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

A Phase II Study of Atorvastatin in Patients With Low Grade or Refractory Non-Hodgkin's Lymphoma

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma, Non-Hodgkin; Leukemia
• Intervention / Treatment: Drug: Atorvastatin

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 Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Dean Felsher
• Collaborators: The Leukemia and Lymphoma Society; Burroughs Wellcome; Damon Runyon Cancer Research Foundation
• Investigators: Principal Investigator: Dean Felsher, Stanford University

Study record dates

Study Major Dates

• Study Start: April 1, 2005
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Actual): December 2, 2017
• Last Update Submitted That Met QC Criteria: October 25, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, Non-Hodgkin; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: IRB-13683; 4328-07 (Other Identifier: Damon Runyon Cancer Research Foundation); 95140 (Other Identifier: Stanford University Alternate IRB Approval Number); LYMNHL0020 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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