Clinical Trials

Date: 2018-10-12

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the 10th International Workshop on Waldenström’s Macroglobulinemia (IWWM)

Company: BeiGene (China)

Product: zanubrutinib - BGB-3111

Action mechanism:

  • kinase inhibitor/Bruton tyrosine kinase inhibitor. BGB-3111 is an investigational, oral, highly selective and potent inhibitor of Bruton tyrosine kinase (BTK). Bruton tyrosine kinase (BTK), a member of the TEC family of kinases, is a signaling molecule positioned within the B-cell receptor signaling cascade. BTK is predominantly expressed in B lymphocytes at various stages of development. Activation of BTK in B cells initiates a series of signaling events that leads to subsequent NF-?B activation and the expression of genes involved in proliferation and survival. Several BTK inhibitors have demonstrated sustained antitumor responses as a single agent in patients with B-cell malignancies.

Disease: chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenstöm's macroglobulinemia

Therapeutic area: Cancer - Oncology

Country: Australia, New Zealand, South Korea, USA

Trial details:

  • The Phase I multicenter, open-label, dose escalation and expansion clinical study of BGB-3111 is designed to assess the safety, tolerability and pharmacokinetic properties and antitumor activities of BGB-3111 as a single agent. Key objectives in the study include determining maximum tolerated dose, if any, recommended phase II dose, pharmacokinetics, and preliminary anti-tumor activity of BGB-3111 in a variety of human tumors. (NCT02343120)

Latest news:

  • • On October 12, 2018, BeiGene announced updated results from the Phase 1 clinical trial of  zanubrutinib, in an oral presentation at the 10th International Workshop on Waldenstöm's macroglobulinemia (WM). As of July 24, 2018, 77 patients with treatment-naïve or relapsed/refractory WM have been enrolled in the trial. Seventy-three patients were evaluable for efficacy in this analysis and the median follow-up time was 22.5 months (4.1-43.9). The median time to response (>PR) was 85 days (55-749). At the time of the data cutoff, 62 patients remained on study treatment.

    • The overall response rate (ORR) was 92 percent (67/73), the major response rate (MRR) was 82 percent, and 41 percent of patients achieved a VGPR, defined as a >90% reduction in baseline IgM levels and improvement of extramedullary disease by CT scan.
    • The 12-month progression-free survival (PFS) was estimated at 89 percent. The median PFS had not yet been reached.
    • The median IgM decreased from 32.7 g/L (5.3-91.9) at baseline to 8.2 g/L (0.3-57.8).
    • The median hemoglobin increased from 8.85 g/dL (6.3-9.8) to 13.4 g/dL (7.7-17.0) among 32 patients with hemoglobin <10 g/dL at baseline.
    • MYD88 genotype was known in 63 patients. In the subset known to have the MYD88L265Pmutation (n=54), the ORR was 94 percent, the major response rate was 89 percent, and the VGPR rate was 46 percent. In the nine patients known to be MYD88WT, a less common genotype that historically has had sub-optimal response to BTK inhibition, the ORR was 89 percent, the major response rate was 67 percent, and the VGPR rate was 22 percent.
    • Treatment with zanubrutinib was generally well-tolerated and the majority of adverse events (AEs) were grade 1 or 2 in severity. The most frequent AEs of any attribution were petechia/purpura/contusion (43%), upper respiratory tract infection (42%), cough (17%), diarrhea (17%), constipation (16%), back pain (16%), and headache (16%).
    • Grade 3-4 AEs of any attribution reported in three or more patients included neutropenia (9%), anemia (7%), hypertension (5%), basal cell carcinoma (5%), renal and urinary disorders (4%), and pneumonia (4%). Serious AEs (SAEs) were seen in 32 patients (42%), with events in five patients (7%) considered possibly related to zanubrutinib treatment: febrile neutropenia, colitis, atrial fibrillation, hemothorax, and pneumonia (n=1 each).
    • Nine patients (12%) discontinued due to AEs: abdominal sepsis (fatal), septic shoulder, worsening bronchiectasis, scedosporium infection, gastric adenocarcinoma (fatal), prostate adenocarcinoma, metastatic neuroendocrine carcinoma, acute myeloid leukemia, or breast cancer (n=1 each, all considered by the investigator to be unrelated to treatment).
    • Atrial fibrillation/flutter occurred in four patients (5%). Major hemorrhage was observed in two patients (3%).
    • Four patients (3%) discontinued study treatment due to disease progression as assessed by investigator and one patient remains on treatment post-disease progression.
    Beigene is currently preparing its first US  New Drug Application (NDA) filing for zanubrutinib, which the company expects to file in the first half of 2019 in patients with Waldenström’s Macroglobulinemia
  • • On June 14, 2017, BeiGene presented updated clinical data from an ongoing Phase 1 study of BTK inhibitor BGB-3111 in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma in a poster at the 14th International Conference on Malignant Lymphoma (14-ICML) in Lugano, Switzerland. The updated Phase 1 data continue to demonstrate that BGB-3111 is well tolerated and highly active in CLL/SLL, with a high overall response rate (94%) and a very low treatment discontinuation rate (3%) at a median follow-up of 10.5 months for efficacy evaluation.
  • The ongoing dose-expansion component is testing doses of 160 mg twice a day (BID) or 320 mg once a day (QD). As of March 31, 2017, 69 patients with CLL or SLL (18 TN, 51 R/R) were enrolled in the study.
  • BGB-3111 was shown to be well tolerated in CLL/SLL. The most frequent adverse events (AEs) (?10%) of any attribution were petechiae/purpura/contusion (46%), fatigue (29%), upper respiratory tract infection (28%), cough (23%), diarrhea (22%), headache (19%), hematuria (15%), nausea (13%), rash (13%), arthralgia (12%), muscle spasms (12%), and urinary tract infection (12%); all of these events were grade 1 or 2 except for one case of grade 3 purpura (subcutaneous hemorrhage), which was the only major bleeding event. Additional adverse events of interest included one case of each grade 2 diarrhea and grade 2 atrial fibrillation. A total of 18 serious AEs (SAEs) occurred in 13 patients, with no SAE occurring in more than one patient. Only one patient discontinued treatment due to an AE, a grade 2 pleural effusion.
  • At the time of the data cutoff, 66 patients (16 TN and 50 R/R) had more than 12 weeks of follow-up and were evaluable for efficacy, and three other patients had less than 12 weeks of follow-up. After a median follow-up of 10.5 months (2.2-26.8 months), the overall response rate (ORR) was 94% (62/66) with complete responses (CRs) in 3% (2/66), partial responses (PRs) in 82% (54/66), and PRs with lymphocytosis (PR-Ls) in 9% (6/66) of patients. Stable disease (SD) was observed in 5% (3/66) of patients. The patient with pleural effusion discontinued treatment prior to week 12 and was not evaluable for response. There was one instance of Hodgkin’s transformation. In TN CLL/SLL, at a median follow-up time of 7.6 months (3.7-11.6 months), the ORR was 100% (16/16) with CRs in 6% (1/16), PRs in 81% (13/16) and PR-Ls in 13% (2/16) of patients. In R/R CLL/SLL, at a median follow-up time of 14.0 months (2.2-26.8 months), the ORR was 92% (46/50) with CRs in 2% (1/50), PRs in 82% (41/50), and PR-Ls in 8% (4/50) of patients. Stable disease was observed in 6% (3/50) patients.
  • • On June 19, 2015, BeiGene announced that the FDA has approved its Investigational New Drug (IND) application for the clinical development of BGB-3111, a proprietary Bruton tyrosine kinase (BTK) inhibitor for the treatment of B-cell malignancies. BGB-3111 is an investigational, oral, highly selective and potent inhibitor of BTK, a critical component of B-cell receptor (BCR) signaling that plays an important role in B-cell malignancies. BGB-3111 is the first BeiGene drug candidate to enter clinical trials in the United StatesBGB-3111 has completed dose-escalation in Australia, and has now moved into proof of concept trials.

Is general: Yes