Digestive System Diseases

All Conditions

Liver Diseases

Gastrointestinal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Oxaliplatin

Liver Extracts

oxaliplatin

This is a phase I study of the experimental anticancer drug oxaliplatin. It is designed to establish the maximum dose of the drug that can be given safely to patients with cancer who have impaired liver function and to determine the drug's side effects. It will also examine how liver function affects the drug's elimination from the body. The liver plays an important role in the elimination of many anticancer drugs, and patients with impaired liver function should not take certain drugs or should take them in reduced doses.

Patients 18 years of age and older with cancer that has metastasized (spread from the original tumor site) and for whom standard treatment is not available or is no longer effective may be eligible for this study. Candidates will be screened with various tests and procedures that may include physical examination, computerized tomography (CT) or magnetic resonance imaging (MRI) scans, chest X-rays, and blood and urine tests.

Participants will be given oxaliplatin in doses determined according to their level of liver function. Patients may have normal liver function or mildly, moderately or severely impaired liver function, or may have had a liver transplant. Oxaliplatin will be infused intravenously (through a vein) over two hours on the first day of 21-day treatment cycles-that is, once every 3 weeks. Treatment will continue as long as the cancer is under control and side effects do not require stopping the drug. Urine will be collected over 48 hours after the infusion to determine how much of the drug is eliminated in urine. Blood tests will be done to monitor safety of the treatment, and imaging studies, such as X-rays, CT and MRI scans, will be done periodically to evaluate the tumor's response to treatment.

Special blood tests will also be done to study how oxaliplatin is eliminated from the body. With the first dose of the drug, blood samples will be collected just before the infusion begins, just before it ends, 15 minutes, 30 minutes, 1, 2, 4, 6, 24, 48, and 72 hours after the infusion, and again 1 week and 3 weeks later. Additional blood samples may be collected at the third treatment cycle.

Oxaliplatin is a diaminocyclohexane platinum derivative with known anticancer activity in solid tumors. The recommended single-agent dose of oxaliplatin in adult cancer patients is 130 mg/m(2) given intravenously over 2 hours every 3 weeks. Hepatic metabolism is the major route of drug elimination for many anti-cancer agents. Although there is limited safety and pharmacokinetic data for oxaliplatin in patients with renal impairment, there is currently no data regarding its disposition in patients with liver dysfunction. This phase I and pharmacologic study of a single agent oxaliplatin is being conducted in adult cancer patients with advanced malignancies and varying degrees of liver dysfunction. Patients will be stratified into five groups based upon their degree of liver dysfunction as assessed by liver function tests. Group A will consist of patients with normal hepatic function to serve as pharmacologic controls. Group E will consist of patients who have received a liver transplant. The remaining 3 groups will start at different doses of oxaliplatin based on hepatic dysfunction and dose escalation in these groups will proceed in a manner in accordance with standard phase I trial with 3 patients per dose level until dose limiting toxicity is observed. Pharmacokinetic monitoring will be performed in all patients on study. The goals of this trial are to define the toxicities and pharmacokinetics of single agent oxaliplatin in this patient population and to determine recommended doses of oxaliplatin in patients with different degrees of hepatic impairment.

Oxaliplatin to Treat Advanced Cancers With Liver Dysfunction

Phase I Study of Oxaliplatin in Patients With Advanced Malignancies and Varying Degrees of Liver Dysfunction

National Cancer Institute (NCI)

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

Carboplatin

Chrysarobin

Cisplatin

Michael Sawyer, MD

Cisplatin is a widely used anti-tumor agent for the treatment of testicular and ovarian cancers. Carboplatin is used extensively for small cell, non small cell lung cancer and ovarian cancer. Oxaliplatin has recently been approved in the United States (US) for treatment of colorectal cancer. A large portion (in the range of 65% to 98%) of cisplatin in the blood plasma was bound to protein within a day after intravenous administration. The binding of cisplatin and other analogues to proteins and enzymes is generally believed to be the cause of several severe side effects such as ototoxicity and nephrotoxicity. The interactions between platinum based chemotherapy drugs and proteins is proposed to play important roles in both drug activity and toxicity. Therefore, a better understanding of the molecular mechanism of platinum-protein interactions may have an impact on optimization of strategies for treatment. The objective is to develop novel approaches and techniques to provide detailed mechanistic, kinetic and high-resolution structural information on the binding of platinum analogues to blood proteins, and to improve treatment efficacy and reduce side effects.

Cisplatin, cis-\[Pt(NH3)2Cl2\], is a widely used antitumor agent for the treatment of testicular and ovarian cancers. Carboplatin is used extensively for small cell, non small cell lung cancer and ovarian cancer. Oxaliplatin has recently been approved in the US for treatment of colorectal cancer. All of these analogues are administered by intravenous injection, and within one day, 65-98% of the platinum in the blood plasma is bound to protein. Binding of cisplatin to proteins reduces urinary excretion of platinum, and causes deposition of platinum in tissues. Binding of cisplatin to proteins and enzymes is generally believed to be the cause of several severe side effects exhibited by these drugs, especially ototoxicity and nephrotoxicity.

Despite numerous studies of platinum-protein binding in the last few decades, the roles of platinum-protein adducts in drug action, and in toxicity of these drugs are not known. Although cisplatin-protein adducts are widely believed to cause the drug's side effects, there are also claims that platinum-protein adducts are important for the drug's activity. Therefore, a better understanding of the molecular mechanism of platinum-protein interactions may have an impact on the optimization of strategies for platinum treatment. It is important to understand basic principles that govern formation and reactivity of platinum-protein adducts because these adducts may be important in defining the therapeutic profile of these drugs. In this quest, the first goal is to develop a reliable technique for these studies. To date, ultraviolet/visible (UV-Vis), fourier transform infrared (FT-IR), and nuclear magnetic resonance (NMR) studies of cisplatin-protein interactions have provided only low-resolution information on the mechanism of the binding or on the nature of the adducts. The researchers propose to investigate the role of platinum-protein adducts in the mechanisms of the drug action and their contributions towards the toxicity of these drug. The short-term objective is to investigate platinum interaction with serum proteins using both nanoelectrospray mass spectrometry (nanoESI-MS) and a combination of size exclusion high performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC/ICP-MS). The long-term objective of this research is to develop biomarkers based on platinum-protein adducts for clinical monitoring.

Initially, metallothionein and human hemoglobin were used as model proteins to develop nESI/MS and HPLC/ICP-MS techniques for studying cisplatin-protein interactions in vitro. The researchers have demonstrated that the combination of size exclusion HPLC/ICP-MS and nanoESI/MS provided new information on the adduct formation and potential reaction mechanism. The size exclusion HPLC with ICP-MS enables monitoring of cisplatin-protein binding under physiological conditions. Nanospray tandem MS offers information on formation of specific complexes and on characteristics of binding. This information is useful for a better understanding of drug toxicity and treatment resistance. The information on platinum-protein interactions allows us to evaluate the utility of both nanoESI/MS and size exclusion HPLC/ICP-MS techniques in providing mechanistic, kinetic and structural information on the binding of platinum to other proteins. The methodology will be further validated by studying the platinum-blood protein adducts in cancer patients undergoing chemotherapeutic treatments. The correlation between the levels of platinum-protein adducts and clinical outcomes will be studied.

The successful completion of this research program should provide the researchers with a better understanding of mechanisms of the drug action and toxicity. This knowledge will be of great importance in clinical monitoring of cancer patients to assist doctors to improve cancer chemotherapy.

Cisplatin, Carboplatin, and Oxaliplatin Interactions With Plasma Proteins

AHS Cancer Control Alberta

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Carcinoma, Non-Small-Cell Lung

Stomach Neoplasms

Recurrence

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Uterine Cervical Neoplasms

Small Cell Lung Carcinoma

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Stomach Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Small Cell Lung Cancer

Irinotecan

Camptothecin

Nedaplatin

UGT1A1 genotyped patients receive CPT-11 with platinum analogues

CPT-11 blocks certain enzymes needed for cell division and DNA repair, and it may kill cancer cells. It is a type of topoisomerase inhibitor and a type of camptothecin analog.

CPT-11

Platinum compounds produce changes in DNA structure, which causes cancer cell death (apoptosis). They are typically used alone or in combination with other chemotherapy drugs.

Platinum analogues

Clinical Study Leader

The purpose of this study is to examine the correlation between UGT1A1 genotypes and the safety of CPT-11 plus platinum analogues (cisplatin, carboplatin and nedaplatin) regimens for patients with lung cancer, cervical cancer, ovarian cancer and gastric cancer.

An Observational Study of CPT-11 Plus Platinum Analogues Regimens and UGT1A1 Genotypes in Solid Tumors

A Prospective Observational Study of the Efficacy and Safety of CPT-11 Plus Platinum Analogues Regimens for UGT1A1 Genotype Guided Patients With Several Solid Tumors

Daiichi Sankyo Co., Ltd.

Kidney Diseases

Neoplasm Metastasis

Renal Insufficiency

Carcinoma, Renal Cell

Kidney Neoplasms

Neoplastic Processes

Urologic Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Renal Cell Carcinoma

Oxaliplatin is an experimental anti-cancer drug that can shrink tumors such as colon cancer. However, because this drug can damage the kidneys, it is necessary to determine what doses of the drug can safely be given to patients with poor kidney function.

Patients with advanced cancer, poorly functioning kidneys, and no good standard treatment options are eligible for this study. Candidates will be screened with imaging tests, such as CT and MRI scans, to determine the size and location of the cancer and with blood and urine tests to evaluate kidney and liver function.

Study participants will receive oxaliplatin intravenously (through a vein) every 3 weeks for as long as the cancer is under control and there are no serious side effects from the drug. If significant side effects develop, the dosage will be reduced, or the drug will be stopped. Blood tests to measure blood cell counts will be done at least once a week, and CT scans, chest X-rays, and MRIs will be done about once every 6 weeks to assess the tumor's response to the treatment. Additional blood tests will be done at the beginning of the first two treatment cycles to measure the amount of oxaliplatin in the blood, and urine will be collected during the first 24 hours of drug treatment to determine how much drug is eliminated by the body in urine.

Oxaliplatin is a diaminocyclohexane platinum derivative with known anticancer activity in solid tumors. The recommended single-agent dose of Oxaliplatin in adult cancer patients with normal renal function is 130 mg/m(2) given intravenously over 2 hours every 3 weeks. Renal excretion is thought to be the major route of drug elimination, but precise dosing guidelines in patients with abnormal renal function have not been determined. This phase I and pharmacologic study of single agent Oxaliplatin is being conducted in adult cancer patients with impaired renal function. Patients will be stratified into four groups based upon their degree of renal impairment as assessed by a 24 hour creatinine clearance. Group A will consist of 12 patients with normal renal function who will serve as pharmacologic controls. The remaining 3 groups will start at different doses of Oxaliplatin based upon their degree of renal dysfunction and dose escalation in these groups will proceed in a manner in accordance with standard phase I trials with 3 patients per dose level until dose limiting toxicity is observed. Pharmacokinetic monitoring will be performed in all patients on study. The goals of this trial are to define the toxicities and pharmacokinetics of single agent Oxaliplatin in this patient population and to determine recommended doses of Oxaliplatin in patient with different degrees of renal dysfunction.

Oxaliplatin in Cancer Patients With Impaired Kidney Function

A Phase I Study of Oxaliplatin in Adult Cancer Patients With Impaired Renal Function

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Oxaliplatin to Treat Advanced Cancers With Liver Dysfunction	NCT00006062	Liver Disease	oxaliplatin	-	National Institutes of Health Clinical Center (CC)
Cisplatin, Carboplatin, and Oxaliplatin Interactions With Plasma Proteins	NCT00131586	Lung Cancer Colorectal Canc...		18 Years -	AHS Cancer Control Alberta
An Observational Study of CPT-11 Plus Platinum Analogues Regimens and UGT1A1 Genotypes in Solid Tumors	NCT01040312	Small Cell Lung... Non-small Cell ... Cervical Cancer Ovarian Cancer Gastric Cancer ...	CPT-11 Platinum analog...	-	Daiichi Sankyo
Oxaliplatin in Cancer Patients With Impaired Kidney Function	NCT00001835	Kidney Disease Neoplasm Neoplasm Metast...	Oxaliplatin	-	National Institutes of Health Clinical Center (CC)
Cisplatin, Carboplatin, and Oxaliplatin Interactions With Plasma Proteins	NCT00131586	Lung Cancer Colorectal Canc...		18 Years -	AHS Cancer Control Alberta

Spots Global Cancer Trial Database for platinum analogues