Ofatumumab in Treating Patients With Previously Untreated Stage II, Stage III, or Stage IV Follicular Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as ofatumumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. PURPOSE: This randomized phase II trial is studying ofatumumab to see how well it works in treating patients with previously untreated stage II, stage III, or stage IV follicular non-Hodgkin lymphoma.

Detailed Description
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OBJECTIVES: Primary To determine the response rate in patients with previously untreated CD20-positive bulky stage II, or stage III or IV follicular non-Hodgkin lymphoma (NHL) treated with a lower- or high-dose of ofatumumab. Secondary To determine the progression-free survival (PFS) of patients treated with these regimens. To determine the toxicity profile of these regimens in these patients. To establish whether the therapeutic effect of single-agent ofatumumab is sufficiently promising to warrant evaluation in subsequent randomized, ofatumumab-based, biologic doublet trials. To evaluate the two ofatumumab doses by independent comparison of response, PFS, and toxicity to a historical control in previously untreated patients with follicular NHL. To prospectively validate the FLIPI2 prognostic index in low- and intermediate-risk patients and compare to low- and intermediate-risk stratified patients by standard FLIPI scoring to determine a more reliable indicator of response and PFS. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive high-dose ofatumumab IV over 2-8 hours on days 1, 8, 15, and 22 and then once monthly in months 3-9. Arm II: Patients receive a lower dose of ofatumumab IV over 2-8 hours on days 1, 8, 15, and 22 and then once monthly in months 3-9. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients may undergo blood and bone marrow sample collection for correlative studies. After completion of study therapy, patients are followed up every 4 months for 2 years and then every 6 months for 8 years.

Official Title
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A Phase II Trial of Ofatumumab (CALGB IND #) in Previously Untreated Follicular Non-Hodgkin's Lymphoma (NHL)

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: ofatumumab


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed follicular non-Hodgkin lymphoma (NHL) meeting 1 of the following criteria: Bulky (i.e., single mass ≥ 7cm in any uni-dimensional measurement) stage II disease Stage III or IV disease WHO grade 1, 2, or 3a disease Bone marrow biopsies allowed provided they are submitted in conjunction with nodal biopsies No fine-needle aspirates for diagnosis Tumor tissue must express the CD20-positive antigen by flow cytometry or IHC At least 1 site of measurable disease that is > 1 cm in diameter in ≥ 1 dimension present either on physical exam or imaging studies Non-measurable disease alone not allowed, including the following: Bone lesions (lesions if present should be noted) Ascites Pleural/pericardial effusion Lymphangitis cutis/pulmonis Bone marrow (involvement by NHL should be noted) Low- or intermediate-risk disease by the Follicular Lymphoma International Prognostic Index (FLIPI) FLIPI score meeting 1 or 2 of the following risk factors: Age > 60 years Involvement of > 4 nodal sites Stage III-IV disease Hemoglobin < 12.0 g/dL LDH normal Risk determined by the following: Low Risk: 0-1 of the above risk factors Intermediate Risk: 2 risk factors Poor Risk: ≥ 3 risk factors No known CNS involvement PATIENT CHARACTERISTICS: ECOG performance status 0-2 ANC ≥ 1,000/μL Platelet count ≥ 75,000/μL Creatinine clearance ≥ 30 mL/min Bilirubin ≤ 2 times upper limit of normal (unless secondary to Gilbert syndrome or hepatic involvement of NHL) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study treatment Patients with HIV infection allowed provided the following criteria are met: No evidence of coinfection with hepatitis B or C CD4+ cell count ≥ 400/mm³ No evidence of resistant strains of HIV HIV viral load < 10,000 copies HIV RNA/mL if not on anti-HIV therapy OR HIV viral load < 50 copies if on anti-HIV therapy No history of AIDS-defining conditions No evidence of active hepatitis B (HBV) or C (HCV) infection (i.e., no positive serology for anti-HBc or anti-HCV antibodies) HBV seropositivity allowed (HBsAg+) provided they are closely monitored for evidence of active HBV infection by HBV DNA testing After completing treatment, HBsAg + patients must be monitored by HBV DNA testing every 2 months for 6 months post-treatment, while continuing lamivudine (required) PRIOR CONCURRENT THERAPY: No prior chemotherapy or immunotherapy (e.g., monoclonal antibody-based therapy) for NHL Prior involved-field radiation therapy allowed More than 2 weeks since prior corticosteroids except for maintenance therapy for a non-malignant disease No concurrent dexamethasone or other steroids as antiemetics No live virus vaccination within 6 weeks prior to study entry No concurrent zidvoudine or stavudine

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive high-dose ofatumumab IV over 2-8 hours on days 1, 8, 15, and 22 and then once monthly in months 3-9. | Biological: ofatumumab<br>* Given IV<br>|
| Experimental: Arm II<br>Patients receive a lower dose of ofatumumab IV over 2-8 hours on days 1, 8, 15, and 22 and then once monthly in months 3-9. | Biological: ofatumumab<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (Complete or Partial Response) by Month 12 | The primary endpoint of this trial is overall response rate (OR=complete response (CR) or partial response (PR)) to 500 mg or 1000 mg dose of ofatumumab in previously untreated patients with CD20+ follicular NHL. The response outcome is defined as the best response during the 12 months of first-line and extended induction treatment. A CR is defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A PR is defined as at least a 50% decrease in the sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses, with no increase observed in the size of other nodes, liver, or spleen and no new sites of disease should be observed. The ORR (percentage of patients) reported below by arm is the percentage of patients whose best response during the 12 months of treatment was CR or PR. | From baseline to month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival Time | The median progression-free survival (PFS) time for each arm was estimated using the Kaplan-Meier method. PFS was calculated as the time from study entry until progression or death, whichever occurred first. Patients were censored at the time last known alive and progression free. Lymph nodes should be considered abnormal if the long axis is > 1.5 cm, regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if its short axis is > 1.0. Lymph nodes ≤ 1.0 cm by ≤ 1.0 cm will not be considered as abnormal for relapse or progressive disease. Progression is defined using the 2007 revised response criteria reported by Cheson et al. as follows: Appearance of any new lesion, At least a 50% increase from nadir in the SPD of any previously involved nodes, At least a 50% increase in the longest diameter of any single previously identified node > 1.0 cm in its short axis. | From date of study entry until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, contiguous stage II grade 1 follicular lymphoma, contiguous stage II grade 2 follicular lymphoma, contiguous stage II grade 3 follicular lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma