Safety and Efficacy Study of Iodine-131 Anti-B1 Antibody Plus CHOP For Untreated Mantle Cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
The primary efficacy endpoint of this study is to determine the duration of response of the sequential administration of Iodine-131 Anti-B1 Antibody followed by six cycles of CHOP for patients with previously untreated Mantle Cell Lymphoma (MCL). The secondary efficacy endpoints for this study are to determine the response rate, confirmed response rate, complete response rate, confirmed complete response rate, duration of response for confirmed responders, duration of response for complete responders, duration of response for confirmed complete responders, progression-free survival, time to treatment failure, and the predictive value of detection of minimal residual disease by molecular techniques on response duration. The pharmacokinetic endpoint is to determine the total body residence time of Iodine-131 Anti-B1 Antibody following the dosimetric dose. The safety endpoints are to determine the incidence of adverse experiences, hematologic toxicity, (e.g., nadir, time to nadir, and time to recovery), use of supportive care, percent of patients converting to human anti-murine antibody (HAMA) positivity, the effects of Iodine-131 Anti-B1 Antibody on the growth and function of hematopoietic progenitor cells, and survival of patients with previously untreated MCL treated with Iodine-131 Anti-B1 Antibody followed by six cycles of CHOP.

Official Title
-----------------
Phase II Study Of Iodine-131 Anti-B1 Antibody Plus CHOP For Patients With Previously Untreated Mantle Cell Lymphoma

Conditions
-----------------
Lymphoma, Mantle-Cell

Intervention / Treatment
-----------------
* Biological: Tositumomab and Iodine I 131 Tositumomab followed by CHOP


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have a confirmed initial diagnosis of mantle cell non-Hodgkin's lymphoma by histology according to the WHO classification . Patients must have Ann Arbor bulky stage II, stage III, or stage IV disease at diagnosis. Bulky stage II disease 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. Patients must have less than an average of 25% of the intratrabecular marrow space involved by NHL in bilateral bone marrow biopsy specimens as assessed microscopically at study entry. A unilateral bone marrow biopsy demonstrating <10% involvement with NHL is also adequate. Patients 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. This must be performed within 42 days of study entry. Patients must have a performance status of at least 60% on the Karnofsky Performance Scale and an anticipated survival of at least 3 months. Patients must have an ANC greater than or equal to 1500 cells/mm3 and a platelet count greater than or equal to 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. Patients 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. Patients must have bi-dimensionally measurable disease. At least one lesion must be greater than or equal to 2.0 x 2.0 cm by computerized tomography scan. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment. Patients must have a cardiac left ventricular ejection fraction of greater than or equal to 50% by ventriculography or echocardiogram. Exclusion Criteria: Patients who have received prior chemotherapy, biologic therapy, steroids, or radiation therapy as treatment for their MCL Patients with active obstructive hydronephrosis Patients with serious illness that would preclude evaluation 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 known HIV infection Patients who are HAMA positive Patients with known brain or leptomeningeal metastases. Patients who are pregnant or breastfeeding. Males and females must agree to use a contraceptive method while on study and for 6 months after receiving Iodine-131 Anti-B1 Antibody. Patients with active infection requiring IV anti-infectives at the time of study enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tositumomab and Iodine I 131 Tositumomab followed by CHOP<br>Tositumomab and Iodine I 131 Tositumomab followed by CHOP | Biological: Tositumomab and Iodine I 131 Tositumomab followed by CHOP<br>* Patients will receive an infusion of unlabeled Tositumomab (450 mg) followed by an infusion of Tositumomab (35 mg) containing 5 mCi of Iodine-131 (dosimetric dose). 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. Patients will then receive an infusion of unlabeled Tositumomab (450 mg) followed by an infusion of 35 mg Tositumomab containing a patient-specific dose of Iodine-131 calculated to deliver a 75 cGy total body radiation dose (therapeutic dose). Patients who have platelet counts of 100,000-149,000 cells/mm3 will receive 65 cGy; obese patients will be dosed based upon 137% of their lean body mass. Patients will be treated with a thyroid blocking agent 24 hours prior to the dosimetric dose and continuing for 14 days following the therapeutic dose. Approximately 13 weeks following the therapeutic dose, CHOP will be administered every 21 days for a total of 6 cycles.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Unconfirmed Response (Complete Response, Complete Response Unconfirmed, and Partial Response) | Participants with response include those with complete response (CR: complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms), complete response unconfirmed (CRu: CR, with one of the following: residual lymph node mass >1.5 centimeters [cm] that has regressed by more than 75% in the sum of the product of the diameters or indeterminate bone marrow), or partial response (PR: >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions). | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Confirmed Response (Confirmed Complete Response, Complete Response Unconfirmed, and Partial Response) | A confirmed response is defined as a response that was confirmed by two separate response evaluations occurring at least 4 weeks apart. Participants with a confirmed response include those with complete response (CR: complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms), complete response unconfirmed (CRu: CR, with one of the following: residual lymph node mass >1.5 cm that has regressed by more than 75% in the sum of the product of the diameters or indeterminate bone marrow), or partial response (PR: >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions). The individual rows for confirmed CR, confirmed CRu, and confirmed PR represent confirmation of the same response. For example, a confirmed CR indicates that a CR was followed by another CR at least 4 weeks later. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Duration of Response for All Confirmed Responders (CR + CRu + PR) | Complete response (CR) is defined as the complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms. Complete response unconfirmed (CRu) is defined as CR, with one of the following: residual lymph node mass >1.5 cm that has regressed by more than 75% in the sum of the product of the diameters or indeterminate bone marrow. Partial response (PR) is defined as a >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions. For participants with CR, CRu, or PR, duration of response is defined as the time from the first documented response to the first documented progression. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Duration of Response for All Unconfirmed Responders (CR + CRu + PR) | Complete response (CR) is defined as the complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms. Complete response unconfirmed is defined as CR, with one of the following: residual lymph node mass >1.5 cm that has regressed by more than 75% in the sum of the product of the diameters or indeterminate bone marrow. Partial response (PR) is defind as a >=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions. Duration of response is defined as the time from the first documented response to the first documented progression. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Duration of Response for Unconfirmed Complete Responders | Complete response is defined as the complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms. Duration of response is defined as the time from the first documented response to the first documented progression. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Duration of Response for Confirmed Complete Responders | Complete response is the complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms. A confirmed response is defined as a response that was confirmed by two separate response evaluations occurring at least 4 weeks apart. Duration of response is defined as the time from the first documented response to the first documented progression. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Progression-free Survival | Progression-free survival is defined as the time from the start of treatment (i.e., the dosimetric dose) to the first documented disease progression or death. Disease progression is defined as a >=25% increase from the nadir value 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 have been greater than 2 centimeters (cm) in diameter by radiographic evaluation or greater than 1 cm in diameter by physical examination. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| 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 treatment withdrawal, decision to seek additional therapy, study removal, disease progression, alternative therapy, or death. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAEs are defined as those events that were fatal or immediately life-threatening, and those events that resulted in hospitalization; prolonged an existing hospitalization; resulted in disability; or was a congenital anomaly. Refer to the general AE/SAE module for a complete list of all AEs and SAEs. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Mean Nadir Value for Absolute Neutrophil Count (ANC) | Nadir is defined as the lowest laboratory value recorded following the administration of study medication. ANC is a measure of the number of neutrophil granulocytes present in the blood. Neutrophils are a type of white blood cell that fights infection. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Mean Nadir Value for Hemoglobin | Nadir is defined as the lowest laboratory value recorded following the administration of study medication. Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Mean Nadir Values for Platelets and White Blood Cell (WBC) Count | Nadir is defined as the lowest laboratory value recorded following the administration of study medication. Platelets and WBCs are types of blood cells. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Time to Nadir for the Indicated Hematology Parameters | Hematology parameters include ANC (calculated), hemoglobin, platelet count, and WBC count. Nadir is defined as the lowest laboratory value recorded following the administration of study medication. Time to nadir is defined as the time from Baseline to the time the lowest value recorded following the therapeutic dose. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Time to Recovery From the Indicated Hematology Parameters | Hematology parameters include ANC (calculated), hemoglobin, platelet count, and WBC count. Nadir is defined as the lowest laboratory value recorded following the administration of study medication. Time to recovery to Baseline for the indicated hematologic parameters is defined as the time required for recovery from nadir values to Baseline values. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Number of Participants Negative for Human Anti-Murine (Mouse) Antibody (HAMA) at Screening Who Converted to HAMA Positivity or Remained Negative During the Course of the Study | The number of participants who developed human anti-murine (mouse) anibodies (HAMA) after treatment was measured. Conversion to HAMA positivity is relative to Screening (participants were evaluable for HAMA analysis if they were HAMA negative at Screening). | Screening; at Week 7, Week 13, then every 6 months until disease progression or death (up to 143 months) | 
| Number of Participants With an Adverse Event of Cytopenia | The effects of iodine I-131 tositumomab on the growth and function of hematopoietic progenitor cells was measured as the number of participants who had cytopenia. An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 
| Overall Survival | Overall survival is defined as the time from the start of treatment to the date of death from any cause. | Every 13 weeks up to 2 years, or every 6 months until disease progression or death (average of 77.8 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP), Tositumomab, Tositumomab and Iodine I-131 tostumomab, Bexxar, Iodine-131 Anti-B1 Antibody, Mantle Cell, radioimmunotherapy