Lymphoma
Conditions
Keywords
contiguous stage II grade 1 follicular lymphoma, contiguous stage II grade 2 follicular lymphoma, contiguous stage II grade 3 follicular lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma
Brief summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving combination chemotherapy together with rituximab and yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells. PURPOSE: This phase II trial is studying giving combination chemotherapy followed by rituximab and yttrium Y 90 ibritumomab tiuxetan to see how well it works in treating patients with relapsed stage II, stage III, or stage IV follicular non-Hodgkin lymphoma.
Detailed description
OBJECTIVES: Primary * To evaluate the 1-year progression-free survival of patients with relapsed stage II-IV follicular non-Hodgkin lymphoma treated with ESHAP chemotherapy for cytoreduction followed by yttrium Y 90 ibritumomab tiuxetan radioimmunotherapy. * To evaluate the median time to progression in these patients. Secondary * To evaluate the overall and complete response rates in patients treated with this regimen. OUTLINE: * ESHAP chemotherapy: Patients receive ESHAP chemotherapy comprising etoposide IV over 1 hour, methylprednisolone IV, cisplatin IV on days 1-4, and cytarabine IV over 2 hours on day 1. Treatment repeats every 28 days for 2 courses in the absence of disease progression or unacceptable toxicity. * Radioimmunotherapy: Between 4-6 weeks after completion of ESHAP chemotherapy, patients receive rituximab IV followed by indium In 111 ibritumomab tiuxetan IV over 10 minutes on day 1. Patients with \< 25% bone marrow involvement and expected biodistribution proceed to treatment. Patients receive rituximab IV followed by yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 7, 8, or 9. After completion of study treatment, patients are followed periodically.
Interventions
DRUGMethylprednisolone
250 mg/m2/day IV over 1 hour days 1,2,3,4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered.
DRUGEtoposide
40 mg/day IV over 1 hour days 1,2,3,4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered.
DRUGCytarabine
2000 mg/m2 IV over 2 hours days 4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered.
DRUGCisplatin
25 mg/m2/day IV at 1mg/min days 1,2,3,4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered.
DRUGRituximab
250 mg/m2 slow IV over days 1, then 7,8 or 9 prior to In Zevalin. Rituximab + Zevalin regimen is given 4-6 weeks after completion of 2 cycles of ESHAP. Treatment can be completed within 7-9 days in an outpatient setting.
DRUGIn-Zevalin
5 mCi slow IV push over 10 minutes days 1. Given within 4 hours after Rituximab.
DRUGY-Zevalin
Platelet counts from 100,000/mm3 to 149,000/mm3 will receive 0.3 mCi/kg. Platelet counts from \>/= 150,000/mm3 will receive 0.4 mCi/kg, not to exceed 32 mCi Y Zevalin. Slow IV push over 10 minutes, days 7,8 or 9 given within 4 hours after Rituximab.
Sponsors
National Cancer Institute (NCI)
University of Arizona
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 follicular non-Hodgkin lymphoma (NHL) * Bulky stage II, stage III, or stage IV disease, Bulky disease is defined as any tumor measuring 10.0 cm or more or occupying ≥ one-third of the chest diameter * In first, second, third, or fourth relapse after chemotherapy * Unilateral or bilateral bone marrow aspirate and biopsy with cytogenetics within the past 42 days * Tumor CD20 positive by either flow cytometry or immunoperoxidase staining of paraffin sections using anti-CD20 antibodies * Bidimensionally measurable disease * Patients with non-measurable disease in addition to measurable disease must have all non-measurable disease assessed within the past 42 days * No presence of CNS lymphoma * No chronic lymphocytic leukemia * No HIV- or AIDS-related lymphoma * No presence of pleural effusion * Zubrod performance status 0-2 * ANC ≥ 1,500/μL (unless decreased counts are due to marrow involvement with NHL) * Platelet count \> 100,000/μL (unless decreased counts are due to marrow involvement with NHL) * Serum creatinine ≤ 2.0 mg/dL * Creatinine clearance ≤ 50 mL/min * Serum bilirubin ≤ 2.0 mg/dL * No renal insufficiency or renal failure * No known HIV positivity * Not pregnant or nursing * No prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer with 5-year disease-free status * No impaired bone marrow reserve, including any of the following: * Hypocellular bone marrow (cellularity ≤ 15%) * Marked ( ≥ 10%) reduction in bone marrow precursors of one or more cell lines (granulocytic, megakaryocytic, erythroid) (beyond that which would be expected for the patient's age and bone marrow cellularity) * History of failed stem cell collection * No serious, non-malignant disease or infection which, in the opinion of the investigator and/or sponsor, would compromise other protocol objectives * At least 3 weeks since all prior therapy (6 weeks for rituximab) and recovered * No prior myeloablative therapies with autologous bone marrow transplantation or peripheral blood stem cell rescue * No prior radioimmunotherapy * No prior external beam radiotherapy to \> 25% of active bone marrow (involved field or regional) * More than 4 weeks since prior major surgery, other than diagnostic surgery
Exclusion criteria
Patients with impaired bone marrow reserve, as indicated by one or more of the following: * Platelet count \< 100,000 cells/mm3 * Hypocellular bone marrow (cellularity \< or = 10%) * Marked (\> 10%) reduction in bone marrow precursors of one or more cell lines (granulocytic, megakaryocytic, erythroid) (beyond that which would be expected for the patient's age and bone marrow cellularity * History of failed stem cell collection Prior radioimmunotherapy Presence of CNS lymphoma. Patients must not have clinical evidence of central nervous system (CNS) involvement by lymphoma. Patients with abnormal liver function: total bilirubin \> 2.0 mg/dL Patients with abnormal renal function: serum creatinine \> 2.0 mg/dL or creatinine clearance \< 50 ml/min. Patients who have received prior external beam radiation therapy to \> 25% of active bone marrow (involved field or regional) Patients who have received G-CSF or GM-CSF therapy within 2 weeks prior to treatment Serious nonmalignant disease or infection which, in the opinion of the investigator and/or the sponsor, would compromise other protocol objectives Major surgery, other than diagnostic surgery, within 4 weeks Patients with pleural effusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival at 1 Year | 1 year | To evaluate the 1-year progression-free survival (PFS) of patients with relapsed follicular non-Hodgkin's lymphoma (NHL) treated with ESHAP chemotherapy for cytoreduction (2 cycles) followed by Ibritumomab tiuxetan (Zevalin) radioimmunotherapy. |
| Median Time to Progression | 5 years | To evaluate the median TTP of patients with relapsed follicular NHL treated with ESHAP chemotherapy for cytoreduction (2 cycles) followed by Ibritumomab tiuxetan (Zevalin) radioimmunotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 5 years | To evaluate the overall (ORR) response rate with relapsed follicular NHL treated with ESHAP chemotherapy for cytoreduction (2 cycles) followed by Ibritumomab tiuxetan (Zevalin) radioimmunotherapy. Descriptive and summary statistics for demographic and clinical variables obtained. The incidences of reported adverse events (AEs) tabulated. Kaplan-Meier survival analysis for PFS and OS performed on TPP. All the analyses were performed using Stata \[12\]. |
| Complete Response Rate | 5 years | To evaluate the complete (CR) response rate with relapsed follicular NHL treated with ESHAP chemotherapy for cytoreduction (2 cycles) followed by Ibritumomab tiuxetan (Zevalin) radioimmunotherapy |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ESHAP Followed by Zevalin and Rituximab Etoposide, Methylprednisolone, Cytarabine, Cisplatin (ESHAP) infusion X 2 Cycles followed by Rituximab and In-Zevalin or Y-Zevalin.
Methylprednisolone: 250 mg/m2/day IV over 1 hour days 1,2,3,4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered.
Etoposide: 40 mg/day IV over 1 hour days 1,2,3,4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered.
Cytarabine: 2000 mg/m2 IV over 2 hours days 4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be administered.
Cisplatin: 25 mg/m2/day IV at 1mg/min days 1,2,3,4 every 28 days for 2 cycles. If bone marrow \<25% involved and expected biodistribution after 2 cycles yttrium-90-ibritumomab tiuxetan (Zevalin) to be admin | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Ineligible | 1 |
| Overall Study | Physician Decision | 3 |
Baseline characteristics
| Characteristic | ESHAP Followed by Zevalin and Rituximab |
|---|---|
| Age, Customized Median age, years | 61 years STANDARD_DEVIATION 11.9 |
| Baseline B Symptoms | 15 Participants |
| Bone marrow involvement | 12 Participants |
| Elevated beta2-microglobin | 11 Participants |
| Follicular Lymphoma International Prognostic Index (FLIPI) 0 | 1 Participants |
| Follicular Lymphoma International Prognostic Index (FLIPI) 1 | 4 Participants |
| Follicular Lymphoma International Prognostic Index (FLIPI) 2 | 10 Participants |
| Follicular Lymphoma International Prognostic Index (FLIPI) 3 | 8 Participants |
| Follicular Lymphoma International Prognostic Index (FLIPI) 4 | 5 Participants |
| Prior chemotherapy regimens Four cycles | 2 Participants |
| Prior chemotherapy regimens One cycle | 16 Participants |
| Prior chemotherapy regimens Three cycles | 3 Participants |
| Prior chemotherapy regimens Two cycles | 7 Participants |
| Prior chemotherapy regimens Zero cycles | 0 Participants |
| Prior transplant history | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 27 Participants |
| Race/Ethnicity, Customized Hispanic | 3 Participants |
| Region of Enrollment United States | 28 participants |
| Response to prior chemotherapy regimens Complete reponse | 9 Participants |
| Response to prior chemotherapy regimens Partial response | 4 Participants |
| Response to prior chemotherapy regimens Progressive disease | 11 Participants |
| Response to prior chemotherapy regimens Stable disease | 1 Participants |
| Response to prior chemotherapy regimens Unknown | 3 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 10 Participants |
| The Follicular Lymphoma International Prognostic Index-2 (FLIPI2) 0 | 4 Participants |
| The Follicular Lymphoma International Prognostic Index-2 (FLIPI2) 1 | 9 Participants |
| The Follicular Lymphoma International Prognostic Index-2 (FLIPI2) 2 | 8 Participants |
| The Follicular Lymphoma International Prognostic Index-2 (FLIPI2) 3 | 5 Participants |
| The Follicular Lymphoma International Prognostic Index-2 (FLIPI2) 4 | 2 Participants |
| Tumor bulk >5cm | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 28 |
| other Total, other adverse events | 27 / 28 |
| serious Total, serious adverse events | 6 / 28 |
Outcome results
Primary
Median Time to Progression
To evaluate the median TTP of patients with relapsed follicular NHL treated with ESHAP chemotherapy for cytoreduction (2 cycles) followed by Ibritumomab tiuxetan (Zevalin) radioimmunotherapy.
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ESHAP Followed by Zevalin and Rituximab | Median Time to Progression | 10 months |
Primary
Progression-free Survival at 1 Year
To evaluate the 1-year progression-free survival (PFS) of patients with relapsed follicular non-Hodgkin's lymphoma (NHL) treated with ESHAP chemotherapy for cytoreduction (2 cycles) followed by Ibritumomab tiuxetan (Zevalin) radioimmunotherapy.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ESHAP Followed by Zevalin and Rituximab | Progression-free Survival at 1 Year | 38 percentage of participants |
Secondary
Complete Response Rate
To evaluate the complete (CR) response rate with relapsed follicular NHL treated with ESHAP chemotherapy for cytoreduction (2 cycles) followed by Ibritumomab tiuxetan (Zevalin) radioimmunotherapy
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ESHAP Followed by Zevalin and Rituximab | Complete Response Rate | 10 Participants |
Secondary
Overall Response Rate
To evaluate the overall (ORR) response rate with relapsed follicular NHL treated with ESHAP chemotherapy for cytoreduction (2 cycles) followed by Ibritumomab tiuxetan (Zevalin) radioimmunotherapy. Descriptive and summary statistics for demographic and clinical variables obtained. The incidences of reported adverse events (AEs) tabulated. Kaplan-Meier survival analysis for PFS and OS performed on TPP. All the analyses were performed using Stata \[12\].
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ESHAP Followed by Zevalin and Rituximab | Overall Response Rate | 77.3 percentage of participants |