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

PRIMARY OBJECTIVES:

I. 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:

I. 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.

Inclusion Criteria:

- 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

- 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

Exclusion Criteria:

- 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

- 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