An Open Label, Time-To-Event Continuous Reassessment Method, Phase I/II Study of the Mammalian Target of Rapamycin (mTOR) Inhibitor RAD001 in Combination With Imatinib (Gleevec) in Patients With Chronic Phase Chronic Myeloid Leukemia (CML) With Persistent Molecular Disease.
- Study subjects must be at least age 18 years or older.
- Study subjects must have an Eastern Cooperative Oncology Group performance status
- Study subjects must provide a signed written informed consent.
- Study subjects must be able to comply with study procedures and follow-up
- Female study subjects: non-fertile (status post hysterectomy (removal of the uterus)
or menopausal (no menstrual period) for 24 consecutive months or agree to use birth
control during the study through the end of last treatment visit. Women of
childbearing potential must have a negative serum pregnancy test within 3 days prior
to administration of RAD001). Use of a single agent for prevention of pregnancy
(oral, implantable, or injectable contraceptives) may be affected by medications that
alter the activity of the cytochrome P450 enzyme, and are therefore, not considered
effective during participation in this clinical trial.If there is ANY chance that
pregnant can occur, there must be a commitment to continue abstinence from
heterosexual intercourse or begin TWO methods of birth control, one highly effective
method and one additional effective method AT THE SAME TIME.
- There must be at least two weeks since any major surgery, completion of radiation, or
completion of all prior systemic anticancer therapy (adequately recovered from the
acute toxicities of any prior therapy).
Study subjects must meet the following disease criteria:
- Diagnosis of Chronic Myelogenous Leukemia according to the World Health Organization.
- Persistent molecular disease as defined by the persistent identification of the
Bcr-Abl transcript using quantitative RT-PCR on at least 2 occasions at least 3
months apart and having completed a minimum of 18 months of treatment with Imatinib
at 400 mg once daily.
- Achieved a complete cytogenetic response. (This shall be measured at least one time
prior to consent to participation in the clinical trial, and shall be reassessed at
the initiation of the clinical trial.)
- Non-hematologic symptoms related to Imatinib therapy that are ≤ Grade 2 in severity
for at least 6 months prior to enrollment.
Study subjects must meet the following organ function criteria:
- Adequate bone marrow function
- Adequate renal and hepatic function
- International normalized ration <1.3 (or <3 on anticoagulants)
Study subjects must meet the following cardiac function criteria:
- No history of uncontrolled angina, congestive heart failure or myocardial infarction
within 6 months of study entry. If there is a suspected clinical history of coronary
artery disease, then the patient must document one of the following within 1 year of
study participation:Left ventricular ejection fraction greater than 40% on multigated
acquisition scan or similar radionuclide angiographic scan; or Left ventricular
fractional shortening greater than 22% on echocardiography exam; or LVEF greater than
40% on echocardiography exam.
- No history of a diagnosis or suspected congenital QRS complex to the end of the T
wave on an electrocardiogram syndrome.
- No history of clinically significant ventricular arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or Torsades de pointes).
- No history of uncontrolled hypertension.
- Study subjects may not have had prior treatment with RAD001, sirolimus, temsirolimus,
- Study subjects may not have a known hypersensitivity to RAD001 or other rapamycin,
sirolimus, temsirolimus or to its excipients.
- Study subjects may not have received an investigational agent received within 28 days
prior to the first dose of study drug.
- Study subjects may not have psychiatric disorders that would interfere with consent,
study participation, or follow-up.
- Study subjects may not have a history of noncompliance to medical regimens.
- Study subjects unwilling to or unable to comply with the protocol are not eligible to
participate in this clinical research trial.
Study subjects that meet any of the following criteria are not eligible to participate in
the clinical research study:
- Diagnosis of an accelerated phase or a blast phase of chronic myeloid leukemia
according to the World Health Organization criteria.
- Clinical evidence suggestive of central nervous system involvement with leukemia
unless a lumbar puncture confirms the absence of leukemia in the cerebrospinal fluid.
- Prior hematopoietic stem cell transplant.
- Prior external beam radiation therapy to the pelvis.
- Diagnosis of another malignancy, unless disease-free for at least 3 years following
the completion of curative intent therapy with the following exceptions: treatment
of non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial
neoplasia, regardless of the disease-free duration - with treatment for the condition
- Known chronic condition requiring the treatment with systemic steroids or another
- Systemic fungal, bacterial, viral, or other infection not controlled (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment).
- Prior seropositive test for the human immunodeficiency virus.
- Uncontrolled diabetes mellitus
- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
- Any other severe concurrent disease, or have a history of serious organ dysfunction
or disease involving the heart, kidney, liver, or other organ system that may place
the patient at undue risk to undergo therapy with RAD001 including:severely impaired
lung function; liver disease such as cirrhosis, chronic active hepatitis or chronic;
persistent hepatitis;other nonmalignant medical illnesses that are uncontrolled or
whose control may be jeopardized by the treatment with the study therapy.
- History of significant bleeding disorder unrelated to cancer, including:Congenital
bleeding disorders (e.g., von Willebrand's disease); Acquired bleeding disorder
within one year (e.g., acquired anti-factor VIII antibodies).