Methoxyamine and Fludarabine Phosphate in Treating Patients With Relapsed or Refractory Hematologic Malignancies

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01658319
First received: July 26, 2012
Last updated: June 19, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
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
Drug: fludarabine phosphate
Drug: methoxyamine
Other: laboratory biomarker analysis
Other: pharmacological study
Genetic: western blotting
Other: mass spectrometry
Genetic: DNA analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Fludarabine and Methoxyamine (TRC102) for Relapsed or Refractory Hematologic Malignancies

Resource links provided by NLM:


Further study details as provided by Case Comprehensive Cancer Center:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of methoxyamine given in conjunction with fludarabine in subjects with relapsed or refractory hematologic malignancies [ Time Frame: one cycle (28 days) ] [ Designated as safety issue: Yes ]
    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.

  • MTD of methoxyamine given in conjunction with fludarabine in subjects with relapsed or refractory hematologic malignancies [ Time Frame: after 6 cycles (at 6 months) ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Number of Participants with Adverse Events as a Measure of Dose limiting toxicities of the combination of methoxyamine and fludarabine [ Time Frame: at 6 cycles (6 months) of treatment ] [ Designated as safety issue: Yes ]
  • Number of Participants with Adverse Events as a Measure of Dose limiting toxicities of the combination of methoxyamine and fludarabine [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics of methoxyamine when given in combination with fludarabine as determined by methoxyamine levels at different time points. [ Time Frame: On day 2, immediately before and 2 hours after the initialmethoxyamine treatment, on days 3-5, and when the patient returns for fludarabine administration and on day 8 ] [ Designated as safety issue: No ]
    The estimated total dose of methoxyamine given over a 60 minute i.v. infusion needed to produce a Cmax of 41.40 ng/mL (60.40 mg) corresponds to 30 mg/m2 (assuming an average BSA of 2 m2), representing a rational and safe starting methoxyamine dose to administer intravenously over 60 minutes.

  • Number of apurinic/pyrimidinic (AP) sites. [ Time Frame: At 0, 2, 24, 27, 48, 72 and 96 hours post fludarabine-treatment ] [ Designated as safety issue: No ]
    Use aldehyde reactive probe (ARP) reagent to measure AP sites formed by fludarabine and blocked by methoxyamine. AP sites will be measured on DNA extracted from patients' mononuclear cells. Analysis of AP site and DNA strand breakage will be used to determine the biologically optimal dose of methoxyamine to be used in combination with fludarabine.

  • Change in miRNA profiles in CLL cells in a cohort of CLL patients [ Time Frame: Baseline and at 2hrs and 27 hours after treatment ] [ Designated as safety issue: Yes ]
    Specific microRNA (miRNA) expression patterns will uniquely predict the clinical response of CLL patients after exposure to Fludarabine alone or in combination with Methoxyamine (MX) in this phase I clinical trial.

  • Number of DNA strand breaks determination by comet assay to monitor drug effects on DNA damage in clinical studies. [ Time Frame: At 0, 2, 24, 27, 48, 72 and 96 hours post fludarabine-treatment ] [ Designated as safety issue: No ]
    Analysis of AP site and DNA strand breakage will be used to determine the biologically optimal dose of methoxyamine to be used in combination with fludarabine.

  • Measure of Proteins (Bcl-2, Bax, cleaved PARP, Topoisomerase I and II, GammaH2AX) [ Time Frame: day 0h (day1), at 24h (day2) and 48h (day3) prior to drug injection at each time point ] [ Designated as safety issue: No ]
    Results of the protein assays will be used to further elucidate how methoxyamine potentiates fludarabine induced apoptosis and to evaluate potential synergy between the 2 agents.


Estimated Enrollment: 30
Study Start Date: May 2011
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy)
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.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: methoxyamine
Given IV
Other Name: TRC102
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Genetic: western blotting
Correlative studies
Other Names:
  • Blotting, Western
  • Western Blot
Other: mass spectrometry
Correlative studies
Genetic: DNA analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01658319

Locations
United States, Ohio
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Principal Investigator: Paolo Caimi, MD Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
  More Information

No publications provided

Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01658319     History of Changes
Other Study ID Numbers: CASE2Y10, NCI-2010-02141
Study First Received: July 26, 2012
Last Updated: June 19, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma, Follicular
Multiple Myeloma
Neoplasms, Plasma Cell
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Myeloid
Hodgkin Disease
Lymphoma, Mantle-Cell
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Large B-Cell, Diffuse
Lymphoma, B-Cell
Burkitt Lymphoma
Lymphoma, Large-Cell, Immunoblastic
Lymphoma, T-Cell
Mycosis Fungoides
Sezary Syndrome
Lymphoma, T-Cell, Cutaneous
Lymphoma
Leukemia
Waldenstrom Macroglobulinemia
Lymphoma, Large-Cell, Anaplastic
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Immunoblastic Lymphadenopathy
Lymphoma, Extranodal NK-T-Cell
Lymphoma, T-Cell, Peripheral
Lymphomatoid Granulomatosis
Intraocular Lymphoma

ClinicalTrials.gov processed this record on October 01, 2014