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).

Study Overview

• Status: Completed
• Conditions: Lymphocytic Leukemia
• Intervention / Treatment: Drug: everolimus; Drug: alemtuzumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion

• 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

Exclusion

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral everolimus thrice weekly for 9 weeks and alemtuzumab subcutaneously thrice weekly for 8 weeks.	Drug: everolimus; Given orally; Other Names: 42-O-(2-Hydroxy)ethyl Rapamycin; Certican; RAD001; Drug: alemtuzumab; Given subcutaneously; Other Names: Campath; Campath-1H; anti-CD52 monoclonal antibody; MoAb CD52; Monoclonal Antibody Campath-1H; Monoclonal Antibody CD52

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response (Complete or Partial Remission)	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	After 2 courses of treatment
Number of Participants With Dose-Limiting Toxicities	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.	1 Month
Test the Safety and Tolerability of the Combination of Everolimus and Alemtuzumab.	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.	Up to 12 months past final treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival Time	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	up to 5 years
Progression-free Survival	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	up to 5 years
Duration of Response	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	up to 5 years
Time to Subsequent Therapy		up to 5 years

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Study Chair: Clive S. Zent, M.D., Mayo Clinic; Principal Investigator: Jose F. Leis, M.D., Mayo Clinic

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: July 6, 2009
• First Submitted That Met QC Criteria: July 7, 2009
• First Posted (Estimate): July 9, 2009

Study Record Updates

• Last Update Posted (Actual): September 26, 2017
• Last Update Submitted That Met QC Criteria: August 28, 2017
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: hematopoietic cancer; lymphoid cancer
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Everolimus; Alemtuzumab
• Other Study ID Numbers: MC088C (Other Identifier: Mayo Clinic Cancer Center); NCI-2009-00935 (Registry Identifier: NCI's CTRO); 08-008775 (Other Identifier: Mayo Clinic IRB)