Tafasitamab + Lenalidomide + R-CHOP Versus R-CHOP in Newly Diagnosed High-intermediate and High Risk DLBCL Patients

Study Overview
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Brief Summary
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This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to compare the efficacy and safety of the humanized monoclonal anti CD19 antibody tafasitamab plus lenalidomide in addition to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) versus R-CHOP in previously untreated, high-intermediate and high-risk patients with newly-diagnosed DLBCL

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial Comparing the Efficacy and Safety of Tafasitamab Plus Lenalidomide in Addition to R-CHOP Versus R-CHOP in Previously Untreated, High-intermediate and High-risk Patients With Newly-diagnosed Diffuse Large B-cell Lymphoma (DLBCL)

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Drug: Tafasitamab
* Drug: Lenalidomide
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone
* Drug: Tafasitamab placebo
* Drug: Lenalidomide placebo


Participation Criteria
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Eligibility Criteria
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Major Inclusion Criteria: Previously untreated patients with local biopsy-proven, CD20-positive DLBCL, including one of the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms are eligible: DLBCL, NOS including GCB type, ABC type T-cell rich large BCL Epstein-Barr virus-positive DLBCL, NOS Anaplastic lymphoma kinase (ALK)-positive large BCL Human herpes virus-8 (HHV8)-positive DLBCL, NOS High-grade BCL with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements (double-hit or triple-hit lymphoma). Please note: Patients must be appropriate candidates for R-CHOP. If an investigator deems a patient with a known double- or triple-hit lymphoma (HGBL) should be treated more aggressively (e.g. dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab [DA-EPOCH-R] or cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) followed by methotrexate and cytarabine [Hyper CVAD]), this patient would not be considered eligible for this study HGBL-NOS DLBCL coexistent with either follicular lymphoma (FL) of any grade, gastric MALT lymphoma or non-gastric MALT lymphoma FL grade 3b Availability of archival or freshly collected tumor tissue sent for retrospective central pathology review IPI status of 3 to 5 (for patients > 60 years of age) or aaIPI 2 to 3 (for patients ≤ 60 years of age) Diagnosis to treatment interval, defined as the time between the date of DLBCL diagnosis (date of the first biopsy specimen containing B Cell lymphoma according to the local pathology report) and the start of treatment (C1D1) ≤ 28 days ECOG performance status of 0, 1, or 2 Left ventricular ejection fraction equal to or greater 50% as assessed by local echocardiography or cardiac multi-gated acquisition (MUGA) scan Adequate hematologic function Female participants: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and refrain from breast feeding and donating eggs; agreement to ongoing pregnancy testing during the course of the study, and after study therapy has ended Male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom and agreement to refrain from donating sperm Major Exclusion Criteria: Any other histological type of lymphoma according to WHO 2016 classification of lymphoid neoplasms, e.g., primary mediastinal (thymic) large B-cell lymphoma, Burkitt's lymphoma, BCL, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma); primary effusion lymphoma; primary cutaneous DLBCL, leg type; primary DLBCL of the CNS; DLBCL arising from CLL or indolent lymphoma History of prior non-hematologic malignancy except for the following: Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer Adequately treated carcinoma in situ without current evidence of disease Any systemic anti-lymphoma and/or investigational therapy prior to the start of C1D1, except for permitted pre-phase treatment Contraindication to any of the individual components of R-CHOP, including prior receipt of anthracyclines Known CNS lymphoma involvement Known active systemic bacterial, viral, fungal, or other infection at screening, including patients with suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay) History or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that in the investigator's opinion would preclude participation in the study or compromise the patient's ability to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tafasitamab plus lenalidomide in addition to R-CHOP<br>Patients will receive tafasitamab plus lenalidomide in addition to R-CHOP for six 21-day cycles: Tafasitamab dose: 12 mg/kg body weight. Each 21-day cycle (cycles 1-6) will comprise of a tafasitamab IV infusion on Day 1, Day 8 and Day 15. Lenalidomide dose: 25 mg as a starting dose per os (orally) once per day on Days 1-10 of each 21-day cycle R-CHOP dose: Rituximab (or locally approved biosimilar) 375 mg/m2, IV Day 1 of every 21-day cycle; Cyclophosphamide 750 mg/m2, IV Day 1 of 21-day cycle; Doxorubicin 50 mg/m2, IV Day 1 of 21-day cycle; Vincristine 1.4 mg/m2 (max 2 mg) IV Day 1 of 21-day cycle; Prednisone/prednisolone 100 mg/day, per os, Day 1-5 of every 21-day cycle | Drug: Tafasitamab<br>* Tafasitamab IV infusion will be administered as per the schedule specified in the respective arm.<br>* Other names: Monjuvi;Drug: Lenalidomide<br>* Lenalidomide PO will be administered as per the schedule specified in the respective arm.<br>Drug: Rituximab<br>* Rituximab IV infusion will be administered as per the schedule specified in the respective arm.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide IV infusion will be administered as per the schedule specified in the respective arm.<br>Drug: Doxorubicin<br>* Doxorubicin IV infusion will be administered as per the schedule specified in the respective arm.<br>Drug: Vincristine<br>* Vincristine IV infusion will be administered as per the schedule specified in the respective arm.<br>Drug: Prednisone<br>* Prednisone PO will be administered as per the schedule specified in the respective arm.<br>|
| Placebo Comparator: Tafasitamab placebo plus lenalidomide placebo in addition to R-CHOP<br>Patients will receive tafasitamab placebo plus lenalidomide placebo in addition to R-CHOP for six 21-day cycles: Tafasitamab placebo: 0.9% saline solution Days 1, 8 and 15 of each 21-day cycle Lenalidomide placebo: Days 1-10 of each 21-day cycle R-CHOP dose: Rituximab (or locally approved biosimilar) 375 mg/m2, IV Day 1 of every 21-day cycle; Cyclophosphamide 750 mg/m2, IV Day 1 of 21-day cycle; Doxorubicin 50 mg/m2, IV Day 1 of 21-day cycle; Vincristine 1.4 mg/m2 (max 2 mg) IV Day 1 of 21-day cycle; Prednisone/prednisolone 100 mg/day, per os, Day 1-5 of every 21-day cycle | Drug: Rituximab<br>* Rituximab IV infusion will be administered as per the schedule specified in the respective arm.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide IV infusion will be administered as per the schedule specified in the respective arm.<br>Drug: Doxorubicin<br>* Doxorubicin IV infusion will be administered as per the schedule specified in the respective arm.<br>Drug: Vincristine<br>* Vincristine IV infusion will be administered as per the schedule specified in the respective arm.<br>Drug: Prednisone<br>* Prednisone PO will be administered as per the schedule specified in the respective arm.<br>Drug: Tafasitamab placebo<br>* 0.9% saline solution IV infusion will be administered as per the schedule specified in the respective arm.<br>Drug: Lenalidomide placebo<br>* Placebo matching to lenalidomide PO will be administered as per the schedule specified in the respective arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS-INV | Progression-Free Survival as assessed by the investigator using the Lugano Response Criteria for Malignant Lymphoma | Time from date of randomization until Progressive Disease or death from any cause. In this trial, the primary endpoint is PFS as assessed by the investigator (up to 43 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFS-INV | Event-Free Survival as assessed by the investigator using the Lugano Response Criteria for Malignant Lymphoma | From randomization until the first occurrence of disease progression or relapse as assessed by the INV using, start of new anti-lymphoma treatment or death from any cause, whichever occurs first (up to 43 months) | 
| OS | Overall Survival | From randomization until the date of death from any cause (up to 62 months) | 
| Metabolic PET-negative CR-rate at EOT by BIRC | Metabolic PET-negative CR rate defined as the proportion of patients who achieved metabolic PET-negative CR as per Lugano 2014 criteria based on PET/CTs performed at the end of the treatment by BIRC | End of treatment, 4-8 weeks after last dose | 
| Metabolic PET-negative CR-rate at EOT by INV | Metabolic PET-negative CR rate defined as the proportion of patients who achieved metabolic PET-negative CR as per Lugano 2014 criteria based on PET/CTs performed at the end of the treatment by the investigator | End of treatment, 4-8 weeks after last dose | 
| ORR as per INV at EOT | Overall response rate defined as the proportion of patients with CR or PR as per Lugano 2014 criteria based on assessment at the end of the treatment by the INV | 6 ± 2 weeks after End of Treatment | 
| Time to next anti-lymphoma treatment (TTNT) | TTNT is defined as the time from randomization date to start of next anti-lymphoma therapy (for any reason including disease progression, treatment toxicity, and patient preference) or death due to any cause, whatever comes first. | From randomization date to start of next anti-lymphoma therapy (for any reason including disease progression, treatment toxicity, and patient preference) or death due to any cause, whatever comes first (up to 43 months) | 
| Duration of Complete Response (CR) as assessed by the investigator | Duration of CR is defined as the time from the date of the first occurrence of a documented CR, to the date of progression, relapse, or death from any cause, whichever is earlier for the subgroup of patients with a Best Overall Response (BOR) of CR. | From the date of the first occurrence of a documented CR, to the date of progression, relapse, or death from any cause, whichever is earlier (up to 43 months) | 
| EFS at 3 years | Event-Free Survival as assessed by the investigator | 36 months after randomization | 
| PFS at 3 years | Progression-Free Survival as assessed by the investigator | 36 months after randomization | 
| OS at 3 years | Overall Survival | 36 months after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL, CD19, monoclonal antibody, tafasitamab, lenalidomide, R-CHOP, Diffuse Large B-cell Lymphoma