A Phase I/II, Multicenter, Open-Label, Study of a Novel Bruton’s Tyrosine Kinase Inhibitor, Orelabrutinib, in Patients with B-Cell Malignancies

Phase 1

• Conditions: B-cell malignancies, including only patients with Grades 1-3a FL, MZL, MCL, and CLL/SLL; MedDRA version: 20.0Level: HLGTClassification code 10025320Term: Lymphomas non-Hodgkin's B-cellSystem Organ Class: 10005329 - Blood and lymphatic system disorders; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2021-006475-42-PL
• Lead Sponsor: InnoCare Pharma Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2022-03-02
• Last Update Posted: 29 April 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 36

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 therapie

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, thalidomid

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified