length of time during and after the treatment of a cancer, that a patient lives with the disease but it does not get worse, as per the National Cancer Institute. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

To evaluate the immune response elicited by the vaccine. We will evaluate the immune cell composition(CD4+ and CD8+ T cells, T regulatory cells, macrophage, etc) in the resected specimens and in the circulating blood.

Massachusetts General Hospital

Principal Investigator

GVAX, up to 6 vaccinations, administered via injection

GVAX

Experimental Treatment Arm

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Cristina R. Ferrone, MD

Number of Patients Who Fail to Receive the First Six Scheduled Vaccinations Because of Toxicity

Progression Free Survival

Only one patient was registered to this study who failed to receive all 6 vaccinations cause FDA put a few studies on hold since the core lab used by the studies was shut down by FDA. This study did not continue to draw blood so not enough data was collected to perform analysis.

Immune Response

Two Year Survival

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy	NCT00852228	Metastatic Colo... Liver Metastase... Hepatic Lesions	IV cetuximab HAI chronomodul... HAI conventiona...	18 Years -	Association pour la Recherche sur le Temps Biologique et la Chronothérapie
Pilot Study of GVAX in Colorectal Cancer Cells	NCT01952730	Colorectal Canc...	GVAX	18 Years -	Massachusetts General Hospital
Pilot Study of GVAX in Colorectal Cancer Cells	NCT01952730	Colorectal Canc...	GVAX	18 Years -	Massachusetts General Hospital

Spots Global Cancer Trial Database for hepatic lesions