A Phase I Open-Label, Multiple-Dose, Dose Escalation and Expansion Study to Investigate the Safety and Pharmacokinetics of the BTK Inhibitor BGB-3111 in Subjects with B-Cell Lymphoid Malignancies
Jan A. Burger
There are 2 parts to this clinical research study: Part 1 and Part 2. The goal of Part 1 was to find the highest tolerable dose of the study drug BGB-3111 that can be given to patients with B-Cell lymphoid cancer. This part of the study has already been completed. The goal of Part 2 of this clinical research study is to learn if the dose found in Part 1 can help to control the disease. The safety of this drug will also be studied. Researchers also want to learn more about what effects the drug may have on the disease. This consent is for Part 2 only. This is the first study using BGB-3111 in humans.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: BGB-3111
Treatment Location: Both at MDACC & and Other Sites
Sponsor: BeiGene Aus Pty Ltd
Part 1 Primary: To determine the safety and tolerability of BGB-3111 in patients with B-cell malignancies. To determine the recommended phase 2 dose (RP2D) and regimen of BGB-3111 when given continuously orally. Secondary: To characterize the pharmacokinetics (PK) of BGB-3111 after drug administration. To determine the extent of Bruton tyrosine kinase (BTK) inhibition in peripheral blood mononuclear cells (PBMCs) after treatment with BGB-3111. To describe the preliminary anti-tumor activity of BGB-3111. Exploratory: To explore the relationship between clinical response to BGB-3111 and both clinical factors and biomarkers. To investigate platelet function inhibition by BGB-3111. To describe specific events of interest: atrial fibrillation and clinical bleeding rates on BGB-3111. To measure changes in host T- and NK subsets, and immune parameters during various phases of treatment. To explore mechanisms of disease resistance in samples from patients who fail to respond, and from those who manifest disease relapse. Part 2 Primary: To further assess the safety and tolerability of BGB-3111, administered orally either once or twice daily, in patients with specified B-cell malignancies. Secondary: To assess the preliminary anti-tumor activity of BGB-3111 at RP2D(s) in subjects with specific B-cell malignancies. To further characterize the PK profile of BGB-3111. To determine the extent of BTK inhibition in PBMCs after treatment with BGB-3111. Exploratory: To compare the extent of BTK inhibition in lymph nodes between different regimens (once a day (QD) vs. twice a day (BID)). To explore the relationship between clinical response to BGB-3111 and both clinical factors and biomarkers. To further investigate platelet function inhibition and immune parameter change by GB-3111. To explore mechanisms of disease resistance in samples from patients who fail to respond, and from those who manifest disease relapse.
IRB Review and Approval Date: 04/10/2017
Recruitment Status: Open
Projected Accrual: 405
1) Aged >/= 18 years, voluntarily consented to the study.
2) Dose escalation: Relapsed or refractory World Health Organization (WHO) classification defined B-lymphoid malignancy following at least one line of therapy, with no therapy of higher priority available, with the exception of Burkitt lymphoma/leukemia, plasma cell myeloma, acute lymphoblastic leukemia, lymphoblastic lymphoma, and plasmablastic lymphoma.
3) Safety, Schedule and Efficacy Expansion: Part 2a: R/R WHO defined MCL, follicular lymphoma (FL), marginal zone lymphoma (MZL) or germinal center B-cell like (GCB) subtype of DLBCL, with at least one site of biopsiable lymph node. --Part 2b: R/R WHO defined DLBCL, non-GCB subtype, defined by Hans algorithm. Subjects must have archival tumor tissues or agree to a tumor biopsy for confirmation of the DLBCL subtype and for exploratory biomarker analysis. --Part 2c and 2e: R/R WHO defined CLL/SLL. --Part 2d: R/R WHO defined WM. --Part 2f: R/R WHO defined WM requiring treatment per the International Workshop on WM guidelines. --Part 2g: R/R WHO defined MCL. --Part 2h: Previously untreated CLL/SLL requiring treatment per IWCLL guidelines. --Part 2i: Previously untreated MCL with age >/= 65 and CIRS>/= 6. --Part 2j: R/R WHO defined HCL.
4) (Continuation of #3) --Part 2k: R/R WHO defined indolent lymphoma (inclusive of follicular lymphoma, marginal zone lymphoma, and MALT lymphoma). --Part 2l: Histologically-confirmed Richter’s Transformation of CLL/SLL. Subjects who previously received a BTK inhibitor other than BGB-3111 are allowed. Subjects to be enrolled must have histologic confirmation of Richter’s transformation prior to enrollment. --Part 2m: WM with failure to achieve a major response (PR or better) after at least 6 months of ibrutinib or acalabrutinib therapy, or with disease progression on ibrutinib or acalabrutinib therapy. A minimal 7-day washout period is required before initiation of BGB-3111 treatment.
5) Requirement for treatment in the opinion of the investigator.
6) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
7) Adequate hematologic function, as defined by neutrophils >/= 1.0 x 10^9/L and platelets >/= 50 x 10^9/L; patients with neutrophils < 1.0 x 10^9/L due to marrow infiltration are allowed to receive growth factors to bring pre-treatment neutrophils to >/= 1.0 x 10^9/L; patients with platelets <50 x 10^9/L due to marrow infiltration are allowed to receive platelet transfusion to bring pre-treatment platelets to >/= 50 x 10^9/L.
8) Adequate renal function, as defined by creatinine clearance of >/= 30 ml/min (as estimated by the Cockcroft-Gault equation/CKD-EPI equation or as measured by nuclear medicine scan or 24 hour urine collection).
9) Adequate liver function, as defined by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 3 x upper limit of normal (ULN), and bilirubin </= 1.5 x ULN (unless documented Gilbert’s syndrome).
10) International normalized ratio (INR) and activated partial thromboplastin time (aPTT) </= 1.5 x ULN.
11) Female subjects of childbearing potential and non-sterile males must practice at least one of the following methods of birth control with partner(s) throughout the study and for 90 days after discontinuing study drug: total abstinence from sexual intercourse, double-barrier contraception, IUD or hormonal contraceptive initiated at least 3 months prior to first dose of study drug.
12) Male subjects must not donate sperm from initial study drug administration, until 90 days after drug discontinuation.
1) Current central nervous system (CNS) involvement by lymphoma or leukemia.
2) Current histologically transformed disease except subjects in Part 2l.
3) Prior BTK inhibitor treatment except subjects in Part 2l and 2m.
4) Allogeneic stem cell transplantation within 6 months, or has active graft versus host disease (GVHD) requiring ongoing immunosuppression.
5) Receipt of the following treatment prior to first dose of BGB-3111: corticosteroids given with anti-neoplastic intent within 7 days, chemotherapy or radiotherapy within 2 weeks, monoclonal antibody within 4 weeks.
6) Not recovered from toxicity of any prior chemotherapy to grade </= 1.
7) History of other active malignancies within 2 years of study entry, with exception of (1) adequately treated in-situ carcinoma of cervix; (2) localized basal cell or squamous cell carcinoma of skin; (3) previous malignancy confined and treated locally (surgery or other modality) with curative intent.
8) Uncontrolled systemic infection requiring parenteral anti-microbial therapy.
9) Major surgery in the past 4 weeks.
10) Known human immunodeficiency virus (HIV), or active hepatitis B or hepatitis C infection (detected positive by polymerase chain reaction (PCR)).
11) Cardiovascular disease resulting in New York Heart Association function status of >/= 3.
12) QTcF > 450 msecs based on the Fridericia's formula) or other significant electrocardiogram (ECG) abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
13) Significant active renal, neurologic, psychiatric, hepatic or endocrinologic disease that in the investigator’s opinion would adversely impact on his/her participating in the study.
14) Inability to comply with study procedures.
15) On medications which are Cytochrome P450 3A4 (CYP3A) inhibitors or strong CYP3A inducers.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
Jan A. Burger
For general questions about clinical trials: