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Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) With Everolimus (RAD001) and Alemtuzumab: A Phase I/II Study

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

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Trial Information

Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) With Everolimus (RAD001) and Alemtuzumab: A Phase I/II Study

PRIMARY OBJECTIVES: I. Test the safety and tolerability of the combination of everolimus
and alemtuzumab. (Phase I) II. Determine the maximum tolerated dose of everolimus in this
combination. (Phase I) III. Assess the rate of overall responses in patients with
relapsed/refractory CLL to treatment with the maximum tolerated dose of everolimus together
with a standard dose of alemtuzumab using conventional NCI-WG 1996 response criteria. (Phase
II) IV. To assess the complete responses to this combination regimen using conventional
NCI-WG 1996 criteria and an expanded definition of response, including CT scans of
chest-abdomen-pelvis, immunohistochemical analysis for residual disease in the bone marrow,
and sensitive flow cytometry for minimal residual disease in patients in complete clinical
remission. V. To monitor and assess toxicity of this regimen. SECONDARY OBJECTIVES: I. To
determine the overall and progression-free survival, duration of response, and time to next
treatment. II. To assess the correlation between the individual prognostic markers (17p-,
p53 gene mutations, 11q-, unmutated VH gene, use of VH3-21, ZAP70+, CD38+, CD49d, B2
microglobulin) and clinical outcome. III. Serial measurement of clinical status and
lymphocyte counts to test the rate of reduction in CLL tumor burden. TERTIARY OBJECTIVES:
I. Determine the effect of everolimus on the sensitivity of CLL cells to alemtuzumab CDC and
ADCC. II. Determine the effect of everolimus on the CLL cell-stroma interaction. III.
Detail the in vivo effect of the everolimus-alemtuzumab regimen on critical aspects of the
immune system in CLL. OUTLINE: This is a phase I, dose escalation study of everolimus
followed by a phase II study. Patients receive oral everolimus thrice weekly for 9 weeks and
alemtuzumab subcutaneously thrice weekly for 7 weeks in the absence of disease progression
or unacceptable toxicity. After completion of study treatment, patients are followed
periodically for up to 5 years. PROJECTED ACCRUAL: A total of 44 patients will be accrued
for this study.

Inclusion Criteria


- Diagnosis of CLL manifested by minimum threshold peripheral lymphocyte count of > 5 x
10^9/L (CLL variant) OR palpable adenopathy >= 1cm or clinically palpable
splenomegaly (SLL variant); AND immunophenotypic demonstrations of a population of B
lymphocytes (as defined by CD19+) which are monoclonal (by light chain exclusion)

- CLL will be diagnosed if these cells have >= 3 of the following characteristics:
CD5+, CD23+, dim surface light chain expression, dim surface CD20 expression, AND
FISH analysis is negative for IGH/CCND1 and/or immunostaining is negative for cyclin
D1 expression to exclude mantle cell lymphoma Previous treatment for CLL Progressive
disease: symptomatic CLL (weight loss>10% within 6 months, extreme fatigue,
fevers>38.5 C, drenching night sweats without evidence of infection) OR evidence of
progressive bone marrow failure (hemoglobin<11g/dL, platelet count<100 x 10^9/L) OR
massive (>6 cm below left costal margin) or progressive palpable splenomegaly OR
massive (>10 cm) or measurable and progressive lymphadenopathy

- Please contact study investigator and/or consult protocol document for specific
details on laboratory criteria CD52 expression by CLL cells Willing to provide
mandatory biospecimen samples for research studies as required by the protocol
Negative serum pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only Willingness to return to the enrolling institution for

- ECOG Performance Status (PS) 0, 1, or 2--Exceptions: Grade 3 allowed if caused by CLL
and not other co-morbidities Provide informed written consent Life expectancy >= 3


- Any of the following comorbid conditions: NYHA class III-IV heart disease, recent
myocardial infarction (< 6 months prior to registration), uncontrolled infection,
infection with the human immunodeficiency virus (HIV/AIDS), serological evidence of
active hepatitis B infection (HBsAg or HBeAg positive) or positive hepatitis C
serology, as further severe immunosuppression with this regimen may occur

- Evidence of active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red
blood cell aplasia Other active primary malignancy requiring treatment or that limits
survival to =< 2 years Any major surgery =< 4 weeks prior to registration Concurrent
investigational drug therapy Any of the following: pregnant women,nursing women, men
or women of childbearing potential who are unwilling to employ adequate contraception
(condoms, diaphragm, birth control pills, injections, intrauterine device [IUD],
surgical sterilization, abstinence, etc.)

- Concomitant use of the following CYP3A4 strong inhibitors: Clarithromycin,
Nefazodone, Telithromycin, Aprepitant, Indinavir, Nelfinavir, Diltiazem,
Borisonazole, Itrazonazole, Ritonavir, Erythromycin, Ketoconazole, Saquinavir,
Fluconazole (may be used if drug levels can be monitored)

- Patients with any known bleeding diathesis (any congenital bleeding disorder that
affects platelet function and/or coagulation including von Willebrand's Disease)

- Severely impaired lung function as defined as spirometry and DLCO that is 50% of the
normal predicted value and/or O2 saturation that is 88% or less at rest on room air
Receiving anticoagulant therapy

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical response (complete or partial remission) (phase II)

Outcome Time Frame:

After 2 courses of treatment

Safety Issue:


Principal Investigator

Clive S. Zent, M.D.

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

July 2009

Completion Date:

Related Keywords:

  • Lymphocytic Leukemia
  • hematopoietic cancer
  • lymphoid cancer
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma



Mayo ClinicRochester, Minnesota  55905
Mayo Clinic in ArizonaScottsdale, Arizona  85259-5404