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Phase I Trial of Fludarabine and Methoxyamine (TRC102) for Relapsed or Refractory Hematologic Malignancies

Phase 1
18 Years
Open (Enrolling)
Adult Nasal Type Extranodal NK/T-cell Lymphoma, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Cutaneous B-cell Non-Hodgkin Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Hepatosplenic T-cell Lymphoma, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Peripheral T-cell Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Multiple Myeloma, Relapsing Chronic Myelogenous Leukemia, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Stage III Chronic Lymphocytic Leukemia, Testicular Lymphoma, Waldenström Macroglobulinemia

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Trial Information

Phase I Trial of Fludarabine and Methoxyamine (TRC102) for Relapsed or Refractory Hematologic Malignancies


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


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

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

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

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD) of methoxyamine given in conjunction with fludarabine in subjects with relapsed or refractory hematologic malignancies

Outcome Description:

Defined as the highest dose tested in which none or only one subject experiences a dose limiting toxicities attributable to the study drug combination during the first cycle of treatment, when 3-6 subjects were treated at that dose and are evaluable for toxicity.

Outcome Time Frame:

one cycle (28 days)

Safety Issue:


Principal Investigator

Paolo Caimi

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

May 2011

Completion Date:

Related Keywords:

  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Hepatosplenic T-cell Lymphoma
  • Intraocular Lymphoma
  • Nodal Marginal Zone B-cell Lymphoma
  • Peripheral T-cell Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Multiple Myeloma
  • Relapsing Chronic Myelogenous Leukemia
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Stage III Chronic Lymphocytic Leukemia
  • Testicular Lymphoma
  • Waldenström Macroglobulinemia
  • Burkitt Lymphoma
  • Hodgkin Disease
  • Immunoblastic Lymphadenopathy
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, T-Cell
  • Leukemia-Lymphoma, Adult T-Cell
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, Non-Hodgkin
  • Lymphomatoid Granulomatosis
  • Waldenstrom Macroglobulinemia
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Mycoses
  • Mycosis Fungoides
  • Sezary Syndrome
  • Lymphoma, B-Cell
  • Lymphoma, Large-Cell, Immunoblastic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma, T-Cell
  • Lymphoma, T-Cell, Cutaneous
  • Lymphoma, T-Cell, Peripheral
  • Lymphoma, Large-Cell, Anaplastic
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Extranodal NK-T-Cell
  • Lymphoma, Mantle-Cell
  • Hematologic Neoplasms



Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center Cleveland, Ohio  44106-5065
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Cleveland, Ohio  44195