Study of Safety and Efficacy of a Sequential Regimen Consisting of Three Cycles of Fludarabine Followed by Tositumomab and Iodine I 131 Tositumomab

Study Overview
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Brief Summary
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This is a single-arm, single institution, phase II study of fludarabine monophosphate followed by Iodine I 131 Tositumomab for patients with previously untreated, advanced-stage (stage III or IV) low-grade, transformed low-grade and follicular non-Hodgkin's lymphoma. The primary objective of the study will be to evaluate the safety of this treatment combination and the secondary endpoint will be to evaluate efficacy.

Official Title
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Fludarabine Monophosphate Followed by Iodine I 131 Tositumomab for Untreated Low-grade and Follicular Non-Hodgkin's Lymphoma

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Biological: Tositumomab and Iodine I 131 Tositumomab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be age 18 years or older. Patients must have a histologically-confirmed diagnosis of low-grade or follicular non-Hodgkin's B-cell lymphoma. Patients must have Ann Arbor stage III or IV extent of disease after completing staging. Patients must have bi-dimensionally measurable disease. At least one lesion must have both perpendicular diameters > 2 cm. Patients must have evidence that their tumor expresses the CD20 antigen by immunohistochemistry or flow cytometry. Patients must have no previous treatment for NHL. Patients must have a Karnofsky performance status of at least 60% and an anticipated survival of at least 3 months. Patients must have absolute granulocyte count greater than or equal to 1500 cells/mm3 and a platelet count > 100,000 cells/mm3 within 14 days of study entry and not require sustained support with hematopoietic cytokines or transfusion of blood products. Patients must have adequate renal and hepatic function. Patients must sign IRB approved informed consent form(s) prior to study entry. Exclusion Criteria: Patients who received systemic steroids within 1 week of study entry, except patients on maintenance steroid therapy for a non-cancerous disease. Patients with evidence of active infection requiring intravenous antibiotics at the time of study entry. Patients with New York Heart Association class III or IV heart disease or other serious illness that would preclude evaluation. Patients with known HIV Infection. Patients with known brain or leptomeningeal metastases. Patients who are pregnant or nursing. Patients of childbearing potential must undergo a pregnancy test at screening and on the day fludarabine treatment is started. Treatment is not to be administered until a negative result is obtained. Males and females must agree to use effective contraception for 6 months following the iodine I 131 tositumomab therapy. Patients with prior malignancy other than lymphoma, except for adequately-treated skin cancer in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 years. Patients with hypersensitivity to fludarabine. Patients who are receiving either approved or non-approved (through another protocol) anti-cancer drugs or biologics. Patients who are HAMA positive. Patients with previous allergic reaction to iodine. This does not include reacting to intravenous iodine containing contrast materials. Inclusion Criteria for Iodine I 131 Tositumomab Therapy Patients who completed 3 cycles of fludarabine. Patients must have absolute granulocyte count ≥ to 1500/mm3, platelet count of ≥ 100,000/mm3 (≥ 150,000/mm3 if > 25% bone marrow involvement at restaging), and not require sustained support with hematopoietic cytokines or transfusions with blood products. Patients must have adequate renal and hepatic function. Exclusion criteria for Antibody Therapy Patients with active obstructive hydronephrosis. Patients with evidence of active infection requiring intravenous antibiotics. Patients who are pregnant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Patients will first receive an abbreviated course of three cycles of fludarabine (25 mg/m2 for 5 days every 5 weeks). Iodine I 131 tositumomab will be initiated 6 to 8 weeks after completion of fludarabine. Patients will undergo dosimetry studies to determine the appropriate patient-specific activity of iodine I 131 tositumomab required to deliver a fixed dose of 75 cGy. The dose will be attenuated to 65 cGy for patients with platelet counts between 100,000 and 150,000/micoliter. | Biological: Tositumomab and Iodine I 131 Tositumomab<br>* Tositumomab and Iodine I 131 Tositumomab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and does not necessarily have to have a causal relationship (association) with this treatment. Therefore, an AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not it was considered to be related to the medicinal product. Laboratory abnormalities were recorded as AEs only if they were associated with clinical sequelae and/or required an intervention. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants With Any Treatment-related Adverse Event (TRAE) | All noxious and unintended responses to a study treatment related to any dose were considered as TRAEs. A response to a study treatment indicates that a causal relationship between a study drug and an adverse event was at least a reasonable possibility, i.e., the relationship cannot be ruled out. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants With Any Grade 3 or Grade 4 Adverse Event | Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No adverse event or within normal limits; 1 = Mild adverse event; 2 = Moderate adverse event; 3 = Severe and undesirable adverse event; 4 = Life-threatening or disabling adverse event; 5 = Death related to adverse event. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants With Any Treatment-related Grade 3 or Grade 4 Adverse Event | All of the treatment-related grade 3 (severe and undesirable) and grade 4 (life-threatening or disabling) adverse events experienced by the participants were recorded. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants With Any Serious Adverse Event (SAE) | An SAE was defined as any event occurring at any dose that results in any of the following outcomes: death, a life threatening adverse drug experience (at immediate risk of death from the experience as it occurred), inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered to be a serious adverse drug experience when based upon appropriate medical judgment. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants With Any Treatment-related SAE | All of the treatment-related SAEs experienced by the participants were recorded. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants With the Indicated Grade 3 and Grade 4 AEs | AEs were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades: 0 = No AE or within normal limits; 1 = Mild AE; 2 = Moderate AE; 3 = Severe and undesirable AE; 4 = Life-threatening or disabling AE; 5 = Death related to AE. mm, millimeters; mm^3, millimeters cubed. Grade 3 and Grade 4 AEs are reported to focus on the most severe AEs. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants With the Indicated Treatment-related AEs Experienced by at Least 10% of Participants in the Combined Regimen | All noxious and unintended responses to a study treatment related to any dose were considered as TRAEs. A response to a study treatment indicates that a causal relationship between a study drug and an adverse event was at least a reasonable possibility, i.e., the relationship cannot be ruled out. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants Who Were Negative for Human Anti-murine Antibodies (HAMA) at Baseline (Study Entry) But Positive or Negative at Weeks 12 and 25 and at Months 12, 18, and 24 | The administration of murine antibodies may form HAMA. A HAMA assay was performed using the ImmunoSTRIP HAMA IgG enzyme-linked immune absorbent assay by a central laboratory (Covance Classic Laboratory Services, Indianapolis, IN). Fludarabine, a known immunosuppressant, might decrease HAMA production in addition to reducing bone marrow involvement. To be positive, a participant had to have a positive HAMA assessment at any follow-up visit (Weeks 12 and 25; Months 12, 18, and 24). | Day 1 to Day 730 (24 Months) after receiving the dosimetric dose | 
| Time to HAMA Positivity From the First TST/I 131 TST Dosimetric Dose for the Participants Achieving HAMA Positivity | Kaplan-Meier estimates of the time to HAMA positivity (days from the first fludarabine dose) was determined for participants who converted to HAMA positivity. | Day 1 to Day 730 (24 Months) after receiving the dosimetric dose | 
| Number of Participants With Elevated Thyroid-Stimulating Hormone (TSH) Levels at Baseline (Study Entry) and Weeks 25, 52, 78, 104, 130, 156, 182, 208, 234, 260, 286, 312, 364, 416, 468, and 512 | The number of participants with elevated TSH levels is reported. An elevated TSH level indicates that an insufficient amount of the thyroid hormone is being produced. Insufficient thyroid hormone production is known as hypothyroidism. The normal range of TSH is between 0.2 and 6.1 milliunits per liter (mU/L). | Baseline (Week -16) and Weeks 25, 52, 78, 104, 130, 156, 182, 208, 234, 260, 286, 312, 364, 416, 468, and 512 | 
| Number of Participants With Thyroid Medication Use Prior to the Therapeutic Dose | Thyroid medication included any prescribed medication for the treatment of thyroid dysfunction. | Baseline (study entry; Week -16) and Week 2 to Week 3 (prior to the therapeutic dose) | 
| Time to Nadir for Hematological Parameters: Absolute Neutrophil Count (ANC), Hemoglobin, and Platelets | Nadir was defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose). | up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose) | 
| Nadir Values for Absolute Neutrophil Count (ANC) | Nadir was defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose). | up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose) | 
| Nadir Values for Hemoglobin | Nadir was defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose). | up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose) | 
| Nadir Values for Platelet Count | Nadir was defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose). | up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose) | 
| Number of Participants With Any Grade 3 or Grade 4 Toxicity (AE) for Hematological Parameters (Absolute Neutrophil Count [ANC], Hemoglobin, and Platelets) | Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades (G): 0=No AE or within normal limits; 1=Mild AE; 2=Moderate AE; 3=Severe and undesirable AE; 4=Life-threatening or disabling AE; 5=Death related to AE. ANC (10^3/mm^3): G1=1.5 to <2.0, G2=1.0 to <1.5, G3=0.5 to < 1.0, G4=<0.5. Hemoglobin (g/dL): G1=10.0 to <12.0, G2=8.0 to <10.0, G3=6.5 to <8.0, G4=< 6.5. Platelets (10^3/microliter): G1=75 to <150, G2=50 to <75, G3=25 to <50, G4=<25. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Duration of Any Grade 3 or Grade 4 Toxicity for Hematological Parameters: Absolute Neutrophil Count (ANC), Hemoglobin, and Platelets | Adverse events were graded using the Common Toxicity Criteria from the Cancer Therapy Evaluation Program, Division of Cancer Therapy, National Cancer Institute. Grades (G): 0=No AE or within normal limits; 1=Mild AE; 2=Moderate AE; 3=Severe and undesirable AE; 4=Life-threatening or disabling AE; 5=Death related to AE. ANC (10^3/mm^3): G1=1.5 to <2.0, G2=1.0 to <1.5, G3=0.5 to < 1.0, G4=<0.5. Hemoglobin (g/dL): G1=10.0 to <12.0, G2=8.0 to <10.0, G3=6.5 to <8.0, G4=< 6.5. Platelets (10^3/microliter): G1=75 to <150, G2=50 to <75, G3=25 to <50, G4=<25. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants With Any Infection at Week 16 Post-Fludarabine Treatment and Week 13 Post-TST Treatment Detected by Laboratory Culture of Participant Sample or Investigator Report | An infection is the colonization of a host organism by a parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease. Colloquially, infections are usually considered to be caused by microscopic organisms or microparasites like viruses, bacteria, and viroids, although larger organisms such as macroparasites and fungi can also infect. | Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) | 
| Number of the Indicated Type of Infection Reported by Investigator Based on Laboratory Testing at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment | An infection is the colonization of a host organism by a parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease. Colloquially, infections are usually considered to be caused by microscopic organisms or microparasites like viruses, bacteria, and viroids, although larger organisms such as macroparasites and fungi can also infect. | Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) | 
| Number of Participants With a Culture Obtained for Infection at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment | Specimen samples of the body fluid are cultured for testing whether the infectious organism is present and grown in the culture media to assess the growth pattern of the organisms present in the specimen. | Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) | 
| Number of Participants With Positive Culture Results for Infections at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment | The culture results could be positive or negative. The positive culture results indicates that the tested participant have the infection under investigation so therapeutic treatment with anti-infective is required. | Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) | 
| Number of Participants With an Anti-infective Administered at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment | Anti-infectives are capable of acting against infection, by inhibiting the spread of an infectious agent or by killing the infectious agent outright. Anti-infective is a general term that encompasses antibacterials, antibiotics, antifungals, antiprotozoans, and antivirals. | Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13) | 
| Number of Participants Who Received Any Supportive Care After Fludarabine Treatment and After TST Treatment | Supportive care involves interventions that help the participants to achieve comfort but do not affect the course of a disease. | First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520) | 
| Number of Participants Receiving the Indicated Type of Supportive Care After Fludarabine Treatment and After TST Treatment | Supportive care involves interventions that help the participants to achieve comfort but do not affect the course of a disease. Supportive care involved administration of granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), red blood cell (RBC) transfusions, erythropoietin, and platelet transfusions. | First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Investigator-assessed Confirmed Responses of Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR) | CR: Complete resolution of disease-related (DR) radiological abnormalities; disappearance of non-Hodgkin's lymphoma-related signs/symptoms. CCR: Complete resolution of DR symptoms except for residual scar tissue. PR: 50% reduction in the sum of the products of the longest perpendicular diameters of measurable lesions with no new lesions. A confirmed response (resp.) (CR/CCR/PR) had to be confirmed by a consecutive resp. (>=28 days later) that was the same/better. Individual confirmed resp. data only counts that resp. confirmed by the same resp.; not all possible combinations are represented. | First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) | 
| Number of Participants With the Investigator-assessed Unconfirmed Responses of Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR) | CR: Complete resolution of disease-related (DR) radiological abnormalities; disappearance of non-Hodgkin's lymphoma-related signs/symptoms. CCR: Complete resolution of DR symptoms except for residual scar tissue. PR: 50% reduction in the sum of the products of the longest perpendicular diameters of measurable lesions with no new lesions. | First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) | 
| Number of Participants With Progression of Disease | Progression of disease is defined as a 50% increase from nadir of the sum of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. Individual lesions must be >2 cm in diameter per radiographic evaluation or >1 cm in diameter by physical examination. All participants without progression of disease were censored. | First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) | 
| Duration of Response for All Confirmed Responders | Duration of response was defined as the time from the first documented response to the first documented disease progression. Partial Response (PR): 50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions with no new lesions. Responders are the participants with CR, or CCR, or PR. | First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) | 
| Number of Participants With Progressive Disease (PD) | PD is defined as a 50% increase from nadir of the sum of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. Individual lesions must be >2 cm in diameter per radiographic evaluation or >1 cm in diameter by physical examination. | First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) | 
| Time to Disease Progression or Death | Time to progression is the time from the treatment start date to the first documented disease progression or death. Disease progression: 50% increase from nadir of the sum of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. Individual lesions must be >2 cm in diameter per radiographic evaluation or >1 cm in diameter by physical examination. | First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) | 
| Number of Participants With a Treatment Failure | Treatment failure is defined as the occurrence of treatment withdrawal, a decision to seek additional therapy, study removal, progression, alternative therapy for lymphoma, or death. | First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) | 
| Time to Treatment Failure | Time to treatment failure is defined as the time from the treatment start date to the first occurrence of treatment withdrawal, a decision to seek additional therapy, study removal, progression, alternative therapy for lymphoma, or death. | First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520) | 
| Number of Participants Who Died During Their Participation in the Study | Participants who died during the study period were evaluated for the overall survival endpoint. | Day of TST/I 131 TST dosimetric dose to date of database release (Week 1 to Week 520); First day of fludarabine cycle 1 to date of database release (Week -16 to Week 520) | 
| Time to Death of Participants During Their Participation in the Study | Time to death is defined as the time from the treatment start date to the date of death. | Day of TST/I 131 TST dosimetric dose to date of database release (Week 1 to Week 520); First day of fludarabine cycle 1 to date of database release (Week -16 to Week 520) |