Dasatinib and Cyclosporine in Treating Patients With Chronic Myelogenous Leukemia Refractory or Intolerant to Imatinib Mesylate

NCT01426334 | Terminated Phase 1

• 5 other identifiers: NCI-2011-03454CDR000070968110-14018890P30CA046934
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 2

Brief Summary

This phase I trial studies the side effects and the best way to give dasatinib and cyclosporine in treating patients with chronic myelogenous leukemia (CML) refractory or intolerant to imatinib mesylate. Dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Cyclosporine may help dasatinib work better by making cancer cells more sensitive to the drug. Giving dasatinib together with cyclosporine may be an effective treatment for CML.

Conditions

Accelerated Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Relapsing Chronic Myelogenous Leukemia

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability of combining dasatinib and cyclosporine, as assessed by the incidence of adverse events and serious adverse events in this patient population

  Serious adverse events, toxicity, and patient withdrawals/discontinuations will be determined by the severity, duration, causality, seriousness, and type of event as defined in the protocol.

  Up to 4 weeks post-treatment

Secondary Outcomes (1)

• Pharmacokinetic profiles of patients taking dasatinib alone versus dasatinib with cyclosporine

  At baseline and on days 7, 21, 49, 77, and 105

Study Arms (1)

Treatment (dasatinib and cyclosporine)

EXPERIMENTAL

Patients receive dasatinib PO QD on days 1-28 and cyclosporine PO BID on days 8-28. Treatment repeats every 28 days for 4 months in the absence of disease progression or unacceptable toxicity.

Drug: dasatinib; Other: diagnostic laboratory biomarker analysis; Other: pharmacological study; Drug: cyclosporine

Interventions

dasatinib DRUG

Given PO

Also known as: BMS-354825, Sprycel

Treatment (dasatinib and cyclosporine)

diagnostic laboratory biomarker analysis OTHER

Correlative studies

Treatment (dasatinib and cyclosporine)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (dasatinib and cyclosporine)

cyclosporine DRUG

Given PO

Also known as: ciclosporin, cyclosporin, cyclosporin A, CYSP, Sandimmune

Treatment (dasatinib and cyclosporine)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically confirmed chronic myelogenous leukemia (CML), Philadelphia chromosome positive (Ph+)
• Patients must have a diagnosis of:
• de novo chronic phase Ph+ CML, and not have received therapy with a tyrosine kinase inhibitor (TKI) for more than 2 weeks prior to enrollment
• OR chronic phase Ph+ CML, without complete molecular remission after 3 months of treatment with imatinib, nilotinib or dasatinib
• OR accelerated phase Ph+ CML, for which allogeneic hematopoietic stem cell transplantation is being planned, and for which no cytotoxic chemotherapy is planned prior to conditioning, and can be reasonably expected to participate for a minimum of one month prior to transplantation
• OR accelerated phase Ph+ CML, for which allogeneic hematopoietic stem cell transplantation is not a therapeutic option (due to age or lack of acceptable donor, for example), and can be reasonably expected to participate for a minimum of one month
• Chronic phase CML shall be defined by the presence of fewer than 15% blasts, fewer than 20% basophils, and fewer than 30% blasts plus promyelocytes in the peripheral blood and bone marrow, no extramedullary involvement except liver and spleen, and no evidence of clonal evolution (O'Brien et al., 2003)
• Treatment failure/refractory disease shall be defined as less than complete hematologic response at 3 months, no cytogenetic response at 6 months, less than partial cytogenetic response at 12 months, less than complete cytogenetic response at 18 months, OR loss of CHR, loss of CCyR, clonal chromosomal abnormalities, detection of imatinib insensitive mutations, or 1 log increase in BCR-ABL transcript level from best molecular response documented on 2 samples at least one month apart (Baccarani et al., 2009)
• Intolerance of TKI therapy shall be defined by non-hematologic toxic effects of any grade leading to intermittent or chronic non-compliance with, repeated dose reduction or delays in continuous dosing, or discontinuation of Imatinib
• Accelerated phase CML shall be defined as the presence of \>= 15-29% blasts, \>= 20% basophils, or \>= 30% blasts plus promyelocytes in the peripheral blood or bone marrow, thrombocytopenia unrelated to therapy, or evidence of cytogenetic clonal evolution (Kantarjian et al., 1993)
• Prior Therapy
• Patients must have discontinued imatinib, nilotinib or dasatinib at least 7 days prior to starting study therapy; this washout period may be omitted at the discretion of the PIs, if it is determined that the washout may adversely affect patient care
• Patients must discontinue hydroxyurea or interferon at least 7 days prior to starting study therapy
• Life expectancy of greater than 1 month
• ECOG performance status =\< 2 (Karnofsky \>= 60%)

You may not qualify if:

• Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or failure to recover from adverse events (except alopecia) to Grade =\< 1 or to baseline (if there is persistent, chronic, stable Grade 2), due to agents administered more than 4 weeks earlier
• Patients may not be receiving any other investigational agents
• Known brain metastases exclude patients from this clinical trial because such patients have a poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; in addition, patients who have active brain metastases may benefit from other concurrent therapy such as radiation or radiosurgery, and should be considered for the most appropriate clinical therapy that may provide symptom relief
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dasatinib or cyclosporine
• Patients who require concurrent treatment with any medications or substances that are potent inhibitors or inducers of CYP3A4 are ineligible; efforts should be made to switch patients with a seizure disorder who are taking enzyme-inducing anticonvulsant agents to other medications
• Patients who require concurrent treatment with proarrhythmic potential
• QTc prolongation (defined as a QTc interval \>= 480 msec) or other significant ECG abnormalities
• Use of antithrombotic and/or anti-platelet agents (e.g., warfarin, heparin, low molecular weight heparin, aspirin, and/or ibuprofen); exception: patients with CML who have significantly elevated platelet counts taking anagrelide are eligible; patients who require \< 2 mg of warfarin per day for central venous catheter prophylaxis are allowed on this study
• Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain dasatinib tablets are excluded; tablets may not be crushed prior to administration
• Patients may not have any clinically significant cardiovascular disease, defined as NYHA class III or higher and as follows:
• Myocardial infarction or ventricular tachyarrhythmia within 6 months
• Prolonged QTc \>= 480 msec (Fridericia correction)
• Ejection fraction less than institutional normal
• Major conduction abnormality (unless a cardiac pacemaker is present)
• Patients with any cardiopulmonary symptoms of unknown cause (e.g. shortness of breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed in addition to electrocardiogram (EKG) to rule out QTc prolongation; the patient may be referred to a cardiologist at the discretion of the principal investigator; patients with underlying cardiopulmonary dysfunction should be excluded from the study

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

University of Colorado Cancer Center - Anschutz Cancer Pavilion

Aurora, Colorado, 80045, United States

Location

University of Colorado

Denver, Colorado, 80217-3364, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Accelerated Phase; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase

Interventions

Dasatinib; Cyclosporine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Christopher Porter

  University of Colorado Cancer Center - Anschutz Cancer Pavilion

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2011
• First Posted: August 31, 2011
• Study Start: September 1, 2011
• Primary Completion: June 1, 2012
• Last Updated: April 2, 2014

Record last verified: 2013-06

Locations

US (2)