Leukemia, Lymphocytic, Chronic, Lymphoma, Small Lymphocytic
Conditions
Keywords
Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia, EL625, cenersen
Brief summary
The purpose of this research study is to see if the investigational drug EL625, when combined with traditional chemotherapy (rituximab, fludarabine, and cyclophosphamide), is effective in Persistent Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)
Detailed description
Chronic lymphocytic leukemia (CLL) and small B-cell lymphocytic lymphoma (SLL) are thought to be different manifestations of the same disease. Treatment options for CLL/SLL range from a watch and wait approach to bone marrow transplant. Currently there is no consensus on the best treatment regimen and new approaches to treatment are needed. EL625 is a 20-mer antisense molecule which binds to a coding region of exon 10 in p53 RNA transcripts. It can bind to both mutant and wild type p53. p53 is involved in regulating apoptosis and DNA repair in cells. When genetic damage occurs p53 is upregulated. As the expression of p53 increases in normal cells they are more likely to undergo apoptosis rather than cell cycle arrest and DNA repair. However in malignant cells, for a given level of DNA damage they are more likely to undergo cell cycle arrest and repair rather than apoptosis. Because EL625 is theorized to increase response to chemotherapy, we propose adding EL625 to a combination of fludarabine, cyclophosphamide and rituximab.
Interventions
DRUGcenersen sodium
2.4 mg/kg/day as a continuous infusion over 24 hours starting on day one and ending on day 4
DRUGRituximab
375 mg/m2 on day 2
DRUGCyclophosphamide
250 mg/m2 on days 2, 3, and 4
DRUGFludarabine
25 mg/m2 on days 2, 3, and 4
Sponsors
Eleos, Inc.
David Rizzieri
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
* Patients with a diagnosis of CLL/SLL who have received at least one prior treatment regimen and have persistent disease (i.e. any evidence of active disease). Patients with a chromosome 17 abnormality or a p53 mutation of any type may be enrolled without having received prior treatment. * Patients must be 18 years of age or older. * Patient has an estimated or measured creatinine clearance ≥30 ml/min at study enrollment. * AST, ALT, total bilirubin \< than 2.5 times the upper limit of normal. * WBC \> 1.5; ANC \>500; Plt \>50,000 unless documented as due to disease * ECOG performance status of 0-2. * Voluntary written informed consent before performance of any study-related procedure not part of normal medical care. * Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for 2 weeks after administration of the study drug. * Male subject agrees to use an acceptable method for contraception for the duration of the study therapy and for 2 weeks after administration of study drug.
Exclusion criteria
* Female who is pregnant or lactating. * 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, resected early stage prostate cancer not requiring systemic treatment or CIS of the cervix or fully treated early stage prostate cancer. * 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 (NYHA class ≥ 2), uncontrolled cardiac arrhythmias, and disseminated intravascular coagulation. * Patients who are unable to refrain from taking acetaminophen * Investigational agent within 14 days of enrolling on the study. * Patients unable or unwilling to refrain from antioxidants including vitamin A, vitamin C, vitamin E, lycopene, lutein, grape seed extract, pycnogenol, green tea extract, and the like. * Patients who have received a prior allogenic stem cell transplant and have at least 2.5% donor cells still evident on engraftment studies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With an Overall Response (Complete Response + Partial Response) | every 3 cycles | Overall Response is the total number of participants with a Complete (CR) or Partial (PR) response. CR requires the absence of lymphadenopathy, hepatomegaly or splenomegaly and constitutional symptoms and a normal CBC; bone marrow must be at least normocellular for age, with less than 30% nucleated cells being lymphocytes with no lymphoid nodules. Partial Response: requires ≥ 50% decrease in one of the following: peripheral blood lymphocyte count, lymphadenopathy, enlargement of liver and/or spleen, or bone marrow involvement by CLL AND at least one hematologic parameter met for 2 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 5 years | Progression is defined as at least one of the following: 1) ≥ 50% increase in the sum of the products of at least two lymph nodes one two consecutive determinations (at least one node must be ≥ 2 cm); appearance of new palpable lymph nodes, 2) ≥ 50% increase in the size of the liver and/or spleen; appearance of palpable hepatomegaly or splenomegaly, which was not previously present, 3) ≥ 50% increase in the absolute number of circulating lymphocytes to at least 5,000/µl or 4)Transformation to a more aggressive histology. |
| Overall Survival | 5 years | — |
Countries
United States
Participant flow
Recruitment details
All patients were enrolled from Duke University Medical Center.
Participants by arm
| Arm | Count |
|---|---|
| All Patients EL625 2.4mg/kg/day as a continuous infusion daily for 4 days combined rituximab 375mg/m2 IV on day 2, fludarabine IV 25mg/m2 over 30 minutes on days 2- 4 and cyclophosphamide IV 250mg/m2 over 1 hour on days 2-4. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Physician Decision | 5 |
| Overall Study | Stem cell transplant | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age Continuous | 62 years |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 8 / 20 |
Outcome results
Primary
Number of Patients With an Overall Response (Complete Response + Partial Response)
Overall Response is the total number of participants with a Complete (CR) or Partial (PR) response. CR requires the absence of lymphadenopathy, hepatomegaly or splenomegaly and constitutional symptoms and a normal CBC; bone marrow must be at least normocellular for age, with less than 30% nucleated cells being lymphocytes with no lymphoid nodules. Partial Response: requires ≥ 50% decrease in one of the following: peripheral blood lymphocyte count, lymphadenopathy, enlargement of liver and/or spleen, or bone marrow involvement by CLL AND at least one hematologic parameter met for 2 months.
Time frame: every 3 cycles
Population: Patients completing at least 2 cycles of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Patients | Number of Patients With an Overall Response (Complete Response + Partial Response) | 9 participants |
Secondary
Overall Survival
Time frame: 5 years
Population: All patients who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients | Overall Survival | 10.6 months |
Secondary
Progression Free Survival
Progression is defined as at least one of the following: 1) ≥ 50% increase in the sum of the products of at least two lymph nodes one two consecutive determinations (at least one node must be ≥ 2 cm); appearance of new palpable lymph nodes, 2) ≥ 50% increase in the size of the liver and/or spleen; appearance of palpable hepatomegaly or splenomegaly, which was not previously present, 3) ≥ 50% increase in the absolute number of circulating lymphocytes to at least 5,000/µl or 4)Transformation to a more aggressive histology.
Time frame: 5 years
Population: All patients who received treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients | Progression Free Survival | 5.3 months |