Symptoms and General Pathology

All Conditions

Neoplasms

Digestive System Diseases

Rare Diseases

Recurrence

Carcinoma

Carcinoma, Hepatocellular

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Primary Liver Cancer

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Bevacizumab

Chlorotrianisene

Liver Extracts

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

bevacizumab

chemotherapy

embolization therapy

hepatic artery infusion

Jeffrey F. Geschwind, MD

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemoembolization kills tumor cells by carrying chemotherapy drugs directly into the tumor and blocking the blood flow to the tumor. Giving bevacizumab together with chemoembolization may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving bevacizumab together with chemoembolization works in treating patients with liver cancer that cannot be removed by surgery.

OBJECTIVES:

Primary

* Improve median progression-free survival of patients with unresectable hepatocellular cancer treated with bevacizumab and transarterial chemoembolization therapy.

Secondary

* Characterize the safety and toxicity of this regimen in these patients.
* Determine the response rate in patients treated with this regimen.

OUTLINE: Patients receive bevacizumab once in weeks 1, 3, and 5. Beginning in week 3, patients also receive transarterial chemoembolization (TACE) therapy. Treatment repeats approximately every 8 weeks for up to 3 courses. Patients achieving \< 100% necrosis by MRI after the first course receive 2 additional courses of bevacizumab and TACE.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Bevacizumab and Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery

Phase II Trial of Bevacizumab Combined With Transarterial Chemoembolization (TACE) for Hepatocellular Carcinoma

This outcome was not assessed. Instead, the primary outcome of time to tumor progression (TTP) of the targeted lesions and secondary outcomes of TTP of nontargeted lesions and overall TTP were assessed and reported.

Time to tumor progression was estimated via Kaplan-Meier methodology using the 23 patients who underwent treatment.

TTP of nontargeted lesions assessed via Kaplan-Meier methodology.

Overall TTP assessed via Kaplan-Meier methodology.

Overall TTP assessed via Kaplan-Meier methodology at 6 months and 1 year

OS assessed via Kaplan-Meier methodology both from initiation of therapy and from the date of diagnosis until death.

Efficacy as assessed by radiographic tumor response using RECIST criteria at baseline, 3 weeks after TACE, and 4 weeks after completion of final cycle.

Complete Response (CR): Disappearance of all lesions targeted by therapy Partial Response (PR): At least 30% decrease in the sum of longest diameter (LD) of lesions targeted by therapy Progressive Disease (PD): At least 20% increase in sum of LD of lesions targeted by therapy Stable Disease (SD): Neither sufficient shrinkage for PR nor sufficient increase for PD.

Efficacy as assessed by radiographic tumor response utilizing the following tumor enhancement criteria:

Complete Response (CR): 100% tumor necrosis of the target lesion(s) upon completion of any of the 3 cycles of TACE therapy Partial Response (PR): Greater than 50% tumor necrosis of target lesion(s) Progressive Disease (PD): Reappearance or increased tumor enhancement greater than 25% in target lesion(s) Stable Disease (SD): Cases that do not meet CR or PR and did not demonstrate evidence of tumor progression.

Safety and toxicity assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v3.0) for all patients (n=26) who received bevacizumab prior to TACE therapy.

Safety and toxicity assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v3.0) for 25 who completed the first cycle of TACE and bevacizumab therapy

Safety and toxicity assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v3.0) for patients (n=14) who completed 2 or 3 cycles of TACE and bevacizumab therapy

National Cancer Institute (NCI)

Northwestern University

Yale University

bevacizumab

chemotherapy

embolization therapy

hepatic artery infusion

Single Arm, Received Bevacizumab and TACE

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Jeff Geschwind, MD

Patients received intravenous bevacizumab (10mg/kg) and chemoembolization for up to 3 cycles over 6 months. After completion of last treatment cycle, follow-up including clinic visits and imaging was performed every 8 to 12 weeks.

PFS analysis was not conducted. No data were collected for this Outcome Measure

Median Progression-free Survival

Time to Tumor Progression (TTP) of Targeted Lesions

TTP of Nontargeted Lesions Within the Liver

Overall TTP

TTP rate at 6 months

TTP rate at 1 year

TTP Rate at 6 Months and 1 Year

OS from start of therapy

OS from date of diagnosis

Overall Survival (OS)

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Overall response rate (CR + PR)

Disease control rate (CR + PR + SD)

Response Rate - Based on Response Evaluation Criteria in Solid Tumors (RECIST)

Response Rate - Based on Tumor Enhancement

Coagulation

Fatigue

Weight loss

Ascites

Anorexia

Nausea

Vomiting

Esophageal varices

Elevated ALT

Elevated AST

Hyperbilirubinemia

Hyponatremia

Encephalopathy

Right upper quadrant pain

Proteinuria

Respiratory

Safety and Treatment Toxicity - Cycle 1 Pre-TACE

Anemia

Leukocytopenia

Lymphopenia

Edema

Ischemia

Night sweats

HEENT

Liver failure

Cellulitis

Colangitis

Hyperglycemia

Hypocalcemia

Hypokalemia

Delirium

Psychosis

Abdominal pain, not otherwise specified (NOS)

Epigastric pain

Chest pain

Pain - other

Dyspnea

Acute renal failure

1 out of the initial 26 patients did not complete the first TACE on protocol and was not included in this assessment.

Safety and Treatment Toxicity - Cycle 1 Post-TACE

Heart failure

Dermatologic

Endocrine

Duodenal perforation

Clostridium difficile

Fracture

Cord compression

Stroke

14 out of the original 26 study participants completed 2 or 3 cycles of TACE and bevacizumab therapy - adverse events associated with these patients for cycles 2 and 3 assessed.

Safety and Treatment Toxicity - Cycles 2 and 3

Overall Study

Neoplasm Metastasis

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Fluorouracil

Oxaliplatin

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Oxaliplatin (via HAI)

5 Fluorouracil (systemic)

Robert K Ausman, M. D.

Edward J Quebbeman, M. D.

William S Rilling, M. D.

Hepatic artery infusion (HAI) with oxaliplatin (OX), systemic 5 fluorouracil (5FU), and leucovorin (HAI/OX/FU) will be implemented using an interventional radiology technique to obviate the need for initial major surgery (catheter placement) in patients who have unresectable liver metastasis from colorectal cancer. The study goal is to reduce tumor size to make possible a complete resection of all lesions. Secondary goals are to reduce or eliminate the complexity usually associated with HAI, to accomplish most or all of the treatment as an outpatient, to reduce costs, and to avoid the hepatotoxicity associated with HAI/floxuridine (FUDR). Oxaliplatin has been selected because of its ease of use, known toxicology, and established efficacy in colorectal cancer.

After entry qualification and registration patients will undergo hepatic artery catheterization via interventional radiology. The catheter will remain in place for two hours while oxaliplatin is infused and then be removed. This treatment will be followed by a 48 hour infusion of 5FU and leucovorin, generally following the principle of FOLFOX 6. These cycles of therapy will be repeated biweekly for six episodes. Hepatic tumor size will be evaluated by CT scan to determine if resectability has been established as the result of tumor size reduction. If so, the patient will be offered resection of the residual lesions in an effort to achieve long term survival.

Hepatic Artery Infusion With Oxaliplatin

Hepatic Arterial Infusion of Oxaliplatin Clinical Trial

Medical College of Wisconsin

Paclitaxel

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

Paclitaxel via Hepatic Artery Infusion (HAI)

Starting dose 150 mg/m\^2 HAI once every 4 weeks

Apostolia M. Tsimberidou, MD, PhD

The goal of this clinical research study is find the highest tolerated dose of paclitaxel that can be given directly into the liver of patients with advanced cancer involving the liver. Researchers also want to collect descriptive information on any effects the drug may have on tumor tissue.

Paclitaxel is designed to work by blocking the mechanisms of cell division in cancer cells, causing them to die.

Before you can start on this study, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will have a complete medical history and physical exam, including measurement of height, weight, and vital signs (blood pressure, temperature, breathing rate, and heart rate). You will have a neurological evaluation evaluating your strength and nerve function. You will be asked to report how a pinprick or a thin brush feel when applied to your skin. About 2 tablespoons of blood and some urine samples will be collected for routine tests. Women who are able to have children must have a negative urine pregnancy test.

If you are eligible to take part in this study, you will begin taking study drugs in cycles of 28 days. You will be hospitalized to receive your chemotherapy. The night of the hospital admission, you will receive fluids (normal saline) in your veins to help decrease the risk of kidney side effects from the chemotherapy. The morning after your admission to the hospital, you will be taken to the interventional radiology suite, and a catheter (a thin plastic tube) will be placed in your groin area and advanced to the liver. You must be on bedrest the entire time that the catheter is in place. After the procedure, you will go to Nuclear Medicine, and a test called "flow study" will be carried out to confirm the right position of the catheter. After your return to the room, the nurses will start the chemotherapy. You will receive paclitaxel nonstop over 24 hours through the catheter (a thin plastic tube) into the artery that carries blood to your liver. You will repeat this procedure once every month.

The catheter will be carefully taped so that it can not move and to prevent it from coming out while you are receiving chemotherapy. You will be asked to lie flat on your back while the treatment takes place. In some cases, the catheter will be removed immediately after your chemotherapy infusions is complete. In some cases, the catheter will remain in longer. You will be on bedrest until the catheter is removed. When the catheter is pulled, pressure will be applied to the groin for 15 minutes. The catheter will be removed by someone experienced in the procedure. The catheter will be placed and removed for each cycle of chemotherapy. Blood (about 2 teaspoons) will be drawn for blood counts and liver function tests, before each dose, to be sure researchers are safely giving you the paclitaxel.

You will be seen by a doctor or advanced practitioner every day while you are in the hospital. You will be hospitalized for about 3-5 days until recovery from all immediate chemotherapy-related side effects. The charges of your hospitalization will be billed to you or your insurance carrier.

You will continue to receive the chemotherapy once every 28 days, unless the disease gets worse or intolerable side effects occur. Every 2 months and at the end of your participation in this study, you will have scans to see if your tumors are growing or shrinking and blood work (about 3 teaspoons) will be performed for safety tests. These tests can be performed at your doctor's office and the results faxed to the study doctor at M. D. Anderson.

In addition, you will be asked to call the research nurse in charge of this study at 713-745-1042 to report on your health status every week for 30 days after the last dose of the drug or until you start a new course of therapy.

This is an investigational study. The chemotherapy you will be given is FDA approved. The cost of being on these medications will be billed to you or your insurance company. About 59 patients will take part in this study. All will be enrolled at M. D. Anderson.

Paclitaxel Administered by HAI to Patients With Advanced Cancer and Dominant Liver Involvement

Phase I Study of Paclitaxel Administered by Hepatic Artery Infusion to Patients With Advanced Cancer and Dominant Liver Involvement

M.D. Anderson Cancer Center

Neoplasms, Second Primary

Irinotecan

Cetuximab

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

Cornelius A Thiels

Cornelius Thiels, DO, MBA

The purpose of this study is to evaluate the surgical outcomes and the quality of life (QOL) in patients undergoing hepatic artery infusion pump placement for colorectal liver metastases (CRLM).

Patient Outcomes After Hepatic Artery Infusion Pump Placement

Patient Reported Outcomes After Hepatic Artery Infusion Pump Placement

Self-reported quality of life and recovery from surgery using a questionnaire to investigate changes over time.

Number of days following hepatic artery infusion pump placement until chemotherapy is started

Complications with hepatic artery infusion pump placement

Complications with hepatic artery infusion chemotherapy

Mayo Clinic

Principal Investigator

Infections

Skin and Connective Tissue Diseases

Herpes Simplex

Virus Diseases

The study was divided into two dose groups, T3011 3×10\^8 plaque forming unit(PFU)/time (HAI) and T3011 1×10\^9 PFU/time (HAI), with a 3+3 dose escalation design. After the completion of the lead-in period, the patient entered the combination therapy period（combination therapy with T3011 hepatic artery infusion , Regorafenib and Toripalimab）,and the dosage of T3011 was determined according to the safety observation results of the lead-in period, the dose of toripalimab was 80mg intravenously, and regorafenib was 80mg orally once a day.

The study was divided into two dose groups, T3011 3×10\^8 PFU/time (HAI) and T3011 1×10\^9 PFU/time (HAI), with a 3+3 dose escalation design. After the completion of the lead-in period, the patient entered the combination therapy period（combination therapy with T3011 hepatic artery infusion , Regorafenib and Toripalimab）,and the dosage of T3011 was determined according to the safety observation results of the lead-in period, the dose of toripalimab was 80mg intravenously, and regorafenib was 80mg orally once a day.

T3011 hepatic artery infusion

The combination therapy period: toripalimab, 80mg intravenous ,D2 and D16, 4 weeks per cycle

toripalimab

The combination therapy period: regorafenib ,80mg orally once a day, D1-D21,4 weeks per cycle

regorafenib

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Bevacizumab and Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery	NCT00335829	Liver Cancer	bevacizumab chemotherapy embolization th... hepatic artery ...	18 Years - 120 Years	Yale University
Bevacizumab and Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery	NCT00335829	Liver Cancer	bevacizumab chemotherapy embolization th... hepatic artery ...	18 Years - 120 Years	Yale University
Hepatic Artery Infusion With Oxaliplatin	NCT00244348	Colorectal Canc... Metastasis Liver Cancer	Oxaliplatin (vi... 5 Fluorouracil ...	18 Years -	Medical College of Wisconsin
Paclitaxel Administered by HAI to Patients With Advanced Cancer and Dominant Liver Involvement	NCT00508326	Advanced Cancer	Paclitaxel	13 Years -	M.D. Anderson Cancer Center
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
Patient Outcomes After Hepatic Artery Infusion Pump Placement	NCT05468593	Colorectal Live... Colorectal Canc...		18 Years -	Mayo Clinic
Bevacizumab and Chemoembolization in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery	NCT00335829	Liver Cancer	bevacizumab chemotherapy embolization th... hepatic artery ...	18 Years - 120 Years	Yale University
A Clinical Study of T3011 in Combination With Toripalimab and Regorafenib in Patients With Colorectal Cancer	NCT06283303	Colorectal Canc...	T3011 hepatic a... toripalimab regorafenib	18 Years -	China Medical University, China
Paclitaxel Administered by HAI to Patients With Advanced Cancer and Dominant Liver Involvement	NCT00508326	Advanced Cancer	Paclitaxel	13 Years -	M.D. Anderson Cancer Center
A Clinical Study of T3011 in Combination With Toripalimab and Regorafenib in Patients With Colorectal Cancer	NCT06283303	Colorectal Canc...	T3011 hepatic a... toripalimab regorafenib	18 Years -	China Medical University, China

Spots Global Cancer Trial Database for hepatic artery infusion