| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Follicular Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10016903 |
| E.1.2 | Term | Follicle centre lymphomas, follicular grade I, II, III |
| E.1.2 | System Organ Class | 10016903 - Follicle centre lymphomas, follicular grade I, II, III |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate efficacy of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy, as measured by overall response rate determined by independent central review. |
|
| E.2.2 | Secondary objectives of the trial |
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) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient eligible to participate in this study must meet all of the following criteria:
-≥ 18 years of age at the time of informed consent
-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
-≥ 2 prior systemic treatments for follicular lymphoma
-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
-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
-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
-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)
-Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
-Life expectancy ≥ 6 months
-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 Cockcroft-Gault or MDRD equation or as measured by nuclear medicine scan or 24-hour 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)
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
i. Oral, intravaginal or transdermal
b. Progestogen-only hormonal contraception associated with the inhibition of ovulation
i. 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.
-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.
-Ability to provide written informed consent and can understand and comply with the requirements of the study.
|
|
| E.4 | Principal exclusion criteria |
Each patient eligible to participate in this study must NOT meet any of the following exclusion criteria:
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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). 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. 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 12 weeks for 24 months, then every 6 months for 24 months, then annually. |
|
| E.5.2 | Secondary end point(s) |
Overall response rate determined by investigator assessment
• 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
• 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
• Overall survival defined as the time from randomization to the date of death due to any reason.
• 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
• 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
• Safety parameters, including AEs, SAEs, clinical laboratory tests, physical exams, and vital signs
• PK parameters such as apparent clearance of the drug from plasma (CL/F) and AUC0-12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Every 12 weeks for 24 months, then every 6 months for 24 months, then annually. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belarus |
| Canada |
| China |
| Korea, Republic of |
| New Zealand |
| Taiwan |
| United States |
| Bulgaria |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
| United Kingdom |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
Print
