A Phase 2 Study combining BGB-3111 with Obinutuzumab compared with Obinutuzumab Monotherapy in Relapsed/Refractory Follicular Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Beigene Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Apr 2018 → 28 Dec 2024

Decision date (initial)

2024-04-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BeiGene Ltd.

External identifiers

EU CT number

2023-509975-17-00

EudraCT number

2017-001552-54

ClinicalTrials.gov

NCT03332017

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

To evaluate efficacy of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy, as measured by overall response rate determined by independent central review.

Secondary objectives 1

1. To evaluate efficacy of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy, as measured by the following: -Overall response rate determined by investigator assessment -Duration of response determined by independent central review and by investigator assessment -Progression-free survival determined by independent central review and by investigator assessment -Overall survival -Rate of complete response or complete metabolic response determined by independent central review and by investigator assessment -Time to response determined by independent central review and by investigator assessment -Patient-reported outcomes • Safety and tolerability • Pharmacokinetics (zanubrutinib plus obinutuzumab arm only)

Conditions and MedDRA coding

Relapsed/Refractory Follicular Lymphoma

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. ≥ 18 years of age at the time of informed consent
2. Histologically confirmed diagnosis of B-cell follicular lymphoma (grade 1, 2 or 3a) based on the WHO 2008 classification of tumors of hematopoietic and lymphoid tissue
3. ≥ 2 prior systemic treatments for follicular lymphoma
4. Previously received an anti-CD20 antibody and an appropriate alkylator-based combination therapy, including a.Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone b.Rituximab, cyclophosphamide, vincristine, and prednisolone c.Bendamustine plus rituximab
5. Disease progression after completion of most recent therapy or refractory disease, defined as failure to achieve CR or PR to most recent therapy, and most recent therapy was an appropriate second-line (or later) systemic therapy for follicular lymphoma
6. Presence of measurable disease, defined as ≥ 1 nodal lesion that is > 2 cm in longest diameter, or ≥ 1 extranodal lesion that is > 1 cm in longest diameter
7. Availability of archival tissue confirming diagnosis of B-cell follicular lymphoma (or if archival tissue is not available, a copy of the pathology report confirming diagnosis of B-cell follicular lymphoma is required)
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
9. Life expectancy ≥ 6 months
10. Adequate organ function defined as: a. Absolute neutrophil count (ANC) > 750/mm3 (without growth factor support within 7 days) b. Platelet > 50,000/mm3 (without growth factor support or transfusion within 7 days) c. Creatinine clearance ≥ 30 mL/min (as estimated by the CockcroftGault or MDRD equation or as measured by nuclear medicine scan or 24hour urine collection) d. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 3.0 × upper limit of normal (ULN) e. Serum total bilirubin < 2.0 × ULN (unless documented Gilbert's syndrome)
11. Female patients of childbearing potential must practice highly effective methods of contraception initiated prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib, or 18 months after the last dose of obinutuzumab, whichever is longer. Highly effective contraceptive methods include the following: a. Combined (estrogen and progestogen containing) hormonal contraception associated with the inhibition of ovulation - Oral, intravaginal or transdermal b. Progestogen-only hormonal contraception associated with the inhibition of ovulation - Oral, injectable, implantable c. An intrauterine device d. Intrauterine hormone-releasing system e. Bilateral tubal occlusion f. Vasectomized partner g. Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment, starting the day prior to first dose of study drug, for the duration of the study, and for ≥ 90 days after the last dose of zanubrutinib, or 18 months after the last dose of obinutuzumab, whichever is longer). Total sexual abstinence should only be used as a contraceptive method if it is in line with the patients' usual and preferred lifestyle. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to investigational medicinal product, and withdrawal are not acceptable methods of contraception. Of note, barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception and if used, this method must be used in combination with another acceptable method listed above. For patients using hormonal contraceptives such as birth control pills or devices, a second barrier method of contraception (eg, condoms) must be used.
12. Male patients if abstinent (as defined above), are eligible if vasectomized or if they agree to the use of barrier contraception in combination with other methods described above during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib or 18 months after the last dose of obinutuzumab, whichever is longer.
13. Ability to provide written informed consent and can understand and comply with the requirements of the study.

Exclusion criteria 21

1. Known central nervous system involvement by leukemia or lymphoma
2. Evidence of transformation from follicular lymphoma to DLBCL or other aggressive histology (such as large cells seen on biopsy or high PET avidity in a single node seen on PET scan)
3. Allogeneic hematopoietic stem cell transplantation within 12 months of study enrollment
4. Prior exposure to a BTK inhibitor
5. 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 Gleason score 6 prostate cancer.
6. Clinically significant cardiovascular disease including the following: a. Myocardial infarction within 6 months before screening b. Unstable angina within 3 months before screening c. New York Heart Association Class III or IV congestive heart failure (see Appendix 4) d. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) e. QTcF > 480 milliseconds based on Fridericia's formula f. History of Mobitz II second-degree or third degree heart block without a permanent pacemaker in place g. Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg at screening
7. 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
8. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
9. Severe or debilitating pulmonary disease
10. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
11. Active fungal, bacterial and/or viral infection requiring systemic therapy
12. Underlying medical conditions that, in the investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of safety or efficacy results
13. Known infection with HIV, or serologic status reflecting active hepatitis B or C infection as follows: a. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (< 20 IU/mL), and if they are willing to undergo monthly monitoring for HBV reactivation. b. Presence of hepatitis C virus (HCV) antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (<15 IU/mL).
14. Major surgery within 4 weeks of the first dose of study drug
15. Pregnant or lactating women
16. Vaccination with a live vaccine within 35 days prior to the first dose of study drug
17. Ongoing alcohol or drug addiction
18. Hypersensitivity to zanubrutinib or obinutuzumab or any of the other ingredients of the study drugs
19. Requires ongoing treatment with a strong CYP3A inhibitor or inducer
20. Concurrent participation in another therapeutic clinical trial.
21. Requires ongoing need for corticosteroid treatment. NOTE: Systemic corticosteroids must be fully tapered off/stopped at least 5 days before day of first study drug.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. The primary endpoint is overall response rate determined by independent central review using Lugano Classification for Non-Hodgkin Lymphoma (NHL), (modified from Cheson et al, 2014).
2. The overall response rate is defined as the proportion of patients who achieve either complete response or partial response as best overall response. Best overall response is defined as best response achieved during the entire follow-up period.
3. However, for the patients in arm B who cross over to arm A, the disease assessment after the crossover will not be included in the derivation of best overall response.

Secondary endpoints 7

1. Duration of response determined by independent central review and by investigator assessment, defined as the time from the date that response criteria are first met to the date that disease progression is objectively documented or death, whichever occurs first
2. Progression-free survival determined by independent central review and by investigator assessment, defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurs first
3. Overall survival defined as the time from randomization to the date of death due to any reason.
4. Rate of complete response or complete metabolic rate determined by independent central review and by investigator assessment, defined as the proportion of patients who achieve complete response or complete metabolic rate as best overall response
5. Time-to-response determined by independent central review and by investigator assessment, defined as the time from randomization to the time the response criteria are first met Patient-reported outcomes measured by EORTC QLQ-C30 and EQ-5D-5L questionnaires
6. Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, and vital signs
7. PK parameters such as apparent clearance of the drug from plasma (CL/F) and AUC0-12

Investigational products

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

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Beigene Ltd.

Sponsor organisation

Beigene Ltd.

Address

Solaris Avenue 94

City

Camana Bay

Postcode

KY1-1108

Country

Cayman Islands

Scientific contact point

Organisation

Beigene Ltd.

Contact name

BeiGene Clinical Support

Public contact point

Organisation

Beigene Ltd.

Contact name

BeiGene Clinical Support

Third parties 6

Locations

5 EU/EEA countries · 23 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 7 files

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

Application history

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