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A Phase II Study of Doxycycline in Relapsed NHL

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ClinicalTrials.gov Identifier: NCT02086591
Recruitment Status : Terminated (Lack of accrual)
First Posted : March 13, 2014
Results First Posted : December 22, 2016
Last Update Posted : December 22, 2016
Sponsor:
Information provided by (Responsible Party):
Carla Casulo, University of Rochester

Brief Summary:
The purpose of this study is to determine whether doxycycline is effective in the treatment of relapsed Non Hodgkin Lymphomas (NHL).

Condition or disease Intervention/treatment Phase
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 Drug: Doxycycline Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Doxycycline in Relapsed NHL
Study Start Date : March 2014
Actual Primary Completion Date : July 2015
Actual Study Completion Date : November 2015


Arm Intervention/treatment
Experimental: Doxycycline
Doxycycline 200 mg twice daily
Drug: Doxycycline



Primary Outcome Measures :
  1. Overall Response Rate [ Time Frame: Three months ]

    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 :
  1. Percentage of Patients With Progression Free Survival [ Time Frame: One year ]
    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.


Other Outcome Measures:
  1. Exploratory Objective [ Time Frame: One year ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02086591


Locations
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United States, New York
University of Rochester
Rochester, New York, United States, 14642
Sponsors and Collaborators
University of Rochester
Investigators
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Principal Investigator: Carla Casulo, MD University of Rochester
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Responsible Party: Carla Casulo, Assistant Professor, University of Rochester
ClinicalTrials.gov Identifier: NCT02086591    
Other Study ID Numbers: 50370
120145 ( Other Identifier: IND )
First Posted: March 13, 2014    Key Record Dates
Results First Posted: December 22, 2016
Last Update Posted: December 22, 2016
Last Verified: October 2016
Keywords provided by Carla Casulo, University of Rochester:
Non Hodgkin Lymphoma
Doxycycline
Additional relevant MeSH terms:
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Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, B-Cell, Marginal Zone
Waldenstrom Macroglobulinemia
Lymphoma, Follicular
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, Lymphoid
Leukemia
Leukemia, B-Cell
Lymphoma, Non-Hodgkin
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Doxycycline
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials