Phase 2 Study of Atorvastatin Safety and Antitumor Effects in Non-Hodgkin's Lymphoma

• Sponsor: Dean Felsher (Other)
• Overall Status: Completed
• CT.gov ID: NCT00185731
• Collaborator: The Leukemia and Lymphoma Society (Other), Damon Runyon Cancer Research Foundation (Other), Burroughs Wellcome (Industry)
• Enrollment: 25
• Location: 1
• Arm: 1
• Duration (Months): 91
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Lymphoma, Non-Hodgkin	Drug: Atorvastatin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Atorvastatin in Patients With Low Grade or Refractory Non-Hodgkin's Lymphoma
• Study Start Date: Apr 1, 2005
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 80 mg Atorvastatin Atorvastatin, 80 mg tablet, will be taken orally by the patient daily, beginning on study day 1.	Drug: Atorvastatin; 80 mg orally once daily; Other Names: Lipitor

Outcome Measures

Primary Outcome Measures

1. Tumor Apoptosis [1 year]

   Expressed as the number of participants whose tumor cells showed an increase in apoptosis during atorvastatin treatment

Secondary Outcome Measures

1. 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.

2. Atorvastatin Toxicity [1 year]

   Assessed as the number of study participants with atorvastatin-related serious adverse events (SAEs).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Dean Felsher
• The Leukemia and Lymphoma Society
• Damon Runyon Cancer Research Foundation
• Burroughs Wellcome

Investigators

• Principal Investigator: Dean Felsher, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dean Felsher, Associate Professor, Stanford University
• ClinicalTrials.gov Identifier: NCT00185731
• Other Study ID Numbers: IRB-13683; 4328-07; 95140; LYMNHL0020
• First Posted: Sep 16, 2005
• Last Update Posted: Dec 2, 2017
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Atorvastatin

Study Results

Participant Flow

Arm/Group Title	Atorvastatin
Arm/Group Description	Atorvastatin, 80mg tablet, orally once daily.
Period Title: Overall Study
STARTED	25
COMPLETED	23
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Atorvastatin
Arm/Group Description	Atorvastatin, 80mg tablet, orally once daily.
Overall Participants	25
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	21 84%
>=65 years	4 16%
Sex: Female, Male (Count of Participants)
Female	14 56%
Male	11 44%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 8%
Not Hispanic or Latino	22 88%
Unknown or Not Reported	1 4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	21 84%
More than one race	0 0%
Unknown or Not Reported	3 12%
Histology (Count of Participants)
Small Lymphocytic Lymphoma	16 64%
Follicular Lymphoma	6 24%
Marginal Zone B-Cell Lymphoma	2 8%
Splenic Marginal Zone B-Cell Lymphoma	1 4%

Outcome Measures

1. Primary Outcome

Title	Tumor Apoptosis
Description	Expressed as the number of participants whose tumor cells showed an increase in apoptosis during atorvastatin treatment
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

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/Group Title	Atorvastatin
Arm/Group Description	Atorvastatin, 80mg tablet, was taken orally by the patient daily, beginning on study day 1. Atorvastatin: 80 mg orally once daily
Measure Participants	22
Count of Participants [Participants]	7 28%

2. Secondary Outcome

Title	Correlation of Tumor Apoptosis to Clinical Response
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	80 mg
Arm/Group Description	Atorvastatin, 80 mg tablet, was taken orally by the patient daily, beginning on study day 1. Atorvastatin: 80 mg orally once daily
Measure Participants	22
Number [Pearson Correlation Coefficient]	-0.26

3. Secondary Outcome

Title	Atorvastatin Toxicity
Description	Assessed as the number of study participants with atorvastatin-related serious adverse events (SAEs).
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

All study participants who received atorvastatin

Arm/Group Title	80 mg Atorvastatin
Arm/Group Description	Atorvastatin, 80 mg tablet, was taken orally by the patient daily, beginning on study day 1. Atorvastatin: 80 mg orally once daily
Measure Participants	24
Count of Participants [Participants]	4 16%

Adverse Events

Adverse Event Reporting Description	1 participant found not to be eligible and was not analyzed
Arm/Group Title	Atorvastatin
Arm/Group Description	Atorvastatin, 80mg tablet, orally once daily.
All Cause Mortality
	Atorvastatin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Atorvastatin
	Affected / at Risk (%)	# Events
Total	4/24 (16.7%)
Gastrointestinal disorders
Diarrhoea	1/24 (4.2%)
General disorders
Pain - Abdominal NOS	1/24 (4.2%)
Hepatobiliary disorders
Cholecystitis	1/24 (4.2%)
Psychiatric disorders
Mood alteration - Anxiety	1/24 (4.2%)
Other (Not Including Serious) Adverse Events
	Atorvastatin
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
low platelets	1/24 (4.2%)
elevated platelets	1/24 (4.2%)
bruising	1/24 (4.2%)
Cardiac disorders
palpitation	1/24 (4.2%)
Gastrointestinal disorders
nausea	3/24 (12.5%)
constipation	2/24 (8.3%)
diarrhea	4/24 (16.7%)
anorexia	1/24 (4.2%)
bloating	1/24 (4.2%)
vomiting	1/24 (4.2%)
General disorders
diaphoresis	1/24 (4.2%)
pain	13/24 (54.2%)
fatigue	1/24 (4.2%)
Hepatobiliary disorders
elevated SGOT (serum glutamic oxaloacetic transaminase)	5/24 (20.8%)
elevated SGPT (serum glutamic pyruvic transaminase)	6/24 (25%)
elevated alk phos (alkaline phosphatase)	3/24 (12.5%)
hyperbilirubinemia	2/24 (8.3%)
Infections and infestations
infection	4/24 (16.7%)
Musculoskeletal and connective tissue disorders
hematoma	2/24 (8.3%)
Vascular disorders
vasculitis	1/24 (4.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.