A Phase II Study of Doxycycline in Relapsed NHL

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.

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.