OPTIM DASATINIB (Optimized Tyrosine Kinase Inhibitors Monotherapy)

Phase 2

Completed

• Conditions: Chronic Myelogenous Leukemia, BCR/ABL Positive
• Interventions: Drug: Dasatinib

• Registration Number: NCT01916785
• Lead Sponsor: Versailles Hospital

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2009-05
• Study First Submitted: 2012-12-18
• Study First Submitted QC: 2013-08-02
• Study First Posted: 2013-08-06
• Primary Completion: 2013-12
• Study Completion: 2013-12
• Status Verified: 2016-08
• Last Update Submitted: 2016-08-19
• Last Update Posted: 2016-08-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 289

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
A1	Dasatinib	Arm A1: Dasatinib dose adjustment based on Cmin ≥3nM value analysed on blood after 7-10 days dasatinib 100mg intake
B	Dasatinib	Arm B : Dasatinib standard dose with Cmin \< 3nM analysed on blood after 7-10 days dasatinib 100mg intake
A2	Dasatinib	Arm A2: Dasatinib standard dose (100mg/d) with Cmin ≥ 3nM analysed on blood after 7-10 days dasatinib 100mg intake

Primary Outcome Measures

Name	Time	Method
Cumulative rate of significant AE	12 months therapy	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

Secondary Outcome Measures

Name	Time	Method
Cumulative duration of dasatinib interruption	12 months therapy	To compare the cumulative duration of dasatinib interruption C. To compare the median dose of dasatinib administered during the first 12 months
Mean dose of dasatinib	12 months therapy	To compare the mean dose of dasatinib administered during the first 12 months
Cumulative rate of complete cytogenetic response	12 months therapy	To compare the cumulative rate of complete cytogenetic response (CCR) at 6, 12 and 18 months, and every 12 months thereafter
Cumulative rate of major molecular response	12 months therapy	To compare the cumulative rate of major molecular response (MMR) at 3, 6, 12, and 18 months, and every 6 months thereafter
Median dose of dasatinib administered	12 months therapy	To compare the median dose of dasatinib administered during the first 12 months
Cumulative rate of complete molecular response	12 months therapy	To compare the cumulative rate of complete molecular response at 3, 6, 12 and 18 months, and every 6 months thereafter
Time to molecular response	12 months therapy	To compare the time to molecular response (major or complete)
Relationship between peak plasmatic level and efficacy	12 months therapy	To analyse the relationship between peak plasmatic level (Cmax) and efficacy in the three arms
Relationship between through plasmatic level and efficacy	12 months therapy	To analyse the relationship between through plasmatic level (Cmin) and efficacy in the three arms
Progression-free survival at 5 years	12 months therapy	To compare the progression-free survival (PFS) at 5 years in the three arms
Overall survival at 5 years	12 months therapy	To compare the overall survival at 5 years in the three arms
Lymphocyte populations before and during dasatinib therapy	12 months therapy	To analyse lymphocyte populations before and during dasatinib therapy (for French participating centers - see appendix 14).
Rate of sustained major molecular remission after dasatinib discontinuation in patients in complete molecular response	12 months therapy	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)
Rate of treatment interruptions	12 months therapy	To compare the rate of treatment interruptions

Trial Locations

Locations (34)

Hôpital Charles LeMoyne; 🇨🇦 Greenfield Park, Canada

Hopital MORVAN; 🇫🇷 Brest, France

Hôpital Maisonneuve-Rosemont; 🇨🇦 Montréal, Canada

CHU Angers; 🇫🇷 Angers, France

Moncton City Hospital; 🇨🇦 Moncton, Canada

Hôpital de l'Enfant Jésus - Centre hospitalier affilié universitaire de Québec; 🇨🇦 Québec, Canada

Hôpital St Antoine; 🇫🇷 Paris, France

Hôpital Purpan; 🇫🇷 Toulouse, France

CH Pierre LeGardeur; 🇨🇦 Lachenaie, Canada

Southern Alberta Cancer Research Institute; 🇨🇦 Calgary, Canada

CH René Dubos; 🇫🇷 Cergy Pontoise, France

Hôpital d'Instruction de Armées Percy; 🇫🇷 Clamart, France

Hôpital d'Annecy; 🇫🇷 Metz Tessy, France

Hôpital Royal Victoria; 🇨🇦 Montréal, Canada

Pavillon Hôtel-Dieu de Québec - Centre hospitalier universitaire de Québec; 🇨🇦 Québec, Canada

Hôpital Claude Huriez; 🇫🇷 Lille, France

Queen elisabeth II Health Sciences Center; 🇨🇦 Halifax, Canada

Hôpital Général Juif - Sir. Mortimer B. Davis; 🇨🇦 Montréal, Canada

Hôpital Avicenne; 🇫🇷 Bobigny, France

Hopital Henri MONDOR; 🇫🇷 Creteil, France

Institut Bergonie; 🇫🇷 Bordeaux, France

CH Lyon Sud; 🇫🇷 Lyon, France

Institut Paoli-Calmettes; 🇫🇷 Marseille, France

C.H.U. Brabois; 🇫🇷 Nancy, France

CHU Hoptel dieu; 🇫🇷 Nantes, France

CHU Caremeau; 🇫🇷 Nimes, France

Hopital Saint Louis; 🇫🇷 Paris, France

Hôpital l'Archet 1; 🇫🇷 Nice, France

Hôpital Necker-Enfants Malades; 🇫🇷 Paris, France

CHU Poitiers; 🇫🇷 Poitiers, France

CHU Rennes - Pontchaillou; 🇫🇷 Rennes, France

Centre René Huguenin; 🇫🇷 Saint Cloud, France

CHRU Bretonneau; 🇫🇷 Tours, France

Central Hospital; 🇫🇷 Versailles, France