OPTIM DASATINIB (Optimized Tyrosine Kinase Inhibitors Monotherapy)

Phase 2CompletedNCT01916785

Versailles Hospital289 enrolled

Overview

This protocol is a multicentric interventional phase II study from the French CML Intergroup (FILMC). The core of the protocol is to explore the efficacy and safety of an optimization strategy consisting in the modulation of the dasatinib daily dose according to the results of repeated plasmatic levels of dasatinib. The objective of this strategy is to improve the overall results of the treatment of early CP-CML in order to avoid the development of resistance and BCR-ABL tyrosine kinase mutations. The study will be conducted in selected FILMC and Canadian centers. The study is sponsored by the Hôpitaux de Versailles and supported by Bristol-Myers Squibb. The dasatinib treatment will be provided by Bristol-Myers Squibb until marketing authorization is granted in that indication.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

289

Conditions

Chronic Myelogenous Leukemia, BCR/ABL Positive

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or female patient ≥ 18 years 2. ECOG Performance Status score 0-2 3. Philadelphia chromosome positive newly diagnosed (≤ 3 months) CP-CML 4. patients not previously treated except with hydroxyurea or imatinib (less than 4 weeks for imatinib) 5. Signed written inform consent 6. Adequate hepatic function defined as: total bilirubin ≤ 2.0 times the institutional ULN; ALT and AST ≤ 2.5 times the institutional upper limit of normal (ULN). 7. Adequate renal function defined as serum creatinine ≤ 3 times the institutional ULN. 8. Women of childbearing potential (WOCBP) must be using an adequate method of contraception. Exclusion Criteria: 1. Patients with BCR-ABL positive, Philadelphia negative CML 2. Patient previously treated with a tyrosine kinase inhibitor (TKI) except with imatinib during less than 4 weeks. 3. Pregnancy 4. Active malignancy 5. Uncontrolled or significant cardiovascular disease 6. Patients with QTc \> 450 ms 7. Significant bleeding disorder unrelated to CML 8. Concurrent severe diseases which exclude the administration of therapy

Locations (34)

Southern Alberta Cancer Research Institute

Calgary, Canada

Hôpital Charles LeMoyne

Greenfield Park, Canada

Queen elisabeth II Health Sciences Center

Halifax, Canada

CH Pierre LeGardeur

Lachenaie, Canada

Moncton City Hospital

Moncton, Canada

Hôpital Général Juif - Sir. Mortimer B. Davis

Montreal, Canada

Hôpital Maisonneuve-Rosemont

Montreal, Canada

Hôpital Royal Victoria

Montreal, Canada

Hôpital de l'Enfant Jésus - Centre hospitalier affilié universitaire de Québec

Québec, Canada

Pavillon Hôtel-Dieu de Québec - Centre hospitalier universitaire de Québec

Québec, Canada

...and 24 more locations

Outcomes

Primary Outcomes

Cumulative rate of significant AE

The cumulative rate of serious AEs defined by grade 3-4 fluid retention, all grade pleural effusion, haematological grade 3-4 AEs related to dasatinib and/or all AE leading to dasatinib discontinuation within the first year of therapy

Time frame: 12 months therapy

Secondary Outcomes

Rate of treatment interruptions

To compare the rate of treatment interruptions

Time frame: 12 months therapy

Cumulative duration of dasatinib interruption

To compare the cumulative duration of dasatinib interruption C. To compare the median dose of dasatinib administered during the first 12 months

Time frame: 12 months therapy

Mean dose of dasatinib

To compare the mean dose of dasatinib administered during the first 12 months

Time frame: 12 months therapy

Cumulative rate of complete cytogenetic response

To compare the cumulative rate of complete cytogenetic response (CCR) at 6, 12 and 18 months, and every 12 months thereafter

Time frame: 12 months therapy

Cumulative rate of major molecular response

To compare the cumulative rate of major molecular response (MMR) at 3, 6, 12, and 18 months, and every 6 months thereafter

Time frame: 12 months therapy

Median dose of dasatinib administered

To compare the median dose of dasatinib administered during the first 12 months

Time frame: 12 months therapy

Cumulative rate of complete molecular response

To compare the cumulative rate of complete molecular response at 3, 6, 12 and 18 months, and every 6 months thereafter

Time frame: 12 months therapy

Time to molecular response

To compare the time to molecular response (major or complete)

Time frame: 12 months therapy

Relationship between peak plasmatic level and efficacy

To analyse the relationship between peak plasmatic level (Cmax) and efficacy in the three arms

Time frame: 12 months therapy

Relationship between through plasmatic level and efficacy

To analyse the relationship between through plasmatic level (Cmin) and efficacy in the three arms

Time frame: 12 months therapy

Progression-free survival at 5 years

To compare the progression-free survival (PFS) at 5 years in the three arms

Time frame: 12 months therapy

Overall survival at 5 years

To compare the overall survival at 5 years in the three arms

Time frame: 12 months therapy

Lymphocyte populations before and during dasatinib therapy

To analyse lymphocyte populations before and during dasatinib therapy (for French participating centers - see appendix 14).

Time frame: 12 months therapy

Rate of sustained major molecular remission after dasatinib discontinuation in patients in complete molecular response

To evaluate the rate of sustained major molecular remission after dasatinib discontinuation in patients in complete molecular response, CMR (undetectable BCR-ABL transcript, BCR-ABL/ABL IS ratio \< 1x10-5)

Time frame: 12 months therapy