Combination of Dasatinib and Peg-Interferon Alpha 2b in First Line for Chronic Myeloid Leukemia in Chronic Phase

Interferon alpha was a therapy used in Chronic Myeloid Leukemia in Chronic phase prior to the advent of tyrosine kinase inhibitors. Synergistic effect of the combination of Peg-IFNα2a with Imatinib was demonstrated in the clinical SPIRIT trial. In this study, the investigators address the question of the efficacy and safety of dasatinib in combination with low dose of Peg-IFNα-2b as frontline therapy for patients with newly diagnosed Chronic Myeloid Leukemia in Chronic phase.

Study Overview

• Status: Completed
• Conditions: Chronic Phase of Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Dasatinib; Drug: Peg-Interferon alpha2b

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed Written Informed Consent.

2. Target Population

   a)18 to 65 years b)Newly diagnosed (≤ 3 months) Philadelphia chromosome positive chronic CP-CML c)Major BCR-ABL transcripts d)Not previously treated for CML except with hydroxyurea or anagrelide e)ECOG Performance Status≤ 2 f)Adequate Organ Function. i)Total bilirubin< 2.0 times the institutional Upper Limit of Normal ii)Hepatic enzymes(AST, ALT )≤ 2.5 ULN iii)Serum Na, K+, Mg2+ and Ca2+ > Lower Limit of Normal (LLN) or supplemented iv)Serum Creatinine< 1.5 ULN g)Women of childbearing potential (WOCBP) must be using an adequate method of contraception.

3. Free subject, without guardianship nor subordination,
4. Health insurance coverage. -

Exclusion Criteria:

1. Patients with BCR-ABL other than M-BCR-ABL, Philadelphia negative CML.
2. Patients previously treated with Tyrosine Kinase Inhibitors (TKIs).

3. Medical history and concurrent diseases :

   1. Hypersensitivity to any of the excipients of dasatinib
   2. Prior treatment with Interferon-α, contraindication to interferon-α, hypersensitivity to any of the excipients of PegIFNα2b,
   3. Concomitant immunosuppressive treatment or corticosteroids,
   4. Preexisting thyroid disease unless it is controlled with conventional treatment, Auto-immune thyroiditis,
   5. Autoimmune disorder, Chronic liver disease,
   6. Prior or ongoing severe psychiatric disease,
   7. Epilepsy or compromised central nervous system(CNS) function,
   8. HIV positivity, chronic hepatitis B or C,
   9. Uncontrolled or significant cardio vascular or pulmonary disease,

   i)Uncontrolled angina, myocardial infarction or congestive heart failure within 6 months, ii)Echocardiography with LVF < 45% or LLN, peak velocity of tricuspid regurgitant flow > 2,8 m/s iii)Pulmonary arterial hypertension (PAH), iv)Any history of clinically significant ventricular or supraventricular arrhythmias, v)Diagnosed congenital long QT syndrome, vi)Prolonged QTc interval > 450 msec (Fredericia) on 3 pre-entry electrocardiogram, vii)Subjects with hypokalemia or hypomagnesemia if it cannot be corrected, j)Other malignant disease during the last 5 years prior to the inclusion except basal cell carcinoma of the skin or carcinoma in situ of the cervix, k)History of significant bleeding disorder unrelated to CML, including: i)Diagnosed congenital bleeding disorders (e.g. von Willebrand's disease), ii)Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding. l)Another severe or life -threatening medical disease.

4. Women who are pregnant or breastfeeding, WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug.

5. Prohibited treatments and/or therapies:

   1. strong inhibitors of the CYP3A4,
   2. category I drugs that are generally accepted to have a risk of causing "Torsades de Pointes", Patients must discontinue the drug minimum 7 days prior to starting dasatinib.
6. History /any condition for poor compliance to the treatment.
7. Inability to freely provide consent through judiciary or administrative condition.
8. Ongoing participation to another study.

Study Plan

How is the study designed?

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dasatinib; Dasatinib,Bristol Myers Squibb	Drug: Dasatinib; Dasatinib 100mg daily starting at inclusion If ANC ≤ 1.5.109/L, platelets ≤ 100.0.109/L or lymphocytes > 4.0.109/L at 3 months, dasatinib will be continued alone, and patients will be still followed in the study; Drug: Peg-Interferon alpha2b; 30 µg weekly starting month 4- month 21
Experimental: Peg-Interferon alpha2b; Peg-Interferon alpha2b (Peg-IFN α2b), Merck	Drug: Dasatinib; Dasatinib 100mg daily starting at inclusion If ANC ≤ 1.5.109/L, platelets ≤ 100.0.109/L or lymphocytes > 4.0.109/L at 3 months, dasatinib will be continued alone, and patients will be still followed in the study; Drug: Peg-Interferon alpha2b; 30 µg weekly starting month 4- month 21

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative rate of molecular response	Molecular response 4.5 (MR4.5) is defined by either a positive BCR-ABL/ABL ratio ≤ 0.0032 on the international scale or by undetectable BCR-ABL with the analysis of at least 32000 copies of ABL (according to the ELN recommendations by N. Cross et al., leukemia 2012). Centralized analyses of molecular response by RTQPCR will be performed for all molecular assessments in this study.	at 12 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of complete cytogenetic response		3, 6, 12, 18, 24 months, and every 12 months thereafter.
Rate of major molecular responses		3, 6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter.
Rate of molecular response	Rate of molecular response 4.5 and 5.0	6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter.
Kinetics and duration	Cumulative rate, Kinetics and duration CCR, MMR, MR4.5, MR5.0	6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter
Rate of PegIFN-α2b and dasatinib discontinuation		24 months

Collaborators and Investigators

• Sponsor: Poitiers University Hospital
• Investigators: Principal Investigator: Lydia ROY, MD, Poitiers University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2013
• Primary Completion (Actual): October 31, 2018
• Study Completion (Actual): October 31, 2018

Study Registration Dates

• First Submitted: May 14, 2013
• First Submitted That Met QC Criteria: June 4, 2013
• First Posted (Estimate): June 7, 2013

Study Record Updates

• Last Update Posted (Actual): February 10, 2020
• Last Update Submitted That Met QC Criteria: February 7, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Protein Kinase Inhibitors; Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2b; Dasatinib
• Other Study ID Numbers: DASA-PegIFN

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No