Safety and Efficacy of Pegylated IFN-alpha 2B Added to Dasatinib in Newly Diagnosed Chronic Phase Myeloid Leukemia

Leukemia, Myeloid, Chronic-Phase Clinical Trial

— NordCML007  

Official title:

A Safety and Efficacy Study of Adding Low Dose Pegylated IFN-alpha 2B to Standard Dose Dasatinib in Patients With Newly Diagnosed Chronic Phase Myeloid Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01725204
• Other study ID #: NordCML007
• Secondary ID: 2011-005989-38
• Status: Completed
• Phase: Phase 2
• First received: November 8, 2012
• Last updated: September 21, 2017
• Start date: September 2012
• Est. completion date: May 2016

Study information

• Verified date: September 2017
• Source: Norwegian University of Science and Technology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with newly diagnosed CML have excellent outcomes with tyrosine kinase inhibitors (TKI). However, a few patients will be cured with TKIs alone, and thus need continued life-long treatment. Some patients achieve complete molecular remission (CMR), and this rate is higher with second generation TKIs compared with imatinib. Some experience with drug discontinuation in CMR has been derived from a few small studies, most notably the French STIM study. Approximately 40 % of patients with a minimum of two years in MR4.5 (4.5 log reduction in molecular response) can stop imatinib without relapse, indicating possible cure. To increase the non-relapse rate is of major importance. To achieve a permanent "cure" without stem cell transplantation is presently the most relevant goal of clinical studies in CML.

The investigators hypothesize that to significantly increase cure rates in CML, therapy should eradicate leukemic stem cells and/or induce or restore anti-CML immunity. Second generation TKIs may have a more profound effect on the stem cell pool as compared to imatinib. This is assessed in our current randomized study with a reduction in leukemic stem cell burden as the primary endpoint (NordCML006). Interferon-alpha (IFN) has a prominent immunomodulatory and antiproliferative mode of action, and has also activity in stem cells. Pegylated IFN in combination with imatinib results in improved therapy responses as compared to imatinib monotherapy. This advantage may translate into higher cure rates.

Dasatinib has a unique dual mechanism of action: it is the most potent of available TKIs and induces immunological effects that are different from those of IFN. Both of these drugs may have immunological adverse-effects when used as a monotherapy. However, immunological adverse-effects may also be markers of anti-leukemia efficacy. A combination of dasatinib and pegylated IFN (PegIFN) may have additive or synergistic effects and should be tested in a clinical study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: May 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Diagnosis of chronic myeloid leukemia in chronic phase (CML-CP) associated with BCR-ABL1 quantifiable by RQ-PCR (IS)

• No other current or planned anti-leukemia therapies excluding hydroxyurea treatment for up to two months.

• ECOG Performance status 0,1, or 2

• Adequate organ function as defined by: Total bilirubin < 1.5 x ULN (ULN = upper limit of normal in a local institution lab) in absence of Gilbert genotype; ASAT and ALAT < 2.5 x ULN. Creatinine < 2x ULN. Potassium, magnesium and phosphate not below LLN (LLN= lower level of normal)

• Life expectancy of more than 12 months in the absence of any intervention

• Patient has given written informed consent to participate in the study

Exclusion Criteria:

• Prior accelerated phase or blast crisis

• Uncontrolled or significant cardiovascular disease, including any of the following:

• A myocardial infarction within 6 months

• Uncontrolled angina within 3 months

• Congestive heart failure within 3 months

• Diagnosed or suspected congenital long QT syndrome

• Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointe)

• Prolonged QTcF interval > 450 msec on pre-entry ECG

• Atypical BCR-ABL1 transcript not quantifiable by RQ-PCR.

• Another primary malignant disease, which requires systemic treatment (chemotherapy or radiation) Severe and/or life-threatening medical disease including acute liver disease

• History of significant congenital or acquired bleeding disorder unrelated to cancer

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dasatinib

• Patients actively receiving therapy with strong CYP3A4 inhibitors and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug

• Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug

• Female patients who are: pregnant, breast feeding or potentially fertile without a negative pregnancy test prior to baseline or unwilling to use contraception on trial

• Previous history of pericarditis or pleuritis

• History of non-compliance, abuse of alcohol, illicit drugs, severe psychiatric disorders or other inability to grant informed consent.

• Current treatment for depression.

• Hypersensitivity to any interferon preparation;

• Autoimmune hepatitis or a history of autoimmune disease;

• Pre-existing thyroid disease unless it can be controlled with conventional treatment;

• Epilepsy and/or compromised central nervous system (CNS) function;

• HCV/HIV patients

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Chronic-Phase

Intervention

Drug:
• Dasatinib + PegIFN

Locations

Country	Name	City	State
Finland	Helsinki University Central Hospital	Helsinki
Norway	Bergen University Central Hospital	Bergen
Norway	Rikshospitalet	Oslo
Norway	Stavanger University Hospital	Stavanger
Norway	University Hospital of Northern Norway	Tromsø
Norway	St Olavs Hospital - Trondheim University Hospital	Trondheim
Sweden	Linköping University Hospital	Linköping
Sweden	Sunderby Sjukhus	Luleå
Sweden	Lund University Hospital	Lund
Sweden	Örebro University Hospital	Örebro
Sweden	Karolinska University Hospital	Stockholm
Sweden	Sundsvall County Hospital	Sundsvall
Sweden	Umeå University Hospital	Umeå
Sweden	Uppsala University Hospital	Uppsala

Sponsors (1)

Lead Sponsor	Collaborator
Norwegian University of Science and Technology

Countries where clinical trial is conducted

Finland,  Norway,  Sweden, 

References & Publications (1)

Hjorth-Hansen H, Stentoft J, Richter J, Koskenvesa P, Höglund M, Dreimane A, Porkka K, Gedde-Dahl T, Gjertsen BT, Gruber FX, Stenke L, Eriksson KM, Markevärn B, Lübking A, Vestergaard H, Udby L, Bjerrum OW, Persson I, Mustjoki S, Olsson-Strömberg U. Safet — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	major molecular response rates	defined as =0.1% BCR-ABL1 on the MMR International Scale	1 year
Secondary	overall survival		2 years
Secondary	quality of life		up to 18 months (after 3, 6, 12, 18 months)
Secondary	Rate of CCgR		up to 18 months (after 3, 6, 12 and 18 months)
Secondary	Rate of MR4.0 and MR4.5		up to 24 months (after 3, 6, 12, 15, 18, and 24 months)