A Phase II Study of Doxycycline in Relapsed NHL

• Sponsor: University of Rochester (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02086591
• Collaborator: (none)
• Enrollment: 7
• Location: 1
• Arm: 1
• Duration (Months): 20
• Patients Per Site Per Month: 0.3

Study Details

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).

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.

Study Design

• Study Type: Interventional
• 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: Mar 1, 2014
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [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 [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Rochester	Rochester	New York	United States	14642

Sponsors and Collaborators

• University of Rochester

Investigators

• Principal Investigator: Carla Casulo, MD, University of Rochester

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Carla Casulo, Assistant Professor, University of Rochester
• ClinicalTrials.gov Identifier: NCT02086591
• Other Study ID Numbers: 50370; 120145
• First Posted: Mar 13, 2014
• Last Update Posted: Dec 22, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by Carla Casulo, Assistant Professor, University of Rochester: Non Hodgkin Lymphoma; Doxycycline
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, B-Cell, Marginal Zone; Waldenstrom Macroglobulinemia; Lymphoma, Follicular; Doxycycline

Study Results

Participant Flow

Arm/Group Title	Doxycycline
Arm/Group Description	Doxycycline 200 mg twice daily Doxycycline
Period Title: Overall Study
STARTED	7
COMPLETED	2
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Doxycycline
Arm/Group Description	Doxycycline 200 mg twice daily Doxycycline
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 42.9%
>=65 years	4 57.1%
Gender (Count of Participants)
Female	2 28.6%
Male	5 71.4%
Region of Enrollment (participants) [Number]
United States	7 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxycycline
Arm/Group Description	Doxycycline 200 mg twice daily Doxycycline
Measure Participants	7
Number [percentage of participants]	28 400%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data was collected on all patients who were enrolled.

Arm/Group Title	Doxycycline
Arm/Group Description	Doxycycline 200 mg twice daily Doxycycline
Measure Participants	7
Number [percentage of participants]	57 814.3%

3. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

No data displayed because Outcome Measure has zero total participants analyzed

Arm/Group Title	Doxycycline
Arm/Group Description	Doxycycline 200 mg twice daily Doxycycline
Measure Participants	0

Adverse Events

Arm/Group Title	Doxycycline
Arm/Group Description	Doxycycline 200 mg twice daily Doxycycline
All Cause Mortality
	Doxycycline
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Doxycycline
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Other (Not Including Serious) Adverse Events
	Doxycycline
	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)
Gastrointestinal disorders
vomiting	2/7 (28.6%)
nausea	6/7 (85.7%)
General disorders
fatigue	2/7 (28.6%)
face edema	1/7 (14.3%)
pain	1/7 (14.3%)
Infections and infestations
sepsis	1/7 (14.3%)
Investigations
alanine aminotransferase increase	1/7 (14.3%)
creatinine increased	1/7 (14.3%)
Musculoskeletal and connective tissue disorders
musculoskeletal and connective tissue disorder	1/7 (14.3%)
Skin and subcutaneous tissue disorders
Photosensitivity	3/7 (42.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.