HuMax-CD20 i(Ofatumumab) n Follicular Lymphoma (FL) Patients Refractory to Rituximab

Study Overview
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Brief Summary
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A Single-Arm, International, Multi-Center Trial of HuMax-CD20 (Ofatumumab), a Fully Human Monoclonal Anti-CD20 Antibody, in Patients With Follicular Lymphoma Who Are Refractory to Rituximab as Monotherapy or in Combination With Chemotherapy

Detailed Description
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Patients in the study will be randomized into two dose groups. Patients in each dose group will receive one infusion of 300 mg of HuMax-CD20 followed by 7 weekly infusions of either 500 or 1000 mg of HuMax-CD20. Disease status will be assessed every 3 months until month 24.

Official Title
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A Single-arm, International, Multi-center Trial of HuMax-CD20, a Fully Human Monoclonal Anti-CD20 Antibody, in Patients With Follicular Lymphoma Who Are Refractory to Rituximab as Monotherapy or in Combination With Chemotherapy

Conditions
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Lymphoma, Follicular

Intervention / Treatment
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* Drug: Ofatumumab
* Drug: Ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patient with follicular lymphoma grade 1 - 2 Refractory to rituximab given as monotherapy or in combination with any chemotherapy or to rituximab given as maintenance treatment following R-chemo, defined as: failure to achieve at least PR to rituximab given as monotherapy or in combination with any chemotherapy; or, disease progression while on rituximab (either given as monotherapy or in combination with any chemotherapy or during rituximab maintenance treatment following R-chemo); or, disease progression in responders within 6 months of the last dose of rituximab (either given as monotherapy or in combination with any chemotherapy or after rituximab maintenance treatment schedule following R-chemo) Tumor verified to be CD20+ positive from excisional lymph node biopsy CT scan in screening phase (based on local evaluation) showing: 2 or more clearly demarcated lesions with a largest diameter ≥ 1.5 cm, or 1 clearly demarcated lesion with a largest diameter ≥ 2,0 cm ECOG Performance Status of 0, 1, or 2 Age ≥ 18 years Following receipt of verbal and written information about the study, the patient must provide signed informed consent before any study related activity is carried out Exclusion Criteria Previous autologous stem cell transplantation within 6 months Previous allogeneic stem cell transplantation More than 1 previous radio immunotherapy regimen Received radio immunotherapy within 3 months Received any Anti-cancer treatment within 4 weeks Received monoclonal antibodies, other than rituximab within 3 months Patients previously treated with anti-CD20 monoclonal antibodies, other than rituximab Life expectancy less than 6 months

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: Single


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Ofatumumab|Eight weekly infusions of ofatumumab. The first infusion of 300mg ofatumunab|
|Drug: Ofatumumab|followed by 7 weekly infusions of 1000mg ofatumumab|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Objective Response (OR) | OR was assessed by an Independent endpoints Review Committee (IRC) according to the standardized response criteria for Non-Hodgkin's lymphoma. Participants with Complete Response (CR; complete disappearance of all detectable disease), Complete Response unconfirmed (CRu; any residual lymph node/nodal mass >1.5 centimeters [cm] in its longest transverse diameter that regressed >75% compared to baseline), or Partial Response (PR; >=50% decrease in the sum of the product of diameters of indicator lesions) were defined as responders for OR. | Start of treatment (Day 1 of Week 0) until 3 months after start of last infusion (up to Week 32) | 
| Number of Participants Classified as Responders and Non-responders for Objective Response (OR) | Based on OR over a 6-month period from start of treatment, participants were classified as responders/non-responders as follows: participants with CR, CRu, or PR were classified as responders, whereas participants with Stable Disease (SD; achieving less than PR but not consistent with PD), Progressive Disease (PD; 50% increase from nadir in the products of the greatest perpendicular diameters of any previously identified node or appearance of any new node >1 cm), or Not Evaluable (NE) participants were classified as non-responders. | 6-month period from the start of treatment. There was a median time of response at Month 5.5 (participants were followed for up to 24 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | The duration of response is defined as the time from the initial response (the first visit at which response was observed) to progression or death. For participants who were lost to follow-up, duration of response was censored at the date of the last attended visit at which the endpoint was assessed. The Kaplan-Meier method was used to estimate duration of response. | From start of treatment (Week 0) until Month 24 | 
| Progression-Free Survival | Progression-free survival (PFS) is defined as the time from randomization until the first radiologically or clinically documented evidence of progression or death due to any cause, if sooner. For participants who were lost to follow-up, PFS was censored at the date of the last attended visit at which the endpoint was assessed. The Kaplan-Meier method was used to estimate PFS. | From start of treatment (Week 0) until Month 24 | 
| Time to Next Follicular Lymphoma (FL) Therapy | Time to next FL (anti-lymphoma) therapy is defined as the time from randomization until the time of first administration of the next anti-lymphoma therapy other than ofatumumab. For participants who were lost to follow-up, the time was censored at the date of the last attended visit at which the endpoint was assessed. | From start of treatment (Week 0) until Month 24 | 
| Overall Survival | Overall survival is defined as the time from randomization until death. For participants who are lost to follow-up, overall survival will be censored at the date of the last attended visit at which the endpoint was assessed. | First dose (Week 0) until 5 years | 
| Percent Change From Screening (Visit 1) in Tumor Size as Assessed by Radiologist 1 (R1) and Radiologist 2 (R2) at Months 3, 6, 9, 12, 18, and 24 | Tumor size was measured by computed tomography (CT) scan and was computed as the sum of product of diameters (SPD) for the indicator lesions. CT scans with contrast of the neck, thorax, abdomen, and pelvis were performed at Screening and during the follow-up period (Month 3, 6, 9, 12, 18, and 24). The change in tumor size from Screening (Visit 1) was presented per Radiologist 1 (R1) and Radiologist 2 (R2). Percent change from Screening (Visit 1, Week -2) = (value at Visits 11, 12, 13, 14, 16, and 18 minus the value at Visit 1 divided by the value at Visit 1) * 100. | Visits 1 (Week -2), 11 (Month 3), 12 (Month 6), 13 (Month 9), 14 (Month 12), 16 (Month 18), and 18 (Month 24) | 
| Percent Change From Baseline (Visit 2) in CD19+ and CD20+ Cells in Peripheral Blood at Visits 11 and 12 | CD19 and CD20 are proteins found on the cell surface of B cells, and they can be detected in peripheral blood by flow cytometry. Flow cytometry of peripheral blood was performed for immediate analysis of cells with cluster of differentiation 19 (CD19+) and CD20+. The analysis will be done until a value is reached that is in the normal range. Percent change from Baseline (Visit 2) = (value at Visits 11 and 12 minus the value at Visit 2 divided by the value at Visit 2) * 100. | Visits 2 (Baseline), 11 (Month 3), and 12 (Month 6) | 
| Number of Participants With Conversion and no Conversion of BCL2 Positive to BCL2 Negative in Peripheral Blood | B-cell lymphoma 2 (BCL2) is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in follicular lymphomas. BCL2 mitochondrial ribonucleic acid (mRNA) was measured by polymerase chain reaction (PCR) from peripheral blood. Participants who had no post-screening data were categorized as Missing. | Screening (Visit 1) until Month 24 (Visit 18) | 
| Number of Participants Who Experienced Any Adverse Event From First Treatment (Visit 2) to Visit 18 (Month 24) | An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. A list of AEs experienced in the study at a frequency threshold of 5% can be found in the AE section. | From first treatment (Visit 2) until Visit 18 (Month 24) | 
| Number of Participants With Positive Human Anti-human Antibodies (HAHA) at Visits 1, 12, 13, and 14 | HAHA are indicators of immunogenicity to ofatumumab. Blood samples were withdrawn from participants at Visits 1, 12, 13, and 18 for analysis of HAHA. Analysis of HAHA was done in batches. | Visits 1 (Screening), 12 (Month 6), 13 (Month 9), and 18 (Month 24) | 
| Complement (CH50) Levels at Visit 1 and at the End of Infusion at Visit 2 | Blood samples were drawn from participants at Visits 1 and 2 for analysis of complement (CH50) levels. Analysis of CH50 was done in batches, and CH50 levels were measured two hours after the end of study medication infusion. Percent change from Screening (Visit 1, Week -2) = (value at Visit 2 minus the value at Visit 1 divided by the value at Visit 1) * 100. | Visits 1 (Week -2) and 2 (Week 0) | 
| Number of Participants Classified as Responders for Fragment C Receptor (FcR) Polymorphism (Poly.) | FcR poly. affect the affinity with which FcRs interact with immunoglobulin molecules and are prognostic factors that are indicative of altered responsiveness to treatment and/or survival. A blood sample was drawn at Visit 1 for analysis (done in batches of several samples) of FcR poly. (Fcgamma RIIIa Valine/Phenylalanine genotypes [TT=thymidine/thymidine, TG=thymidine/guanine, GG=guanine/guanine] and Fcgamma RIIa Arginine/Histidine genotypes [AA=adenine/adenine, AG=adenine/guanine, GG=guanine/guanine]). Responders must have met the criteria for CR, CRu, or PR at either Month 3 or Month 6. Fc receptor polymorphisms and C1qA-276 results are not included in this results summary. | From first treatment (Visit 2) until Visit 12 (Month 6) | 
| Ctrough and Cmax at the Eighth Infusion (Visit 9, Week 7) | Cmax is defined as the maximum concentration of drug in plasma samples. Ctrough is defined as the trough plasma concentration (measured concentration at the end of a dosing interval [taken directly before the start of the next infusion]). | Visit 9 (Week 7; up to 10 months after dose) | 
| AUC(0-inf) and AUC(0-168) After the Eighth Infusion (Visit 9, Week 7) | AUC is defined as the area under the ofatumumab concentration-time curve as a measure of drug exposure. AUC(0-168) is AUC from the start of infusion to 168 hours after the start of the infusion; AUC(0-inf) is AUC from the start of infusion extrapolated to infinity. | Visit 9 (Week 7; up to 10 months after dose) | 
| t1/2 After the Eighth Infusion (Visit 9, Week 7) | t1/2 is defined as terminal half-life, which is the time required for the amount of the drug in the body to decrease by half. | Visit 9 (Week 7; up to 10 months after dose) | 
| CL After the Eighth Infusion (Visit 9, Week 7) | CL is the clearance of drug from plasma, which is defined as the volume of plasma from which drug is removed per unit time. | Visit 9 (Week 7; up to 10 months after dose) | 
| Vss After the Eighth Infusion (Visit 9, Week 7) | Vss is the volume of distribution at steady state of ofatumumab. | Visit 9 (Week 7; to up 10 months after dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ofatumumab, rituximab, NHL, CD20, refractory