Exploiting Synergy in Chronic Myelogenous Leukemia: A Phase Ib Evaluation of Dasatinib Plus Cyclosporine in Patients With Ph+ Leukemia Refractory to or Intolerant of Imatinib Mesylate (ESCAPE1b Trial)
- Patients must have histologically or cytologically confirmed chronic myelogenous
leukemia, Philadelphia chromosome positive
- Patients must have a diagnosis of:
- Chronic phase Ph+ CML refractory to or intolerance of treatment with Imatinib
therapy. 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
- 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.
- 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 with Imatinib 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 Imatinib 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 at least 7 days prior to starting study
- Patients may not have been treated with nilotinib or dasatinib prior to starting
- Patients must discontinue hydroxyurea or interferon at least 7 days prior to
starting study therapy.
- Age >18 years.
- Because no dosing or adverse event data are currently available on the use of
dasatinib in combination with cyclosporine in patients <18 years of age, children
are excluded from this study, but will be eligible for future pediatric trials.
- Life expectancy of greater than 1 month.
- ECOG performance status <=2 (Karnofsky =>60%; see Appendix A).
- Patients must have normal organ and marrow function as defined below:
- 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 m2 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
- 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. (See Appendix B for lists of
specifically prohibited medications or substances.) 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
- 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 (See appendix D).
- 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.
- Prior therapy with dasatinib or nilotinib.
Inclusion of Women and Minorities:
- Both men and women and members of all racial and ethnic groups are eligible for this