BI 695500 vs Rituxan First Line Treatment in Patients With Low Tumor Burden Follicular Lymphoma

Study Overview
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Brief Summary
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This is a Phase III, multicenter, randomized, double-blind, parallel-arm, active comparator trial to evaluate BI 695500 versus rituximab as a first-line immunotherapy treatment in patients with LTBFL. Patients will be randomly assigned in a 1:1 ratio to receive 375 mg/m2 of BI 695500 or rituximab via intravenous (IV) infusion once a week for 4 weeks (total of 4 dosages administered on Days 1, 8, 15, and 22). Disease assessments will be performed at the End of Study (EOS) Visit at Week 30.

Official Title
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A Phase III, Randomized, Double-blind, Multi-center, Multi-national Trial to Evaluate Efficacy and Safety of BI 695500 Versus Rituximab as a First-line Immunotherapy Treatment in Patients With Low Tumor Burden Follicular Lymphoma

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Rituximab
* Drug: BI 695500


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Written informed consent that is consistent with ICH GCP guidelines and local legislations. Male or female patients, at least 18 years of age at Screening. Histologically-confirmed, stage II - IV NHL (CD20+ FL of Grades 1, 2, or 3a). Low tumor burden according to the GELF criteria Diagnostic biopsies will be centrally reviewed by expert pathologists to confirm correct histology in accordance with WHO guidelines. If the interval since diagnosis is > 12 months, a new biopsy will be required to confirm the histology remained unchanged. Patients not previously treated for their FL, including any previous treatment for FL under clinical trials. ECOG performance status of 0 to 1. Have at least one measurable lesion as per the International Working Group (IWG) criteria 2007 at Screening (lesion clearly measurable in at least two perpendicular dimensions Adequate hematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow) within 28 days prior to randomization Adequate renal and liver function: For participants of reproductive potential (males and females), use of a medically acceptable method of contraception during the trial Exclusion criteria: Transformation to high-grade lymphoma (secondary to low-grade lymphoma) prior to study entry. Circulating tumor cells = 5 × 109/L. Presence or history of central nervous system lymphoma. Patients receiving current treatment with corticosteroids must not be receiving a dose exceeding 20 mg/day prednisone or equivalent. Patients with prior or concomitant malignancies within 5 years prior to Screening Major surgery within 28 days prior to randomization. Active, chronic or persistent infection that might worsen with immunosuppressive treatment; positive for HIV or tuberculosis (TB) at Screening. Patients who are confirmed positive and those who have active infections are excluded from the trial participation. Patients with serological evidence of HBV infection. Patients seropositive because of HBV vaccine are eligible. HBV positive patients may participate following consultation with a hepatitis expert regarding monitoring and use of HBV antiviral therapy, and provided they agree to receive treatment as indicated. Serious underlying medical conditions, that, per the Investigator¿s discretion, could impair the ability of the patient to participate in the trial. Known hypersensitivity or allergy to murine products. History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to any component of the trial medication. Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit. Prior treatment with BI 695500 and/or rituximab. Patients who received any prior therapy using mAbs will be excluded; this does not apply to other biological drugs such as growth factors or anticoagulants. Treatment within a clinical trial within 4 weeks prior to initiation of trial treatment. Patients who have received treatment with a drug that has not received regulatory approval for any indication within 4 weeks or a minimum of 5 half-lives, whichever is longer, of the initial dose of trial medication. Any other co-existing medical or psychological condition(s) that will preclude participation in the trial or compromise ability to give informed consent and/or comply with study procedures. Pregnancy or breast feeding. For women of childbearing potential, a positive serum pregnancy test at the Screening Visit. Patients who have significant cardiac disease, including but not limited to congestive heart failure of Class III or IV of the NYHA classification; uncontrolled angina or arrhythmia; any uncontrolled or severe cardiovascular or cerebrovascular disease; or uncontrolled hypertension.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 695500<br>375 mg/m2; One intravenous infusion once a week for 4 weeks | Drug: BI 695500<br>* BI 695500 375 mg/M2<br>|
| Active Comparator: Rituximab (US reference product)<br>375 mg/m2; One intravenous infusion once a week for 4 weeks | Drug: Rituximab<br>* BI 695500 375 mg/M2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Measured as Overall Response Rate (ORR) at Week 30 for BI 695500 Versus Rituximab | The primary objective of this trial was to evaluate statistical equivalence of efficacy as assessed by Overall Response (measured as Overall Response Rate (ORR)) at Week 30 for treatment with BI 695500 versus rituximab (Rituxan®) in patients with untreated low tumor burden follicular lymphoma (LTBFL). The overall response measured as Overall Response Rate (ORR), which is the completed response (CR) and the partial response (PR) at Week 30, approximately 26 weeks after the completion of study treatment, as defined by International Working Group (IWG) criteria 2007 via an independent radiology assessment. Two patient were randomized and treated with BI 695500, whereas no patient was treated with rituximab in this trial. | From first administration of study medication until 30 weeks thereafter. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extrapolated Area Under the Concentration-time Curve of BI 695500 or Rituximab at Steady State Over the Interval 0 Hour (h) to the Next Dose of Trial Medication (AUC0-τ, ss) | Extrapolated area under the concentration-time curve of BI 695500 or rituximab in plasma at steady state over the interval 0 hour (h) to the next dose of trial medication (AUC0-τ, ss) established by population pharmacokinetics. | Sample timepoints Day 1, 8, 22, 23-24 (24-48 hours from start of Cycle 4 infusion), 24-26 (48-96 hours from start of Cycle 4 infusion), 26-36 (96-336 hours from start of Cycle 4 infusion), 78, 134, 204 | 
| Immunogenicity at Week 30 | Immunogenicity (rate of anti-drug antibodies) at Week 30 presented as the number of participants having Immunogenicity at Week 30. This endpoint was not summarized for arm ' rituximab ', as two patient were randomized and treated with BI 695500, thus no patient was treated with rituximab in this trial. | Day 204 or end of study |