Lymphoma, B-Cell, Lymphoma, Non-Hodgkin
Conditions
Keywords
B-Cell NHL
Brief summary
This research is being done to develop new treatment for non-hodgkin's lymphoma in subjects whose cancer has returned or resisted treatment with chemotherapy. The investigational drug clofarabine is being used in this study. An investigational drug is one that has not been approved by the United States Food and Drug Administration (FDA).
Detailed description
The safety profile of clofarabine appears acceptable within the target populations studied to date in the clinical studies, with numerous responses observed in heavily pre-treated patients with relapsed/refractory ALL or AML. Dose escalation of clofarabine in patients with solid tumors and lymphoproliferative disorders has been limited because grade 3 and 4 myelosuppression was considered acceptable in patients with acute leukemia, provided that hematologic recovery occurred within 6 weeks of therapy , and dose escalation has proceeded as high as 40 mg/m2 in this patient population. Furthermore, no responses were observed in a recent trial in which patients with relapsed CLL were treated with clofarabine 2 mg/m2, an indolent B-cell lymphoproliferative disorder indicating that low doses are likely to be ineffective in patients with aggressive NHL. (Personal Communication with ILEX Products, INC.) This Phase I/II study will evaluate escalating doses of clofarabine in patients with relapsed and refractory diffuse large cell B-cell NHL starting at a dose of 4 mg/m2/day for 5 consecutive days and repeated every 28 days for a maximum of 6 cycles. This dosing regimen should be evaluated in this patient population because there is no standard therapy at relapse and grade 3 and 4 myelosuppression is frequently observed with traditional NHL salvage. Additionally, patients will receive granulocyte colony stimulating factors at the discretion of the investigator. Antifungal and antibacterial prophylaxis will be administered to minimize the risk of infection.
Interventions
DRUGCLOFARABINE
4 mg/m\^2 days 1-5 of every cycle for a maximum of 6 cycles
Sponsors
Genzyme, a Sanofi Company
Oncology Specialists, S.C.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients who are at least 18 years old with histology confirmed diffuse large cell B-cell NHL who have failed prior systemic chemotherapy with or without monoclonal antibody-based therapies. * Measurable disease determined by Ct or PET scans or bone marrow involvement, defined as lesions that can be accurately measured in two dimensions by CT or PET scan with the longest diameter accurately as greater than or equal to 1.0 cm or palpable lesions with both diameters greater than or equal to 2.0 cm. PET scan measurable disease is defined based on SUV value as determined by nuclear medicine evaluation. * Eastern Cooperative Oncology Group (ECOG) performance status of 0,1,or 2. * Life expectancy greater than 12 weeks. * Laboratory values obtained less than or equal to 14 days prior to registration: * Absolute neutrophil count (ANC) greater than or equal to 1500. * White blood cell (WBC) count greater than 3.0. * Platelets greater than or equal to 100. * Hemoglobin (HG) greater than 9.0 g/dL. * Total bilirubin less than or equal to 2.0 mg/dL. * Aspartate transaminase (AST)/alanine transaminase (ALT) less than or equal to 3 times the upper limit of normal (ULN). Higher values are acceptable if it is deemed that they are related to liver involvement with NHL. * Serum creatinine less than or equal to 2.0 mg/dL. * Cardiac function on pretreatment MUGA scan or echocardiogram that is considered normal by institutional standards. * Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent. * Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment. * Male and female patients must use an effective contraceptive method during the study and for a minium of 6 months after study treatment.
Exclusion criteria
* Previously untreated NHL. * Received previous treatment with clofarabine. * History of T-cell lymphoma. * Bulky disease (ie, any single mass greater than 10 cm or circulating malignant cells greater than or equal to 24,000 cells/ul. * Patients with known AIDS-related or HIV-positive lymphoma. * Autologous bone marrow or stem cell transplant within 3 months of study entry. * History of allogeneic bone marrow transplant or organ transplant. * Prior radiotherapy to the only site of measurable disease. * Any medical condition that requires chronic use of oral high-dose corticosteroids. ( in excess of 1 mg/kg/day). * Autoimmune thrombocytopenia. * Use if investigational agents within 30 days or any anticancer therapy within 3 weeks before study entry. The patient must have recovered from all acute toxicities from any previous therapy. * Patients with an active, uncontrolled systemic infection considered to be opportunistic, life threatening, or clinically significant at the time of treatment or with a known or suspected fungal infection (ie, patients of parenteral antifungal therapy). * HIV-positive status. * Active secondary malignancy. * Pregnant or lactating patients. * Any significant concurrent disease, illness , or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow-up, or interpretation of study results. * Patients with active or untreated central nervous lymphoma (CNS) lymphoma.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I Maximum Tolerated Dose | days 1 -28, maximum 6 cycles | Maximum Tolerated Dose for Clofarabine. Cohorts of 3 patients each will receive doses of clofarabine increased in increments as follows: 4, 6, 8, 10, 12,…etc mg/m2/day for 5 days. The dose level immediately below the MTD will be used to treat patients in the Phase II part of the study. Starting dose of 4 mg/m2. |
| Phase II Overall Response | 5 years | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity | 5 years | Number of Participants with Toxicity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Clofarabine Clofarabine 4 mg/m\^2 days 1-5 of every cycle for a maximum of 6 cycles. | 33 |
| Total | 33 |
Baseline characteristics
| Characteristic | Clofarabine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 20 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Age, Continuous | 69 years |
| Region of Enrollment United States | 33 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 33 |
| serious Total, serious adverse events | 21 / 33 |
Outcome results
Primary
Phase II Overall Response
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: 5 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Clofarabine | Phase II Overall Response | patients achieving a complete response | 7 Participants |
| Clofarabine | Phase II Overall Response | patients achieving a partial response | 6 Participants |
| Clofarabine | Phase II Overall Response | Patients not achieving a response | 20 Participants |
Primary
Phase I Maximum Tolerated Dose
Maximum Tolerated Dose for Clofarabine. Cohorts of 3 patients each will receive doses of clofarabine increased in increments as follows: 4, 6, 8, 10, 12,…etc mg/m2/day for 5 days. The dose level immediately below the MTD will be used to treat patients in the Phase II part of the study. Starting dose of 4 mg/m2.
Time frame: days 1 -28, maximum 6 cycles
Population: Per protocol guidelines for accrual to the cohorts.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clofarabine | Phase I Maximum Tolerated Dose | 6 mg/m^2 |
Secondary
Toxicity
Number of Participants with Toxicity
Time frame: 5 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Clofarabine | Toxicity | grade 3 or higher neutropenia or thrombocytopenia | 20 Participants |
| Clofarabine | Toxicity | neutropenia or thrombocytopenia less than grade 2 | 13 Participants |