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A Phase II Study of Doxycycline in Relapsed NHL

Primary Purpose

Adult Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma Recurrent, Lymphoma, Follicular

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Doxycycline
Sponsored by
University of Rochester
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Diffuse Large B-Cell Lymphoma focused on measuring Non Hodgkin Lymphoma, Doxycycline

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Relapsed aggressive or indolent NHL following any prior treatment of the following etiologies:

    • Diffuse large B cell lymphoma (DLBCL)
    • Mantle cell lymphoma (MCL)
    • Follicular lymphoma (FL)
    • Marginal zone lymphoma (MZL)
    • Lymphoplasmacytic lymphoma (LPL)
    • Waldenstrom's macroglobulinemia (WM)
    • Small lymphocytic lymphoma (SLL)
    • Chronic lymphocytic leukemia (CLL)
    • T cell lymphoma (TCL)
  • Ages ≥ 18
  • Karnofsky Performance Status (KPS) ≥ 60% or Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2
  • Life expectancy of at least 3 months
  • Measurable disease in at least one target lesion, assessable by radiographic examination with Fludeoxyglucose-Positron Emission Tomography (FDG-PET) or computed tomography (CT), bone marrow evaluation showing involvement, or peripheral blood showing involvement of lymphoma

  • Adequate organ function:

    • Absolute neutrophil count (ANC) > 500 cells/mL and platelet count > 50,000 cells/mL unless felt to be secondary to lymphoma at which any count is permissible.
    • Adequate renal function as determined by Creatinine (Cr) < 1.5x upper limit of normal (ULN) or estimated creatinine clearance of ≥ 60mL/min
    • Adequate hepatic function as determined by total bilirubin < 1.5x upper limit of normal (ULN) (unless known Gilbert syndrome), alanine aminotransferase (ALT)and aspartate aminotransferase (AST) < 2.5x upper limit of normal (ULN)

Exclusion Criteria:

  • Known sensitivity or allergy to tetracyclines
  • Lack of measurable disease by computed tomography (CT) or Fludeoxyglucose-Positron Emission Tomography (FDG-PET)
  • Karnofsky Performance Status (KPS) <60% or Eastern Cooperative Oncology Group Performance Status (ECOG PS) >2
  • Curative treatment is indicated or possible
  • Inadequate organ function as measured by not fulfilling above criteria
  • Pregnancy, positive serum human chorionic gonadotropin (hCG) within 28 days of enrollment, or breast-feeding.

Sites / Locations

  • University of Rochester

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Doxycycline

Arm Description

Doxycycline 200 mg twice daily

Outcomes

Primary Outcome Measures

Overall Response Rate
Overall response rate is defined as the percentage of patients with disease progression. Progression is defined as: Appearance of a new lesion on fluorodeoxyglucose (FDG)-positron emission tomography or computerized tomography ≥50% increase in sum of the product of the node dimensions (SPD) of more than one node or in greatest diameter of any previously identified node >1 cm in its short axis from nadir. To be considered progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must increase by 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.

Secondary Outcome Measures

Percentage of Patients With Progression Free Survival
Progression free survival is defined as the percentage of patients with stable disease or no death. Stable disease is defined as less than a partial response but is not progressive disease. Partial Response (PR)-At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses as determined byFDG-PET for CT scan. No increase should be observed in the size of other nodes, liver, or spleen. Patients who achieve a CR by the above criteria, but who have persistent morphologic bone marrow involvement will be considered partial responders. When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients should be considered partial responders.

Full Information

First Posted
February 26, 2014
Last Updated
October 27, 2016
Sponsor
University of Rochester
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1. Study Identification

Unique Protocol Identification Number
NCT02086591
Brief Title
A Phase II Study of Doxycycline in Relapsed NHL
Official Title
A Phase II Study of Doxycycline in Relapsed NHL
Study Type
Interventional

2. Study Status

Record Verification Date
October 2016
Overall Recruitment Status
Terminated
Why Stopped
Lack of accrual
Study Start Date
March 2014 (undefined)
Primary Completion Date
July 2015 (Actual)
Study Completion Date
November 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Rochester

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine whether doxycycline is effective in the treatment of relapsed Non Hodgkin Lymphomas (NHL).
Detailed Description
The long-term objective of this proposal is to develop more effective and less toxic therapeutic approaches for relapsed and refractory Non Hodgkin Lymphomas (NHL). Given the incurability of indolent lymphomas, innovative strategies for treatment are needed. For aggressive lymphomas such as Diffuse Large B Cell Lymphoma (DLBCL), novel treatments are particularly relevant since one third of patients have disease that will relapse or is refractory to standard therapy. Outcomes for this remaining group of patients are very poor. To address this unmet need, we have identified the antimicrobial agent doxycycline as a novel drug repurposed for lymphoma treatment based on results from a small molecule screen against Diffuse Large B Cell Lymphoma (DLBCL). Through preclinical work in his laboratory, my basic science collaborator Dr. Jiyong Zhao has found that doxycycline inhibits proliferation and survival in both activated B cell (ABC) type and germinal center B (GCB) type Diffuse Large B Cell Lymphoma (DLBCL) cell lines, as well as in Burkitt lymphoma (BL) and follicular lymphoma (FL) cell lines. Based on this preliminary data, we propose an open label, single center phase II study of doxycycline in patients with relapsed Non Hodgkin Lymphomas (NHL). We have selected a dose and schedule (200 mg BID by mouth daily) based on maximum antimicrobial dose use, and acceptance of tolerability in several studies. The planned correlative studies should help to identify potential biomarkers for response to doxycycline, such as plasma matrix metalloproteinase 9 (MMP9), and provide further insight into potential mechanisms of doxycyline action hypothesized from results of prior laboratory studies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma Recurrent, Lymphoma, Follicular, Marginal Zone B-Cell Lymphoma, Malignant Lymphoma - Lymphoplasmacytic, Waldenstrom Macroglobulinemia, Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia (CLL), T-Cell Lymphoma
Keywords
Non Hodgkin Lymphoma, Doxycycline

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Doxycycline
Arm Type
Experimental
Arm Description
Doxycycline 200 mg twice daily
Intervention Type
Drug
Intervention Name(s)
Doxycycline
Primary Outcome Measure Information:
Title
Overall Response Rate
Description
Overall response rate is defined as the percentage of patients with disease progression. Progression is defined as: Appearance of a new lesion on fluorodeoxyglucose (FDG)-positron emission tomography or computerized tomography ≥50% increase in sum of the product of the node dimensions (SPD) of more than one node or in greatest diameter of any previously identified node >1 cm in its short axis from nadir. To be considered progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must increase by 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.
Time Frame
Three months
Secondary Outcome Measure Information:
Title
Percentage of Patients With Progression Free Survival
Description
Progression free survival is defined as the percentage of patients with stable disease or no death. Stable disease is defined as less than a partial response but is not progressive disease. Partial Response (PR)-At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses as determined byFDG-PET for CT scan. No increase should be observed in the size of other nodes, liver, or spleen. Patients who achieve a CR by the above criteria, but who have persistent morphologic bone marrow involvement will be considered partial responders. When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients should be considered partial responders.
Time Frame
One year
Other Pre-specified Outcome Measures:
Title
Exploratory Objective
Description
To investigate change in plasma matrix metalloproteinase 9 (MMP9) levels as a biomarker of treatment response; to assess plasma matrix metalloproteinase 9 (MMP9) expression by immunohistochemistry (IHC) and correlate to response in order to test the hypothesis that elevated intratumoral levels of plasma matrix metalloproteinase 9 (MMP9) can predict response to doxycycline. To assess activation/expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kb) and Signal transducer and activator of transcription 3 (STAT 3) pathways in archived tumor by immunohistochemistry (IHC) to predict response or resistance to doxycycline.
Time Frame
One year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Relapsed aggressive or indolent NHL following any prior treatment of the following etiologies: Diffuse large B cell lymphoma (DLBCL) Mantle cell lymphoma (MCL) Follicular lymphoma (FL) Marginal zone lymphoma (MZL) Lymphoplasmacytic lymphoma (LPL) Waldenstrom's macroglobulinemia (WM) Small lymphocytic lymphoma (SLL) Chronic lymphocytic leukemia (CLL) T cell lymphoma (TCL) Ages ≥ 18 Karnofsky Performance Status (KPS) ≥ 60% or Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2 Life expectancy of at least 3 months Measurable disease in at least one target lesion, assessable by radiographic examination with Fludeoxyglucose-Positron Emission Tomography (FDG-PET) or computed tomography (CT), bone marrow evaluation showing involvement, or peripheral blood showing involvement of lymphoma Adequate organ function: Absolute neutrophil count (ANC) > 500 cells/mL and platelet count > 50,000 cells/mL unless felt to be secondary to lymphoma at which any count is permissible. Adequate renal function as determined by Creatinine (Cr) < 1.5x upper limit of normal (ULN) or estimated creatinine clearance of ≥ 60mL/min Adequate hepatic function as determined by total bilirubin < 1.5x upper limit of normal (ULN) (unless known Gilbert syndrome), alanine aminotransferase (ALT)and aspartate aminotransferase (AST) < 2.5x upper limit of normal (ULN) Exclusion Criteria: Known sensitivity or allergy to tetracyclines Lack of measurable disease by computed tomography (CT) or Fludeoxyglucose-Positron Emission Tomography (FDG-PET) Karnofsky Performance Status (KPS) <60% or Eastern Cooperative Oncology Group Performance Status (ECOG PS) >2 Curative treatment is indicated or possible Inadequate organ function as measured by not fulfilling above criteria Pregnancy, positive serum human chorionic gonadotropin (hCG) within 28 days of enrollment, or breast-feeding.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carla Casulo, MD
Organizational Affiliation
University of Rochester
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Rochester
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States

12. IPD Sharing Statement

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A Phase II Study of Doxycycline in Relapsed NHL

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