None listed
Conditions
Interventions
Drug : Phase I : The initial dose escalation phase will follow a traditional 3+3 design. Patient enrollment will start at dose level 1.
- Dose level 1) Zanubrutinib: P.O. 160 mg qd (D1-21), Rituximab:
Sponsors
Asan Medical Center
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed non-GCB DLBCL with R/R disease without secondary CNS involvement* (Cohort A) or relapsed/refractory DLBCL with secondary CNS involvement*† or relapsed/refractory PCNSL of DLBCL subtype** (Cohort B) *Following first-line treatment with rituximab in combination with an anthracycline-containing regimen †Patients who are refractory to methotrexate treatment in case of isolated CNS disease **Following first-line treatment with methotrexate-containing regimen 2. Age of = 19 years old 3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1.5 cm in its longest dimension, or one bi-dimensionally measurable extranodal lesion, defined as > 1.0 cm in its longest diameter (Cohort A only) 5. Adequate laboratory parameters within 14 days - Absolute neutrophil count (ANC) = 1000/mm3 regardless of growth factor support - Platelets = 75,000/mm3 independent of transfusion support - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 3 x upper limit of normal (ULN) - Total bilirubin = 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin - Estimated Glomerular Filtration Rate = 40 mL/min/1.73m2) 6. Provision of a signed written informed consent 7. Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and for at least 12 months after the last dose of study drug(s) and must have a negative urine (or serum) pregnancy test = 7 days before initial treatment 8. Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study and for = 90 days after the last dose of study drug (a ‘sterile’ male is defined as one for whom azoospermia has been previously demonstrate in a semen sample examination as definitive evidence of infertility). *Very effective contraception • Intrauterine device • Bilateral atretic oviduct (A surgical procedure to prevent fertilization of an ovum) • Vasectomy of female subject’s male partner (Surgical success of vasectomy confirmed by medical evaluation) • Hormonal contraception associated with suppression of ovulation : Oral contraception pill (Estrogen/progestin pill or progestin alone pill), Skin contraceptive patch, intravaginal contraceptive ring, or subcutaneous contraceptive injection • Sexual abstinence (only abstinence from sexual intercourse with members of the opposite sex for the entire period of study-related risks is acceptable) 9. Life expectancy = 6 months.
Exclusion criteria
Exclusion criteria: 1. History of another primary cancer other than DLBLCL, unless the subject has been free of the disease for = 3 years with the exception of the following non-invasive malignancies: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin in situ (stage 0), carcinoma in situ of the cervix, carcinoma in situ of the breast, early gastric cancer, incidental histologic finding of prostate cancer (T1a or T1b) or prostate, cancer that is curative 2. History of allogenic stem cell transplantation (patients with history of autologous stem cell transplantation can be enrolled to the study) 3. Prior history of solid organ transplantation or other cause of severe immunodeficiency 4. Intravascular DLBCL 5. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products 6. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s , precludes the patient’s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results 7. Recent major surgery within 4 weeks before the start of C1D1, other than superficial lymph node biopsies for diagnosis 8. Known diagnosis of HIV infection (HIV testing is not mandatory). However, HIV+ patients with sustained negative viral load can be enrolled. 9. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below: • HBV: Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction (PCR) evaluation before enrollment. Patients who are hepatitis B PCR positive will be excluded. • HCV: positive hepatitis C antibody. If positive hepatitis C antibody result, patient will need to have a negative result for hepatitis C ribonucleic acid (RNA) before enrollment. Patients who are hepatitis C RNA positive will be excluded. 10. Pregnant, breastfeeding, or possibly pregnant. 11. Alcohol or substance abuse disorder 12. Unable to swallow drug or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction 13. Prior treatment with a BTK inhibitor (including Zanubrutinib) 14. Clinically significant cardiovascular disease including the following: • Myocardial infarction = 6 months before screening. • Unstable angina = 3 months before screening. • New York Heart Association class 3 or 4 congestive heart failure (see Appendix 3). • History of clinically significant arrhythmia (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes). • QTcF (Fridericia’s correction) > 480 msec. • History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. • Uncontrolled hypertension as indicated by = 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic blood pressure > 105 mm Hg at screening. 15. History of stroke or intracranial hemorrhage = 6 months before screening. 16. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 1 : Determining the maximum tolerated dose (MTD) of zanubrutinib in combination with R-ICE;Phase 2: - Arm A: Overall response rate after 3 cycles of zanubrutinib + R-ICE (ZR-ICE) - Arm B: Complete response rate (CR or CRu) after 3 cycles of zanubrutinib + R-ICE (ZR-ICE) | — |
Secondary
| Measure | Time frame |
|---|---|
| Complete response rate (CRR) ;Overall response rate (ORR) ;Safety profile ;Phase 2 : Duration of response (DOR);Phase 2 : Progression-free survival (PFS);Phase 2 : Event-free survival (EFS): ;Phase 2 : Overall survival;Phase 2 : Autologous stem cell transplantation (ASCT) rate for the patients who are candidate for ASCT;Evaluation of the genomic landscape and its correlation with efficacy (ORR, CRR, PFS, EFS, OS) using whole-genome sequencing and RNA sequencing ;Patient-reported outcomes (EORTC QLQ-C30) | — |
Countries
Korea, Republic of
Contacts
Public ContactNa Eun Lee
Asan Medical Center
Outcome results
None listed