Methoxyamine and Fludarabine Phosphate in Treating Patients With Relapsed or Refractory Hematologic Malignancies
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|ClinicalTrials.gov Identifier: NCT01658319|
Recruitment Status : Completed
First Posted : August 7, 2012
Last Update Posted : August 13, 2015
|Condition or disease||Intervention/treatment||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|
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.
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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Trial of Fludarabine and Methoxyamine (TRC102) for Relapsed or Refractory Hematologic Malignancies|
|Study Start Date :||May 2011|
|Actual Primary Completion Date :||February 2015|
|Actual Study Completion Date :||May 2015|
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
Other Name: TRC102
Other: laboratory biomarker analysis
Other: pharmacological study
Other Name: pharmacological studies
Genetic: western blotting
Other: mass spectrometry
Genetic: DNA analysis
- 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) ]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) ]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.
- 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 ]
- Number of Participants with Adverse Events as a Measure of Dose limiting toxicities of the combination of methoxyamine and fludarabine [ Time Frame: 1 year ]
- 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 ]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 ]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 ]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 ]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 ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01658319
|United States, Ohio|
|Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center|
|Cleveland, Ohio, United States, 44106|
|Principal Investigator:||Paolo Caimi, MD||Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center|