| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/refractory primary or secondary central nervous system lymphoma or primary vitreoretinal lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the central nervous system |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10007953 |
| E.1.2 | Term | Central nervous system lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036685 |
| E.1.2 | Term | Primary central nervous system lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1b Dose Escalation
• To determine the safety and tolerability of escalating doses of GB5121
• To determine the optimal biological dose (OBD) and/or maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of GB5121
Phase 1b Expansion
• To determine the safety and tolerability of the RP2D of GB5121
Phase 2
• To assess ORR according to IPCG criteria |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b Expansion
• To assess the objective response rate (ORR) according to the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria
Phase 2
• To assess duration of response (DOR)
• To assess confirmed complete response (CR)
• To assess ORR according to local Investigator assessment
• To assess PFS
• To assess PFS at week 24 (PFS-24)
• To assess overall survival (OS)
• To evaluate the safety and tolerability of GB5121 at the RP2D
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1b Dose Escalation and Expansion:
1. Patients who are at least 18 years of age at the time of signing the informed consent form (ICF) prior to initiation of any study specific activities/procedures.
2. Patients must have histologically/cytologically confirmed PCNSL, primary vitreoretinal lymphoma (PVRL), or CNS-only involvement of a systemic B-cell lymphoma.
3. All patients must have relapsed/refractory disease and must have received all possible standard-of-care CNS-directed treatment regimens or patients for which further standard-of-care treatment options are contraindicated or declined.
4. Patients must be able to tolerate gadolinium-enhanced MRI scans, or contrast-enhanced CT.
5. Patients with parenchymal lesions must have baseline imaging (gadolinium-enhanced MRI or if contraindicated, contrast-enhanced CT, of the brain) within 28 days prior to first study drug dose. For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells and/or imaging findings consistent with leptomeningeal disease after informed consent and prior to first study dose (at the discretion of the Investigator).
6. Patients with parenchymal lesions must have measurable disease (disease that has at least one lesion ≥ 10 mm in the longest diameter) on imaging (gadolinium-enhanced MRI or if contraindicated, contrast-enhanced CT, of the brain) prior to first study dose.
7. Patients must be able to tolerate and consent for a lumbar puncture and/or have pre-existing placement of an Ommaya reservoir, unless clinically contraindicated.
8. Patients must have recovered to ≤ Grade 1 toxicity from prior therapy.
9. Patients, when available, should be able to submit at minimum 3 and up to 20 unstained formalin-fixed, paraffin-embedded (FFPE) slides from the initial tissue diagnosis, preferably prior to study enrollment.
10. Patients must have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
11. Demonstrate adequate bone marrow and organ function as defined in the protocol. All screening laboratories for organ functions should be performed within 14 days of initiating the study drug.
12. Female patients must be:
a. Of non-childbearing potential: Evidence of post-menopausal status. Refer to Appendix 4 (Section 10.4) for definitions; or
b. If of childbearing potential, patient must use a highly effective method of contraception for the duration of treatment and for at least 30 days following the last dose of GB5121. Refer to Appendix 4 (Section 10.4) for contraception guidance.
c. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to receiving the first dose of study drug.
13. Male patients who are not abstinent who are partners of women of childbearing potential must use 2 highly effective method of contraception throughout the entire study period. Refer to Appendix 4 (Section 10.4) for contraception guidance. Those with partners using hormonal contraceptives must also be using an additional approved method of contraception (as described previously).
14. Male and female patients must refrain from donating sperm or eggs from informed consent through at least 30 days after last dose of GB5121 for females and 90 days for males.
15. Patients provide written informed consent for the study which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Phase 2:
criteria specific to phase 2, the remaining criteria are identical with phase 1b
2. Patients with histologically/cytologically confirmed PCNSL.
5. Patients with parenchymal lesions must have baseline imaging (gadolinium-enhanced MRI or if contraindicated, contrast-enhanced CT, of the brain) after informed consent and prior to first study drug dose. For subjects with leptomeningeal disease only, CSF cytology must document lymphoma cells and/or imaging findings consistent with leptomeningeal disease after informed consent and prior to first study dose (at the discretion of the Investigator). |
|
| E.4 | Principal exclusion criteria |
Phase 1b Dose Escalation and Expansion:
1. Patients are concurrently using other approved or investigational antineoplastic agents.
2. Patients have an active concurrent malignancy requiring active therapy.
3. Patients are allergic to components of the study drug (Section 5.1).
4. Patients have a known bleeding diathesis (eg, von Willebrand's disease) or hemophilia.
5. Patients who require therapeutic anticoagulation, including dual antiplatelet agents. Patients who have received therapeutic anticoagulation, including dual antiplatelet agents, within 5 half-lives of the anticoagulant, or 14 days, whichever is longer, prior to starting the study drug. Patients who require the use of antiplatelet agents should be discussed with the Sponsor's Medical Monitor.
6. Patients have significant abnormalities on screening electrocardiogram (ECG) and active and significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, uncontrolled hypertension, valvular disease, pericarditis, or
myocardial infarction within 6 months of screening.
7. Patients with any of the following will be excluded:
a. A marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval > 480 ms [CTCAE grade 2]) using Frederica's QT correction formula.
b. A history of additional risk factors for Torsades de Pointes (eg, heart failure, hypokalemia, family history of long QT syndrome).
c. The use of concomitant medications that prolong the QT/QTc interval (Section 10.6).
8. Patients are known to have a history of active or chronic infection with hepatitis C virus (HCV), hepatitis B virus (HBV), as determined by serologic tests.
9. Known history of infection with HIV.
10. Patients are known to have an uncontrolled active infection.
11. Patients have a history of stroke or intracranial hemorrhage within 6 months prior to enrollment.
12. Patients have a life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the Investigator, could compromise the patient's safety or put the study outcomes at undue risk.
13. Patients have an inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (including malabsorption syndrome, resection of the small bowel, or poorly controlled inflammatory bowel disease).
14. Women who are pregnant or nursing (lactating).
15. Patients have received chemotherapy, monoclonal antibodies, or targeted anticancer therapy within ≤ 2 weeks or 5 half-lives, whichever is longer, prior to starting the study drug, or the patient has not recovered from the side effects of such therapy.
16. Patients have received external beam radiation therapy (WBRT, SRS) to the CNS within 21 days of the first dose of the study drug.
17. Patients do not meet prior and concomitant medication criteria (Section 5.5.3).
18. Patients have previously received a BTK inhibitor. Patients who have previously received a BTK inhibitor, but discontinued therapyfor reasons other than disease progression are eligible.
19. Patients require > 8 mg/day of dexamethasone or the equivalent.
20. Patients underwent major systemic surgery within ≤ 2 weeks prior to enrolling in the study, or who has not recovered from the side effects of such surgery, or who plans to have surgery within 2 weeks of the first dose of the study drug.
21. Patients have undergone prior allogeneic stem cell transplant (autologous stem cell transplant is NOT an exclusion).
22. CAR-T (chimeric antigen receptor T cell) therapy within 60 days of the first dose of GB5121 or ongoing immunosuppressive therapy post CAR-T therapy at the time of screening, clinically significant graft-versus-host disease (GVHD), or need for anticytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy.
23. Received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Approved COVID-19 vaccines are allowed (Emergency Use Authorization and/or full approval).
24. Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 2 weeks prior to the first dose of study drug.
Phase 2:
criteria specific to phase 2, the remaining criteria are identical with phase 1b
1. Patients with SCNSL or PVRL. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b Dose Escalation:
• Incidence of AEs, DLTs, and SAEs
• OBD and/or MTD and RP2D of GB5121
Phase 1b Expansion
• Incidence of AEs and SAEs
Phase 2
• ORR according to the IPCG criteria by Blinded Independent Central Review (BICR) Committee |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Two month intervals or throughout the study as appropriate, except for those performed at protocol-specified time points. |
|
| E.5.2 | Secondary end point(s) |
Phase 1b Expansion
• ORR according to the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria by Investigator Assessment
Phase 2
• Duration of Response (DOR) by BICR Committee
• Confirmed complete response (CR) by BICR Committee
• ORR according to the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria by Investigator Assessment
• Median PFS
• PFS at week 24 (PFS-24)
• Median Overall survival (OS)
• Incidence of AEs and serious AEs (SAEs) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Two month intervals or throughout the study as appropriate, except for those performed at protocol-specified time points. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose Escalation and Expansion |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 35 |
| 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 |
| Canada |
| Israel |
| New Zealand |
| United States |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| United Kingdom |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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