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Study to Treat Relapsed Follicular Non-Hodgkin's Lymphoma With Radiation and Bexxar

Primary Purpose

Non-Hodgkin's Lymphoma, Follicular Lymphoma

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Iodine I -01 Tositumomab (Bexxar)

External Beam Radiation Therapy

About this trial

This is an interventional treatment trial for Non-Hodgkin's Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

Relapsed Stage I-IV (no evidence of bone marrow involvement) Follicular Non- Hodgkin's Lymphoma (NHF). Patients must have received at least 1 prior therapeutic regimen of chemotherapy or Rituximab and demonstrated progression as demonstrated by biopsy.
One or more of the relapsed sites must be 5 cm or greater in dimension as assessed on two dimensional imaging from CT or MRI scan.
Biopsy at time of relapse confirming continued presence of CD 20 positive follicular lymphoma.
No anti-cancer therapy for 3 weeks (six weeks if Rituximab, nitrosourea or Mitomycin C) prior to study initiation, and fully recovered from all toxicities associated with prior surgery, chemotherapy, or immunotherapy.
An IRB-approved signed informed consent.
Expected survival rate greater than 3 months.
Prestudy performance status of 0 or 1 according to the World Health Organization (WHO) criteria
Acceptable hematologic status within two weeks prior to patient registration, including:
- Absolute neutrophil count (ANC) ([segmented neutrophils + bands] x total white blood cells) greater than 1,500/mm^3
- Platelet counts greater than 100,000/mm^3
Female patients who are not pregnant or lactating.
Men and women of reproductive potential who are following accepted birth control methods (as determined by the treating physician, however, abstinence is not an acceptable method).
Patients previously on Phase II drugs if no long-term toxicity is expected, and the patient has been off the drug for eight or more weeks with no significant post-treatment toxicities observed.

Exclusion Criteria

Patients with impaired bone marrow reserve, as indicated by one or more of the following:
Prior myeloablative therapies with bone marrow transplantation (either autologous or allogeneic) or peripheral blood stem cell (PBSC) rescue.
Platelet count > 100,000 cells/mm^3
Hypocellular bone marrow
Marked reduction in bone marrow precursors of one or more cell lines (granulocytic,megakaryocytic, erythroid).
History of failed stem cell collection
Presence of bone marrow involvement with follicular lymphoma (FL) > 25% based on bone marrow biopsy done within 2 months of enrollment.
Evidence of transformation from original FL to a more aggressive NHL histology.
Prior radioimmunotherapy.
All relapsed sites are < 5 cm in dimension as assessed on two dimensional imaging from CT or MRI scan.
Presence of CNS (central nervous system) involvement.
Presence of primary Non-Hodgkin Lymphoma (NHL) of bone.
Patients with HIV or AIDS-related lymphoma.
Patients with abnormal renal function: serum creatinine > 2.0 mg/dL.
Patients who have received prior external beam radiation therapy within three months of registration.
Patients who have received G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony stimulating factor) therapy within two 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 four weeks.
Presence of anti-murine antibody (HAMA) reactivity.

Sites / Locations

University of Florida

Outcomes

Primary Outcome Measures

The Primary Endpoint of the Study Will be to Determine the Feasibility of Combining External Beam Radiotherapy (EBRT) and Bexxar by Assessing the Toxicities Associated With the Treatment.

13 patients will be enrolled initially and followed for 3 months. If less than 10 of these patients reach a grade III or IV toxicity, then 12 more patients will be enrolled and the study will be deemed feasible. If 11 or more of the first group experience grade III/IV toxicity, the trial will stop early.

Secondary Outcome Measures

The Secondary Endpoint Will be to Assess Response Rates and Patterns of Failure in Patients Treated With Bexxar and External Beam Radiotherapy (EBRT).

Tumor response to treatment is measured using the RECIST criteria: Response Evaluation Criteria in Solid Tumors which defines Complete Response, Partial Response, Progressive Disease, and Stable Disease, by using tumor measurements as seen on CT or MRI

Full Information

NCT ID

NCT00475332

First Posted

May 16, 2007

Last Updated

January 9, 2012

Sponsor

University of Florida

Collaborators

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT00475332

Brief Title

Study to Treat Relapsed Follicular Non-Hodgkin's Lymphoma With Radiation and Bexxar

Official Title

Feasibility Study of External Beam Radiotherapy and Iodine-131 Tositumomab (Bexxar) for Patients With Relapsed Follicular Non-Hodgkin's Lymphoma

Study Type

Interventional

2. Study Status

Record Verification Date

January 2012

Overall Recruitment Status

Terminated

Why Stopped

PI left our institution

Study Start Date

September 2007 (undefined)

Primary Completion Date

April 2009 (Actual)

Study Completion Date

April 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Florida

Collaborators

GlaxoSmithKline

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this study is to determine the feasibility of treating relapsed follicular lymphoma with a combination of Bexxar and External Beam Radiotherapy (EBRT). Patients will receive EBRT (20 Gy in 10 fractions) followed by Bexxar.

Detailed Description

Total dose delivered and tumor size are important predictors of local control in the treatment of low-grade Non-Hodgkin's Lymphoma (NHL). The basic principle is that larger nodal masses require increased doses of External Beam Radiotherapy (EBRT) to achieve local control. Radioimmunotherapy (RIT) seems to share this same characteristic. Review of the published literature on both Bexxar and Zevalin reveals that one of the most important predictors of treatment failure is nodal volume and its apparent relationship to dose delivered by RIT. The best tumor dosimetry for RIT is from Dr. Wiseman et al reporting on the dosimetry of Zevalin (PMID:11418315). He showed that tumors ≥15 cm^3 received only 1082 cGy with Zevalin, whereas the average dose delivered in tumors <15 cm^3 was 4763 cGy. Recently, Gokhale et al (PMID:16111589) published their experience with Zevalin at Cleveland Clinic and showed a significant correlation with pretreatment tumor volume and response to therapy. In their experience, tumors ≥5 cm had an 83% rate of local recurrence versus 28% for tumors <5 cm. This dosing paradox (bigger masses, which require more dose, receive less with RIT) may be diminished by the delivery of additional EBRT. This is the hypothesis that underlies the pilot study. The dosimetric data available for Bexxar is more heterogeneous but confirms the observations seen with Zevalin. In patients previously untreated for low-grade Non-Hodgkin's Lymphoma (NHL), Koral et al (PMID:12621015) showed an increased likelihood of achieving a complete response (CR) if tumor doses were >650 cGy. Previous work by these same authors showed a trend for larger tumor volumes receiving less dose (PMID:10994741). The most compelling data for this relationship comes from the clinical trials done using Bexxar. Both in the pivotal trial (PMID:11579112) and the recently published trial treating naïve patients (PMID:15689582), tumor volume was a significant predictor of response to Bexxar. In the pivotal trial, smaller tumor burden was the only factor predicting longer duration of response. Whereas EBRT might be able to provide reliable radiation dose, the use of Bexxar may provide the therapeutic equivalent of central lymphatic irradiation, which would permit the use of true involved field radiotherapy. Investigators have previously noted that increased EBRT field size is associated with increased short-term and long-term toxicity. The toxicities associated with the treatment of radiotherapy are related to the site treated, but do not necessarily include the dose limiting toxicity of Bexxar, which is primarily hematologic and transient. As the toxicity of RT and Bexxar may not overlap, the combination of both may allow an increase in the therapeutic window for both radiotherapy and Bexxar therapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Non-Hodgkin's Lymphoma, Follicular Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

2 (Actual)

8. Arms, Groups, and Interventions

Intervention Type

Drug

Intervention Name(s)

Iodine I -01 Tositumomab (Bexxar)

Intervention Description

Patients will be treated in two dosing phases, each phase includes two infusions. The first phase, termed "dosimetric dose," involves an intravenous administration of 450 mg unlabeled tositumomab followed by an intravenous administration of 5 mCi (0.18 GBq) of I-131 tositumomab for the purpose of determining the rate of whole body clearance of radioactivity (residence time) so that the administered activity (mCi or GBq) to deliver a 75 cGy (or 65 cGy for patients with baseline platelet count from 100,000 to 149,999/mm^3) total body radiation dose can be calculated.

Intervention Type

Procedure

Intervention Name(s)

External Beam Radiation Therapy

Intervention Description

All patients are to receive 20 Gy in 10 fractions of 200 cGy to the PTV

Primary Outcome Measure Information:

Title

The Primary Endpoint of the Study Will be to Determine the Feasibility of Combining External Beam Radiotherapy (EBRT) and Bexxar by Assessing the Toxicities Associated With the Treatment.

Description

Time Frame

2 yr 3 mos

Secondary Outcome Measure Information:

Title

The Secondary Endpoint Will be to Assess Response Rates and Patterns of Failure in Patients Treated With Bexxar and External Beam Radiotherapy (EBRT).

Description

Time Frame

2 yr 3 mos

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria Relapsed Stage I-IV (no evidence of bone marrow involvement) Follicular Non- Hodgkin's Lymphoma (NHF). Patients must have received at least 1 prior therapeutic regimen of chemotherapy or Rituximab and demonstrated progression as demonstrated by biopsy. One or more of the relapsed sites must be 5 cm or greater in dimension as assessed on two dimensional imaging from CT or MRI scan. Biopsy at time of relapse confirming continued presence of CD 20 positive follicular lymphoma. No anti-cancer therapy for 3 weeks (six weeks if Rituximab, nitrosourea or Mitomycin C) prior to study initiation, and fully recovered from all toxicities associated with prior surgery, chemotherapy, or immunotherapy. An IRB-approved signed informed consent. Expected survival rate greater than 3 months. Prestudy performance status of 0 or 1 according to the World Health Organization (WHO) criteria Acceptable hematologic status within two weeks prior to patient registration, including: Absolute neutrophil count (ANC) ([segmented neutrophils + bands] x total white blood cells) greater than 1,500/mm^3 Platelet counts greater than 100,000/mm^3 Female patients who are not pregnant or lactating. Men and women of reproductive potential who are following accepted birth control methods (as determined by the treating physician, however, abstinence is not an acceptable method). Patients previously on Phase II drugs if no long-term toxicity is expected, and the patient has been off the drug for eight or more weeks with no significant post-treatment toxicities observed. Exclusion Criteria Patients with impaired bone marrow reserve, as indicated by one or more of the following: Prior myeloablative therapies with bone marrow transplantation (either autologous or allogeneic) or peripheral blood stem cell (PBSC) rescue. Platelet count > 100,000 cells/mm^3 Hypocellular bone marrow Marked reduction in bone marrow precursors of one or more cell lines (granulocytic,megakaryocytic, erythroid). History of failed stem cell collection Presence of bone marrow involvement with follicular lymphoma (FL) > 25% based on bone marrow biopsy done within 2 months of enrollment. Evidence of transformation from original FL to a more aggressive NHL histology. Prior radioimmunotherapy. All relapsed sites are < 5 cm in dimension as assessed on two dimensional imaging from CT or MRI scan. Presence of CNS (central nervous system) involvement. Presence of primary Non-Hodgkin Lymphoma (NHL) of bone. Patients with HIV or AIDS-related lymphoma. Patients with abnormal renal function: serum creatinine > 2.0 mg/dL. Patients who have received prior external beam radiation therapy within three months of registration. Patients who have received G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony stimulating factor) therapy within two 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 four weeks. Presence of anti-murine antibody (HAMA) reactivity.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert J Amdur, MD

Organizational Affiliation

University of Florida

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Florida

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

11418315

Citation

Wiseman GA, White CA, Sparks RB, Erwin WD, Podoloff DA, Lamonica D, Bartlett NL, Parker JA, Dunn WL, Spies SM, Belanger R, Witzig TE, Leigh BR. Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. Crit Rev Oncol Hematol. 2001 Jul-Aug;39(1-2):181-94. doi: 10.1016/s1040-8428(01)00107-x.

Results Reference

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PubMed Identifier

12621015

Citation

Koral KF, Dewaraja Y, Li J, Lin Q, Regan DD, Zasadny KR, Rommelfanger SG, Francis IR, Kaminski MS, Wahl RL. Update on hybrid conjugate-view SPECT tumor dosimetry and response in 131I-tositumomab therapy of previously untreated lymphoma patients. J Nucl Med. 2003 Mar;44(3):457-64.

Results Reference

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PubMed Identifier

10994741

Citation

Koral KF, Dewaraja Y, Li J, Barrett CL, Regan DD, Zasadny KR, Rommelfanger SG, Francis IR, Kaminski MS, Wahl RL. Initial results for Hybrid SPECT--conjugate-view tumor dosimetry in 131I-anti-B1 antibody therapy of previously untreated patients with lymphoma. J Nucl Med. 2000 Sep;41(9):1579-86.

Results Reference

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PubMed Identifier

16111589

Citation

Gokhale AS, Mayadev J, Pohlman B, Macklis RM. Gamma camera scans and pretreatment tumor volumes as predictors of response and progression after Y-90 anti-CD20 radioimmunotherapy. Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):194-201. doi: 10.1016/j.ijrobp.2005.01.017.

Results Reference

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PubMed Identifier

11579112

Citation

Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, Lister TA, Stagg RJ, Tidmarsh GF, Kroll S, Wahl RL, Knox SJ, Vose JM. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2001 Oct 1;19(19):3918-28. doi: 10.1200/JCO.2001.19.19.3918.

Results Reference

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PubMed Identifier

15689582

Citation

Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, Zasadny K, Regan D, Kison P, Fisher S, Kroll S, Wahl RL. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005 Feb 3;352(5):441-9. doi: 10.1056/NEJMoa041511.

Results Reference

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Study to Treat Relapsed Follicular Non-Hodgkin's Lymphoma With Radiation and Bexxar

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