Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Capecitabine

Patients who experienced severe toxicity (at least one grade 4 side effect) with capecitabine chemotherapy

Patients who experienced dose-limiting toxicity (at least one grade 3, or recurrent grade 2, side effect)with capecitabine chemotherapy

Patients who have experienced low/no toxicity (none or only side effects at grade 1 \& 2) with capecitabine chemotherapy.

Phlebotomy

Vicente Valero, MD

The goal of this laboratory research study is to identify possible differences in a gene among patients with breast cancer that cannot be treated by surgery. Researchers want to find out if differences in this gene may increase the risk of side effects from capecitabine.

If you agree to take part in this study, 1 blood sample (about 2 tablespoons) will be drawn for use in genetic research.

If you are unable to provide a blood sample, researchers will collect leftover tissue samples from your previously collected tumor tissue (from the time of the breast cancer diagnosis). The tumor samples will be used for genetic research.

After the blood draw or tissue collection, your participation in this study will be over.

The blood samples for the genetic research will be stored at Myriad Laboratories. Before your blood and/or tissue is sent to Myriad Laboratories for banking, your name and any personal identifying information will be coded to protect your privacy. M. D. Anderson will not have oversight of any leftover tissue and/or blood that will be banked by Myriad Laboratories for additional research.

This is an investigational study. Up to 210 patients will take part in this study. All will be enrolled at M. D. Anderson.

5 to 7.5 milliliter (mL) sample of blood. Alternatively, DNA will be extracted from 10um slices of formalin-fixed paraffin-embedded tissue from previously collected tumor tissue (from the time of the breast cancer diagnosis).

Association of Dihydropyrimidine Dehydrogenase (DPYD) Variants With Toxicity Related to Capecitabine

A Retrospective Analysis of the Association of Dihydropyrimidine Dehydrogenase (DPYD) Variants With Toxicity Related to Capecitabine

Myrexis Inc.

M.D. Anderson Cancer Center

Fluorouracil

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Patients are screened for a DPD-deficiency. Patients with a DPYD\*2A mutation are eligible for intervention with capecitabine/5-FU .

Patients to treat with capecitabine/5-FU will be screened prior to start of therapy for DPYD\*2A. Patients heterozygous or homozygous mutant for DPYD\*2A receive dose reductions of capecitabine/5-FU of at least 50% in the first two courses. In case this dose is tolerated well, doses will be increased.

In addition, the pharmacokinetics of capecitabine/5-FU and their metabolites will be assessed in these patients.

Capecitabine, 5-fluorouracil

Jan HM Schellens, MD, PhD

The primary purpose of this study is to prospectively determine whether capecitabine and 5-FU-induced toxicity is preventable by dose reduction prior to start of the first administration in patients heterozygous or homozygous mutant for DPYD\*2A, and to determine whether this strategy is cost-effective. Secondly, an individualized treatment algorithm for capecitabine and 5-FU therapy in DPYD\*2A mutant patients will be developed and the pharmacokinetic profile of capecitabine and 5-FU will be assessed.

Patients exhibiting a genetically determined disorder (DPYD\*2A) in the metabolic degradation of the frequently used anticancer agents capecitabine and 5-FU (fluoropyrimidines) are at high risk of development of severe and life-threatening toxicity during standard treatment with these compounds. Treatment and recovery of this fluoropyrimidine-induced severe toxicity often requires prolonged periods of hospitalization.

Screening for DPYD\*2A in patients to treat with fluoropyrimidine drugs with subsequent dose adjustments in mutant individuals prior to start of therapy will possibly reduce the number of severe toxicity events. Furthermore, by reducing the frequency and/or duration of hospitalization, substantial medical costs can be saved, making this a cost-effective strategy.

Pharmacogenomic and Pharmacokinetic Safety and Cost-saving Analysis in Patients Treated With Fluoropyrimidines

The Netherlands Cancer Institute

Prof. dr. J.H.M. Schellens

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Lymphosarcoma

Micronutrients

Hematinics

Vitamins

Leucovorin

Eniluracil

Antidotes

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Enzyme Inhibitors

Folate

Vitamin B9

5-Fluorouracil

Ethynyluracil

This is a dose escalation study.

During the first period of this study, an initial pharmacological assessment of fluorouracil administered intravenously along with oral leucovorin calcium is made. Leucovorin calcium is given orally bid on days 1-3. Fluorouracil is given as a 24 hour infusion on day 2.

After a 2 week rest period and resolution of any toxicities experienced during the first period of treatment, patients are given an escalating dose of fluorouracil with fixed doses of leucovorin calcium and ethynyluracil. Ethynyluracil and leucovorin calcium are given bid orally on days 1-3 of each week. Fluorouracil is given bid orally on day 2 of each week. Treatment is repeated for three weeks followed by a one week rest period.

3 to 6 patients are enrolled at each dose level. Dose escalation proceeds until the maximum tolerated dose (MTD) is determined. MTD is defined as the dose preceding that at which 2 or more patients experience dose limiting toxicity.

The primary purpose of this Phase I protocol is to develop an orally administered regimen of fluorouracil (5-FU) given with fixed doses of leucovorin (LV) and 776C85 (GW776), a mechanism-based inhibitor of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme involved in the catabolism of 5-FU. In the presence of 776C85, 5-FU is cleared by renal mechanisms. The schedule employed is intended to mimic the pharmacologic profile associated with a 24 hour weekly continuous infusion of 5-FU without the need for an indwelling central venous catheter. The target population is adult cancer patients with solid tumors.

The first week, each patient will receive a single dose of 5-FU given by 24 hour continuous IV infusion at its recommended Phase II dose with low-dose oral LV. In the third week, the patient will begin 776C85 (GW776) and LV PO on days 1, 2, 3 at fixed doses. Oral 5-FU will be given on day 2, and the dose will be escalated in successive cohorts of patients. Treatment will be repeated weekly for three weeks, followed by a one week break. The dose of 5-FU will be adjusted according to individual tolerance. Cohorts of three patients will be entered at each dose level of 5-FU, which will be escalated until dose-limiting toxicity is seen (guidelines are outlined in the following schema). Treatment will be continued indefinitely until evidence of disease progression, provided the patient is tolerating therapy and wishes to continue.

Biochemical monitoring suggests that there is profound and sustained inhibition of DPD with a single dose of 20 mg PO 776C85 days 1-3 each week for three of four weeks. Once the MTD has been defined for the once daily dosing on days 1, 2, 3 schedule, a simplified schedule will be evaluated in which a single dose of 776C85 on day 1 in the evening, with oral leucovorin days 1 and 2, and 5-FU given day 2 as a single dose.

Since the pharmaceutical company has decided to go with a combined tablet of eniluracil/5-FU for future studies, the new schedule will be oral leucovorin on days 1 \& 2, with 776C85 and 5-FU both given day 2 as a single dose.

A Phase I Trial of 5-Fluorouracil Given With 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients With Solid Tumors

National Cancer Institute (NCI)

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Central Nervous System Depressants

Psychotropic Drugs

Lithium Carbonate

Prior to treatment by fluoropyrimidines,a DPD deficiency is identified by a joint phenotypic-pharmacogenetic approach.

For patients included in this arm, a blood sample will be taken prior to treatment by fluoropyrimidines but not analysed. If grade 3 or 4 toxicity levels are encountered during treatment, DPD deficiency will be detected.

Prior to treatment by 5-FU, a DPD deficiency is identified thanks to just one blood sample (lithium heparinate).

Blood sample for phenotypic and pharmacogenetic analysis.

Blood sample (lithium heparinate) will be taken prior to treatment but not analysed.

Olivier Capitain, MD, PhD

The aim of this study is to demonstrate the medical and financial benefit of pre-therapeutic screening of DPD deficiency for predicting toxicity to fluoropyrimidines.

The fluoropyrimidines, of which 5-Fluorouracil is the most important, represent a family of medication that is used in particular in cancerology. They are molecules widely used in cancerology since they can be found in nearly 45% of chemotherapy protocols and in the treatment of about 50% of cancers (colorectum, oesophagus, stomach, breast, upper digestive and respiratory tracts). They are not only used in metastatic situations but also more and more in adjuvant situations, in other words for patients treated for a localised tumour, presenting a risk of relapse. A severe toxic risk cannot be tolerated in these conditions, and the doctor should assure the maximum level of safety for his patients. These medicines are the cause of 3% of grade IV toxicity from the first or second administration, and for 0.3% of deaths. To this one can add on a total of 20 to 25% grade III-IV toxic events.

Anticancer treatment is mostly administered by body size and in the best of cases after a few basic biological examinations such as a haemogram and renal status, without taking into consideration any individual particularities, whether genetic or epigenetic. Among potential toxicity risk factors one can find individual metabolic differences linked to genetic modifications of metabolism enzymes as well as differences in the chemical receptors and transporters.

For fluoropyrimidines, a polymorphism was found for the dihydropyrimidine dehydrogenase gene (DPD), a major catabolism enzyme. A deficit of this enzyme is a major counter-indication for the use of these medicines.

Early determination of DPD status would allow identification of patients at risk and would thus help in subsequent dose adjustment or selection of other treatment modalities.

Pre-therapeutic Identification of Dihydropyrimidine Dehydrogenase Gene (DPD) Deficiency for Predicting Toxicity to Fluoropyrimidines

The Medical-financial Evaluation of Pre-therapeutic Screening by a Joint Phenotypic-pharmacogenetic Approach for Metabolic Fluoropyrimidine Enzyme Deficiency in Terms of Serious Toxicity Risk Prevention : a Multicentric Case Study

The percentage of severe toxicity (grade IV) will be analyzed in each arm. We expect a reduction of the early, severe, grade IV acute side-effects from 3% to 0.6% in the detected group with adapted doses.

We expect a reduction of the number of grade III-IV toxic events, whenever they occur, from 25% to 5% in the detected group with adapted doses.

The current mortality rate of 3 per thousand patients will be cut to 0 in the detected group with adapted doses.

We will carry out a comparison of the prevention costs and the costs related to treating patients with toxicity. Direct costs and indirect costs will be taken into account.

Institut Cancerologie de l'Ouest

Oxaliplatin

S-1 40 mg/m2 administered orally BID after breakfast and evening meal from Day 1 through Day 14 with a single dose of oxaliplatin 130 mg/m2 will be administered as an 2-hour IV infusion following the morning dose of S-1 on Day 1. The combination therapy will be repeated every 3 weeks.

S-1 plus oxaliplatin

WENCHAO LIU, Professor

WENCHAO LIU, professor

In this study, the relationship between DPD and the effects of S-1 combined with oxaliplatin chemotherapy were investigated in 200 patients with gastrointestinal carcinoma.

A new oral DPD inhibitory fluoropyrimidine (DIF), S-1, is reportedly effective against gastrointestinal carcinoma. In this study, the relationship between activity of DPD in peripheral blood and the effects of chemotherapy were investigated in 200 patients treated with first-line S-1 combined with platinum chemotherapy for gastrointestinal carcinoma.

Study of DPD for Predicting Efficacy and Safety to S-1 Plus Oxaliplatin in Gastrointestinal Cancer

Study of Dihydropyrimidine Dehydrogenase for Predicting Efficacy and Safety to S-1 Plus Oxaliplatin in Gastrointestinal Cancer

Tumor response was evaluated by RECIST 1.1. The relationship between DPD activity and the objective tumor response will be evaluated by Cox's proportional hazards regression model.

The relationship between DPD activity and the overall survival will be evaluated by Cox's proportional hazards regression model.

The relationship between DPD activity and the PFS will be evaluated by Cox's proportional hazards regression model.

The relationship between DPD activity and the drug-related toxicity incidence will be evaluated by Cox's proportional hazards regression model.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Association of Dihydropyrimidine Dehydrogenase (DPYD) Variants With Toxicity Related to Capecitabine	NCT00478686	Breast Cancer	Phlebotomy	-	M.D. Anderson Cancer Center
Pharmacogenomic and Pharmacokinetic Safety and Cost-saving Analysis in Patients Treated With Fluoropyrimidines	NCT00838370	Neoplasms	Capecitabine, 5...	18 Years -	The Netherlands Cancer Institute
Association of Dihydropyrimidine Dehydrogenase (DPYD) Variants With Toxicity Related to Capecitabine	NCT00478686	Breast Cancer	Phlebotomy	-	M.D. Anderson Cancer Center
A Phase I Trial of 5-Fluorouracil Given With 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients With Solid Tumors	NCT00001579	Lymphoma Neoplasms	5-Fluorouracil Ethynyluracil Leucovorin	-	National Institutes of Health Clinical Center (CC)
Pre-therapeutic Identification of Dihydropyrimidine Dehydrogenase Gene (DPD) Deficiency for Predicting Toxicity to Fluoropyrimidines	NCT01547923	Colorectal Canc... Intravenous 5 F...	Blood sample fo... Blood sample fo...	18 Years -	Institut Cancerologie de l'Ouest
Pharmacogenomic and Pharmacokinetic Safety and Cost-saving Analysis in Patients Treated With Fluoropyrimidines	NCT00838370	Neoplasms	Capecitabine, 5...	18 Years -	The Netherlands Cancer Institute
Study of DPD for Predicting Efficacy and Safety to S-1 Plus Oxaliplatin in Gastrointestinal Cancer	NCT01608646	Gastrointestina...	S-1 plus oxalip...	18 Years -	Xijing Hospital
Study of DPD for Predicting Efficacy and Safety to S-1 Plus Oxaliplatin in Gastrointestinal Cancer	NCT01608646	Gastrointestina...	S-1 plus oxalip...	18 Years -	Xijing Hospital

Spots Global Cancer Trial Database for dihydropyrimidine dehydrogenase