Methoxyamine and Fludarabine Phosphate in Treating Patients With Relapsed or Refractory Hematologic Malignancies
Methoxyamine and Fludarabine Phosphate in Treating Patients With Relapsed or Refractory Hematologic Malignancies
This phase I trial is studying the side effects and best dose of methoxyamine when given
 together with fludarabine phosphate in treating patients with relapsed or refractory
 hematologic malignancies. Drugs used in chemotherapy, such as methoxyamine and fludarabine
 phosphate, work in different ways to stop the growth of cancer cells, either by killing the
 cells or by stopping them from dividing. Giving methoxyamine together with fludarabine
 phosphate may kill more cancer cells.
PRIMARY OBJECTIVES:

 I. To determine the maximum tolerated dose (MTD) of methoxyamine given in conjunction with
 fludarabine (fludarabine phosphate) in subjects with relapsed or refractory hematologic
 malignancies.

 SECONDARY OBJECTIVES:

 I. To determine the dose limiting toxicities of the combination of methoxyamine and
 fludarabine.

 II. To determine the pharmacokinetics of methoxyamine when given in combination with
 fludarabine.

 III. To evaluate pharmacodynamic endpoints including apurinic/apyrimidinic (AP) sites and
 deoxyribonucleic acid (DNA) strand breaks in blood mononuclear cells to explore the in vivo
 mechanism of action of methoxyamine and identify the biologically optimal dose to be combined
 with fludarabine.

 VI. To determine the disease specific toxicity and biologic activity in a cohort of chronic
 lymphocytic leukemia (CLL) patients.

 OUTLINE: This is a dose-escalation study of methoxyamine.

 Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days 1-5 and
 methoxyamine IV over 1 hour on day 1 (day 2 of course 1). Treatment repeats every 28 days for
 up to 6 courses in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 3 months for up to 1
 year.
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. Non - hematologic acute treatment related
 toxicities must have resolved to a grade 2 or less, whereas non hematologic chronic
 treatment related toxicities must be stable or shown improvement in the 4 weeks
 preceding enrollment. Because of the nature of the diseases treated in this protocol,
 hematologic toxicities are not included in this criterion and must meet the
 eligibility criteria described above. 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