Phase I Trial of Fludarabine and Methoxyamine (TRC102) for Relapsed or Refractory Hematologic Malignancies
Inclusion Criteria:
- Subjects must have a histologically confirmed hematologic malignancy that has
relapsed or proven refractory (in any time frame) to one or more prior therapies,
limited to the following subtypes:
- Non-Hodgkin lymphoma (NHL), including cutaneous lymphoma
- Hodgkin lymphoma (HL)
- Chronic lymphocytic leukemia (CLL)
- Chronic myeloid leukemia (CML)
- Multiple myeloma
- Patients must have progressed through standard curative treatment options in the case
of NHL and HL or not be candidates for curative therapy
- Patients must have measurable disease, and must meet criteria justifying a need to
initiate therapy, criteria for measurable disease and criteria for initiating therapy
for purposes of this study are defined as follows:
- NHL/HL: measurable disease by radiographic criteria (>= 1 cm by computed tomography);
or any degree of bone marrow involvement with lymphoma by morphologic analysis; or
measurable skin involvement according to cutaneous lymphoma response criteria;
criteria for initiating therapy include aggressive histology (diffuse large B cell
lymphoma, nodal T cell lymphomas, Hodgkin lymphoma) or presence of any of the
following: systemic symptoms, bulk >= 5 cm, >= 3 nodal sites, marrow compromise
remaining within limits of adequate function as defined below, splenomegaly >= 16 cm,
disease-related effusion, risk of local compressive symptoms, or circulating lymphoma
cells
- CLL: measurable disease requires B lymphocytes equal or greater than 5,000/μL, or
lymphadenopathy (>= 1 cm by computed tomography), or bone marrow involvement of any
degree; in addition, patients must have one of the following: Rai stage III
(hemoglobin < 11gm/dL) or IV (platelets < 100,000/uL) disease, progressive
splenomegaly, hepatomegaly or lymphadenopathy, weight loss > 10% over the preceding 6
month period, grade 2 or 3 fatigue, fevers > 100.5 or night sweats without evidence
for infection, progressive lymphocytosis with an increase of > 50% over a 2 month
period or an anticipated doubling time of < 6 months
- Chronic Myeloid Leukemia: measurable disease requires peripheral or bone marrow
evidence of CML by hematologic, cytogenetic, or molecular analysis; any patient meets
criteria for initiating therapy who has failed >= 1 prior treatment with a tyrosine
kinase inhibitor (relapsed or refractory)
- Multiple myeloma: measurable disease and presence of end-organ damage; measurable
disease includes any of the following: abnormal free light chain (FLC) ratio, an
M-component in the serum or urine, clonal plasma cells in the bone marrow and/or a
documented clonal plasmacytoma; end-organ damage includes any of the following:
calcium elevation (> 11.5 mg/dl), anemia (hemoglobin < 10 g/dl), bone disease (lytic
lesions or osteopenia), or renal involvement (proteinuria or any known nephropathy)
as long as Cr < 1.5 mg/dL
- Prior chemotherapy and/or radiation are allowed; at least 3 weeks must have elapsed
since prior large-field radiation therapy; patients must have been off previous
anti-cancer therapy for at least 3 weeks and recovered from all treatment related
toxicity; at least 12 weeks must have passed since radioimmunotherapy; prior
fludarabine treatment is not restricted
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Life expectancy > 12 weeks
- Absolute neutrophil count > 750/ul
- Platelets > 50,000/ul
- Hemoglobin > 9.0 g/dl
- Total bilirubin < 1.5 mg/dl
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) <
2.5 x institutional upper limit of normal
- Creatinine < 1.5 mg/dl and/or creatinine clearance > 60 mL/min/1.73 m^2
- Women of childbearing 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; should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients may not be receiving any other investigational agents or have received other
investigational agents for at least 3 weeks
- 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 and lactating women are excluded from this study
- New York Heart Association (NYHA) classification III or IV heart disease
- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases
- Known seizure disorder
- Known human immunodeficiency virus (HIV) or chronic hepatitis (B or C) infection
- Patients unwilling or unable for any reason (personal, medical, or psychiatric) to
comply with the protocol
- Patients with known hypersensitivity to fludarabine or a history of purine analog
associated autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura