Lymphoma, Follicular
Conditions
Keywords
follicular lymphoma, Velcade, VR-FND
Brief summary
The purpose of this study is to evaluate the effectiveness and safety of combining bortezomib (Velcade) with rituximab, fludarabine, mitoxantrone, and dexamethasone in treating patients with follicular cell lymphoma.
Detailed description
This is a phase II study using the combination of bortezomib, rituximab, fludarabine, mitoxantrone and dexamethasone. The combination will given over a 28 day cycle. In addition each patient will receive Pneumocystis carinii Pneumonia (PCP) prophylaxis with Trimethoprim/sulfamethoxazole (TMP/Sulfa) or equivalent agent. On day 4 the physician has the option of starting granulocyte colony-stimulating factor (GCSF), granulocyte macrophage colony-stimulating factor (GMCSF), or pegylated GCSF. All patients who receive at least one dose of the drug will be evaluated for toxicity. Patients will be treated with the agent for at least 2 cycles to be considered eligible for evaluation of response. The chemotherapy dosing will continue until there is evidence of disease progression, a second recurrence of unacceptable toxicity, or a maximum of 8 courses of therapy.
Interventions
DRUGBortezomib
Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle
DRUGRituximab
Rituximab 375 mg/m2 IV on day 1
DRUGFludarabine
Fludarabine 25 mg/m2 IV on days 1,2,3
DRUGMitoxantrone
Mitoxantrone 10 mg/m2 IV on day 2
DRUGDexamethasone
Dexamethasone 20 mg orally on days 1,2,3,4,5
Sponsors
Millennium Pharmaceuticals, Inc.
Duke University
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
* Diagnosis of grade 1-3 follicular lymphoma with persistent, relapsed, or refractory disease to at least one prior regimen. * No prior bortezomib therapy. * Voluntary written informed consent. * Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control. * Male subject agrees to use an acceptable method for contraception for the duration of the study therapy. * 18 years of age or older. * aspartate aminotransferase (AST),alanine aminotransferase (ALT), total bilirubin \< 3 times the upper limit of normal unless documented by the treating physician to be secondary to underlying lymphoma. * Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
Exclusion criteria
* Platelet count of \< 50,000 within 14 days before enrollment unless documented by the treating physician to be due to the disease. * Absolute neutrophil count of \< 1000 within 14 days before enrollment unless documented by the treating physician to be due to disease. * Estimated or measured creatinine clearance of less than 30 ml/min within 14 days before enrollment. * ≥Grade 2 peripheral neuropathy within 14 days before enrollment. * Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia. * Patient has hypersensitivity to boron, mannitol or any drug included in the current protocol. * Female subject is pregnant or lactating. * Received other investigational drugs for this disease within 14 days of enrollment * Serious medical or psychiatric illness likely to interfere with participation in this clinical study. * Known HIV+ status. * Cardiac ejection fraction less than 35% at study entry measured by echocardiogram, Multigated Acquisition (MUGA) or cardiac MRI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete and Partial Response | 1 year | * Complete Response: Complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms and normalization of biochemical abnormalities (eg. LDH) definitely assignable to follicular lymphoma. * Partial Response requires the following: * greater than or equal to 50% decrease in the SPD of the 6 largest dominant nodes of nodal masses. * No increase in size of other nodes, liver, or spleen. * Splenic and hepatic nodes must regress by at least 50% in sum of the products (SPD). * Bone marrow assessment in irrelevant for determination of Partial Response since it is not measurable disease; however, if positive the type of cell should be reported. * No new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | up to 4 years | Duration of response is measured from time of treatment to time of disease progression |
| Percentage of Subjects Experiencing Progression Free Survival | up to 2 years | Progression free survival is measured from treatment to progression or death, whichever comes first. Progressive disease is measured as: 50% or greater increase from nadir in the sum of the products (SPD) of any previously identified abnormal node and the appearance of any new lesions during or at the end of treatment. |
| Percentage of Subjects Experiencing Overall Survival | up to 2 years | Overall survival is from the day of enrollment to date of death from any cause. |
| Number of Participants With a Grade 3-4 Hematologic Toxicity. | up to 1 year | Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC). |
| Number of Participants With Neuropathy, Any Grade | up to 1 year | Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC). |
Countries
United States
Participant flow
Pre-assignment details
Of the 14 subjects consented, 2 were screen failures so only 12 subjects received the study drug.
Participants by arm
| Arm | Count |
|---|---|
| VR-FND Bortezomib (VELCADER) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab.
Each cycle will be repeated every 28 days for 8 cycles maximum.
Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle
Rituximab: Rituximab 375 mg/m2 IV on day 1
Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3
Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2
Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5 | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | VR-FND |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 59 years |
| Region of Enrollment United States | 14 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Complete and Partial Response
* Complete Response: Complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms and normalization of biochemical abnormalities (eg. LDH) definitely assignable to follicular lymphoma. * Partial Response requires the following: * greater than or equal to 50% decrease in the SPD of the 6 largest dominant nodes of nodal masses. * No increase in size of other nodes, liver, or spleen. * Splenic and hepatic nodes must regress by at least 50% in sum of the products (SPD). * Bone marrow assessment in irrelevant for determination of Partial Response since it is not measurable disease; however, if positive the type of cell should be reported. * No new lesions.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VR-FND | Complete and Partial Response | 64 percentage of participants |
Secondary
Duration of Response
Duration of response is measured from time of treatment to time of disease progression
Time frame: up to 4 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VR-FND | Duration of Response | 16.47143 months |
Secondary
Number of Participants With a Grade 3-4 Hematologic Toxicity.
Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC).
Time frame: up to 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VR-FND | Number of Participants With a Grade 3-4 Hematologic Toxicity. | 7 participants |
Secondary
Number of Participants With Neuropathy, Any Grade
Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC).
Time frame: up to 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VR-FND | Number of Participants With Neuropathy, Any Grade | 6 participants |
Secondary
Percentage of Subjects Experiencing Overall Survival
Overall survival is from the day of enrollment to date of death from any cause.
Time frame: up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VR-FND | Percentage of Subjects Experiencing Overall Survival | 27 percentage of participants |
Secondary
Percentage of Subjects Experiencing Progression Free Survival
Progression free survival is measured from treatment to progression or death, whichever comes first. Progressive disease is measured as: 50% or greater increase from nadir in the sum of the products (SPD) of any previously identified abnormal node and the appearance of any new lesions during or at the end of treatment.
Time frame: up to 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VR-FND | Percentage of Subjects Experiencing Progression Free Survival | 17 percentage of participants |