A multi-center, open-label, balanced, randomized, two-treatment, two-period, two-sequence, two-way crossover, steady-state bioequivalence study of Imatinib Mesylate Tablets 400mg of Hetero Labs Limited, India with GLEEVEC® (Imatinib Mesylate) Tablets 400mg of Novartis Pharmaceuticals Corporation, NJ 07936 among patients with chronic myeloid leukemia or gastrointestinal stromal tumors established on a stable dose of 400mg for Imatinib Mesylate Tablets
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 34
- 试验地点
- 5
- 主要终点
- The primary objective of the study is to assess whether the test product is bioequivalent to reference product after dosing subjects for 14 days on 400mg once a day Imatinib
研究概览
简要总结
Imatinib Mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in Chronic Myeloid Leukemia (CML). Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF-and SCF-mediated cellular events. In vitro, Imatinib inhibits proliferation and induces apoptosis in Gastrointestinal Stromal Tumor (GIST) cells, which express an activating c-kit mutation.Present trial is a multi-center, open-label, balanced, randomized, two-treatment, two-period, two-sequence, two-way crossover, steady-state bioequivalence study of Imatinib Mesylate Tablets 400mg of Hetero Labs Limited, India with GLEEVEC® (Imatinib Mesylate) Tablets 400mg of Novartis Pharmaceuticals Corporation, NJ 07936 among patients with chronic myeloid leukemia or gastrointestinal stromal tumors established on a stable dose of 400mg for Imatinib Mesylate Tablets under fed condition.
The present study includes two periods – each of 7 days (period-I: days 1-7; period-II: days 8-15) with no wash-out period between them. As per randomization schedule, subjects will be instructed to receive test or reference products of stabilized dose of Imatanib 400 mg tablets per day in each of the study period.
Pre-dose PK samples will be collected on days -5, 6, 12 and 13 during each study period. Post-dose PK samples will be collected on day-7 and 14 of each study period at 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours post dose.
Plasma samples will be analyzed for Imatinib using a validated analytical method in accordance with USFDA Guidelines and in-house SOPs of bioanalytical laboratory. Safety of the subjects will be monitored during the entire study period. Test product will be considered bioequivalent to reference product, if 90% CI for ratio of geometric least square means based on log transformed primary PK parameters - Cmax,ss and AUC0-Ï„,ss fall within acceptable BE limits of 80.00% to 125.00% for Imatinib.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 65.00 Year(s)（—）
- 性别
- All
入选标准
- •A patient fulfilling all the following criteria will be included in the present study: 1) Patients Willing to provide written informed consent for participation in the study; Having ability to comprehend the nature and purpose of the study; Willing to be available for the entire study period and to comply with protocol requirements.
- •Disease population and treatment condition – Patients with documented clinical diagnosis of Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase under their first three months of treatment at stabilized 400mg dose of Imatinib Tablets once daily; OR Patients with documented clinical diagnosis of Kit (CD117) positive gastrointestinal stromal tumors (GIST) at stabilized 400mg dose of Imatinib Tablets once daily.
- •Patients for whom a titration away from the stabilized once daily dose of 400mg of Imatinib is unlikely for a study duration; 4) Age of 18-65 years (both inclusive); 5) Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 2 (both inclusive); 6) Patients with life expectancy of at least 3 months; 7) Adequate organ function, defined as following: a)Hemoglobin > 9.0 g/dL b)Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 c)Platelet count ≥ 100,000/ mm3 d)Total bilirubin <1.5 x Upper Limit of Normal (ULN) e)SGPT / SGOT < 2.5 x ULN f)Serum Creatinine < 1.5 x ULN 8) With a normal or clinically non-significant laboratory values (apart from those mentioned above) as determined by hematological, biochemistry tests and urine analysis; 9) With a normal or clinically non-significant 12-lead ECG; 10) With a normal or clinically non-significant 2D Echo; 11) Non-smokers or ex-smoker or mild / moderate smokers and willing to abstain from chewing or smoking any tobacco containing product at least 72.00 hrs prior to first dosing of the study and throughout study; 12) Willing to abstain from alcohol or alcoholic products within 24.00 hrs prior to first dosing of the study and throughout the study; 13) Willing to abstain from, xanthine or its derivative containing food or beverages (e.g. chocolates, tea, coffee or cola drinks) within 72.00 hrs prior to first dosing of the study and throughout the study; 14) Willing to abstain from grapefruit or its juice within 72.00 hrs prior to first dosing of the study and throughout the study; 15) In case of female patients: a) Negative urine pregnancy test during screening and, negative serum β-HCG test at baseline visits and at check-in for housing during each study period; b) Patients with child bearing potential or those within their first two years of onset of menopausal syndrome must either abstain from sexual intercourse, or must be using at least 2 reliable and acceptable methods of birth control till 14 days after last dose in the study (Reliable/acceptable birth control methods include barrier methods such as diaphragm/condom with spermicide or who are surgically sterile (bilateral tubal ligation, bilateral salpingectomy, bilateral oophorectomy or hysterectomy has been performed), but must not use hormonal contraceptive (either oral/implants)).
排除标准
- •A patient fulfilling any one of the following criteria will be excluded from the study: 1)Institutionalized patients; 2)A history of allergic or hypersensitive reactions to Imatinib Mesylate or related group of drugs or to any of the excipients of formulation which in the opinion of an investigator, would compromise the safety of the patient or the study; 3)Patients with Ph+ CML in accelerated phase or blast crisis phase; 4)Patients receiving any treatment for CML prior to study entry for longer than 2 weeks with the exception of Hydroxyurea and/or Anagrelide and/or Imatinib; 5)History of another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention; 6)Significant history or current evidence of chronic – infections, cardiovascular, renal, hepatic, ophthalmic, pulmonary, neurological, metabolic (endocrine), hematological, gastrointestinal, immunological or psychiatric diseases, or organ dysfunction, which in the opinion of an investigator, would compromise the safety of the patient or the study; 7)History of heart failure, renal insufficiency, hypereosinophilic syndrome (HES), myelodysplastic syndrome (MDS)/ myeloproliferative disease (MPD) or acute systemic mastocytosis (ASM) 8)Patients who are at clinically high risk of developing tumor lysis syndrome during the study; 9)Patients with history of bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) with Imatinib or any other drug treatment; 10)Patients with a history of ascites, and rapid weight gain with or without superficial edema; 11)Previous/current history of hematopoietic stem cell transplantation; 12)History or currently under significant bleeding disorder unrelated to CML and/or receiving concomitant therapy of Warfarin (coumarin anticoagulants) or history of usage of coumarin anticoagulants in the previous three months prior to study start (dosing); 13)History of difficulty in swallowing which could affect drug absorption; 14)A medical or surgical condition that might interfere with the absorption, metabolism, or excretion of Imatinib Mesylate during the study; 15)History of significant hematological disorder (drug-induced or idiopathic); 16)History of significant liver disease; 17)History or requirement of therapy with CYP3A4 activity inducer or inhibitor drug within 14 days prior to first dosing of the study and till study completion; 18)Concurrent use of other drugs known to suppress bone marrow function; 19)Patients who have undergone thyroidectomy and/or receiving Levothyroxine 20)Expected significant changes in doses of concomitant medications during the study 21)Expected incompliance with outpatient medications; 22)A history of alcohol or drug dependence during the 6-month period immediately prior to first dosing of the study; 23)Positive alcohol breath or urine drug of abuse tests during randomization, or at check-in for housing during each study period; 24)Positive test for Human Immunodeficiency Virus (HIV) type I/II antibodies or Hepatitis B surface antigen (HbsAg) or Hepatitis C virus (HCV) antibodies; 25)In case of female patients: a)Planning to become pregnant; b)Lactating or nursing patients; 26)Participated in any clinical investigation requiring repeated blood sampling, blood donation, or have blood loss of >200 mL in past 8 weeks or participated in any clinical study within 90 days prior to first dosing of the study; 27)Any major illness or hospitalization within 90 days prior to first dosing of the study; 28)History of difficulty in accessibility of veins in arms.
结局指标
主要结局
The primary objective of the study is to assess whether the test product is bioequivalent to reference product after dosing subjects for 14 days on 400mg once a day Imatinib
时间窗: The primary objective of the study is to assess whether the test product is bioequivalent to reference product after dosing subjects for 14 days on 400mg once a day Imatinib
次要结局
- The secondary objective is assessment of safety and tolerability profile of test and reference products.(During each study period, pre-dose samples will be collected on days - 5, 6, 12 and 13 for morning dose. Post-dose PK samples will be collected on day-7 and 14 of each study period at 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours post dose)