Open Label Multicenter Study of CVP Followed by Iodine-131 Anti-B1 Antibody for Subjects With Untreated Low-Grade Non Hodgkin's Lymphoma.

Study Overview
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Brief Summary
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This is a phase II, open-label, multicenter study of the efficacy and safety of sequential administration of CVP x 6 followed by tositumomab and iodine I 131 tositumomab (formerly referred to as tositumomab and iodine I 131 tositumomab). All patients who complete three cycles of CVP, regardless of response, will be eligible for treatment with tositumomab and iodine I 131 tositumomab. Subjects who have rapidly progressive disease prior to completing three cycles of CVP may be removed from study. In order to proceed to tositumomab and iodine I 131 tositumomab therapy, patients must have completed six cycles of CVP within 20 weeks as described. Patients may proceed to Iodine-131 Anti-B1 Antibody if they have progressive disease documented at the response evaluation following 6 cycles of CVP. In addition, patients must still meet the eligibility inclusion exclusion criteria based upon the week 20 assessments, as applicable. Patients must also have an average of ≤25% bone marrow involved by NHL to receive treatment with tositumomab and iodine I 131 tositumomab. The dosimetric dose of tositumomab and iodine I 131 tositumomab must be given within 28 days of the response evaluation following CVP and no later than 56 days from the first day of the sixth cycle of CVP.

Detailed Description
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This is a phase II, open-label, multicenter study of the efficacy and safety sequential administration of cycolophosphamide, vacristine, and prednisone (CVP) x6 cycles followed by tositumomab and iodine I 131 tositumomab for previously untreated subjects with low-grade Non-Hodgkin's Lymphoma (NHL). CVP will be repeated every 21 days for a total of six cycles. tositumomab and iodine I 131 tositumomab will begin within 56 days following the first day of the sixth cycle of CVP. Subjects will undergo two dosing phase for the tositumomab and iodine I 131 tositumomab therapy. In the first phase, dosimetric dose, patients will receive an infusion of unlabeled Anti-B1 Antibody (450mg) over 60 minutes followed by a 30 minute infusion (including a 10-minutes flush) of Anti-B1 (35mg) containing 5mCi of Iodine-131. Whole body gamma camera scans will be obtained on Day 0; Day 2, 3, or 4 and Day 6 or 7 following the dosimetric dose. Using the dosimetric data from three time points, a patient-specific dose of Iodine-131 will be calculated to deliver the desired total body dose of radiotherapy. In the second phase, termed the therapeutic dose, patients will receive 60-minute infusion of unlabeled Anti-B1 Antibody (450 mg) followed by a 30-minute infusion (including a 10-minute flush) of 35 mg Anti-B1 Antibody labeled with the subjects -specific dose of Iodine-131 calculate to deliver a 75cGy total body radiation dose. Subjects who have platelet counts of 100,000-149,999 cells/mm3 will receive 65 cGy; obese patients will be dosed base upon 137% of their lean body mass. Subjects will be treated with saturated solution potassium iodide (SSKI), Lugol's solution, or potassium iodide tablets starting at least 24 hours prior to the first infusion of the tositumomab and iodine I 131 tositumomab (i.e., the dosimetric dose) and continuing for 14 days following the least infusion of tositumomab and iodine I 131 tositumomab (i.e., the therapeutic dose).

Official Title
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Phase II Multicenter Study of Cyclophosphamide, Vincristine, and Prednisone (CVP) Followed by Iodine-131 Anti-B1 Antibody for Patients With Untreated Low-grade Non-Hodgkin's Lymphoma (NHL).

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Biological: cycolophosphamide, vacristine, and pednisone (CVP) x6 cycles followed by tositumomab and iodine I 131 tositumomab.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have a histologically confirmed initial diagnosis of low-grade non-Hodgkin's B-cell lymphoma according to the International Working Formulation (IWF) (32) (i.e., small lymphocytic with or without plasmacytoid differentiation; follicular small cleaved cell; or follicular, mixed small cleaved and large cell). Subjects must have Ann Arbor Stage III, Stage IV, or bulky Stage II disease at diagnosis. Bulky Stage II is defined as a mediastinal mass greater than one-third of the maximum chest diameter, or any other mass greater than or equal to 10 cm in maximum diameter. Subjects must have evidence that their tumor tissue expresses the CD20 antigen. Immunoperoxidase stains of paraffin-embedded tissue showing positive reactivity with L26 antibody or immunoperoxidase stains of frozen tissue showing positive reactivity with Anti B1 Antibody (Coulter Clone®) or similar commercially available CD20 antibody or evidence of CD20 positivity by flow cytometry are acceptable evidence of CD20 positivity. Testing of tumor tissue from any time in the course of the patient's disease is acceptable. Subjects must have a performance status of at least 60% on the Karnofsky Performance Scale and an anticipated survival of at least 3 months. Subjects must have an ANC≥1500 cells/mm3 and a platelet count ≥100,000 cells/mm3 within 14 days of study enrollment. These blood counts must be sustained without support of hematopoietic cytokines or transfusion of blood products. Subjects must have adequate renal function (defined as serum creatinine <1.5 times the upper limit of normal) and hepatic function (defined as total bilirubin <1.5 times the upper limit of normal and AST <5 times the upper limit of normal) within 14 days of study enrollment. Subjects must have bi-dimensionally measurable disease. At least one lesion must be ≥2.0x2.0 cm by computerized tomography scan. Subjects must be at least 18 years of age. Subjects of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment. Subjects must give written informed consent and sign an IRB-approved informed consent form prior to study enrollment. Exclusion Criteria: Subjects who have received prior chemotherapy, biologic therapy, steroids, or radiation therapy as treatment for their NHL. Subjects with active obstructive hydronephrosis. Subjects with New York Heart Association class III or IV heart disease or other serious illness that would preclude evaluation. Subjects 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 who have been disease-free of another cancer for greater than 5 years must be carefully assessed at the time of study entry to rule out recurrent disease. Subjects with known HIV infection. Subjects who are HAMA positive. Subjects with known brain or leptomeningeal metastases. Subjects who are pregnant or breastfeeding. Males and females must agree to use a contraceptive method from enrollment to 6 months after receiving Iodine 131 Anti B1 Antibody. Subjects with active infection requiring IV anti-infectives at the time of study enrollment. Subjects with intermediate- or high-grade NHL.

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
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: open-label, single arm<br>cycolophosphamide, vacristine, and pednisone (CVP) x6 cycles followed by tositumomab and iodine I 131 tositumomab. CVP will be repeated every 21 days for a total of six cycles. tositumomab and iodine I 131 tositumomab will begin within 56 days following the first day of the sixth cycle of CVP. Patient will undergo two dosing phase for the tositumomab and iodine I 131 tositumomab therapy. | Biological: cycolophosphamide, vacristine, and pednisone (CVP) x6 cycles followed by tositumomab and iodine I 131 tositumomab.<br>* cycolophosphamide, vacristine, and pednisone (CVP) x6 cycles followed by tositumomab and iodine I 131 tositumomab. CVP will be repeated every 21 days for a total of six cycles. tositumomab and iodine I 131 tositumomab will begin within 56 days following the first day of the sixth cycle of CVP. Patient will undergo two dosing phase for the tositumomab and iodine I 131 tositumomab therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants (Par.) With Unconfirmed Response (Complete Response, Complete Response/Unconfirmed, or Partial Response), as Assessed by the Investigator | Par. with response include those with Complete Response (CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease), Complete Response/unconfirmed (CRu: complete resolution of all disease-related symptoms; residual lymph node mass >1.5 centimeters in the greatest transverse diameter that has regressed by >75%, indeterminate bone marrow, are present), or Partial Response (PR: >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions). | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Number of Participants (Par.) With Confirmed Response (Complete Response [CR], Complete Response/Unconfirmed [CRu], or Partial Response [PR]), as Assessed by the Investigator | CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. CRu: complete resolution of all disease-related symptoms; residual lymph node mass >1.5 centimeters in the greatest transverse diameter that has regressed by >75%, indeterminate bone marrow, are present. PR: >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions. Confirmed response required CR, CRu, or PR, which were confirmed by 2 separate response evaluations >=4 weeks apart. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Unconfirmed Complete Response (CR), as Assessed by the Investigator | CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease, if present before therapy. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Number of Participants With Confirmed Complete Response (CR), as Assessed by the Investigator | CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease, if present before therapy. Confirmed response required CR, which was confirmed by 2 separate response evaluations >=4 weeks apart. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Duration of Response (DOR), as Assessed by the Investigator | DOR=the time from the first documented response (for par. with CR, CRu, or PR) until disease progression (DP). DP=a >=50% increase from the nadir value (lowest laboratory value recorded following administration of study medication) of the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. Individual lesions must be >1.5 centimeters (cm) in diameter by radiographic evaluation or >1 cm in diameter by physical examination. Responses had to be confirmed by 2 separate evaluations occurring >=4 weeks apart. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| DOR for Unconfirmed and Confirmed Complete Response, as Assessed by the Investigator | DOR=the time from the first documented response (for par. with CR) until disease progression (DP). DP=a >=50% increase from the nadir value (lowest laboratory value recorded following administration of study medication) of the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. Individual lesions must be >1.5 centimeters (cm) in diameter by radiographic evaluation or >1 cm in diameter by physical examination. Responses had to be confirmed by 2 separate evaluations occurring >=4 weeks apart. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Time to Progression of Disease or Death, as Assessed by the Investigator | Time to progression or progression-free survival is defined as the time from the dosimetric dose to the first documented occurrence of disease progression or death. Disease progression is defined as a >=50% increase from the nadir value (lowest laboratory value recorded following administration of the study medication) of the sum of the products of the longest perpendicular diameters of all measurable lesions or the appearance of any new lesion. Individual lesions must be >1.5 cm in diameter by radiographic evaluation or >1 cm in diameter by physical examination. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Time to Treatment Failure, as Assessed by the Investigator | Time to treatment failure is defined as the time from the start of treatment to the first occurrence of study withdrawal, progression, or death. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Total Body Residence Time (TBRT; Average Amount of Time TST Spends in the Body, Calculated From the Rate of TB Clearance of Radioactivity During the Dosimetric Dose [DD]) of Iodine 131 TST Antibody Following the DD | To determine TBRT, the percent-injected activity (PIA) is calculated from the background-corrected (BC) total body count (TBC) at D 0; D 2/3/4; and D 7. The time from the DD to the acquisition of whole body count (WBC) is then determined. The PIA remaining at each time point (TP) is then calculated by dividing the BC WBC for that TP by the BC WBC from the first TP (D 0) * 100. To determine RT, a best-fit line from 100% (pre-plotted D 0 value) through 2 plotted points (other TPs) is made. TBRT=the x-axis value at the point where the line intersects the horizontal 37% injected activity line. | Day (D) 0; D 2, 3, or 4; and D 6 or 7 | 
| Time to Nadir for Hematological Parameters: Absolute Neutrophil Count (ANC), Hemoglobin, Platelets, and White Blood Cell (WBC) Count | Nadir is defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or the dosimetric dose for participants who did not receive the therapeutic dose). | Up to 120 days following the therapeutic dose (given on Study Day 7, following the dosimetric dose) (or the dosimetric dose for participants who did not receive the therapeutic dose) | 
| Time to Recovery (TTR) to Baseline (BL) for Hematologic Laboratory (Lab.) Evaluations | TTR to BL grade (gr.) for par. with a Gr. 0 toxicity (tox.=lab. value outside the normal range) at BL=time from the last administration of study drug (SD) to the first post-nadir (PN) date with Gr. 0 toxicity with no other Gr. 1-4 toxicities recorded within the next week. For par. with a higher gr. tox. at BL, TTR=time from the last administration of SD to the first PN date with the BL gr. or better with no other higher gr. toxicities recorded during the next week. Each lab. established its own reference range using data from its own equipment/methods; there is no standard reference range. | Up to 120 days following the therapeutic dose (given on Study Day 7, following the dosimetric dose) (or the dosimetric dose for participants who did not receive the therapeutic dose) | 
| Nadir Values for Absolute Neutrophil Count (ANC) | Nadir is defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or the dosimetric dose for participants who did not receive the therapeutic dose). | Up to 120 days following the therapeutic dose (given on Study Day 7, following the dosimetric dose) (or the dosimetric dose for participants who did not receive the therapeutic dose) | 
| Nadir Values for Hemoglobin | Nadir is defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or the dosimetric dose for participants who did not receive the therapeutic dose). | Up to 120 days following the therapeutic dose (given on Study Day 7, following the dosimetric dose) (or the dosimetric dose for participants who did not receive the therapeutic dose) | 
| Nadir Values for Platelet Count | Nadir is defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or the dosimetric dose for participants who did not receive the therapeutic dose). | Up to 120 days following the therapeutic dose (given on Study Day 7, following the dosimetric dose) (or the dosimetric dose for participants who did not receive the therapeutic dose) | 
| Nadir Values for WBC Count | Nadir is defined as the lowest laboratory value recorded up to 120 days following the therapeutic dose (or the dosimetric dose for participants who did not receive the therapeutic dose). | Up to 120 days following the therapeutic dose (given on Study Day 7, following the dosimetric dose) (or the dosimetric dose for participants who did not receive the therapeutic dose) | 
| Number of Participants With the Indicated Grade 3 or Grade 4 Adverse Events (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. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Number of Participants With the Indicated Grade 3 or Grade 4 AEs Possibly or Probably Related to Study Drug | 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. The Investigator assessed whether the AE was possibly or probably related to study drug. In addition, all laboratory-derived hematologic toxicities (values outside the normal range) were assumed to be possibly or probably related to study drug. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Number of Participants With Any Treatment-related Serious Adverse Event (SAE) | An SAE is 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. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Number of Participants With the Indicated Primary Cause of Death | The primary cause of death of the participants was assessed by the Investigator. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Number of Participants Who Received Any Supportive Care | Supportive care is defined as interventions that help the participants achieve comfort but do not affect the course of a disease. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 
| Number of Participants Who Were Negative for Human Anti-murine Antibodies (HAMA) at Baseline (Study Entry) But Positive or Negative at Month 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). To be positive, a participant had to have a positive HAMA assessment during the first 24 months. | Day 1 to Day 730 (24 months) after receiving the dosimetric dose | 
| Overall Survival | Overall survival is defined as the time from the treatment start date to the date of death from any cause. | Par. were evaluated until death/disease progression or for 2 years in Study BEX104514. Par. who completed 2 years in Study BEX104514 were followed in Study BEX104528 for up to 130 months. Data are included from Study BEX104514 and Study BEX104528. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Hodgkin's Lymphoma, tositumomab and iodine I 131 tositumomab, Bexxar, cycolophosphamide, vacristine, and pednisone