Recurrent Mantle Cell Lymphoma Clinical Trial
Official title:
Phase I Trial of Fludarabine and Methoxyamine (TRC102) for 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.
Status | Completed |
Enrollment | 20 |
Est. completion date | May 2015 |
Est. primary completion date | February 2015 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years and older |
Eligibility |
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 |
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
United States | Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center | Cleveland | Ohio |
Lead Sponsor | Collaborator |
---|---|
Case Comprehensive Cancer Center | National Cancer Institute (NCI) |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Maximum Tolerated Dose (MTD) of methoxyamine given in conjunction with fludarabine in subjects with relapsed or refractory hematologic malignancies | 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. | one cycle (28 days) | Yes |
Primary | MTD of methoxyamine given in conjunction with fludarabine in subjects with relapsed or refractory hematologic malignancies | 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. | after 6 cycles (at 6 months) | Yes |
Secondary | Number of Participants with Adverse Events as a Measure of Dose limiting toxicities of the combination of methoxyamine and fludarabine | at 6 cycles (6 months) of treatment | Yes | |
Secondary | Number of Participants with Adverse Events as a Measure of Dose limiting toxicities of the combination of methoxyamine and fludarabine | 1 year | Yes | |
Secondary | Pharmacokinetics of methoxyamine when given in combination with fludarabine as determined by methoxyamine levels at different time points. | 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. | 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 | No |
Secondary | Number of apurinic/pyrimidinic (AP) sites. | 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. | At 0, 2, 24, 27, 48, 72 and 96 hours post fludarabine-treatment | No |
Secondary | Change in miRNA profiles in CLL cells in a cohort of CLL patients | 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. | Baseline and at 2hrs and 27 hours after treatment | Yes |
Secondary | Number of DNA strand breaks determination by comet assay to monitor drug effects on DNA damage in clinical studies. | 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. | At 0, 2, 24, 27, 48, 72 and 96 hours post fludarabine-treatment | No |
Secondary | Measure of Proteins (Bcl-2, Bax, cleaved PARP, Topoisomerase I and II, GammaH2AX) | 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. | day 0h (day1), at 24h (day2) and 48h (day3) prior to drug injection at each time point | No |
Status | Clinical Trial | Phase | |
---|---|---|---|
Withdrawn |
NCT04635683 -
Lenalidomide, Umbralisib, and Ublituximab for the Treatment of Relapsed or Refractory Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma
|
Phase 1 | |
Completed |
NCT01527045 -
Donor Atorvastatin Treatment in Preventing Severe Acute GVHD After Nonmyeloablative Peripheral Blood Stem Cell Transplant in Patients With Hematological Malignancies
|
Phase 2 | |
Active, not recruiting |
NCT02153580 -
Cellular Immunotherapy Following Chemotherapy in Treating Patients With Recurrent Non-Hodgkin Lymphomas, Chronic Lymphocytic Leukemia, or B-Cell Prolymphocytic Leukemia
|
Phase 1 | |
Active, not recruiting |
NCT01955499 -
Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
|
Phase 1 | |
Terminated |
NCT02109224 -
Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection
|
Phase 1 | |
Completed |
NCT01427881 -
Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies
|
Phase 2 | |
Completed |
NCT01233921 -
Palifermin in Preventing Chronic Graft-Versus-Host Disease in Patients Who Have Undergone Donor Stem Cell Transplant for Hematologic Cancer
|
N/A | |
Completed |
NCT01093586 -
Donor Umbilical Cord Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
|
Phase 2 | |
Terminated |
NCT00383565 -
FR901228 in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma
|
Phase 2 | |
Completed |
NCT00253630 -
Vorinostat in Treating Patients With Low-Grade Non-Hodgkin's Lymphoma
|
Phase 2 | |
Completed |
NCT00078858 -
Mycophenolate Mofetil and Cyclosporine in Reducing Graft-Versus-Host Disease in Patients With Hematologic Malignancies or Metastatic Kidney Cancer Undergoing Donor Stem Cell Transplant
|
Phase 1/Phase 2 | |
Completed |
NCT00006473 -
Oxaliplatin in Treating Patients With Relapsed or Refractory Non-Hodgkin's Lymphoma
|
Phase 2 | |
Completed |
NCT00003196 -
Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma
|
N/A | |
Active, not recruiting |
NCT01318317 -
Genetically Engineered Lymphocyte Therapy After Peripheral Blood Stem Cell Transplant in Treating Patients With High-Risk, Intermediate-Grade, B-cell Non-Hodgkin Lymphoma
|
Phase 1/Phase 2 | |
Terminated |
NCT01678443 -
Monoclonal Antibody Therapy Before Stem Cell Transplant in Treating Patients With Relapsed or Refractory Lymphoid Malignancies
|
Phase 1 | |
Completed |
NCT01921387 -
Radiolabeled Monoclonal Antibody and Combination Chemotherapy Before Stem Cell Transplant in Treating Patients With High-Risk Lymphoid Malignancies
|
Phase 1/Phase 2 | |
Active, not recruiting |
NCT01815749 -
Genetically Modified T-cell Infusion Following Peripheral Blood Stem Cell Transplant in Treating Patients With Recurrent or High-Risk Non-Hodgkin Lymphoma
|
Phase 1 | |
Recruiting |
NCT04007029 -
Modified Immune Cells (CD19/CD20 CAR-T Cells) in Treating Patients With Recurrent or Refractory B-Cell Lymphoma or Chronic Lymphocytic Leukemia
|
Phase 1 | |
Completed |
NCT01267812 -
Bortezomib and Rituximab in Treating Patients With Mantle Cell Lymphoma Who Have Previously Undergone Stem Cell Transplantation
|
Phase 2 | |
Completed |
NCT01588015 -
Vaccine Therapy in Preventing Cytomegalovirus Infection in Patients With Hematological Malignancies Undergoing Donor Stem Cell Transplant
|
Phase 1 |