Everolimus and Alemtuzumab in Treating Patients With Recurrent Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00935792
Recruitment Status : Completed
First Posted : July 9, 2009
Results First Posted : December 12, 2016
Last Update Posted : September 26, 2017
Information provided by (Responsible Party):
Mayo Clinic

July 6, 2009
July 9, 2009
April 29, 2016
December 12, 2016
September 26, 2017
July 2009
December 2015   (Final data collection date for primary outcome measure)
  • Clinical Response (Complete or Partial Remission) [ Time Frame: After 2 courses of treatment ]
    CR requires all of the following for a period of at least 2months:Absence of lymphadenopathy.No hepatomegaly or splenomegaly.Absence of constitutional symptoms.• Neutrophils>1500/ul•Platelets>100,000/ul • Hemoglobin >11.0gm/dl• Peripheral blood lymphocytes <4000/uLBonemarrow. normocellular with<30%of nucleated cells being lymphocytes.PR requires two for 2+months.≥50%decrease in peripheral blood lymphocyte count from the pretreatment baseline value.≥ 50%reduction in the sum of the products of the maximal perpendicular diameters of the largest measured node or nodal masses in the right and left cervical, axillary, and inguinal lymph node regions.≥ 50%reduction in size of liver and/or spleen noting the maximal distance below the respective costal margins of palpable hepatosplenomegaly during rest.Neutrophils>1500/ul or50%improvement over baseline. Platelets>100,000/ul or50%increase over baseline. Hemoglobin>11.0 gm/dl or50%increase over baseline without transfusions
  • Number of Participants With Dose-Limiting Toxicities [ Time Frame: 1 Month ]

    The maximum tolerated dose is the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients. A total of 6 patients treated at the MTD will be sufficient to identify common toxicities at the MTD. Dose-limiting toxicity will be defined as an adverse event attributed (definitely, probably, or possibly) to the study treatment and meeting the following criteria.

    Hematologic: ANC ≤ 0.3 x 109/L or platelet count < 10 x 109/L Other nonhematologic: ≥grade 3 as per NCI Common Terminology Criteria for Adverse Events v3.0 except for fatigue, hyperlipidemia, and hyperglycemia.

  • Test the Safety and Tolerability of the Combination of Everolimus and Alemtuzumab. [ Time Frame: Up to 12 months past final treatment ]
    The number and severity of all adverse events will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion. This will provide an indication of the level of tolerance for this treatment combination in this patient group. Below is the number of patients that experienced a grade 3+ Adverse event that was at least possibly related to Treatment.
  • Toxicity as assessed by NCI CTCAE v3.0 (phase I)
  • Clinical response (complete or partial remission) (phase II) [ Time Frame: After 2 courses of treatment ]
  • Maximum tolerated dose of a combination of everolimus and alemtuzumab (phase I)
Complete list of historical versions of study NCT00935792 on Archive Site
  • Survival Time [ Time Frame: up to 5 years ]
    Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier
  • Progression-free Survival [ Time Frame: up to 5 years ]
    Progression-free survival time is defined as the time from registration to progression or death due to any cause. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier
  • Duration of Response [ Time Frame: up to 5 years ]
    Duration of response is defined for all evaluable patients who have achieved a clinical response as the date at which the patient's objective status is first noted to be a Complete Response or Partial Response to the earliest date progression is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier
  • Time to Subsequent Therapy [ Time Frame: up to 5 years ]
  • Survival Time
  • Progression-free Survival
  • Duration of Response
  • Time to Subsequent Therapy
  • Number of complete responses
  • Serial measurements of clinical status and lymphocyte counts
  • IgVH gene mutation, CD38, CD49d, ZAP-70, and FISH status [ Time Frame: At baseline ]
Not Provided
Not Provided
Everolimus and Alemtuzumab in Treating Patients With Recurrent Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) With Everolimus (RAD001) and Alemtuzumab: A Phase I/II Study

RATIONALE: Everolimus may stop the growth of cancer cells by blocking some of the signaling molecules needed for cell growth. Monoclonal antibodies, such as alemtuzumab, can bind to and kill malignant lymphocytes.

PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with alemtuzumab and will see how well they work in treating patients with recurrent chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL).

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.
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Lymphocytic Leukemia
  • Drug: alemtuzumab
    Given subcutaneously
    Other Names:
    • anti-CD52 monoclonal antibody
    • MoAb CD52
    • Monoclonal Antibody Campath-1H
    • Campath-1H
    • Monoclonal Antibody CD52
    • Campath
  • Drug: everolimus
    Given orally
    Other Names:
    • Certican
    • RAD001
    • 42-O-(2-Hydroxy)ethyl Rapamycin
Experimental: Arm I
Patients receive oral everolimus thrice weekly for 9 weeks and alemtuzumab subcutaneously thrice weekly for 8 weeks.
  • Drug: alemtuzumab
  • Drug: everolimus
Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
December 2015
December 2015   (Final data collection date for primary outcome measure)


  • 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 follow-up
  • 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 months


  • 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
Sexes Eligible for Study: All
18 Years to 120 Years   (Adult, Senior)
Contact information is only displayed when the study is recruiting subjects
United States
MC088C ( Other Identifier: Mayo Clinic Cancer Center )
NCI-2009-00935 ( Registry Identifier: NCI's CTRO )
08-008775 ( Other Identifier: Mayo Clinic IRB )
Not Provided
Not Provided
Mayo Clinic
Mayo Clinic
Not Provided
Study Chair: Clive S. Zent, M.D. Mayo Clinic
Principal Investigator: Jose F. Leis, M.D. Mayo Clinic
Mayo Clinic
January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP