Leukemia, Lymphoma, Non-Hodgkin
Conditions
Brief summary
This is an approach which can inflict significant toxicity. An alternative is to block expression of oncogenes which are over-expressed only in cancer cells, a therapeutic approach which could reduce toxicity to the host while maximizing destruction of the oncogene-dependent malignant cells.
Detailed description
Atorvastatin has been shown to decrease levels of active oncogenes in preclinical studies with murine and human lymphoma cell lines, and administration of statins leads to shrinkage of lymphoma in murine models. Therefore, it may be possible for atorvastatin to decrease levels of active oncogenes in human lymphomas. Further, upon decrease in levels of active oncogenes, human lymphomas may regress. Atorvastatin is a commonly prescribed drug for hypercholesterolemia: targeting the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme may also be a way to decrease activation of oncogenes in human lymphoma, with minimal toxicity. For human low grade non-Hodgkin lymphoma, no curative treatment is available; therefore new, non-toxic and targeted therapies are sought for this disease.
Interventions
DRUGAtorvastatin
80 mg orally once daily
Sponsors
The Leukemia and Lymphoma Society
Damon Runyon Cancer Research Foundation
Burroughs Wellcome
Dean Felsher
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
* \> 18 years old * Disease criteria: Confirmed by Stanford Pathology to be one of the following Non-Hodgkin's Lymphoma (NHL) subtypes: * Chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL) * Extranodal marginal zone B-cell lymphoma * Nodal marginal zone B-cell lymphoma * Splenic marginal zone B-cell lymphoma * Treatment criteria * Untreated: watchful waiting currently appropriate (includes CLL stage 0) o OR * Prior treatment: watchful waiting currently appropriate o OR * Refractory disease * Staging within 4 weeks prior to enrollment (SLL, marginal zone lymphoma) * CT chest (date) * CT abdomen (date) * CT pelvis (date) OR * Staging within 4 weeks prior to enrollment (CLL: CT not required) * Total white blood cell count (WBC) (Value) (date) * Absolute lymphoma cell count (ALC) (Value) (date) * Measurable disease (Site) (Size) OR * CLL (only): elevated absolute lymphoma cell count * Disease amenable to biopsy (must check at least one): * Circulating tumor cells * Positive bone marrow * Palpable involved site (such as lymph node) measuring \> 1.5 cm * Eastern Cooperative Oncology Group performance status \<2 (Karnofsky \>60) * Life expectancy of greater than 3 months * Patients must have adequate organ and marrow function * Absolute neutrophil count \> 1,000/uL * Platelets \> 30,000/uL * Total bilirubin within normal institutional limits * Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ratio \< 2.5 x institutional upper limit of normal * Creatinine within normal institutional limits OR creatinine clearance \> 60 mL/min/1.73 m² for patients with creatinine levels above institutional normal. * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Women of child-bearing potential must have negative BetaHCG at enrollment
Exclusion criteria
* Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study * Not recovered from adverse events due to agents administered more than four weeks earlier * Has stable low grade lymphoma has had rituximab within 3 months Patient with relapsed or refractory disease has had rituximab within 1 month * Not recovered from adverse events due to surgery performed 4 weeks earlier * Receiving any other investigational agent. Known brain metastases * Taken any statin within the past 6 months prior to enrollment in the trial * Currently abuses alcohol * Currently takes cyclosporin or gemfibrozil Patient has a prior history of rhabdomyolysis * Has uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant: Patients are not excluded if they are breastfeeding at the time of enrollment, but breastfeeding should be discontinued if the mother is treated with atorvastatin. * HIV-positive patients receiving combination anti-retroviral therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Apoptosis | 1 year | Expressed as the number of participants whose tumor cells showed an increase in apoptosis during atorvastatin treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of Tumor Apoptosis to Clinical Response | 1 year | The validity of tumor apoptosis as a biologic endpoint was assessed by correlation to clinical response. A correlation substantially less than 1 is interpreted as a poor correlation, while a correlation near +1 or -1 is interpreted as a strong correlation. |
| Atorvastatin Toxicity | 1 year | Assessed as the number of study participants with atorvastatin-related serious adverse events (SAEs). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin Atorvastatin, 80mg tablet, orally once daily. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Not Eligible | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Atorvastatin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Histology Follicular Lymphoma | 6 Participants |
| Histology Marginal Zone B-Cell Lymphoma | 2 Participants |
| Histology Small Lymphocytic Lymphoma | 16 Participants |
| Histology Splenic Marginal Zone B-Cell Lymphoma | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 3 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Sex: Female, Male Female | 14 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 | 24 / 24 |
| serious Total, serious adverse events | 4 / 24 |
Outcome results
Primary
Tumor Apoptosis
Expressed as the number of participants whose tumor cells showed an increase in apoptosis during atorvastatin treatment
Time frame: 1 year
Population: 24 participants had tumors sampled for primary endpoint as per protocol. However, 1 withdrew, and only 22 of remaining participants had adequate tumor samples for analysis of apoptosis at baseline and at subsequent time points.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Atorvastatin | Tumor Apoptosis | 7 Participants |
Secondary
Atorvastatin Toxicity
Assessed as the number of study participants with atorvastatin-related serious adverse events (SAEs).
Time frame: 1 year
Population: All study participants who received atorvastatin
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Atorvastatin | Atorvastatin Toxicity | 4 Participants |
Secondary
Correlation of Tumor Apoptosis to Clinical Response
The validity of tumor apoptosis as a biologic endpoint was assessed by correlation to clinical response. A correlation substantially less than 1 is interpreted as a poor correlation, while a correlation near +1 or -1 is interpreted as a strong correlation.
Time frame: 1 year
Population: 24 participants had tumors sampled for primary endpoint as per protocol. However, 1 withdrew and 1 had an inadequate tumor samples for analysis, leaving only 22 remaining participants for analysis of apoptosis at baseline and at subsequent time points.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Correlation of Tumor Apoptosis to Clinical Response | -0.26 Pearson Correlation Coefficient |