Brief Title
Methoxyamine and Fludarabine Phosphate in Treating Patients With Relapsed or Refractory Hematologic Malignancies
Official Title
Phase I Trial of Fludarabine and Methoxyamine (TRC102) for Relapsed or Refractory Hematologic Malignancies
Brief Summary
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.
Detailed Description
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.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Maximum Tolerated Dose (MTD) of methoxyamine given in conjunction with fludarabine in subjects with relapsed or refractory hematologic malignancies
Secondary Outcome
Number of Participants with Adverse Events as a Measure of Dose limiting toxicities of the combination of methoxyamine and fludarabine
Condition
Adult Nasal Type Extranodal NK/T-cell Lymphoma
Intervention
fludarabine phosphate
Study Arms / Comparison Groups
Treatment (chemotherapy)
Description: Patients receive fludarabine phosphate 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
20
Start Date
May 2011
Completion Date
May 2015
Primary Completion Date
February 2015
Eligibility Criteria
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
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Paolo Caimi, MD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01658319
Organization ID
CASE2Y10
Secondary IDs
NCI-2010-02141
Responsible Party
Sponsor
Study Sponsor
Case Comprehensive Cancer Center
Collaborators
National Cancer Institute (NCI)
Study Sponsor
Paolo Caimi, MD, Principal Investigator, Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
Verification Date
August 2015