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Accelerated Phase Chronic Myelogenous LeukemiaPhase 1NCT01426334

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

A Phase 1 study testing dasatinib, diagnostic laboratory biomarker analysis and pharmacological study in people with Accelerated Phase Chronic Myelogenous Leukemia and Chronic Myelogenous Leukemia, BCR-ABL1 Positive, run by National Cancer Institute (NCI) at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
dasatinib, diagnostic laboratory biomarker analysis and pharmacological study
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4 participants
Where
2 sitesUnited States
Study dates
Sep 2011to Jun 2012
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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 refractory to or with intolerance of treatment with imatinib or nilotinib therapy; patients being treated with dasatinib who have refractory disease may be considered for inclusion, at the discretion of the PIs, if other therapeutic options are not deemed likely to be efficacious (e.g. previous intolerance or refractoriness to nilotinib); evaluation for and consideration of hematopoietic stem cell transplantation as appropriate to the patient's condition by the patient's primary treating hematologist/oncologist should occur prior to enrollment in this trial
  • 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
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  • 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%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,000/mcL
  • Absolute CD4+ count >= 350/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • The effects of dasatinib on the developing human fetus are unknown; for this reason and because PTK inhibitors are known to be teratogenic, women of childbearing potential must have a negative pregnancy test within 7 days of study entry; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for a minimum of 30 days following discontinuation of study therapy; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; lactating women must agree not to nurse a child while on this trial or within 30 days of discontinuation of study therapy
  • Ability to understand and the willingness to sign a written informed consent document

Who cannot join

  • 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
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  • 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
  • Uncontrolled intercurrent illness including, but not limited to, the following: ongoing or active infection; history of significant bleeding disorder, including congenital (von Willebrand's disease) or acquired (anti-factor VIII antibodies) disorders; large pleural effusions; or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because animal studies with dasatinib have shown embryolethality and fetal skeletal alterations at non-toxic maternal doses; because there is an unknown but potential risk for adverse events in nursing human infants secondary to treatment of the mother with dasatinib, breastfeeding should be discontinued if the mother is treated with dasatinib
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dasatinib; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • Known congenital or acquired immunodeficiency
  • CD4+ count less than 350/µl
  • Mutation in Bcr-Abl known to confer resistance to dasatinib; (N.B. patients for whom Bcr-Abl mutations have not been assessed, will have this assessment in screening; they will be allowed to enroll and initiate therapy; if screening analysis reveals Bcr-Abl mutation known to confer resistance to dasatinib, the patient will be discontinued from study participation)
  • Prior hematopoietic stem cell transplantation

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • University of Colorado Cancer Center - Anschutz Cancer Pavilion

    Aurora, Colorado, 80045

  • University of Colorado

    Denver, Colorado, 80217-3364

Other trials in United States

About this study

Official title: Exploiting Synergy in Chronic Myelogenous Leukemia: A Phase Ib Evaluation of Dasatinib Plus Cyclosporine in Patients With Ph+ Leukemia (ESCAPE1b)

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To define the safety and tolerability of cyclosporine A in combination with dasatinib in adults with Bcr-Abl+ chronic myelogenous leukemia in chronic phase, or when used in specified patients with accelerated phase CML.

SECONDARY OBJECTIVES:

  1. To assess pharmacokinetic parameters of dasatinib when combined with cyclosporine.

II. To assess whether the combination of dasatinib and cyclosporine alters T cell number and function.

III. To assess the feasibility of determining phosphorylation of Src in peripheral blood mononuclear cells by flow cytometry as a surrogate measure of dasatinib activity.

OUTLINE:

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

Patients undergo peripheral blood sample collection at baseline and periodically during treatment for pharmacokinetic and pharmacodynamic studies and T-cell number and function by flow cytometry.

After completion of study treatment, patients are followed up for 4 weeks.

Being tested
dasatinib, diagnostic laboratory biomarker analysis, pharmacological study, cyclosporine
Medical subject headings
Leukemia, Myeloid, Accelerated Phase, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myeloid, Chronic-Phase

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • dasatinibDrug

    Also called BMS-354825, Sprycel

    Given PO

  • diagnostic laboratory biomarker analysisOther

    Correlative studies

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • cyclosporineDrug

    Also called ciclosporin, cyclosporin, cyclosporin A, CYSP

    Given PO

Study groups in NCT01426334
Study groupRoleWhat they receive
Treatment (dasatinib and cyclosporine)ExperimentalPatients 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.
Receives: Drug: dasatinib; Other: diagnostic laboratory biomarker analysis; Other: pharmacological study; Drug: cyclosporine

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to 4 weeks post-treatment

Secondary outcomes (1)

  1. Pharmacokinetic profiles of patients taking dasatinib alone versus dasatinib with cyclosporine

    Exposure to dasatinib will be determined and compared using peak levels (Cmax) and areas under the curve (AUC). Paired t-tests will be used to determine statistical significance.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Aug 2011 (estimated)
  2. Study startSep 2011
  3. Primary completionJun 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01426334
Sponsor's protocol ID
NCI-2011-03454
Other IDs
NCI-2011-03454, CDR0000709681, 10-1401, 10-1401, 8890, P30CA046934
Status last verified
Jun 2013
First submitted
30 Aug 2011
Last updated
2 Apr 2014
Results posted
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing dasatinib, diagnostic laboratory biomarker analysis and pharmacological study in people with Accelerated Phase Chronic Myelogenous Leukemia and Chronic Myelogenous Leukemia, BCR-ABL1 Positive, run by National Cancer Institute (NCI) at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 2 Apr 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early. Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety and tolerability of combining dasatinib and cyclosporine, as assessed by the incidence of adverse events and serious adverse events in this patient population (time frame: Up to 4 weeks post-treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01426334.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Apr 2014.

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