Bioequivalence Study of Temozolomide in Patients With Primary Tumors of the Central Nervous System

Study Overview
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Brief Summary
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The purpose of this crossover, single-dose, bioequivalence study is to compare the rate and extent of absorption of Temozolomide after the administration of the study product (Dralitem®, Monte Verde S.A.) and the reference product (Temodal®, Schering Plough) in primary Central Nervous System patients.

Detailed Description
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Prospective, randomized, two-period, two treatment, two-way crossover bioequivalence study of two Temozolomide oral formulations (Dralitem vs. Temodal), in primary Central Nervous System tumor patients under fasting conditions. Open label to the patients and investigators and blind to the bioanalytical and clinical laboratories. Study plan: days -21 to 0 (Recruitment period); days 1 to 5 (Treatment period); days 6 to 21 (Safety surveillance period). Sample size: 24 patients will be randomized. The patients will be administered Temozolomide 200 mg/m2 on the first two days (Dralitem) of the treatment cycle. They will be admitted to the study clinical site on the evening of day 2. In the morning of day 3 they will be randomized into two groups of equal size. According to the assigned random number, each subject will receive a single oral dose of Temozolomide 200mg/m2 from either Monte Verde Sociedad Anónima (SA) product (Dralitem) or from Schering-Plough product (Temodal). The single dose of 200 mg/m2 will be reached with three different Temozolomide capsule strengths: 20, 100 and 250 mg. Drugs will be administered with 200-240 ml of water in semi-sitting upright position. The following day (day 4) each subject will receive an oral dose of Temozolomide 200 mg/m2 of the product that did not receive the day before. On days 3 and 4 after drug administration, blood samples will be obtained for pharmacokinetic evaluation. The patient will be discharged from the clinical site on day 4 after completion of sampling for pharmacokinetic analysis. On day 5, all patients will receive Temozolomide 200 mg/m2 (Dralitem). On days 3 and 4, samples of venous blood will be withdrawn from the forearm vein of each volunteer at the following time points: 0 (pre-dose) and 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours post-dose after each period administration. The washout period between the treatment arms was 10 hours, on days 3 and 4. Samples will be processed according to the validated method MANA (Método Analítico) - PLB (Proyecto Laboratorio Bioanalítico) 004 - TEM (Temozolomide) - 01/01. Measurement of plasma concentration of Temozolomide was performed using High Performance Liquid Chromatography (HPLC) followed by detection by tandem mass spectrometry (MS / MS). The area under the curve (AUC) and the Cmax levels of the drug vs. time will be obtained for each subject. The resulting values of the logarithmic transformation of these parameters will be used for statistical comparisons (mixed effects ANOVA). The limits of the 90% confidence interval for the ratio of log transformed pharmacokinetic parameters will be calculated. Bioequivalence criteria: each calculated confidence interval should be within the acceptance range from 80.00 to 125.00.

Official Title
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A Randomized, Open Label, Two-way Crossover, Single Dose Bioequivalence Study Comparing Dralitem® Capsules to the Reference Drug Temodal® Capsules in Patients With Primary Tumors of the Central Nervous System Under Fasting Conditions

Conditions
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Brain Neoplasms, Malignant, Primary

Intervention / Treatment
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* Drug: Temozolomide
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients with primary malignant tumors of the central nervous system (CNS) excluding subjects with primary CNS lymphoma. Age> 21 years. There should be a gap of two weeks between the last surgery and/or radiotherapy procedure and the day of randomization. If the procedure were intrabdominal, the gap should be of four weeks. Patients with neutrophils> 1.5 x 109 / L and platelets> 100 x 109 / L. Signed written informed consent for participation in the trial. Exclusion Criteria: Known hypersensitivity to Temozolomide or any other ingredient of the pharmaceutical formulation. Any situation (eg. vomiting) that may interfere with the absorption of the product under study. Chemotherapy or biological therapy within four weeks prior to administering the products under study. Patients who experience any symptoms of toxicity to prior antineoplastic therapies upon administration of the products under study. Participation in other clinical research studies during the 90 days before the start of this study. History of alcohol or drugs abuse. History of severe allergic reactions to any type of antigen. History of gastrointestinal surgery (except uncomplicated appendectomy, of at least three months old). Patients whose clinical status would affect the safety of the products under study or interfere with the pharmacokinetic evaluation, at the discretion of the investigator. Pregnant women or women planning to become pregnant during the study.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Temodal<br>Temozolomide (Schering-Plough) 200 mg/m2, single oral dose. | Drug: Temozolomide<br> <br> * Other names: Temodal;|
| Experimental: Dralitem<br>Temozolomide (Monte Verde S.A.) 200 mg/m2, single oral dose | Drug: Temozolomide<br> <br> * Other names: Dralitem;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Rate of absorption of Temozolomide (Cmax) will be measured after the oral administration of the test product (Dralitem®, Monte Verde S.A.) or the reference product (Temodal®, Schering-Plough). | 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours on Days 3 and 4 | 
| AUC0-t | Extent of absorption of Temozolomide from time (0) to the last quantifiable concentration (t) will be measured after the oral administration of the test product (Dralitem®, Monte Verde S.A.) or the reference product (Temodal®, Schering-Plough) | 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours on Days 3 and 4 | 
| AUC0-∞ | Extent of absorption of Temozolomide from time (0) to infinity (∞) will be measured after oral administration of the test product (Dralitem®, Monte Verde S.A.) or the reference product (Temodal®, Schering-Plough). | 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 hours on Days 3 and 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs and SAEs will be collected from the start of study treatment and until two weeks post last dose. If AEs or SAEs extend in time and are not resolved before the end of the 2-week follow up period, this period shall last until the event/s are resolved. | Up to two weeks post last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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brain neoplasm, bioequivalence, temozolomide