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A Phase I/II Study of Dasatinib and Rituximab for Relapsed/Refractory Chronic Lymphocytic Leukemia

Phase 1/Phase 2
18 Years
Open (Enrolling)
Chronic Lymphocytic Leukemia

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Trial Information

A Phase I/II Study of Dasatinib and Rituximab for Relapsed/Refractory Chronic Lymphocytic Leukemia

In phase I, patients will be enrolled in a standard "3+3" dose escalation scheme with two
dasatinib cohort doses of 100 mg QD and 140 mg QD x 28 days/cycle with rituximab 500 mg/m2
on day 1 of each cycle (375 mg/m2 on day 1 of cycle 1 only). During the first cycle of each
dose cohort patients will receive dasatinib on days -7 to 0 to allow for pharmacokinetic and
pharmacodynamic analysis of single agent dasatinib dosing. Cohorts will be assessed for
DLTs during the first 2 cycles. Treatment will continue for 6 cycles or until intolerable
toxicity or disease progression. It is estimated that accrual of 3-6 patients will be
completed in 4-6 months depending on DLTs observed.

The dasatinib dose established in phase I will move forward to the phase II setting. If
there are no DLTs, the phase II dose will be chosen based on PD parameters. Dasatinib will
be administered for 28 days/cycle with rituximab 500 mg/m2 on day 1 of each cycle (375 mg/m2
on day 1 of cycle 1 only) for 6 cycles or until intolerable toxicity or disease progression.
For this portion of the study, up to an additional 22 patients will be enrolled over a
6-month period for a total of 28 patients at the chosen dose level.

For both, phase I and II, patients will complete up to six cycles of D+R therapy and
endpoints will be evaluated 8 weeks after treatment. Patients will be followed until disease
progression, study withdrawal or death. Patients with a PR or CR will be eligible to remain
on dasatinib alone.

Inclusion Criteria


1. Confirmed immunohistological diagnosis of B-cell CLL and Rai Stage III or IV disease,
or stage 0-II disease that meets NCIWG criteria for active disease as indicated by
any one of the following disease-related symptoms:

- Weight loss ≥ 10% within the previous 6 months

- Extreme fatigue

- Fever greater than 100.5 degrees Fahrenheit for ≥ 2 weeks without evidence of

- Night sweats without evidence of infection

- Evidence of progressive marrow failure based on the development or worsening of
anemia (< 10 g/dL) or thrombocytopenia (< 100,000 cells/mL)

- Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid

- Massive (> 6 cm below the left costal margin) or progressive splenomegaly

- Bulky (>10 cm in cluster) or progressive lymphadenopathy

- Progressive lymphocytosis with > 50% increase over a 2-month period, or
anticipated doubling time < 6 months

2. Relapsed/ Refractory CLL that has progress with ≥1 prior treatment including a purine
nucleoside analog-containing regimen, alkylating agent, or antibody (rituximab or
alemtuzumab) or intolerance to purine nucleoside analog-containing therapy or
unwilling to receive chemotherapy treatment.

3. Age 18 or older

4. ECOG Performance Status 0-2 (Appendix B)

5. Adequate organ function:

- Serum creatinine < 2x the institutional upper limit of normal (ULN)

- Total bilirubin < 2x the institutional ULN

- AST, ALT < 2.5x the institutional ULN

- Serum sodium, potassium, magnesium, phosphate and calcium > the institutional
lower limit of normal (LLN)

6. Ability to take oral medication (dasatinib must be swallowed whole)

7. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (sensitivity ≤ 25 IU/L HCG) within 72 hrs prior to the start of study drug

8. Persons of reproductive potential must agree to use an adequate method of
contraception throughout treatment and for at least 4 weeks after study drug is

9. Ability to understand and the willingness to sign a written informed consent document


1. No prior CLL-related treatment within 28 days before starting treatment with

2. No concurrent use of other investigation agent.

3. Concurrent medical condition which may increase the risk of toxicity, including:

- Uncontrolled or significant cardiovascular disease, including:

- Myocardial infarction, congestive heart failure or uncontrolled angina
within 6 months

- Diagnosed congenital long QT syndrome

- Any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes)

- Prolonged QTcF interval on pre-entry ECG (> 450 msec)

- 2nd/3rd degree heart block, uncontrolled hypertension or heart rate < 50

- History of significant bleeding disorder unrelated to CLL, including:

- Diagnosed congenital bleeding disorder (e.g., von Willebrand's disease)

- Diagnosed acquired bleeding disorder within one year (e.g., acquired
anti-factor VIII antibodies)

- Ongoing or recent significant GI bleeding within 3 months

- Hypokalemia or hypomagnesemia if it cannot be corrected

- Pleural or pericardial effusion of any grade

- Past or current malignancy, except for:

- Cervical carcinoma Stage 1B or less

- Non-invasive basal cell and squamous cell skin carcinoma

- Malignant melanoma with a complete response of a duration of > 10 years

- Other cancer diagnoses with a complete response of a duration of > 5 years

- Major systemic or other illness including active infection or active secondary
malignancy that would, in the opinion of the Investigator, interfere with the
patient's ability to comply with the protocol, compromise patient safety, or
interfere with the interpretation of the study results

4. No history of allergic reaction to dasatinib.

5. Use of Prohibited Concomitant Medications

Subjects requiring any of the following prohibited therapies should not be enrolled:

- Bisphosphonates Intravenous bisphosphonates will be withheld for the first 8
weeks of treatment due to the risk of hypocalcemia. After the need for Ca2+
supplementation has been assessed and levels documented to be >LLN, subjects on
prior bisphosphonate may be restarted with caution at the Investigator's

- CYP3A4 Inhibitors/Inducers/Substrates Dasatinib is primarily metabolized by the
CYP3A4 enzyme. Therefore, potent inhibitors of CYP3A4 are prohibited during
study; for such medications, a wash-out period of ≥ 7 days is required prior to
starting dasatinib. Subjects should be advised not to consume substantial
quantities of grapefruit juice.

- Drugs that may increase dasatinib plasma concentrations:

CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and
drugs that inhibit CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin,
clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir,
telithromycin) may increase exposure to dasatinib and should be avoided.

In patients receiving treatment with dasatinib, close monitoring for toxicity and a
dasatinib dose reduction should be considered if systemic administration of a potent
CYP3A4 inhibitor cannot be avoided.

-Drugs that may decrease dasatinib plasma concentration: CYP3A4 Inducers: Drugs that
induce CYP3A4 activity may decrease dasatinib plasma concentrations. In patients in
whom CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampicin,
phenobarbital) are indicated, alternative agents with less enzyme induction potential
should be used. If dasatinib must be administered with a CYP3A4 inducer, a dose
increase in dasatinib should be considered and approved by the principal

-Drugs that may have their plasma concentration altered by dasatinib: CYP3A4
Substrates: CYP3A4 substrates known to have a narrow therapeutic index such as
alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide,
quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine)
should be administered with caution in patients receiving dasatinib.

- Less-potent inhibitors, inducers, and substrates of CYP3A4 are restricted.

- St. John's Wort (Hypericum perforatum):

May decrease dasatinib plasma concentrations unpredictably. Patients receiving
dasatinib should not take St. John's wort.

- Antacids Nonclinical data demonstrate that the solubility of dasatinib is pH
dependent. Simultaneous administration of dasatinib with antacids should be
avoided. If antacid therapy is needed, the antacid dose should be administered
at least 2 hours prior to or 2 hours after the dose of dasatinib.

- H2 Blockers/Proton Pump Inhibitors Long-term suppression of gastric acid
secretion by H2 blockers or proton pump inhibitors (eg, famotidine and
omeprazole) is likely to reduce dasatinib exposure. The concomitant use of H2
blockers or proton pump inhibitors with dasatinib is not recommended. The use of
antacids should be considered in place of H2 blockers or proton pump inhibitors
in patients receiving dasatinib therapy.

- Medications that prolong QT Interval

Subjects enrolled in this study should not take or begin to take concomitant
medications known to prolong the QT interval. If such medications are already being
taken by the patient before study starts, a wash-out period of ≥ 7days is required
prior to starting dasatinib. Medications known to prolong the QT interval and/or are
generally accepted to have a risk of causing Torsades de Pointes ventricular
arrhythmia are (see

- Quinidine, procainamide, disopyramide

- Amiodarone, sotalol, ibutilide, dofetilide

- Erythromycin, clarithromycin

- Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide

- Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine Should the
Investigator believe that beginning therapy with a potentially QT prolonging
medication (other than the ones explicitly prohibited) is vital to an individual
subject's care, the Investigator must check that the subject's prior on-therapy
ECG has not shown a QTcF ≥ 450 msec or an increase in QTc ≥ 60 msec over the
baseline value.

- Anticoagulants and Medications that inhibit Platelet Function Caution
should be exercised if patients are required to take medications that
inhibit platelet function or anticoagulants.

Subjects enrolled in this study should not take concomitant medications that durably
inhibit platelet function. For such medications, a wash-out period of ≥ 7days is
required prior to starting dasatinib. (Agents that inhibit platelet function
transiently or inhibit coagulation by other mechanisms are restricted.)

Medications that directly and durably inhibit platelet function include:

- aspirin or aspirin-containing combinations, clopidogrel, dipyridamole

- tirofiban, dipyridamole, epoprostenol, eptifibatide, cilostazol, abciximab,
ticlopidine, cilostazol

Medications that directly and durably inhibit anticoagulation include:

- warfarin, heparin/low molecular weight heparin [e.g., danaparoid, dalteparin,
tinzaparin, enoxaparin]

- Exceptions: low-dose warfarin for prophylaxis to prevent catheter thrombosis,
and heparin for flushes of IV lines.

6. Women who are pregnant (including having a positive pregnancy test) or breastfeeding,
or unable/unwilling to practice an acceptable method to avoid pregnancy for the
entire study period and for at least 4 weeks after cessation of study drug, or men
who are sexual partners thereof.

- Sexually active women of childbearing potential (WOCBP) must use an effective
method of birth control during the course of the study, in a manner such that
risk of failure is minimized. Prior to study enrollment, WOCBP must be advised
of the importance of avoiding pregnancy during trial participation and the
potential risk factors for an unintentional pregnancy.

- All WOCBP MUST have a negative pregnancy test prior to first receiving
dasatinib. If the pregnancy test is positive, the patient must not receive
dasatinib and must not be enrolled in the study.

7. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious) illness

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase I: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of D+R therapy in patients with relapsed/refractory CLL

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Januario Castro, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Associate Clinical Professor, Blood and Bone Marrow Transplant Division


United States: Institutional Review Board

Study ID:

UCSD 110054 - Prev 080422



Start Date:

May 2009

Completion Date:

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • Chronic Lymphocytic Leukemia
  • CLL
  • Dasatinib
  • Rituximab
  • Relapsed
  • Refractory
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid



University of California San Diego Moores Cancer Center La Jolla, California