Phase 3 Randomized, Double-Blind Study of Brentuximab Vedotin, Lenalidomide, and Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma
- Trial ID
- 2023-503384-41-00
- Protocol
- SGN35-031
- Sponsor
- Seagen Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate and compare **progression-free survival (PFS)** between two treatment arms in both the intent-to-treat (ITT) population and the CD30-positive population. This is clinically relevant as PFS is a critical endpoint in assessing the efficacy of treatments for **relapsed or refractory diffuse large B-cell lymphoma (DLBCL)**, providing insights into the duration patients remain free from disease progression.
Secondary objectives include:
- Evaluating and comparing the objective response rate (ORR) between the two treatment arms in the ITT population.
- Evaluating and comparing overall survival (OS) between the two treatment arms in the ITT population.
- Evaluating and comparing OS between the two treatment arms in the CD30-positive population.
Participants
The clinical trial involves a total of **134 participants** diagnosed with **relapsed or refractory diffuse large B-cell lymphoma (DLBCL)**. The study population includes both male and female subjects aged 18 and older, with an **Eastern Cooperative Oncology Group (ECOG) performance status** score ranging from 0 to 2, indicating a general health status that allows for participation in clinical research. Participants were selected based on their diagnosis of relapsed or refractory DLBCL, with specific subtypes eligible for enrollment. The trial includes individuals who are ineligible for hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy due to various medical or logistical reasons. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific reproductive health guidelines, including the use of contraception. The trial population is diverse, including individuals with co-morbidities and those who are part of a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across different patient profiles.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, active-comparator, multicenter, Phase 3 study**. It aims to evaluate the efficacy of **brentuximab vedotin** in combination with **lenalidomide** and **rituximab** in subjects with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The primary objective is to assess and compare progression-free survival (PFS) between the two treatment arms in both the intent-to-treat (ITT) and CD30-positive populations. The trial is expected to conclude by May 24, 2025, with recruitment having commenced on April 22, 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as histological confirmation of DLBCL and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as positron emission tomography (PET) and computed tomography (CT) imaging, laboratory tests, and physical examinations. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is approximately 30 days, corresponding to the maximum treatment period. However, conditions such as adverse events, disease progression, or withdrawal of consent may lead to early termination from the study. Participants are required to adhere to specific contraceptive measures and provide informed consent prior to enrollment. The trial's design ensures rigorous evaluation of the investigational treatment's efficacy and safety, contributing valuable data to the understanding of therapeutic options for relapsed or refractory DLBCL.
Treatment
The clinical trial involves the administration of several treatments, including **Brentuximab Vedotin**, **Rituximab**, **Lenalidomide**, and a placebo. **Brentuximab Vedotin** is provided in the form of a powder for concentrate for solution for infusion. It is administered via subcutaneous injection with a maximum daily dose of 1400 mg and a total dose not exceeding 1400 mg over a treatment period of 30 days. This experimental medication is used to evaluate its efficacy in combination with other treatments for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
**Rituximab** is a chimeric monoclonal antibody, administered as a subcutaneous injection. The pharmaceutical form is identified as PHF00230MIG. The maximum daily and total dose for Rituximab is also 1400 mg, with a treatment period of up to 30 days. Rituximab serves as an active comparator in the study, providing a benchmark for evaluating the efficacy of the experimental treatment.
**Lenalidomide** is provided in the form of hard capsules, specifically Revlimid 5 mg hard capsules. It is administered orally with a maximum daily dose of 20 mg and a total dose not exceeding 50 mg over a 30-day treatment period. Lenalidomide is an immunomodulatory drug and acts as a comparator in the trial, allowing for the assessment of the experimental treatment's effectiveness in comparison to standard-of-care therapy.
The placebo used in the trial is designed to mimic the administration of **Brentuximab Vedotin** without containing the active substance. The placebo is utilized to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thus minimizing bias in the evaluation of treatment outcomes.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating and comparing **progression-free survival (PFS)** between the two treatment arms in both the intent-to-treat (ITT) population and the CD30-positive population. The primary endpoints include PFS per blinded independent central review (BICR) in these populations. Secondary endpoints will assess the overall response rate (ORR) per BICR and overall survival (OS) in both the ITT and CD30-positive populations.
Measurements for these endpoints will be conducted using validated methods, with PFS and ORR determined by BICR. The schedule for these assessments will be aligned with the trial protocol, ensuring consistent and reliable data collection throughout the study duration. The trial is designed to rigorously evaluate the efficacy of brentuximab vedotin in combination with lenalidomide and rituximab in subjects with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
Inclusion and Exclusion Criteria
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 the most recent local pathology assessment for the purposes of study eligibility and stratification. The following subtypes of DLBCL are eligible for enrollment: a. Not otherwise specified (NOS) b. Intravascular large B-cell lymphoma c. DLBCL associated with chronic inflammation d. EBV-positive NOS e. ALK-positive f. T-cell-/histiocyte-rich large B-cell lymphoma g. Primary mediastinal large B-cell lymphoma h. High-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 (double-/triple-hit lymphoma) i. High-grade NOS B-cell lymphomas j. Primary cutaneous DLBCL (leg type) k. DLBCL arising from transformed indolent lymphomas/leukemias
- Participants must have R/R disease following ≥2 lines of prior systemic therapy. For participants with transformed DLBCL (subtype k), 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: a. One or more co-morbidities, including cardiac, pulmonary, renal or hepatic dysfunction that in the opinion of the Investigator make the subject medically unfit to receive HSCT or CAR-T therapy. b. Active disease following induction and salvage chemotherapy c. Inadequate stem cell mobilization (for HSCT) d. Relapse following prior HSCT or CAR-T e. 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 for the determination of CD30 expression, which will be centrally determined by visual assessment for any detectable level of CD30 on tumor cells by IHC. The most recent biopsy available that contains viable DLBCL tissue should be submitted. If the CD30 results from the central pathology lab are not available prior to randomization, the subject may be stratified based on % CD30 expression from the local pathology lab. Participants who are stratified based on local pathology lab results must have the same archived tumor tissue sent in for central CD30 evaluation within 2 weeks of enrollment.
- Age 18 and older
- 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 > 1.5 cm by computed tomography (CT), as assessed by the site radiologist within 28 days of Day 1. a. PET and CT imaging performed prior to consent but within 28 days of Day 1 can be used
- The following baseline laboratory data within 28 days of Day 1: a. Absolute neutrophil count (ANC) ≥1000/μL. If recent G-CSF has been used, the ANC result must be ≥14 days after last dose of pegylated G-CSF or ≥7 days after last dose of G-CSF. b. Platelet count ≥50,000/μL at least 7 days after last treatment for DLBCL with no platelet transfusion during this 7-day period. c. For participants whose last therapy was CAR-T therapy, the ANC and platelet count requirements must be met at least twice during screening, with the measurements at least 7 days apart. d. Hemoglobin ≥8.0 g/dL and have not received a transfusion in the 7 days prior to testing e. Serum bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for participants with Gilbert’s disease or documented hepatic involvement with lymphoma. f. Estimated glomerular filtration rate (eGFR) ≥45 mL/min using the Cockcroft-Gault (C-G) formula, with serum creatinine (Scr) reported in mg/dL. o eGFR (mL/min) = ([140 – age] x weight [kg] x 0.85 [if female]) / (Scr x 72) g. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN or 5.0 x ULN for participants with documented hepatic involvement with lymphoma. h. Labs performed prior to consent but within 28 days of Day 1 can be used.
- Participants of childbearing potential, as defined in Section 4.3, under the following conditions. a. Must avoid pregnancy for at least 4 weeks before beginning lenalidomide therapy, during therapy, during dose interruptions, and for at least 12 months after completing therapy. Participants must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of birth control simultaneously: one highly effective form of contraception – tubal ligation, intrauterine device (IUD), hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap (see Appendix C), beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions, and continuing for 12 months following discontinuation of study drug (brentuximab vedotin, rituximab, or lenalidomide). Two negative beta human chorionic gonadotropin (β-HCG) pregnancy tests must be obtained prior to initiating therapy. The first test must be a serum β-HCG pregnancy test and the second test can either be a serum or urine β-HCG pregnancy test. The first test should be performed within 10 to 14 days and the second test performed within 24 hours prior to receiving lenalidomide therapy. Afterwards, a serum β-HCG pregnancy test must be administered weekly during the first month, then at least monthly thereafter in females with regular menstrual cycles or every 2 weeks in participants with irregular menstrual cycles. b. Must agree not to try to become pregnant during the study and for at least 12 months after the final dose of study drug. c. Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 12 months after the final dose of study drug. d. If sexually active in a way that could lead to pregnancy, must consistently use 2 methods of birth control as described in Inclusion criterion 9a, starting at time of informed consent and continuing throughout the study and for at least 12 months after the final dose of study drug
- Participants who can father children, under the following conditions: a. Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 12 months after the final dose of study drug. b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 methods of birth control (see Appendix C) starting at time of informed consent and continuing throughout the study and for at least 12 months after the final dose of study drug. c. If sexually active with a person who is pregnant or breastfeeding, must consistently use one of the contraception options (see Appendix C) starting at time of informed consent and continuing throughout the study and for at least 12 months after the final dose of study drug
- The following requirements for participants who are known to be human immunodeficiency virus (HIV) positive: ● CD4+ T-cell counts ≥350 cells/mm3 within 28 days of Day 1 ● No acquired immune deficiency syndrome-defining opportunistic infection within the past 12 months ● On established highly active antiretroviral therapy for at least 4 weeks with an HIV viral load less than 400 copies/mL within 28 days of Day 1 (see Section 5.6.2 for participants receiving strong CYP3A inhibitors).
- The subject must provide written informed consent
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. Exceptions are malignancies with a negligible risk of metastasis or death (eg, 5-year OS ≥90%), such as carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
- 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
- Participants who are breastfeeding
- Known hypersensitivity to any study drug or excipient contained in the drug formulation of the study drugs
- Any contraindication to associated study treatments
- Known to be positive for hepatitis B by surface antigen expression. Participants who are hepatitis B surface antigen (HBsAg) negative but hepatitis B core antibody (HBcAb) positive are eligible, but should start hepatitis B prophylaxis therapy prior to receiving the first dose of rituximab. Known to be positive for hepatitis C (HCV) infection (either confirmed positive by polymerase chain reaction [PCR] or on antiviral therapy for hepatitis C within the last 6 months). Participants who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks
- Participants with previous allogeneic HSCT if they meet either of the following criteria: ● <100 days from HSCT ● Active acute or chronic graft-versus-host disease (GVHD) or receiving immunosuppressive therapy as treatment for or prophylaxis against GVHD
- Previous treatment with brentuximab vedotin or lenalidomide. a. 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, pulmonary embolism, 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 (see Appendix D).
- Grade 2 or higher peripheral sensory or motor neuropathy at baseline
- Other serious underlying medical condition that, in the opinion of the investigator, would impair the subject’s ability to receive or tolerate the planned treatment, and complete study assessments
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 22 Apr 2021 | 9 |
 Czechia | Not Recruiting | 22 Apr 2021 | 2 |
 Denmark | Not Recruiting | 22 Apr 2021 | 6 |
 France | Not Recruiting | 22 Apr 2021 | 42 |
 Italy | Not Recruiting | 22 Apr 2021 | 7 |
 Poland | Not Recruiting | 22 Apr 2021 | 1 |
 Spain | Not Recruiting | 22 Apr 2021 | 17 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo BRENTUXIMAB"VEDOTIN" | Placebo | N/A | — | — | — | N/A |
RITUXIMAB | Comparator | PHF00230MIG | SUBCUTANEOUS INJECTION | 1400 | 30 | SCP24437829 |
BRENTUXIMAB VEDOTIN | Test | — | SUBCUTANEOUS INJECTION | 1400 | 30 | SUB32397 |
Revlimid 5 mg hard capsules | Comparator | HARD CAPSULES | ORAL | 20 | 30 | PRD9264284 |