Brentuximab Vedotin Plus Lenalidomide and Rituximab for the Treatment of Relapsed/Refractory DLBCL

• Brentuximab vedotin (Drug): 1.2 mg/kg administered into the vein (IV; intravenously) infusion every 3 weeks
• Rituximab (Drug): 375 mg/m\^2 administered via intravenous infusion on Cycle 1 Day 1. 1400 mg injected under the skin (subcutaneous) permitted every 3 weeks from Cycle 2 Day 1 through end of treatment.
• Lenalidomide (Drug): 20 mg given by mouth (orally) daily
• Placebo (Other): Administered via intravenous infusion every 3 weeks

Primary outcomes

• Overall Survival (OS) [From the date of randomization until date of death or censoring date, whichever occurred first (maximum up to 50 months)]: OS was defined as the time from the date of randomization to the date of death due to any cause. Participants who had not died were censored at the last known alive date or the data cutoff date, whichever was earlier. OS was estimated using the Kaplan-Meier method.

Secondary outcomes

• Progression-Free Survival (PFS) as Assessed by Investigator Per Lugano 2014 [From date of randomization until the first documentation of PD or to death due to any cause, whichever occurred first (maximum up to 50 months)]: PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or to death due to any cause, whichever occurred first, based on the investigator assessment of tumor response according to the criteria defined by the Lugano Classification, 2014.
• Objective Response Rate (ORR) as Assessed by Investigator Per Lugano 2014 [From the date of randomization until PD or initiation of new anticancer therapy (maximum up to 50 months)]: ORR per Lugano 2014 by investigator was defined as the percentage of participants with a response assessment of complete response (CR) or partial response (PR) per the Lugano 2014 response criteria as assessed by the investigator.
• Complete Response (CR) Rate as Assessed by Investigator Per Lugano 2014 [From the date of randomization until PD or initiation of new anticancer therapy (maximum up to 50 months)]: CR rate per Lugano 2014 by investigator was defined as the percentage of participants with a best response of CR per the Lugano 2014 response criteria as assessed by the investigator.
• Duration of Response (DOR) as Assessed by Investigator Per Lugano 2014 [From the date of first documented response of CR or PR to the first documented PD or death from any cause, whichever occurred first (maximum up to 50 months)]: DOR was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of tumor progression per the Lugano 2014 response criteria, as assessed by the investigator, or death due to any cause, whichever occurred first.
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) [From first dose of study treatment (Day 1) up to 30 days after last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later (maximum up to 50 months)]: An adverse event (AE) was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later. AEs included both serious AE (SAEs) and all other AEs. An AE was classified as an SAE if it met one of the following criteria: fatal, life threatening, required or prolonged hospitalization, disabling/ incapacitating, congenital anomaly or birth defect, medically significant.
• Number of Participants With TEAEs Based on Maximum Severity [From first dose of study treatment (Day 1) up to 30 days after last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later (maximum up to 50 months)]: An AE was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later. AE severity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v) 5.0 where, grade 1=mild AE; grade 2=moderate AE; grade 3=severe AE; grade 4= life-threatening; urgent intervention indicated; and grade 5= death related to AE.
• Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) [From first dose of study treatment (Day 1) up to 30 days after last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later (maximum up to 50 months)]: TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later. An AE was classified as an SAE if it met one of the following criteria: fatal, life threatening, required or prolonged hospitalization, disabling/ incapacitating, congenital anomaly or birth defect, medically significant.
• Number of Participants With TEAEs: Through Study Completion Date [From first dose of study treatment (Day 1) through study completion]: An AE was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily had a causal relationship with this treatment. TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later. AEs included both SAEs and all other AEs.
• Number of Participants With TEAEs Based on Maximum Severity: Through Study Completion Date [From first dose of study treatment (Day 1) through study completion]: An AE was any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which did not necessarily had a causal relationship with this treatment. TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later. AE severity graded using the NCI-CTCAE v 5.0 where, grade 1=mild AE; grade 2=moderate AE; grade 3=severe AE; grade 4= life-threatening; urgent intervention indicated; and grade 5= death related to AE.
• Number of Participants With TESAEs: Through Study Completion Date [From first dose of study treatment (Day 1) through study completion]: TEAEs were defined as events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later. An AE was classified as an SAE if it met one of the following criteria: fatal, life threatening, required or prolonged hospitalization, disabling/ incapacitating, congenital anomaly or birth defect, medically significant.
• OS in Cluster of Differentiation 30 (CD30)-Positive Participants [From the date of randomization until date of death or censoring date, whichever occurred first (maximum up to 50 months)]: OS was defined as the time from the date of randomization to the date of death due to any cause. OS was evaluated in participants with CD30 expression status using a predefined cutoff of >= 1%. Participants with CD30 tumor expression >= 1% were classified as CD30-positive. CD30 positivity was defined as >=1% of target lymphoid cells demonstrating membrane, cytoplasmic, and/or Golgi staining for CD30 at any intensity above background staining, as determined relative to the corresponding negative control. Participants who had not died were censored at the last known alive date or the data cutoff date, whichever was earlier.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Participants with relapsed or refractory diffuse and transformed large B-cell lymphoma (R/R DLBCL). DLBCL and cell of origin (GCB versus non-GCB) will be histologically determined by local pathology assessment for the purposes of study eligibility and stratification.
* Participants must have R/R disease following 2 or more lines of prior systemic therapy.

  * For participants with transformed DLBCL, at least the last systemic therapy used must have been for DLBCL
* Participants must be HSCT or CAR-T ineligible according to the investigator and must meet at least one of the following criteria:

  1. One or more co-morbidities, including cardiac, pulmonary, renal or hepatic dysfunction that in the opinion of the Investigator make the participant medically unfit to received HSCT or CAR-T therapy
  2. Active disease following induction and salvage chemotherapy
  3. Inadequate stem cell mobilization (for HSCT)
  4. Relapse following prior HSCT or CAR-T
  5. Unable to receive CAR-T therapy due to financial, geographic, insurance, or manufacturing issues
* Participants must have tumor tissue submitted to the central pathology lab. The tumor tissue submitted should be from the most recent biopsy that contains DLBCL.
* An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2
* Participants must have fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and bidimensional measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist within 28 days of Day 1.

Exclusion Criteria:

* History of another malignancy within 2 years before the first dose of study drug or any evidence of residual disease from a previously diagnosed malignancy
* History of progressive multifocal leukoencephalopathy (PML)
* Active cerebral/meningeal disease related to the underlying malignancy. Participants with a history of cerebral/meningeal disease related to the underlying malignancy are allowed if prior CNS disease has been effectively treated and without progression for at least 3 months.
* Any uncontrolled Grade 3 or higher (per NCI CTCAE version 5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study drug. Routine antimicrobial prophylaxis is permitted
* Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with immunotherapy that is not completed 3 weeks prior to first dose of study drug, unless underlying disease has progressed on treatment
* Previous treatment with brentuximab vedotin or lenalidomide.

  * Previous treatment with other vedotin-based ADCs is permitted if the last dose is at least 6 months prior to Day 1.
* Current therapy with immunosuppressive medications (including steroids), other systemic anti-neoplastic, or investigational agents

  a) Prednisone (or equivalent) ≤10 mg/day may be used for non-lymphomatous purposes
* Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to the first dose of study drugs
* Congestive heart failure, Class III or IV, by the NYHA criteria
* Grade 2 or higher peripheral sensory or motor neuropathy at baseline

Participant flow

Outcome results

• Overall Survival (OS) (Primary), Median, Months: Brentuximab Vedotin + Lenalidomide + Rituximab 14.8 (10.3 to 21.5); Placebo + Lenalidomide + Rituximab 7.8 (5.7 to 11.7) (p =0.0127)
• Progression-Free Survival (PFS) as Assessed by Investigator Per Lugano 2014 (Secondary), Median, Months: Brentuximab Vedotin + Lenalidomide + Rituximab 4.2 (3.0 to 7.1); Placebo + Lenalidomide + Rituximab 2.6 (1.4 to 3.1) (p =0.0012)
• Objective Response Rate (ORR) as Assessed by Investigator Per Lugano 2014 (Secondary), Number, Percentage of participants: Brentuximab Vedotin + Lenalidomide + Rituximab 64.3 (54.7 to 73.1); Placebo + Lenalidomide + Rituximab 41.5 (32.5 to 51.0) (p =0.0006)
• Complete Response (CR) Rate as Assessed by Investigator Per Lugano 2014 (Secondary), Number, Percentage of participants: Brentuximab Vedotin + Lenalidomide + Rituximab 41.1 (31.9 to 50.8); Placebo + Lenalidomide + Rituximab 18.6 (12.1 to 26.9)
• Duration of Response (DOR) as Assessed by Investigator Per Lugano 2014 (Secondary), Median, Months: Brentuximab Vedotin + Lenalidomide + Rituximab 8.3 (4.1 to 15.3); Placebo + Lenalidomide + Rituximab 4.1 (2.8 to 8.1)
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Secondary), Count of participants, Participants: Brentuximab Vedotin + Lenalidomide + Rituximab 109; Placebo + Lenalidomide + Rituximab 113
• Number of Participants With TEAEs Based on Maximum Severity (Secondary), Count of participants, Participants: Brentuximab Vedotin + Lenalidomide + Rituximab 1; Placebo + Lenalidomide + Rituximab 5
• Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) (Secondary), Count of participants, Participants: Brentuximab Vedotin + Lenalidomide + Rituximab 73; Placebo + Lenalidomide + Rituximab 59
• Number of Participants With TEAEs: Through Study Completion Date (Secondary)
• Number of Participants With TEAEs Based on Maximum Severity: Through Study Completion Date (Secondary)
• Number of Participants With TESAEs: Through Study Completion Date (Secondary)
• OS in Cluster of Differentiation 30 (CD30)-Positive Participants (Secondary), Median, Months: Brentuximab Vedotin + Lenalidomide + Rituximab 14.2 (7.1 to 39.4); Placebo + Lenalidomide + Rituximab 8.8 (6.0 to 24.4)

Adverse events

Time frame: SAEs and other AEs: From first dose of study treatment (Day 1) up to 30 days after last dose of brentuximab vedotin or lenalidomide or 110 days after last dose of rituximab, whichever was later (maximum up to 50 months)'. All cause mortality: From the date of randomization until date of death or censoring date, whichever occurred first (maximum up to 50 months)

Serious adverse events by term

77 more terms not shown.

Other adverse events by term

43 more sites not listed.

• Results publication: Bartlett NL, Hahn U, Kim WS, Fleury I, Laribi K, Bergua JM, Bouabdallah K, Forward N, Bijou F, MacDonald D, Portell CA, Ghesquieres H, Nowakowski G, Yasenchak CA, Patterson M, Ho L, Rustia E, Fanale M, Jie F, Kim JA. Brentuximab Vedotin Combination for Relapsed Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2025 Mar 20;43(9):1061-1072. doi: 10.1200/JCO-24-02242. Epub 2025 Jan 7. PMID 39772655
• Results publication: Ward JP, Berrien-Elliott MM, Gomez F, Luo J, Becker-Hapak M, Cashen AF, Wagner-Johnston ND, Maddocks K, Mosior M, Foster M, Krysiak K, Schmidt A, Skidmore ZL, Desai S, Watkins MP, Fischer A, Griffith M, Griffith OL, Fehniger TA, Bartlett NL. Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma. Blood. 2022 Mar 31;139(13):1999-2010. doi: 10.1182/blood.2021011894. PMID 34780623

• Study Protocol (PDF, 2025-08-27)
• Statistical Analysis Plan (PDF, 2024-01-18)

• Pfizer CT.gov Call Center, Study director, Pfizer

NIH grants: 2023