Lymphoma, Non-Hodgkin
Conditions
Keywords
expanded access study, refractory low-grade non-Hodgkin's Lymphoma, Bexxar®, Iodine I 131 Tositumomab, EAP, relapsed low-grade non-Hodgkin's lymphoma
Brief summary
This is a single arm, multi-center, expanded access study of Iodine I 131 Tositumomab (BEXXAR) therapeutic regimen for patients with relapsed or refractory low-grade or transformed low-grade non-Hodgkin's B-cell lymphoma. The primary objective is to make Iodine I 131 Tositumomab more broadly available to patients. Secondary endpoints will be to obtain additional safety and efficacy information for this treatment regimen. Post study drug administration follow-ups will continue for up to ten years. These will include blood-work and adverse event assessments for 13 weeks post dosing, patient response evaluations at Week 13, Months 6, 12, 18, 24, and Long-Term Follow-ups every 6 months until the elapse of 5 years from the dosimetric dose and then annually thereafter through year 10. Thyroid function will be monitored annually during Long-term follow-up.
Interventions
BIOLOGICALIodine I 131 Tositumomab Therapeutic Regimen
Patients will receive unlabeled Tositumomab (450 mg) followed by Tositumomab (35 mg) which has been trace-labeled with 5 mCi of Iodine-131 (dosimetric dose). Whole body counts using a gamma camera will be obtained 3 times between Days 0 and 7 following the dosimetric dose to determine a patient-specific mCi dose of Iodine-131 calculated to deliver the desired total body dose of radiation (either 65 cGy or 75 cGy). The therapeutic dose is administered 7-14 days after the dosimetric dose. Patients will receive unlabeled Tositumomab (450 mg) followed by Tositumomab (35 mg) labeled with the patient-specific dose of Iodine-131 (median dose in previous studies was approximately 85 mCi). Patients who are obese will be dosed based upon 137% of their calculated lean body mass. Patients will be treated with thyroid blocking medication at least 24 hours prior to the dosimetric dose and continuing for 14 days following the therapeutic dose.
Sponsors
GlaxoSmithKline
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Inclusion criteria
* Histologically confirmed diagnosis of low- grade NHL or transformed low-grade NHL (tumor must be CD 20 positive). * Prior treatment with at least one chemotherapy regimen and have relapsed or progressed, or failed to achieve an objective response on last chemotherapy regimen. * Karnofsky performance status of at least 60% and anticipated survival of at least 3 months. * Absolute granulocyte of \>/= 1,500/mm3. * Platelet count of \>/= 100,000/mm3, and not require sustained support of hematopoietic cytokines, or transfusion of blood products. * Adequate renal function (i.e., \<1.5x Upper Limit of Normal), and hepatic transaminases (AST \<5 times ULN). * Signed IRB/IEC-approved informed consent.
Exclusion criteria
* Patients with a mean of \>25% of the intratrabecular marrow space involved with lymphoma. * Patients who received cytotoxic chemotherapy, radiation therapy, immunotherapy, or cytokine treatment within 4 weeks prior to study entry (6 weeks for nitrosurea compounds) or who exhibit persistent clinical evidence of toxicity. * Patients who have undergone stem cell or bone marrow transplant, active obstructive hydronephrosis, active infection, New York Heart Association Class III or IV heart disease or other serious illness that would preclude evaluation. * Known HIV infection. * Pregnant or nursing patients. * Patients with prior malignancy other than lymphoma, except for adequately-treated skin cancer, in-situ cervical cancer, or cancer for which the patient has been disease-free for 5 years. * Patients with progressive disease within 1 year of irradiation arising in a field that has been previously irradiated with more than 3500 cGy. * Patients who received prior radioimmunotherapy, known brain or leptomeningeal metastases, HAMA positivity. * Patients who are receiving either approved or non-approved (through another protocol) anti-cancer drugs or biologics.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression or Death | From the treatment start date to the first documented incidence of disease progression (PD) or death (up to 161 months) | Time to progression is defined as the time from the treatment start date to the first documented incidence of disease progression (PD) or death. PD is defined as greater than or equal to a 50% increase from nadir in the SPPD for all measurable disease. Lesion changes believed to represent measurement variation associated with radiographic technique should not be classified as PD. |
| Number of Participants With Unconfirmed Response (Complete Response or Partial Response) and Unconfirmed Complete Response | From randomization until the first documented complete response or partial response (up to 161 months) | A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms) or partial response (PR: greater than or equal to a 50% decrease in the sum of the product of perpendicular diameter \[SPPD\] determined at Baseline; no increase in the size of the other nodes, liver, or spleen; no new sites of disease). Response was evaluated by an investigator per guidelines developed by The International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. |
| Number of Participants With Confirmed Response (Complete Response or Partial Response) and Confirmed Complete Response | From randomization until the first documented complete response or partial response (up to 161 months) | A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms) or partial response (PR: greater than or equal to a 50% decrease in the sum of the product of perpendicular diameter \[SPPD\] determined at Baseline; no increase in the size of the other nodes, liver, or spleen; no new sites of disease). Response was evaluated by an investigator per guidelines developed by The International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. A confirmed response (CR and PR) requires that the response be confirmed by another response (same or better) at least 4 weeks apart. |
| Duration of Response for Participants With Unconfirmed Response (CR+PR) | From the time of the first documented response (CR or PR) until disease progression (up to 161 months) | Duration of response is defined as the time from the first documented CR (the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms) or PR (greater than or equal to a 50% decrease in the SPPD determined at Baseline; no increase in the size of the other nodes, liver, or spleen; no new sites of disease) until disease progression (PD). PD is defined as greater than or equal to a 50% increase from nadir in the SPPD for all measurable disease. Lesion changes believed to represent measurement variation associated with radiographic technique should not be classified as PD. Response was evaluated by an investigator per guidelines developed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. |
| Duration of Response for Participants With Confirmed Response (CR+PR) | From the time of the first documented response (CR or PR) until disease progression (up to 161 months) | Duration of response is defined as the time from the first documented CR (the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms) or PR (greater than or equal to a 50% decrease in the SPPD determined at Baseline; no increase in the size of the other nodes, liver, or spleen; no new sites of disease) until disease progression (PD). PD is defined as greater than or equal to a 50% increase from nadir in the SPPD for all measurable disease. Lesion changes believed to represent measurement variation associated with radiographic technique should not be classified as PD. Response was evaluated by an investigator per guidelines developed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. A confirmed response (CR and PR) requires that the response be confirmed by another response (same or better) at least 4 weeks apart. |
| Duration of Response (DOR) in Unconfirmed Complete Responders | From the time of the first documented unconfirmed CR until PD (up to 161 months) | DOR is defined as the time from the first documented response to the first documented disease progression. Unconfirmed CR is defined as the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms. Response was evaluated by an investigator per guidelines developed by The International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. |
| Duration of Response (DOR) in Confirmed Complete Responders | From the time of the first documented CR until PD (up to 161 months) | DOR is defined as the time from the first documented response to the first documented disease progression. CR is defined as the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms. A confirmed response (CR and PR) requires that the response be confirmed by another response (same or better) at least 4 weeks apart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure | From the dosimetric dose to the first occurrence of the following: treatment withdrawal, decision to seek additional therapy, study removal, disease progression, receipt of alternative therapy, or death (up to 161 months) | Time to treatment failure is defined as the time from the date of the dosimetric dose to the first occurrence of the following: treatment withdrawal, decision to seek additional therapy, study removal, disease progression, receipt of alternative therapy for lymphoma, or death study withdrawal for any reason. Participants withdrawn for reasons other than progression or death were censored at their date of withdrawal. |
Participant flow
Pre-assignment details
NHL=Non-Hodgkin's Lymphoma.
Participants by arm
| Arm | Count |
|---|---|
| Tositumomab and Iodine I-131 Tositumomab Participants were treated with a saturated solution of potassium iodide (KI), Lugol's solution, or KI tablets starting at least 24 hours prior to the first infusion of Iodine I-131 Tositumomab (TST) and continuing for 14 days following the last infusion of Iodine I-131 TST. Participants received treatment in two phases. The dosimetric dose was administered in Phase 1 as 450 milligrams (mg) of TST infused over 1 hour (preceded by the administration of oral acetaminophen and an antihistamine), followed by 5 millicurie (mCi) of Iodine I-131 TST infused over 20 minutes (min), followed by a 10-min normal saline flush. The therapeutic dose, administered 7-14 days after the dosimetric dose, was administered as 450 mg of TST infused over 1 hour (preceded by the administration of oral acetaminophen and an antihistamine), followed by the appropriate activity (mCi) of Iodine I-131 TST infused over 20 min, followed by a 10-min normal saline flush. | 765 |
| Total | 765 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Completed 2 Years of Follow-up | 62 |
| Overall Study | Death | 84 |
| Overall Study | Lost to Follow-up | 92 |
| Overall Study | Progressive Disease | 359 |
| Overall Study | Reason Not Specified | 34 |
| Overall Study | Received Other NHL Therapy | 7 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Tositumomab and Iodine I-131 Tositumomab |
|---|---|
| Age, Continuous | 58.8 Years STANDARD_DEVIATION 11.5 |
| Gender Female | 354 Participants |
| Gender Male | 411 Participants |
| Race/Ethnicity, Customized Arab | 1 participants |
| Race/Ethnicity, Customized Asian | 7 participants |
| Race/Ethnicity, Customized Black | 20 participants |
| Race/Ethnicity, Customized Hispanic | 19 participants |
| Race/Ethnicity, Customized Indian | 2 participants |
| Race/Ethnicity, Customized Iranian | 1 participants |
| Race/Ethnicity, Customized Middle Eastern | 1 participants |
| Race/Ethnicity, Customized Native American | 1 participants |
| Race/Ethnicity, Customized Peruvian | 1 participants |
| Race/Ethnicity, Customized Portuguese | 1 participants |
| Race/Ethnicity, Customized White | 711 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 650 / 765 |
| serious Total, serious adverse events | 204 / 765 |
Outcome results
Primary
Duration of Response (DOR) in Confirmed Complete Responders
DOR is defined as the time from the first documented response to the first documented disease progression. CR is defined as the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms. A confirmed response (CR and PR) requires that the response be confirmed by another response (same or better) at least 4 weeks apart.
Time frame: From the time of the first documented CR until PD (up to 161 months)
Population: ITT Population. Only those participants with a confirmed CR were included in this analysis of duration of response. Participants who did not have disease progression were censored in the analysis at the date of their last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tositumomab and Iodine I-131 Tositumomab | Duration of Response (DOR) in Confirmed Complete Responders | NA Months |
Primary
Duration of Response (DOR) in Unconfirmed Complete Responders
DOR is defined as the time from the first documented response to the first documented disease progression. Unconfirmed CR is defined as the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms. Response was evaluated by an investigator per guidelines developed by The International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma.
Time frame: From the time of the first documented unconfirmed CR until PD (up to 161 months)
Population: ITT Population. Only those participants with an unconfirmed CR were included in this analysis of duration of response. Participants who did not have disease progression were censored in the analysis at the date of their last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tositumomab and Iodine I-131 Tositumomab | Duration of Response (DOR) in Unconfirmed Complete Responders | NA Months |
Primary
Duration of Response for Participants With Confirmed Response (CR+PR)
Duration of response is defined as the time from the first documented CR (the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms) or PR (greater than or equal to a 50% decrease in the SPPD determined at Baseline; no increase in the size of the other nodes, liver, or spleen; no new sites of disease) until disease progression (PD). PD is defined as greater than or equal to a 50% increase from nadir in the SPPD for all measurable disease. Lesion changes believed to represent measurement variation associated with radiographic technique should not be classified as PD. Response was evaluated by an investigator per guidelines developed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. A confirmed response (CR and PR) requires that the response be confirmed by another response (same or better) at least 4 weeks apart.
Time frame: From the time of the first documented response (CR or PR) until disease progression (up to 161 months)
Population: ITT Population. Only those participants with a confirmed CR or PR were analyzed for duration of confirmed response. Participants who did not have disease progression were censored in the analysis at the date of their last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tositumomab and Iodine I-131 Tositumomab | Duration of Response for Participants With Confirmed Response (CR+PR) | NA Months |
Primary
Duration of Response for Participants With Unconfirmed Response (CR+PR)
Duration of response is defined as the time from the first documented CR (the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms) or PR (greater than or equal to a 50% decrease in the SPPD determined at Baseline; no increase in the size of the other nodes, liver, or spleen; no new sites of disease) until disease progression (PD). PD is defined as greater than or equal to a 50% increase from nadir in the SPPD for all measurable disease. Lesion changes believed to represent measurement variation associated with radiographic technique should not be classified as PD. Response was evaluated by an investigator per guidelines developed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma.
Time frame: From the time of the first documented response (CR or PR) until disease progression (up to 161 months)
Population: ITT Population. Only those participants with an unconfirmed CR or PR were analyzed for duration of unconfirmed response. Participants who did not have disease progression were censored in the analysis at the date of their last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tositumomab and Iodine I-131 Tositumomab | Duration of Response for Participants With Unconfirmed Response (CR+PR) | 21.0 Months |
Primary
Number of Participants With Confirmed Response (Complete Response or Partial Response) and Confirmed Complete Response
A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms) or partial response (PR: greater than or equal to a 50% decrease in the sum of the product of perpendicular diameter \[SPPD\] determined at Baseline; no increase in the size of the other nodes, liver, or spleen; no new sites of disease). Response was evaluated by an investigator per guidelines developed by The International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. A confirmed response (CR and PR) requires that the response be confirmed by another response (same or better) at least 4 weeks apart.
Time frame: From randomization until the first documented complete response or partial response (up to 161 months)
Population: Intent-to-Treat (ITT) Population: participants receiving any study drug. Only those participants evaluable for confirmed response (those with at least one response assessment) were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tositumomab and Iodine I-131 Tositumomab | Number of Participants With Confirmed Response (Complete Response or Partial Response) and Confirmed Complete Response | CR or PR | 339 Participants |
| Tositumomab and Iodine I-131 Tositumomab | Number of Participants With Confirmed Response (Complete Response or Partial Response) and Confirmed Complete Response | CR | 196 Participants |
Primary
Number of Participants With Unconfirmed Response (Complete Response or Partial Response) and Unconfirmed Complete Response
A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all detectable clinical and radiographic evidence of disease and all disease-related symptoms) or partial response (PR: greater than or equal to a 50% decrease in the sum of the product of perpendicular diameter \[SPPD\] determined at Baseline; no increase in the size of the other nodes, liver, or spleen; no new sites of disease). Response was evaluated by an investigator per guidelines developed by The International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma.
Time frame: From randomization until the first documented complete response or partial response (up to 161 months)
Population: Intent-to-Treat (ITT) Population: participants receiving any study drug. Only those participants evaluable for unconfirmed response (those with at least one response assessment) were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tositumomab and Iodine I-131 Tositumomab | Number of Participants With Unconfirmed Response (Complete Response or Partial Response) and Unconfirmed Complete Response | CR or PR | 437 Participants |
| Tositumomab and Iodine I-131 Tositumomab | Number of Participants With Unconfirmed Response (Complete Response or Partial Response) and Unconfirmed Complete Response | CR | 238 Participants |
Primary
Time to Progression or Death
Time to progression is defined as the time from the treatment start date to the first documented incidence of disease progression (PD) or death. PD is defined as greater than or equal to a 50% increase from nadir in the SPPD for all measurable disease. Lesion changes believed to represent measurement variation associated with radiographic technique should not be classified as PD.
Time frame: From the treatment start date to the first documented incidence of disease progression (PD) or death (up to 161 months)
Population: ITT Population. Participants who did not have disease progression or death were censored in the analysis at the date of their last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tositumomab and Iodine I-131 Tositumomab | Time to Progression or Death | 9.2 Months |
Secondary
Time to Treatment Failure
Time to treatment failure is defined as the time from the date of the dosimetric dose to the first occurrence of the following: treatment withdrawal, decision to seek additional therapy, study removal, disease progression, receipt of alternative therapy for lymphoma, or death study withdrawal for any reason. Participants withdrawn for reasons other than progression or death were censored at their date of withdrawal.
Time frame: From the dosimetric dose to the first occurrence of the following: treatment withdrawal, decision to seek additional therapy, study removal, disease progression, receipt of alternative therapy, or death (up to 161 months)
Population: ITT Population. Participants who did not experience treatment failure were censored at the date of their last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tositumomab and Iodine I-131 Tositumomab | Time to Treatment Failure | 9.0 Months |