Treatment Study of Denintuzumab Mafodotin (SGN-CD19A) Plus RICE Versus RICE Alone for Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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The purpose of this randomized, open-label study is to evaluate the safety and efficacy of denintuzumab mafodotin plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) when compared to RICE alone in the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or Grade 3b follicular lymphoma. Eligible patients must also be candidates for autologous stem cell transplant. Patients will be randomly assigned in a 1:1 ratio to receive 3 cycles of study treatment with either denintuzumab mafodotin + RICE or RICE alone. The study will assess whether there is a difference between the 2 groups in the side effects that are reported and the number of patients who achieve complete remission at the end of their study treatment.

Official Title
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A Randomized, Open-Label Phase 2 Study of Denintuzumab Mafodotin (SGN-CD19A) Plus Rituximab, Ifosfamide, Carboplatin, and Etoposide (19A+RICE) Chemotherapy vs. RICE in the Treatment of Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Who Are Candidates for Autologous Stem Cell Transplant

Conditions
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Lymphoma, B-cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Follicular, Grade 3b, Follicular Lymphoma, Grade 3b

Intervention / Treatment
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* Drug: denintuzumab mafodotin
* Drug: rituximab
* Drug: ifosfamide
* Drug: carboplatin
* Drug: etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL; including de novo and transformed DLBCL) or Grade 3b follicular lymphoma Available representative tissue from the most recent biopsy after the last therapy; if such tissue is not available, a fresh biopsy must be obtained Received only frontline CD20-directed immunotherapy with anthracycline- or anthracenedione-based multi-agent chemotherapy. Monotherapy rituximab or other CD20-directed immunotherapy as maintenance therapy prior to frontline chemotherapy, and radiotherapy in a limited field or as part of the frontline treatment plan are permitted. Achieved a response of stable disease, partial response, or complete response following the last cycle of frontline treatment. In addition, patients must have relapsed less than or equal to 6 months from the completion of frontline therapy at the time of initial dosing in this clinical trial. Considered eligible for high-dose chemotherapy followed by autologous stem cell transplant (ASCT) Fluorodeoxyglucose (FDG)-avid disease by positive emission tomography (PET), and measurable disease greater than 1.5 cm in diameter Eastern Cooperative Oncology Group (ECOG) performance less than or equal to 2 Adequate kidney and hematologic function assessed from baseline laboratory data Exclusion Criteria: Previous history of indolent lymphoma treated with more than 1 multi-agent chemotherapy regimen or previous cancer therapy for recurrent DLBCL or Grade 3b follicular lymphoma History of autologous or allogeneic stem cell transplant History of another primary invasive cancer, hematologic malignancy, or myelodysplastic syndrome that has not been in remission for at least 1 year History of progressive multifocal leukoencephalopathy (PML) Cerebral/meningeal disease related to the underlying malignancy that has not been definitively treated Known urinary tract obstruction Patients with the following ocular conditions: corneal disorders, monocular vision (i.e., best corrected visual acuity greater than or equal to 20/200 in one eye), or active ocular disorders requiring treatment

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: 19A+RICE<br>Denintuzumab mafodotin plus rituximab, ifosfamide, carboplatin, and etoposide | Drug: denintuzumab mafodotin<br>* Denintuzumab mafodotin 3 mg/kg by intravenous (IV) infusion, every 3 weeks for up to 3 cycles.<br>* Other names: SGN-CD19A;Drug: rituximab<br>* 375 mg/m^2 by IV infusion, every 3 weeks for up to 3 cycles<br>Drug: ifosfamide<br>* 5000 mg/m^2 by IV infusion over a 24-hour period, every 3 weeks for up to 3 cycles<br>Drug: carboplatin<br>* AUC 5mg/mL x min by IV infusion, every 3 weeks for up to 3 cycles<br>Drug: etoposide<br>* 100 mg/m^2 per day by IV infusion for 3 days, every 3 weeks for up to 3 cycles<br>|
| Active Comparator: RICE<br>Rituximab, ifosfamide, carboplatin, and etoposide | Drug: rituximab<br>* 375 mg/m^2 by IV infusion, every 3 weeks for up to 3 cycles<br>Drug: ifosfamide<br>* 5000 mg/m^2 by IV infusion over a 24-hour period, every 3 weeks for up to 3 cycles<br>Drug: carboplatin<br>* AUC 5mg/mL x min by IV infusion, every 3 weeks for up to 3 cycles<br>Drug: etoposide<br>* 100 mg/m^2 per day by IV infusion for 3 days, every 3 weeks for up to 3 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission Rate Per Independent Review Facility | Number of patients with complete metabolic response by PET (positive emission tomography) and CT (computed tomography) scans, or complete radiologic response by CT only. | Up to 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | Treatment-emergent adverse events (TEAEs) are presented and defined as newly occurring (not present at baseline) or worsening after first dose of investigational product. AE severity and seriousness are assessed independently. 'Severity' characterizes the intensity of an AE and is graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. An AE is considered 'serious' if it is life-threatening, fatal, requires hospitalization, or is otherwise considered to be medically significant. | Up to 4 months | 
| Number of Participants With Laboratory Abnormalities | Number of participants who experienced a maximum post-baseline laboratory toxicity of Grade 3 or higher (per National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03). | Up to 4 months | 
| Objective Response Rate (ORR) | ORR is defined as the proportion of patients with complete remission (CR) or partial remission (PR) per independent review facility (IRF) at the end of treatment. | Up to 4 months | 
| Duration of Complete Response (CR) | Defined as the time from the start of the first radiographic documentation of CR per investigator to the first documentation of progressive disease, death due to any cause, or receipt of subsequent anticancer therapy, whichever comes first. | Up to 27.9 months | 
| Duration of Objective Response (OR) | Duration of OR is defined as the time from the start of the first radiographic documentation of OR per investigator to the first documentation of PD, death due to any cause, or receipt of subsequent anticancer therapy, whichever comes first. | Up to 27.9 months | 
| Progression-free Survival (PFS) | PFS is defined as the time from randomization to first documentation of disease progression per investigator, death due to any cause, or receipt of subsequent anticancer therapy, whichever comes first. | Up to 30 months | 
| Overall Survival (OS) | OS is defined as the time from date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time will be censored at the last date the patient is known to be alive. | Up to 30 months | 
| Number of Patients Achieving Peripheral Blood Stem Cell (PBSC) Mobilization | Defined as the number of patients who are able to adequately mobilize PBSC per investigator assessment on or after completion of study treatment, prior to subsequent anticancer therapy. | Up to 30 months | 
| Number of Patients Receiving Autologous Stem Cell Transplant (ASCT) | Number of patients receiving ASCT after completion of study treatment (EOT), prior to subsequent anticancer therapy. | Up to 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms, Antibodies, Monoclonal, Antibody-Drug Conjugate, Antigens, CD19, Autologous Stem Cell Transplant, Drug Therapy, Follicular Lymphoma Grade 3b, Hematologic Diseases, Immune System Diseases, Immunoproliferative Disorders, Immunotherapy, Lymphatic Diseases, Lymphoma, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Non-Hodgkin, Monomethylauristatin F, Neoplasms by Histologic Type, Transformed Lymphoma / DLBCL, Rituximab, Ifosfamide, Carboplatin, Etoposide