A Study of Zanubrutinib Versus Lenalidomide in Participants With Relapsed/Refractory Follicular or Marginal Zone Lymphoma (MAHOGANY)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

BeOne Medicines AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

28 Sep 2023 → ongoing

Decision date (initial)

2023-08-14

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

BeiGene Ltd

External identifiers

EU CT number

2022-502548-12-00

WHO UTN

U1111-1289-7511

ClinicalTrials.gov

NCT05100862

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

R/R FL cohort: To compare the efficacy of zanubrutinib plus obinutuzumab (ZO) versus lenalidomide plus rituximab (R2) in patients with R/R FL
R/R MZL cohort: To compare the efficacy of zanubrutinib plus rituximab (ZR) versus R2 in patients with R/R MZL

Secondary objectives 6

1. R/R FL and R/R MZL cohorts: To compare the efficacy of ZO versus R2 in patients with R/R FL.
2. R/R FL and R/R MZL cohorts: To compare the efficacy of ZR versus R2 in patients with R/R MZL.
3. R/R FL and R/R MZL cohorts: To compare Health-related Quality of Life (HRQoL) of ZO versus R2 in patients with R/R FL and ZR versus R2 in patients with R/R MZL.
4. R/R FL and R/R MZL cohorts: To compare the safety and tolerability of ZO versus R2 in patients with R/R FL and ZR versus R2 in patients with R/R MZL
5. R/R FL cohort: To compare the efficacy of ZO versus R2 in patients with R/R FL
6. R/R MZL cohort: To compare the efficacy of ZR versus R2 in patients with R/R MZL

Conditions and MedDRA coding

marginal zone lymphoma

Regulatory references

Scientific advice from competent authorities

Beigene Ltd.

EMA paediatric investigation plan (PIP)

EMEA-002354-PIP02-18

Plan to share IPD

Yes

IPD plan description

BeiGene shares data on completed studies responsibly and provides qualified scientific and medical researchers access to data and supporting documentation for clinical trials in dossiers for medicines and indications after submission and approval in the United States, China, and Europe. Clinical trials supporting subsequent local approvals, new indications, or combination products are eligible for sharing once corresponding regulatory approvals are achieved. BeiGene shares data only when permitted by applicable data privacy and security laws and regulations, and shared when it is feasible to do so without compromising the privacy of study participants. Qualified researchers with appropriate competencies who are engaged in novel scientific research may submit a request for participant-level data along with a research proposal for BeiGene review. Research teams must include a biostatistician and sign a Data Sharing Agreement prior to receiving access to clinical trial data.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Age of ≥ 18 years at the time of informed consent.
2. Able to provide written informed consent and understand and comply with study requirements.
3. Women of childbearing potential (WOCBP [1]; Section 6.3) must: a. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for up to 1 month after the last dose of zanubrutinib, and according to the approved obinutuzumab and rituximab product/PI, whichever is longer. b. Have 2 negative pregnancy tests (minimum sensitivity 25 mIU/mL) as verified by the investigator prior to starting study treatment (between Days -14 and -10 before the first dose of study treatment, and the other test is performed ≤ 24 hours before the start of lenalidomide). She must agree to ongoing pregnancy testing during the study, and after end of study treatment. This applies even if the patient practices true abstinence from heterosexual contact. c. Either commit to true abstinence [2] from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with 2 forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption during screening for all WOCBP, and during the study treatment for WOCBP in Arm B and Arm D (including dose interruptions), and for at least 28 days after the last dose of lenalidomide.
4. Male patients are eligible if: a. Abstinent, vasectomized, or if they agree to use barrier contraception (condom) with other methods (Section 6.4; even vasectomized male patients receiving lenalidomide must practice true abstinence) or agree to use a condom during sexual contact with a pregnant woman or a WOCBP)] during the study treatment period and for up to 1 week after the last dose of zanubrutinib, for ≥ 28 days after the last dose of lenalidomide, and according to the approved obinutuzumab and rituximab product/PI, whichever is longer. b. Agree to not donate semen or sperm during study treatment and for up to 1 week after the last dose of zanubrutinib, for at least 28 days after the last dose of lenalidomide, and according to the approved obinutuzumab and rituximab product/PI, whichever is longer.
5. All patients must: a. Have an understanding that the study treatment could have a potential teratogenic risk. b. Agree to abstain from donating blood while taking study treatment and for 4 weeks after discontinuation of study treatment therapy. c. Agree not to share study medication with another person. d. Agree to be counseled about pregnancy precautions and risk of fetal exposure. e. Female patients must agree to abstain from breastfeeding during study participation and for ≥ 14 days after the last dose of zanubrutinib, for ≥ 28 days after the last dose of lenalidomide, and according to the approved obinutuzumab and rituximab product/PI, whichever is longer.
6. Histologically confirmed Grade 1-3a FL or MZL according to World Health Organization 2016 classification. All three subtypes of MZL (extranodal, nodal, and splenic) are eligible. NOTE: A formalin-fixed, paraffin-embedded specimen must be available for central review. If an archival specimen is not available, or if there is suspicion of transformation, a re-biopsy is required before randomization.
7. Previously treated with at least one line of systemic therapy (for Grade 1-3a FL or MZL) including anti-CD20 monoclonal antibody (≥ 4 doses as consecutive monotherapy or ≥ 2 doses as consecutive combination therapy). Must have a documented failure to achieve at least PR during the most recent systemic therapy or documented progressive disease after the most recent systemic therapy. Systemic therapy does not include Helicobacter pylori eradication or local involved field radiotherapy.
8. Need for systemic therapy for FL or MZL if, based on the investigators’ assessment, the patient has ≥ 1 of the following symptoms: a. Local symptoms from progressive disease and/ or bulky disease. b. Compromise of normal organ function from progressive disease. c. B-symptoms including fevers, weight loss, and night sweats. d. Symptomatic extranodal disease such as effusions. e. Severe cytopenias from BM infiltration, (leukocytes < 1.0 x 109/L and/or platelets < 100 x 109/L), autoimmune hemolytic anemia or thrombocytopenia, or hypersplenism. f. An increase in disease tempo. g. Gastrointestinal bleeding (related to lymphoma).
9. Measurable disease by CT or magnetic resonance imaging (MRI). Measurable disease as defined by ≥ 1 nodal lesion that is > 1.5 cm in longest diameter and/or ≥ 1 extranodal lesion that is > 1.0 cm in longest diameter, and lesion(s) measurable in 2 perpendicular diameters, as defined by the Lugano classification (Cheson et al 2014). Site of measurable disease cannot be previously irradiated.
10. ECOG performance status of 0 to 2.
11. Life expectancy ≥ 6 months.
12. Adequate BM function, defined as: a. Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 (1.0 x 109/L), except for the patients with BM involvement or hypersplenism by FL or MZL, or for patients with benign neutropenia associated with ethnicity (Kanapuru et al 2023,), in which case ANC must be ≥ 750 cells/mm3. NOTE: The screening hematology values confirming the patient meets the ANC requirement must be dated at least 14 days following the most recent administration of peg-filgrastim (or other pegylated myeloid growth factors) and at least 7 days following the most recent administration of filgrastim or other myeloid growth factors. b. Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without growth factor support or platelet transfusion within 7 days) except for patients with BM involvement or hypersplenism by FL or MZL, in which case platelet count must be ≥ 50,000 cells/mm3 (50 x 109/L) (without growth factor support or platelet transfusion within 7 days). c. Hemoglobin ≥ 8.0 g/dL (80.0 g/L; 5 mmol/L; without growth factor support or red blood cell transfusion within 7 days).
13. Adequate organ function, defined as: a. CrCl of ≥ 30 mL/min (as estimated by the Cockcroft-Gault equation, MDRD or CKD-EPI equations, see Appendix 7). b. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase and alanine aminotransferase/serum glutamic pyruvic transaminase ≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN if liver involvement by FL or MZL. c. Serum total bilirubin ≤ 2.0 x ULN or ≤ 5 x ULN due to Gilbert’s syndrome or documented liver or pancreatic involvement by FL or MZL.
14. Must have a documented failure to achieve at least PR during the most recent systemic therapy or documented progressive disease after the most recent systemic therapy. Systemic therapy does not include H. pylori eradication or local involved field radiotherapy.

Exclusion criteria 28

1. Transformation to aggressive lymphoma, such as diffuse large B-cell lymphoma or Grade 3b FL. If transformation is suspected, a biopsy of the suspected area is required to exclude transformation. NOTE: Patients with a prior history of transformation may be enrolled if 1) they have received at least one prior line of treatment for FL or MZL AND 2) interval between end of treatment for transformation and enrollment is more than 2 years AND 3) current relapse as Grade 1-3a FL or MZL confirmed.
2. Requiring ongoing need for corticosteroid treatment, except for adrenal replacement. NOTE: Systemic corticosteroids must be fully tapered off/stopped ≥ 5 days before the first dose of study treatment.
3. Clinically significant cardiovascular disease including the following: a. Myocardial infarction ≤ 6 months before screening. b. Unstable angina ≤ 3 months before screening. c. New York Heart Association class 3 or 4 congestive heart failure (see Appendix 4). d. History of clinically significant arrhythmia (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes). e. QTcF (Fridericia’s correction) > 480 msec. f. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. g. Uncontrolled hypertension as indicated by ≥ 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and/or diastolic blood pressure > 105 mm Hg at screening.
4. Prior malignancy within the past 2 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized prostate cancer (Gleason score of ≤ 6).
5. History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
6. History of stroke or intracranial hemorrhage ≤ 180 days before the first dose of study treatment.
7. Severe or debilitating pulmonary disease.
8. Inability to swallow capsules or gastrointestinal disfunction such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery, inflammatory bowel disease, or bowel obstruction.
9. Active fungal, bacterial, and/or viral infection that requires systemic therapy. Note: Patients with infections that are managed by oral antibiotics and who are otherwise clinically stable are not excluded from study participation
10. Confirmed central nervous system involvement by FL or MZL.
11. Underlying medical conditions that, in the investigator’s opinion, will render the administration of study treatment hazardous or obscure the interpretation of safety.
12. Severely immunocompromised state.
13. History or active infection with human immunodeficiency virus (seropositive patients with sustained undetectable viral load may be enrolled).
14. Serologic status reflecting active viral HBV or HCV infection as follows: a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but without HBsAg, are eligible if HBV DNA is undetectable (NOTE: the limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL), and if they are willing to undergo monthly monitoring for HBV reactivation. b. Presence of HCV antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (NOTE: the limit of detection for HCV RNA must have a sensitivity of < 15 IU/mL) and if they are willing to undergo monthly monitoring for HCV reactivation.
15. Major surgery ≤ 4 weeks before the first dose of study treatment or planned during study.
16. Prior treatment with a BTK inhibitor (including zanubrutinib)
17. Prior treatment with lenalidomide (or drugs from the same class, ie, immunomodulatory drugs or cereblon E3 ligase modulatory drugs), including but not limited to combination with rituximab, and without response (response is defined as best overall response that is PR or CR) or with short remission (short remission defined as: a response was achieved but the DOR was < 24 months).
18. Last dose of prior therapy for FL or MZL, including herbal medicine with anti neoplastic intent ≤ 21 days before the first dose of study treatment with additional exclusion requirements: a. Treatment with monoclonal antibody-based therapy (including bispecifics antibody) ≤ 28 days before the first dose of study treatment. b. Chimeric antigen receptor T-cell therapy ≤ 180 days before the first dose of study treatment. c. Allogeneic hematopoietic cell transplantation ≤ 1 year before the first dose of study treatment. d. Autologous hematopoietic stem cell transplantation ≤ 3 months before the first dose of study treatment
19. Any chemotherapy or radiation treatment for non-FL or MZL indications ≤ 21 days before the first dose of study treatment.
20. Ongoing toxicity of ≥ Grade 2 from prior anticancer therapy (except for alopecia, ANC, and platelets. For ANC and platelets, please follow inclusion criterion #9).
21. Pregnant, planning to become pregnant, or lactating women.
22. Vaccination with a live vaccine ≤ 35 days before the first dose of study treatment.
23. Hypersensitivity to zanubrutinib, lenalidomide, obinutuzumab or rituximab, murine products, thalidomide, or any of the other ingredients/excipients of the study drugs, with exception of minor (Grade 1-2), immediate infusion-related reactions to anti-CD20 antibodies.
24. Requiring ongoing therapy with strong or moderate cytochrome P450 3A (CYP3A) inducers.
25. Use of strong/moderate CYP3A inhibitors (see Appendix 5) within 7 days or 5 half-lives prior to the first dose of zanubrutinib; usage of strong/moderate CYP3A inducers (see Appendix 4) within 14 days prior to the first dose of zanubrutinib.
26. Patients who are at a risk for a thromboembolic event and are not willing to take venous thromboembolism (VTE) prophylaxis.
27. Neuropathy of Grade > 1.
28. Plan to receive another investigational drug on study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. R/R FL cohort: Progression-free survival (PFS) assessed by a Blinded Independent Review Committee (BIRC) in accordance with the 2014 modification of the International Working Group on non-Hodgkin lymphoma (NHL) Criteria (Lugano 2014 criteria) based on positron emission tomography and computed tomography (PET/CT based Lugano 2014 criteria) (Cheson et al 2014)
2. R/R MZL cohort: PFS assessed by BIRC in accordance with CT based Lugano 2014 criteria

Secondary endpoints 7

1. R/R FL cohort: Overall response rate (ORR) assessed by BIRC in accordance with PET/CT-based Lugano 2014 criteria.
2. R/R FL cohort: Overall survival (OS)
3. R/R MZL cohort: ORR determined by BIRC (CT based Lugano 2014 criteria)
4. R/R FL cohort: PFS by investigator, ORR by Investigator, Duration of response (DOR), Complete response rate (CRR), time to response (TTR) and time to next anti-lymphoma treatment (TTNT) with PET/CT based Lugano 2014 criteria
5. R/R MZL cohort: OS, PFS by investigator, ORR by Investigator, DOR, CRR, TTR, TTNT with PET/CT based and CT based Lugano 2014 criteria
6. R/R FL and R/R MZL cohorts: Patient-reported outcomes (PROs) questionnaires: the European Organization for Research on Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-C30], National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 [FLymSI 18], and European Quality of Life 5Dimension 5Level Questionnaire [EQ 5D 5L)
7. R/R FL and R/R MZL cohorts: Incidence rate of adverse event, lab abnormalities, and vitals.

Investigational products

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

Test 2

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

BeOne Medicines AG

Sponsor organisation

BeOne Medicines AG

Address

Aeschengraben 27

City

Basel

Postcode

4051

Country

Switzerland

Scientific contact point

Organisation

BeOne Medicines AG

Contact name

BeOne Medical Officer

Public contact point

Organisation

BeOne Medicines AG

Contact name

BeOne Medical Officer

Third parties 18

Locations

14 EU/EEA countries · 76 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 290 files

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

Application history

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