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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Seagen Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Circulatory and Respiratory Physiological Phenomena [G09], Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

22 Dec 2020 → ongoing

Decision date (initial)

2023-10-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Seagen Inc.

External identifiers

EU CT number

2023-503384-41-00

EudraCT number

2020-002686-33

ClinicalTrials.gov

NCT04404283

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

Evaluate and compare overall survival (OS) between the 2 treatment arms in the intent-to-treat (ITT) population.

Secondary objectives 2

1. 1. Evaluate and compare progression-free survival (PFS) per Lugano 2014 by investigator between the 2 treatment arms in the ITT population
2. 2. Evaluate and compare the objective response rate (ORR) per Lugano 2014 by investigator between the 2 treatment arms in the ITT population

Conditions and MedDRA coding

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 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
2. 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.
3. 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.
4. 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.
5. Age 18 and older
6. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2
7. 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
8. 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.
9. 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
10. 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
11. 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).
12. The subject must provide written informed consent

Exclusion criteria 16

1. 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
2. History of progressive multifocal leukoencephalopathy (PML).
3. 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
4. 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
5. 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
6. Participants who are breastfeeding
7. Known hypersensitivity to any study drug or excipient contained in the drug formulation of the study drugs
8. Any contraindication to associated study treatments
9. 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
10. 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
11. 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
12. 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
13. 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
14. Congestive heart failure, Class III or IV, by the NYHA criteria (see Appendix D).
15. Grade 2 or higher peripheral sensory or motor neuropathy at baseline
16. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. OS (Overall Survival)

Secondary endpoints 6

1. PFS (progression-free survival) per Lugano 2014 by investigator
2. CR (complete response) rate per Lugano 2014 by investigator
3. DOR (duration of response) per Lugano 2014 by investigator
4. Incidence, severity, and seriousness of adverse events (AEs) per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0
5. OS in CD30-positive participants
6. ORR (objective response rate) per Lugano 2014 by investigator

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Seagen Inc.

Sponsor organisation

Seagen Inc.

Address

21823 30th Drive Southeast

City

Bothell

Postcode

98021-3907

Country

United States

Scientific contact point

Organisation

Seagen Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Seagen Inc.

Contact name

Clinical Medical Lead

Third parties 14

Locations

7 EU/EEA countries · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 77 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications