| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| B-cell malignancies, including only patients with Grades 1-3a FL, MZL, MCL, and CLL/SLL |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10025320 |
| E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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| 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 |
Part 1: Dose Escalation
Primary
• To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) for orelabrutinib.
Part 2: Dose Expansion
Primary
• To assess anti-tumor activity of orelabrutinib in 2 arms of patients with lymphoma:
Arm 1: relapsed and refractory (r/r) mantle cell lymphoma (MCL).
Arm 2: other types of B-cell malignancies, including r/r follicular lymphoma (FL), r/r marginal zone lymphoma (MZL), chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) with/without prior treatment. |
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| E.2.2 | Secondary objectives of the trial |
Part 1: Dose Escalation
Secondary – Safety
• To evaluate the safety and tolerability of orelabrutinib when it is administered orally.
Secondary – Efficacy
• To assess preliminary anti-tumor activity of orelabrutinib provided data permit.
Secondary - Pharmacokinetics
• To characterize the pharmacokinetics of orelabrutinib when administered orally.
Part 2: Dose Expansion
Secondary – Safety
• To evaluate the safety and tolerability of orelabrutinib in each arm.
Secondary – Efficacy
• To assess additional anti-tumor activity of orelabrutinib in each arm.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion and Exclusion Criteria for Part 1 Dose Escalation
1. Signed Informed Consent.
2. All subjects must meet criteria for requiring therapy at time of enrollment.
3. Age ≥ 18 years.
4. Patients with histologically confirmed relapsed or refractory B-cell malignancies, including only patients with Grades 1-3a FL, MZL, MCL, and CLL/SLL.
5. Patient must had received ≥ 1 or ≤ 4 prior therapies with documented failure to achieve at least partial response, or disease progression after the most recent systemic treatment.
6. Patient must have ≥ 1 measurable lesion site on CT scan.
7. ECOG performance status of 0 ~1.
8. Life expectancy (in the opinion of the investigator) of ≥ 4 months.
9. Adequate liver function at time of screening: Total bilirubin ≤ 2.0 x ULN.
10. Coagulation test: at time of screening, international normalized ratio (INR) ≤ 1.5, and the activated partial thromboplastin time (APTT) ≤ 1.5× ULN.
11. Adequate hematological function at time of screening.
12. Adequate renal function at time of screening: serum creatinine ≤ 1.5 × ULN or creatinine clearance by Cockcroft-Gault formula ≥ 60 mL/min.
13. Negative test results for HBV ([HBsAg (-)] and non-active HBV or HCV infection.
14. Negative serum pregnancy test within 7 days prior to study treatment in women of childbearing potential. Women who are not of childbearing potential or considered to be postmenopausal (≥ 12 months of non-therapy amenorrhea) or surgically sterile (absence of ovaries and/or uterus) are not required to have a pregnancy test.
15. Patients must agree to either remain completely abstinent or to use two effective contraceptive methods.
Inclusion and Exclusion Criteria for Part 2 Dose Expansion
1. Signed Informed Consent.
2. All subjects must meet criteria for requiring therapy at time of enrollment (see treatment indications below).
3. Age ≥ 18 years.
4. Patients with histologically confirmed B-cell malignancies, including:
• patients with r/r MCL.
• patients with other types of B-cell malignancies, including:
• CLL/SLL with/without prior treatment.
• r/r FL.
• r/r MZL.
5. For r/r FL, patients must have received ≥ 2 or ≤ 4 prior therapies with documented failure to achieve at least a partial response or disease progression after the most recent systemic treatment. For other r/r lymphoma, patients must have received ≥ 1 or ≤ 4 prior therapies with documented failure to achieve at least a partial response or disease progression after the most recent systemic treatment.
6. Patient must have ≥ 1 measurable lesion site on CT scan (nodal lesions must have an LDi > 15 mm; extranodal lesions must have an LDi > 10 mm). Lesions in anatomical locations (such as extremities or soft tissue lesions) that are not well visualized by CT may be measured by MRI instead (Subjects with spleen-only disease are considered not having measurable disease).
7. ECOG performance status of 0~1.
8. Life expectancy (in the opinion of the investigator) of 4 months.
9. Adequate liver function at time of screening: Total bilirubin 2.0 × ULN (Patients with documented history of Gilbert’s Syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible); AST/ALT 2.5 × ULN.
10. Coagulation test: at time of screening, international normalized ratio (INR) ≤1.5, and the activated partial thromboplastin time (APTT) ≤ 1.5× ULN.
11. Adequate hematological function at time of screening: complete blood count tests should be independent of support therapies (i.e., growth factors, or transfusion) and fulfill these criteria: neutrophil count 1.5 × 109 /L, platelet count 75 × 109/L, hemoglobin 80 g/L; if presence of bone marrow infiltration, neutrophil count 1.0 × 109 /L and platelet count 50 × 109 /L.
12. Adequate renal function at time of screening: serum creatinine ≤ 1.5 × ULN or creatinine clearance by Cockcroft-Gault formula 60 mL/min.
13. Negative test results for HBV ([HBsAg (-)] and non-active HBV or HCV infection:
• Patients who are positive for anti-HBc antibody must be negative for HBV DNA by PCR to be eligible for study participation.
• Patients who are positive for HCV antibody must be negative for HCV RNA by PCR to be eligible for study participation.
14. Negative serum pregnancy test within 7 days prior to study treatment in women of childbearing potential. Women who are not of childbearing potential, postmenopausal (12 months of non-therapy amenorrhea) or surgically sterile (absence of ovaries and/or uterus) are not required to have a pregnancy test.
15. Patients must agree to either remain completely abstinent or to use two effective contraceptive methods (list of effective contraceptive methods are provided in APPENDIX 5) that result in a failure rate of < 1 % per year from screening until (a) 1 month if the patient is a male or (b) 2 months if patient is a female after the last dose of orelabrutinib. |
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| E.4 | Principal exclusion criteria |
Part 2 Dose Expansion
1. Pregnant or breast-feeding or intending to become pregnant during the study.
2. Prior treatment with systemic immunotherapeutic agents, including but not limited to cytokine therapy and anti-CTLA4, anti-PD1 and anti-PDL1 therapeutic antibodies, within 12 weeks or five half-lives of the drug, whichever is shorter, before first dose of orelabrutinib.
3. Patients with known allergies to ICP-022 or its excipients.
4. Treatment with any chemotherapeutic agent, or treatment with any other investigational therapies including but not limited to anti-cancer agent (defined as treatment for which there is currently no regulatory authority approved indication) within 4 weeks prior to first dose of ICP-022.
5. History of allogeneic stem-cell (or other organ) transplantation.
6. Any external beam radiation therapy within 6 weeks prior to the first dose of the study drug.
7. Concurrent use of warfarin or other vitamin K antagonists or anticoagulation therapies.
8. Concurrent use of a strong CYP3A inhibitor. Subjects who have received a strong CYP3A inhibitor prior to entering the study must have discontinued therapy for at least 5 half-lives of the prohibited medication.
9. Active uncontrolled infections.
10. Recent infection requiring IV anti-infective treatment that was completed ≤ 14 days before the first dose of study drug.
11. Known infection with HIV, seropositive status.
12. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0) ≤ Grade 1, or to the levels dictated in the eligibility criteria with the exception of alopecia
13. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).
14. Medically apparent CNS lymphoma or leptomeningeal disease.
15. Current or previous history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
• Patients with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits as judged by the investigator, are allowed.
16. Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, uncontrolled hypertension, history of relevant pulmonary disorders, abusing of alcohol or illegal drugs including non-prescribed marijuana within last 6 months from screening.
17. Major surgery or significant traumatic injury < 28 days prior to the first dose of ICP-022 (excluding biopsies) or anticipation of the need for major surgery during study treatment.
18. Patients with another invasive malignancy in the last 2 years (with the exception of basal cell carcinoma and tumors deemed by the investigator to be of low likelihood for recurrence).
19. Significant cardiovascular disease such as New York Heart Association (NYHA) Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina).
20. Significant active pulmonary disease (e.g., bronchospasm and/or obstructive pulmonary disease).
21. Administration of a live, attenuated vaccine within 28 days before Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study.
22. Received systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) with the exception of corticosteroid treatment < 20 mg/day prednisone or equivalent within 7 days prior to first dose of ICP-022
• Inhaled and topical steroids are permitted.
23. Unable to swallow tablets or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
24. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug.
25. Prior treatment with any BTK inhibitors for patients in Arm 1 (r/r MCL). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1: Dose Escalation
• Incidence of dose-limiting toxicities (DLTs) during the DLT observation period.
Part 2: Dose Expansion
• The primary endpoint of the study is defined as the achievement of ORR (assessed by the IRC for Arm 1, assessed by the investigator for Arm 2) according to 2014 Lugano Classification criteria International Working Group on NHL Criteria (IWGNHL), and the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) published in 2008 and modifications. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: Dose Escalation
• 28 days
Part 2: Dose Expansion
• 6 months after the last patient initiation of orelabrutinib treatment
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| E.5.2 | Secondary end point(s) |
Part 1: Dose Escalation
Secondary – Safety
• Incidence, seriousness, frequency, severity, and timing of adverse events (AEs) and serious adverse events (SAEs). AEs/SAEs will be graded according to NCI-CTCAE v5.0
• Changes from baseline in vital signs, ECGs, and clinical laboratory results during and following study treatment administration.
Secondary – Efficacy
• Objective response rate (ORR).
Secondary - Pharmacokinetics
The following PK parameters will be derived from the plasma concentration-time profile of orelabrutinib following administration when appropriate, as data allow:
• Elimination half-life (T1/2)
• Total plasma exposure - Area under the concentration-time curve (AUC)
• Time to reach maximum observed plasma concentration (Tmax)
• Maximum plasma concentration observed (Cmax)
• Minimum plasma concentration (Cmin) under steady-state conditions within a dosing interval
• Other PK parameters such as clearance (CL), and volume of distribution (Vd), may also be calculated as data allow.
Part 2: Dose Expansion
Secondary – Safety
• AEs and SAEs.
• Changes from baseline in vital signs, ECGs, and clinical laboratory results, etc.
Secondary – Efficacy
• Duration of response (DOR), Disease control rate (DCR), Progression-free survival (PFS), Overall survival (OS), etc.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 6 months after last patient in |
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| 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 | 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) | 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 |
| tolerability, efficacy, safety, and pharmacokinetics |
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| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Ukraine |
| Israel |
| Russian Federation |
| United States |
| Poland |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| The end of the study is defined as last patient last visit (LPLV). |
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| 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 | 3 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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