Study of Brentuximab Vedotin Combined With RCHOP or RCHP in Front-line Treatment of Patients With Diffuse Large B-cell Lymphoma (DLBCL)

Study Overview
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Brief Summary
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This study has 3 parts. The purpose of Part 1 of this study is to assess the safety and efficacy of brentuximab vedotin in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (known as BV+RCHOP) in patients with DLBCL who have never been treated. Patients will be randomly assigned in a 1:1 ratio to receive RCHOP together with 1 of 2 doses of brentuximab vedotin. Patients will be tested to see if there is a difference in side effects between the 2 groups. The purpose of Part 2 of this study is to assess the safety and efficacy of brentuximab vedotin in combination with RCHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) (known as BV+RCHP) in patients with CD30-positive DLBCL who have never been treated. Patients will be enrolled to receive RCHP together with 1.8mg/kg of brentuximab vedotin. The purpose of Part 3 of this study is to assess the safety and efficacy of BV+RCHP compared to standard RCHOP in patients with CD30-positive DLBCL that have never been treated. Patients will be randomly assigned in a 1:1 ratio to receive either BV+RCHP or RCHOP. Patients will be tested to see if there is a difference in side effects between the 2 groups.

Detailed Description
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In the first part of this study, patients in the 2 groups were tested to see if there was a difference in the response to treatment and whether there were differences in the side effects (unwanted effects). The second and third parts of the study are being done to see if there are any side effects (unwanted effects) of the higher dose of brentuximab vedotin when combined with a modified version of RCHOP that omits vincristine. The third part of the study is being done to see if there is a difference between BV+RCHP and RCHOP in the response to treatment.

Official Title
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A Phase 2 Study of Brentuximab Vedotin in Combination With Standard of Care Treatment (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone [RCHOP]) or RCHP (Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone) as Front-line Therapy in Patients With Diffuse Large B-cell Lymphoma (DLBCL)

Conditions
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Lymphoma, B-cell, Lymphoma, Large B-cell, Diffuse

Intervention / Treatment
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* Drug: brentuximab vedotin
* Drug: brentuximab vedotin
* Drug: rituximab
* Drug: vincristine
* Drug: cyclophosphamide
* Drug: prednisone
* Drug: doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treatment-naive patients with systemic de novo or transformed diffuse large B cell lymphoma (DLBCL) or follicular non-Hodgkin lymphoma (NHL) grade 3b International Prognostic Index (IPI) score greater than or equal to 3 for patients greater than 60 years of age or age-adjusted IPI (aaIPI) score of 2 or 3 for patients less than or equal to 60 years of age Stage IAX (bulk defined as single lymph node mass >10 cm in diameter), IB-IV disease Measurable disease of at least 1.5 cm Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 Patients in Parts 2 and 3 must have histologically confirmed diagnosis of CD30-positive DLBCL Exclusion Criteria: Previous history of treated indolent lymphoma History of another primary malignancy that has not been in remission for 3 years

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: Part 1: BV(1.2 mg/kg) + RCHOP<br>Brentuximab vedotin 1.2 mg/kg plus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone Part 1 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin when administered in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients in this arm were randomized into the 1.2 mg/kg brentuximab vedotin dosing cohort, to be administered in combination with RCHOP. | Drug: brentuximab vedotin<br>* 1.2 mg/kg by IV infusion every 3 weeks for up to 6 cycles<br>* Other names: Adcetris, SGN-35;Drug: rituximab<br>* 375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: vincristine<br>* 1.4 mg/m2 every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total)<br>Drug: cyclophosphamide<br>* 750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: prednisone<br>* 100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles<br>Drug: doxorubicin<br>* 50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>|
| Experimental: Part 1: BV(1.8 mg/kg) + RCHOP<br>Brentuximab vedotin 1.8 mg/kg plus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone Part 1 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin when administered in combination with standard RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients in this arm were randomized into the 1.8 mg/kg brentuximab vedotin dosing cohort, to be administered in combination with RCHOP. | Drug: brentuximab vedotin<br>* 1.8 mg/kg by IV infusion every 3 weeks for up to 6 cycles<br>* Other names: Adcetris, SGN-35;Drug: rituximab<br>* 375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: vincristine<br>* 1.4 mg/m2 every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total)<br>Drug: cyclophosphamide<br>* 750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: prednisone<br>* 100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles<br>Drug: doxorubicin<br>* 50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>|
| Experimental: Part 2: BV(1.8 mg/kg) + RCHP<br>Brentuximab vedotin 1.8 mg/kg plus rituximab, cyclophosphamide, doxorubicin, prednisone Part 2 of the study is a phase 2, non-randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when administered in combination with RCHP chemotherapy (rituximab, cyclophosphamide, doxorubicin, and prednisone). Patients in this treatment arm were enrolled into a dosing cohort with 1.8 mg/kg brentuximab vedotin administered in combination with RCHP. | Drug: brentuximab vedotin<br>* 1.8 mg/kg by IV infusion every 3 weeks for up to 6 cycles<br>* Other names: Adcetris, SGN-35;Drug: rituximab<br>* 375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: cyclophosphamide<br>* 750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: prednisone<br>* 100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles<br>Drug: doxorubicin<br>* 50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>|
| Active Comparator: Part 3: RCHOP<br>Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone Part 3 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when administered in combination with RCHP chemotherapy compared to RCHOP chemotherapy alone. Patients in this treatment arm were randomized to receive RCHOP treatment alone. | Drug: rituximab<br>* 375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: vincristine<br>* 1.4 mg/m2 every 3 weeks by IV infusion for up to 6 cycles (dose capped at 2 mg total)<br>Drug: cyclophosphamide<br>* 750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: prednisone<br>* 100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles<br>Drug: doxorubicin<br>* 50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>|
| Experimental: Part 3: BV(1.8 mg/kg) + RCHP<br>Brentuximab vedotin 1.8 mg/kg plus rituximab, cyclophosphamide, doxorubicin, prednisone Part 3 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when administered in combination with RCHP chemotherapy compared to RCHOP chemotherapy alone. Patients in this treatment arm were randomized to receive RCHOP treatment alone. Randomization in this part of the study is for the purpose of evaluating the safety of 1.8 mg/kg brentuximab vedotin in combination with RCHP versus standard RCHOP chemotherapy. Part 3 of the study is a phase 2, randomized, open-label, multicenter study designed to evaluate the antitumor activity and safety of brentuximab vedotin 1.8 mg/kg when administered in combination with RCHP chemotherapy compared to RCHOP chemotherapy alone. Patients in this treatment arm were randomized to receive 1.8 mg/kg brentuximab vedotin administered in combination with RCHP. | Drug: brentuximab vedotin<br>* 1.8 mg/kg by IV infusion every 3 weeks for up to 6 cycles<br>* Other names: Adcetris, SGN-35;Drug: rituximab<br>* 375 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: cyclophosphamide<br>* 750 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>Drug: prednisone<br>* 100 mg on Days 1 to 5 of each 3-week cycle, orally for up to 6 cycles<br>Drug: doxorubicin<br>* 50 mg/m2 every 3 weeks by IV infusion for up to 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission Rate | Number (count) of participants that achieved remission according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). | Up to 6 months | 
| Incidence of Adverse Events | Number (count) of participants that experienced at least 1 adverse event. | Up to 6 months | 
| Incidence of Laboratory Abnormalities | Number (count) of participants that experienced a Grade 3 or higher maximum post-baseline laboratory toxicity (hematology and chemistry). Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), v4.03. Grade 1 = mild, no intervention needed; Grade 2 = moderate, minimal intervention needed; Grade 3 = severe or medically significant, hospitalization is required; Grade 4 = life-threatening, urgent intervention needed; Grade 5 = death related to adverse event. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Number (count) of participants that achieved complete or partial remission at the end of treatment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007) | Up to 6 months | 
| Progression-free Survival | Median progression-free survival (in months) and observed minimum-maximum range. | Up to approximately 4 years | 
| Overall Survival | Median overall survival (in months) and observed minimum-maximum range. | Up to approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibodies, Monoclonal, Antibody-Drug Conjugate, Antigens, CD30, Drug Therapy, Hematologic Diseases, Lymphoma, B-cell, Lymphoma, Large B-cell, Diffuse, Monomethyl auristatin E