Ofatumumab (Humax-CD20) With CHOP (Cyclophosphamide,Doxorubicin, Vincristine, Predisolone) in Follicular Lymphoma (FL) Patients

Study Overview
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Brief Summary
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To investigate the efficacy in two dose regimens of ofatumumab in combination with CHOP (cyclophosphamide,doxorubicin, vincristine,prednisolone) in previously untreated patients with Follicular Lymphoma (FL)

Official Title
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An Open-labeled, Randomized, Two-dose, Parallel Group Trial of Ofatumumab, a Fully Human Monoclonal Anti-CD20 Antibody, in Combination With CHOP, in Patients With Previously Untreated Follicular Lymphoma (FL).

Conditions
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Lymphoma, Follicular

Intervention / Treatment
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* Drug: Ofatumumab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisolone, Prednisone or equivalent


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with Follicular Lymphoma (FL) Confirmed diagnosis of Follicular lymphoma 18 years or above Verbal and written information about the study Exclusion Criteria: No previous treatment for Follicular Lymphoma Clinical suspicion that the Follicular Lymphoma has transformed to aggressive lymphoma Several diseases such as malignancies etc. Screening laboratory values Current participation in any other interventional clinical study Breast feeding women or pregnant women Women of childbearing potential not willing to use adequate contraception

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 |
| --- | --- |
| Active Comparator: Active Comparator 1<br>Each patient will receive a total of 6 infusions with ofatumumab in combination with CHOP every 3 weeks. The first infusion will be 300mg followed by 5 infusions of 500mg | Drug: Ofatumumab<br>* ofatumumab 300mg, 500mg or 1000mg should be diluted into 1000mL pyrogen free saline and administered as an IV infusion.Duration of infusion will be approximately 4 hours.Infusions should be given every 3 weeks until a total of 6 infusions has been given<br>Drug: Cyclophosphamide<br>* Cyclophosphamide 750 mg/m2 iv for 1 day, 24-48h post-ofatumumab infusion start<br>* Other names: CHOP;Drug: Doxorubicin<br>* Doxorubicin : 50mg/m2 iv for 1 day, 24-48h post-ofatumumumab infusion start<br>* Other names: CHOP;Drug: Vincristine<br>* Vincristine : 1.4mg/m2 iv for 1 day, 24-48h post-ofatumumab infusion start<br>* Other names: CHOP;Drug: Prednisolone, Prednisone or equivalent<br>* 100mg p.o daily for 5 days, 24-48h post-ofatumumab infusion start<br>* Other names: CHOP;|
| Active Comparator: Active Comparator 2<br>Each patient will receive a total of 6 infusions with ofatumumab in combination with CHOP every 3 weeks. The first infusion will be 300mg followed by 5 infusions of 1000mg | Drug: Ofatumumab<br>* ofatumumab 300mg, 500mg or 1000mg should be diluted into 1000mL pyrogen free saline and administered as an IV infusion.Duration of infusion will be approximately 4 hours.Infusions should be given every 3 weeks until a total of 6 infusions has been given<br>Drug: Cyclophosphamide<br>* Cyclophosphamide 750 mg/m2 iv for 1 day, 24-48h post-ofatumumab infusion start<br>* Other names: CHOP;Drug: Doxorubicin<br>* Doxorubicin : 50mg/m2 iv for 1 day, 24-48h post-ofatumumumab infusion start<br>* Other names: CHOP;Drug: Vincristine<br>* Vincristine : 1.4mg/m2 iv for 1 day, 24-48h post-ofatumumab infusion start<br>* Other names: CHOP;Drug: Prednisolone, Prednisone or equivalent<br>* 100mg p.o daily for 5 days, 24-48h post-ofatumumab infusion start<br>* Other names: CHOP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Indicated Overall Best Response (OBR) at Visit 26 (3 Months After the Last Infusion of Ofatumumab) | Based on standardized response criteria for NHL, responders included participants with CR (complete disappearance of all detectable clinical and radiographic evidence of disease), CRu (more than a 75% decrease in LN size compared to baseline), and PR (>=50% decrease in LN size and evidence of new lesions). Non-responders included participants with stable disease (SD; <50% decrease in LN size from baseline) and progressive disease (PD; >=50% increase in LN size and evidence of new lesions). | Maximum of 23 months after the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Remission (CR) at Visit 26 | Participants were evaluated for response by an Independent Endpoint Review Committee in accordance with the standardized response criteria for NHL. Participants with CR were defined as those with the complete disappearance of all detectable clinical and radiographic evidence of disease. | Maximum of 23 months after the start of treatment | 
| Median Percent Change From Visit 1 (Screening, Week -2) in Tumor Size at Visit 33 (24 Months After the Last Infusion of Ofatumumab) | The tumor size for a participant was computed as the sum of product of diameters (SPD) for the indicator lesions. Reduction in tumor size was calculated as percent change from Visit 1 until Visit 33, separately by radiologist 1 and radiologist 2. Percent change from Visit 1 (Screening, Week -2) = (value at Visit 33 minus value at Visit 1 divided by value at Visit 1) * 100. | Maximum of 24 months after the last infusion of Ofatumumab (Visit 33; median of 33.8 months) | 
| Time to New Anti-follicular Lymphoma (FL) Therapy | Time to new FL therapy is defined as the time from randomization until the time of first administration of the new FL therapy other than ofatumumab. Time to new FL therapy will be censored if participants are lost to follow-up. The censoring date in such cases will be the date of the last attended visit at which the endpoint was assessed. | Followed up to 5 years | 
| Progression-Free Survival (PFS) | PFS is defined as the time from randomization until progression or death. | Followed up to 5 years | 
| 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. | Followed up to 5 years | 
| Percent Change From Visit 1 (Screening) in Peripheral CD19+ and CD20+ Cell Counts at Visit 33 (24 Months After the Last Infusion of Ofatumumab) | The peripheral blood for each participant was collected and analyzed for CD19+ and CD20+ cell counts. CD19+ and CD20+ are B-cell types which are used as an index of a participant's response to treatment. | Maximum of 24 months after the last infusion of Ofatumumab (Visit 33; median of 33.8 months) | 
| Number of Participants Who Experienced Any Adverse Event (AEs) From First Treatment to Visit 33 (24 Months After Last Infusion) | An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with the treatment. A list of AEs experienced in the study with a frequency threshold of 5% can be found in the AE section. | Up to 22 months after study start | 
| Number of Participants With Positive Human Anti-human Antibodies (HAHA) at Visits 1, 28, and 33 | HAHA are indicators of immunogenicity to ofatumumab. Blood samples were drawn from participants at Visits 1, 28, and 33 for analysis of HAHA. | Visits 1 (Screening), 28 (9 months after last dose), and 33 (24 months after last dose) | 
| Median Percent Change From Visit 1 (Screening) in Serum Complement (CH50) Levels at Visit 22 | The peripheral blood for each participant was collected and analyzed for serum complement CH50 levels. Cluster of Differentiation index 50 (CD50) is a human gene which is used as an index of immune response. CD50Percent change from Visit 1 (Screening, Week -2) = (value at Visit 22 minus value at Visit 1 divided by value at Visit 1) * 100. | Visit 1 (Screening, Week -2) and Visit 22 (Week 15) | 
| Number of Participants Who Had a Conversion of BCL-2 t(14;18)-Positive to Negative by Polymerase Chain Reaction (PCR) in Peripheral Blood and Bone Marrow Aspirate and Its Durability Post-therapy | This is a genetic prognostic marker of FL response. The former sponsor decided to not analyze these samples; therefore, no results are presented. | Maximum of 6 years follow-up | 
| Cmax and Ctrough at the Sixth Infusion (Week 15, Visit 22) | 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 next administration]). | Week 15 (Visit 22) | 
| AUC(0-inf) and AUC(0-504) After the Sixth Infusion (Week 15, Visit 22) | AUC is defined as the area under the ofatumumab concentration-time curve as a measure of drug exposure. AUC(0-504) is AUC from the start of infusion to 504 hours after the start of the infusion; AUC(0-inf) is AUC from the start of infusion extrapolated to infinity. | Week 15 (Visit 22) | 
| Half Life (t1/2) of Ofatumumab at the Sixth Infusion (Week 15, Visit 22) | Half life is defined as the period of time required for the amount of drug in the body to be reduced by half. | Week 15 (Visit 22) | 
| CL After the Sixth Infusion (Week 15, Visit 22) | CL is the clearance of drug from plasma, which is defined as the volume of plasma from which the drug is cleared per unit time. | Week 15 (Visit 22) | 
| Vss at the Sixth Infusion (Week 15, Visit 22) | Vss is defined as the volume of distribution at steady state of ofatumumab. | Week 15 (Visit 22) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CHOP (cyclophosphamide,doxorubicin,vincristine,prednisolone), ofatumumab