Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
B-Cell Chronic Lymphocytic Leukemia, Leukemia
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.
Interventions
DRUGperifosine
Perifosine 50 mg will be taken orally twice a day for a maximum of six 28-day cycles
Sponsors
Keryx Biopharmaceuticals
Keryx / AOI Pharmaceuticals, Inc.
Daphne Friedman
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response | after 3 months of treatment | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | up to a maximum of 2 years | 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 | up to a maximum of 2 years | 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. |
Countries
United States
Participant flow
Recruitment details
All patients were recruited from Duke University Medical Center between 8/2009 and 7/2011
Pre-assignment details
One patient was a screen failure and did not go on to participate in the study.
Participants by arm
| Arm | Count |
|---|---|
| Perifosine Perifosine 50 mg twice a day for a total of six 28-day cycles. | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Perifosine |
|---|---|
| Age Continuous | 69.5 years |
| Age, Customized <=18 years | 0 participants |
| Age, Customized >=65 years | 13 participants |
| Age, Customized Between 18 and 65 years | 3 participants |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 16 / 16 |
Outcome results
Primary
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
Time frame: after 3 months of treatment
Population: Patients who completed 3 months of therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Perifosine | Overall Response | 1 participants |
Primary
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
Time frame: after 6 months of treatment
Population: Patients who completed 6 months of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Perifosine | Overall Response | 0 participants |
Secondary
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.
Time frame: up to a maximum of 2 years
Population: All treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Perifosine | Event-free Survival | 118 Days |
Secondary
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.
Time frame: up to a maximum of 2 years
Population: All treated patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Perifosine | Overall Survival | 289.5 Days |