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Perifosine in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Primary Purpose

Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
perifosine
Sponsored by
Daphne Friedman
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring B-Cell Chronic Lymphocytic Leukemia, Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • A diagnosis of CLL or SLL based on iwCLL diagnostic criteria.
  • Prior therapy for CLL (no limit on number of prior regimens).
  • Patients requiring therapy, based on at least one of the iwCLL criteria.
  • 18 years of age or older.
  • Performance status ECOG 0, 1, or 2.
  • An estimated or measured creatinine clearance ≥30 ml/min at study enrollment.
  • AST, ALT, and total bilirubin ≤ 2.5 times the upper limit of normal, unless due to CLL/SLL.
  • Female subject who is either post-menopausal or surgically sterilized or male or female subject willing to use an acceptable method of birth control for the duration of the study therapy and for 2 weeks after study therapy completion.

Exclusion Criteria:

  • Female subject is pregnant or lactating.
  • Patient has received other investigational drugs for this disease within 14 days of enrollment.
  • Patient with known HIV prior to enrollment.
  • Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  • Patients with another malignancy within the last three years (from documentation of remission) other than basal or squamous cell skin cancer or CIS of the cervix or early stage prostate cancer not requiring systemic treatment.
  • Patients who underwent allogeneic stem cell transplant and have at least 2% donor cells engrafted will be excluded.
  • Significant cardiac or vascular events within 6 months: acute MI, unstable angina, severe peripheral vascular disease (ischemic pain at rest class 3 or worse, non-healing ulcers/wounds, congestive heart failure (NHYA class ≥ 2), uncontrolled cardiac arrhythmias.
  • Known severe hypersensitivity to perifosine or any component of the formulation.
  • Life expectancy less than six months due to co-morbid illness
  • Active autoimmune hemolytic anemia or immune thrombocytopenia, requiring current steroid therapy.
  • De novo prolymphocytic leukemia (PLL) or PLL arising from CLL (≥ 55% prolymphocytes).
  • Richter's transformation

Sites / Locations

  • Duke University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Perifosine

Arm Description

Perifosine 50 mg twice a day for a total of six 28-day cycles.

Outcomes

Primary Outcome Measures

Overall Response
Per International Workshop on Chronic Lymphocytic Leukemia, Complete Response (CR):normal CBC; absence of the following: clonal lymphocytes in blood and marrow, lymphadenopathy, hepatomegaly or splenomegaly, and constitutional symptoms; and bone marrow has <30% lymphocytes, is normocellular, and is without B-lymphoid nodules. Partial Response(PR): one of the following: decrease lymphadenopathy ≥ 50%; decrease of liver and/or spleen size ≥ 50%, any constitutional symptoms, Polymorphonuclear leukocytes ≥ 1,500/µl or a 50% improvement, or decrease of circulating clonal B lymphocytes ≥ 50% AND one of the following: Platelets ≥ 100,000/µl or a 50% improvement, Hemoglobin ≥ 11.0 g/dl or a 50% improvement, Bone marrow has ≥ 30% lymphocytes, or B-lymphoid nodules, or not done. Overall Response (OR)= CR+PR
Overall Response
Per International Workshop on Chronic Lymphocytic Leukemia, Complete Response (CR):normal CBC; absence of the following: clonal lymphocytes in blood and marrow, lymphadenopathy, hepatomegaly or splenomegaly, and constitutional symptoms; and bone marrow has <30% lymphocytes, is normocellular, and is without B-lymphoid nodules. Partial Response(PR): one of the following: decrease lymphadenopathy ≥ 50%; decrease of liver and/or spleen size ≥ 50%, any constitutional symptoms, Polymorphonuclear leukocytes ≥ 1,500/µl or a 50% improvement, or decrease of circulating clonal B lymphocytes ≥ 50% AND one of the following: Platelets ≥ 100,000/µl or a 50% improvement, Hemoglobin ≥ 11.0 g/dl or a 50% improvement, Bone marrow has ≥ 30% lymphocytes, or B-lymphoid nodules, or not done. Overall Response (OR)= CR+PR

Secondary Outcome Measures

Overall Survival
Overall survival is defined as the length of time between discontinuation of perifosine until death or 2 year's followup, whichever comes first.
Event-free Survival
Event-free survival will be defined as the length of time between the discontinuation of study treatment and disease progression, next therapy, or death,whichever comes first, up to a maximum of 2 years.

Full Information

First Posted
March 30, 2009
Last Updated
May 19, 2013
Sponsor
Daphne Friedman
Collaborators
Keryx Biopharmaceuticals, Keryx / AOI Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00873457
Brief Title
Perifosine in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Official Title
Phase II Trial of Perifosine in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
May 2013
Overall Recruitment Status
Completed
Study Start Date
August 2009 (undefined)
Primary Completion Date
October 2011 (Actual)
Study Completion Date
April 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Daphne Friedman
Collaborators
Keryx Biopharmaceuticals, Keryx / AOI Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Perifosine inhibits the AKT pathway (a way cells communicate with each other). This pathway is felt to be important in the development of several types of cancers including chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). It is thought perifosine may be able to block this pathway and lead to an improvement in the CLL or SLL. The purpose of this trial is to see if perifosine is an effective treatment for relapsed or refractory CLL or SLL. Another purpose of this study is to look at the effect perifosine has on cells.
Detailed Description
Chronic lymphocytic leukemia and small B-cell lymphocytic lymphoma represent different manifestations of the same disease. CLL/SLL (hereafter denoted by CLL) is a clonal disorder of small B lymphocytes expressing a characteristic morphology and immunophenotype. The B cells express CD19, dim CD 20, dim CD 5, CD 23, CD 43, CD 79a, and weakly express surface immunoglobin. CLL can present asymptomatically in 25% of patients when diagnosed on a complete blood count. It also can present with diffuse painless lymphadenopathy and, in a smaller number of patients, B symptoms. CLL is characterized by accumulation of circulating B cells predominantly in the G0 phase of the cell cycle. These cells are resistant to apoptosis. CLL has been found to have aberrant signaling in several pathways including NF-kB, Akt/PI3K, and JNK/STAT pathways. Akt is important in promoting CLL survival and viability, as seen in in vitro experiments where blocking its activity results in apoptosis. Thus an AKT inhibitor may lead to increased apoptosis and may have a role in the treatment of this disease. Treatment options for CLL range from a watch and wait approach to high dose chemotherapy with stem cell support. Currently, there is no consensus on the best treatment regimen, since no treatment has been shown to improve survival in randomized prospective clinical trials. New approaches to treatment, especially those with lower toxicity rates, are needed. Perifosine has been shown to inhibit or otherwise modify signaling through a number of different signal transduction pathways, including Akt, MAPK, and JNK. These pathways are involved in the development of cancers and resistance to chemotherapy. Perifosine is of particular interest, especially due to the difficulty in discovery of drugs that inhibit these pathways with minimal toxicity. The effect of perifosine on CLL cells has been tested in the laboratory and has been shown to be an active agent against primary CLL cells in vitro.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Keywords
B-Cell Chronic Lymphocytic Leukemia, Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Perifosine
Arm Type
Experimental
Arm Description
Perifosine 50 mg twice a day for a total of six 28-day cycles.
Intervention Type
Drug
Intervention Name(s)
perifosine
Other Intervention Name(s)
D-21266
Intervention Description
Perifosine 50 mg will be taken orally twice a day for a maximum of six 28-day cycles
Primary Outcome Measure Information:
Title
Overall Response
Description
Per International Workshop on Chronic Lymphocytic Leukemia, Complete Response (CR):normal CBC; absence of the following: clonal lymphocytes in blood and marrow, lymphadenopathy, hepatomegaly or splenomegaly, and constitutional symptoms; and bone marrow has <30% lymphocytes, is normocellular, and is without B-lymphoid nodules. Partial Response(PR): one of the following: decrease lymphadenopathy ≥ 50%; decrease of liver and/or spleen size ≥ 50%, any constitutional symptoms, Polymorphonuclear leukocytes ≥ 1,500/µl or a 50% improvement, or decrease of circulating clonal B lymphocytes ≥ 50% AND one of the following: Platelets ≥ 100,000/µl or a 50% improvement, Hemoglobin ≥ 11.0 g/dl or a 50% improvement, Bone marrow has ≥ 30% lymphocytes, or B-lymphoid nodules, or not done. Overall Response (OR)= CR+PR
Time Frame
after 3 months of treatment
Title
Overall Response
Description
Per International Workshop on Chronic Lymphocytic Leukemia, Complete Response (CR):normal CBC; absence of the following: clonal lymphocytes in blood and marrow, lymphadenopathy, hepatomegaly or splenomegaly, and constitutional symptoms; and bone marrow has <30% lymphocytes, is normocellular, and is without B-lymphoid nodules. Partial Response(PR): one of the following: decrease lymphadenopathy ≥ 50%; decrease of liver and/or spleen size ≥ 50%, any constitutional symptoms, Polymorphonuclear leukocytes ≥ 1,500/µl or a 50% improvement, or decrease of circulating clonal B lymphocytes ≥ 50% AND one of the following: Platelets ≥ 100,000/µl or a 50% improvement, Hemoglobin ≥ 11.0 g/dl or a 50% improvement, Bone marrow has ≥ 30% lymphocytes, or B-lymphoid nodules, or not done. Overall Response (OR)= CR+PR
Time Frame
after 6 months of treatment
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Overall survival is defined as the length of time between discontinuation of perifosine until death or 2 year's followup, whichever comes first.
Time Frame
up to a maximum of 2 years
Title
Event-free Survival
Description
Event-free survival will be defined as the length of time between the discontinuation of study treatment and disease progression, next therapy, or death,whichever comes first, up to a maximum of 2 years.
Time Frame
up to a maximum of 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: A diagnosis of CLL or SLL based on iwCLL diagnostic criteria. Prior therapy for CLL (no limit on number of prior regimens). Patients requiring therapy, based on at least one of the iwCLL criteria. 18 years of age or older. Performance status ECOG 0, 1, or 2. An estimated or measured creatinine clearance ≥30 ml/min at study enrollment. AST, ALT, and total bilirubin ≤ 2.5 times the upper limit of normal, unless due to CLL/SLL. Female subject who is either post-menopausal or surgically sterilized or male or female subject willing to use an acceptable method of birth control for the duration of the study therapy and for 2 weeks after study therapy completion. Exclusion Criteria: Female subject is pregnant or lactating. Patient has received other investigational drugs for this disease within 14 days of enrollment. Patient with known HIV prior to enrollment. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. Patients with another malignancy within the last three years (from documentation of remission) other than basal or squamous cell skin cancer or CIS of the cervix or early stage prostate cancer not requiring systemic treatment. Patients who underwent allogeneic stem cell transplant and have at least 2% donor cells engrafted will be excluded. Significant cardiac or vascular events within 6 months: acute MI, unstable angina, severe peripheral vascular disease (ischemic pain at rest class 3 or worse, non-healing ulcers/wounds, congestive heart failure (NHYA class ≥ 2), uncontrolled cardiac arrhythmias. Known severe hypersensitivity to perifosine or any component of the formulation. Life expectancy less than six months due to co-morbid illness Active autoimmune hemolytic anemia or immune thrombocytopenia, requiring current steroid therapy. De novo prolymphocytic leukemia (PLL) or PLL arising from CLL (≥ 55% prolymphocytes). Richter's transformation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daphne Friedman, MD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

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Perifosine in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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