scholarly journals Exposure-Response Relationship of the Bruton Tyrosine Kinase Inhibitor, Zanubrutinib (BGB-3111) in Patients with Hematologic Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5063-5063
Author(s):  
Ying Ou ◽  
Kun Wang ◽  
Lucy Liu ◽  
Ashutosh Jindal ◽  
Yuying Gao ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Adverse Events ◽  
B Cell ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Bleeding Events ◽  
B Cell Malignancies ◽  
Exposure Response ◽  
Bruton Tyrosine Kinase

Background: Zanubrutinib (BGB-3111) is a highly selective, potent, irreversible inhibitor of Bruton tyrosine kinase (BTK), currently in phase 3 development for the treatment of hematologic malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenström's macroglobulinemia (WM). In a dose escalation study evaluating doses of 40, 80, 160, and 320 mg once daily and 160 mg twice daily, no dose limiting toxicities were observed and maximum tolerated dose (MTD) was not established. Objective responses have been observed in patients with various B-cell malignancies (including CLL, MCL, WM) at all tested dose levels. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (Tam et al. Blood 2016;128:642). To support dose selection, this exposure-response (E-R) analysis evaluated exposure-safety and exposure-efficacy (in MCL) relationships in patients with B-cell malignancies receiving zanubrutinib monotherapy. Methods: A population pharmacokinetic (PopPK) model was developed from 600 subjects enrolled in 9 clinical studies in patients with B-cell malignancies and healthy volunteers. Exposure data such as steady-state area under the plasma concentration time curve (AUC0-24,ss), maximum observed plasma concentration (Cmax ) or steady state trough concentration (Cmin) derived from the PopPK analysis were used in the E-R analysis. Exposure-efficacy analyses were performed using exposure metrics and overall response rate (ORR) data from two studies in patients with relapsed/refractory (R/R) MCL (n=51), including Study 206, a pivotal Phase 2 study conducted in China and study AU-003, a global Phase 1, dose escalation/cohort expansion study. The efficacy endpoint evaluated was ORR, as assessed by an independent review committee (IRC) as well as by investigators, according to 2014 Lugano Classification. Exposure-safety analyses were conducted using data from 4 studies in patients with B-cell malignancies (n=372) receiving zanubrutinib as monotherapy at a total daily dose from 40 mg to 320 mg. The safety endpoints evaluated included Grade ≥ 3 adverse events (AE) and AEs of interests, including neutropenia, thrombocytopenia, anemia, infections/infestations, all events of secondary primary malignancies, all events of atrial fibrillation and flutter, major bleeding events, and any bleeding events. Results: PopPK analysis demonstrated that race, body weight, age, CrCL, sex, tumor type, and use of acid-reducing agents did not show a statistically significant impact on the PK of zanubrutinib. The PK profile of zanubrutinib was comparable between Asians and non-Asians, which allows for bridging of clinical efficacy and safety data across the pivotal studies conducted globally (AU-003) and in China (206). The analysis showed that the median AUC0-24,ss and Cmax values were 1736 ng·h/mL and 275 ng/mL in responders compared with 1326 ng·h/mL and 175 ng/mL in nonresponders, respectively. Although overall median exposure (AUC0-24,ss, Cmax) was higher in responders compared with nonresponders, no significant E-R relationship was identified for efficacy based on probability of observing ORR and logistic regression model (Fig 1). The E-R relationships based on investigator assessments were consistent with those based on IRC assessments. For the exposure-safety analysis, the exposure ranges were similar in patients experiencing adverse events of interests relative to those who were not. There were no evident E-R relationships between PK exposure (AUC0-24,ss, Cmax, or Cmin) and the probability to have adverse events of interest (eg., Fig. 2). Conclusion: E-R analyses indicate that higher plasma exposures of zanubrutinib were not associated with higher probability to have adverse events across the dose range of 40 mg to 320 mg in patients with B-cell malignancies. This result supports the recommended dose of 160 mg twice daily in patients with MCL, based on high rates of objective response in patients with R/R MCL, generally favorable safety and tolerability profiles, and complete and sustained BTK occupancy in PBMCs and target tissues at this dose. Disclosures Ou: BeiGene: Employment. Jindal:BeiGene: Employment. Sahasranaman:BeiGene: Employment, Equity Ownership.

scholarly journals Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1103
Author(s):  
Philipp von Hundelshausen ◽  
Wolfgang Siess
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Phase 1 ◽  
The Novel ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase ◽  
Dermatological Disorders ◽  
Reversible Covalent

Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi.

scholarly journals Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Danling Gu ◽  
Hanning Tang ◽  
Jiazhu Wu ◽  
Jianyong Li ◽  
Yi Miao
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Clinical Studies ◽  
Acquired Resistance ◽  
B Cell Malignancies ◽  
Bcr Signaling ◽  
Bruton Tyrosine Kinase ◽  
Covalent Inhibitors ◽  
Btk Inhibitors

AbstractB cell receptor (BCR) signaling is involved in the pathogenesis of B cell malignancies. Activation of BCR signaling promotes the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is a key component of BCR signaling, establishing BTK as an important therapeutic target. Several covalent BTK inhibitors have shown remarkable efficacy in the treatment of B cell malignancies, especially chronic lymphocytic leukemia. However, acquired resistance to covalent BTK inhibitors is not rare in B cell malignancies. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481)  mutations, which disrupt the binding of covalent BTK inhibitors. Additionally, adverse events due to the off-target inhibition of kinases other than BTK by covalent inhibitors are common. Alternative therapeutic options are needed if acquired resistance or intolerable adverse events occur. Non-covalent BTK inhibitors do not bind to C481, therefore providing a potentially effective option to patients with B cell malignancies, including those who have developed resistance to covalent BTK inhibitors. Preliminary clinical studies have suggested that non-covalent BTK inhibitors are effective and well-tolerated. In this review, we discussed the rationale for the use of non-covalent BTK inhibitors and the preclinical and clinical studies of non-covalent BTK inhibitors in B cell malignancies.

scholarly journals Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Hussein A. Abbas ◽  
William G. Wierda
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase ◽  
Btk Inhibitor

Bruton tyrosine kinase (BTK) is a validated target for treatment of B-cell malignancies, and oral inhibitors of BTK have emerged as a standard of care for these diseases. Acalabrutinib is a second generation, highly selective, potent, covalent BTK inhibitor that exhibits minimal off-target activity in in vitro assays, providing the potential to improve tolerability over the first-in-class BTK inhibitor, ibrutinib. Acalabrutinib was approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) in the US in 2017 and 2019, respectively. Acalabrutinib is also undergoing trials for other B-cell malignancies, both as monotherapy and in combinations. In this review, we discuss results from clinical trials evaluating the efficacy and safety of acalabrutinib in patients with CLL, MCL, and Waldenstrom’s macroglobulinemia. Recent phase 3 data showed that acalabrutinib improved progression-free survival (PFS) compared with rituximab plus idelalisib or rituximab plus bendamustine in patients with relapsed/refractory CLL, and acalabrutinib with or without obinutuzumab improved PFS compared with chlorambucil plus obinutuzumab in patients with treatment-naïve CLL. Overall, acalabrutinib had a tolerable safety profile, with most adverse events being grade 1/2 severity (most commonly headache and diarrhea) and a low rate of discontinuation due to adverse events.

IMO-8400, an Antagonist of Toll-like Receptors 7, 8, and 9, in Development for Genetically Defined B-Cell Lymphomas: Safety and Activity in Phase 1 and Phase 2 Clinical Trials

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3101-3101 ◽  
Author(s):  
Louis Brenner ◽  
Robert D. Arbeit ◽  
Tim Sullivan
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
B Cell ◽  
Phase 1 ◽  
Phase 2 ◽  
B Cell Malignancies ◽  
Dna And Rna ◽  
Phase 2 Trial ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Background. Toll-like receptors (TLRs) are pathogen-associated molecular pattern recognition receptors of the innate immune system. TLRs 7 and 9, which are expressed in human B-cells, respond to DNA- and RNA-based ligands by initiating a signaling cascade mediated through NF-κB, IRAK1/4, BTK, and JAK/STAT. DNA- and RNA-based ligands for TLRs 7 and 9 also are generated as damage-associated molecular patterns in certain autoimmune diseases and malignancies. MYD88 is a key adaptor molecule in TLR signaling. Recently, the oncogenic mutation MYD88 L265P mutation has been described and reported to occur in patients with activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), Waldenström’s macroglobulinemia (WM), and other B-cell malignancies. MYD88 L265P drives over-expression of TLR 7 and 9 signaling, creating an anti-apoptotic microenvironment that promotes cancer cell survival and proliferation. Recent epidemiological data confirm a strong association between the presence of MYD88 L265P and poor outcomes in patients with DLBCL. Specific targeting of signaling initiated by TLRs 7 and 9 therefore is a novel approach to the treatment of B-cell lymphomas harboring the MYD88 L265P mutation. Preclinical data presented at AACR 2014, including from xenograft tumor studies, show that IMO-8400 inhibits cell signaling and reduces tumor growth in WM and DLBCL models harboring the MYD88 L265P mutation. Clinical data from 2 completed trials of IMO-8400 are presented here. Clinical Trial Designs. In a first-in-man Phase 1 trial in healthy subjects, IMO-8400 was administered by s.c. injection at single dosages of 0.1, 0.3, and 0.6 mg/kg and for four weeks at 0.3 and 0.6 mg/kg/week (each n=6). Goals of the Phase 1 trial included safety and tolerability evaluation through single- and multiple-dose escalation, and assessment of TLR engagement. Subsequently, a randomized, placebo-controlled Phase 2 trial was conducted with IMO-8400 in patients with moderate to severe plaque psoriasis at dosages of 0.075, 0.15, 0.3, and 0.6 mg/kg/week for 12 weeks (n=8 or 9 per dosage). Goals of the Phase 2 trial included safety and tolerability assessment over a 12-week treatment period, and evaluation of clinical proof of concept in a disease that involves TLR7 and 9 over-activation. Clinical Trial Results. IMO-8400 was well tolerated across all dose regimens in both studies, with no treatment-related severe or serious adverse events, no drug-related treatment discontinuations, and no pattern of systemic adverse events or laboratory changes. The only treatment-related adverse events in more than one subject were injection site reactions, comprised of generally mild erythema with occasional induration, pruritus, tenderness or pain. In neither trial were there adverse or consistent shifts in laboratory parameters. Specifically, any changes in white or red blood cell parameters, platelet numbers, and liver enzymes or other serum chemistry parameters were similar following IMO-8400 treatment or after placebo treatment. In the Phase 2 trial, clinical proof of mechanism was demonstrated by increased frequency of improvements in psoriasis disease activity in IMO-8400-treated patients across multiple dose levels relative to placebo-treated patients. Conclusion. Antagonism of TLRs 7 and 9 is a novel, scientifically-driven approach to the treatment of B-cell malignancies characterized by presence of the MYD88 L265P oncogenic mutation. IMO-8400, a clinical-stage drug candidate, was well tolerated in clinical trials conducted in healthy subjects and patients with psoriasis, having demonstrated no myelosuppression or any pattern of hematological or other toxicity in 12-week treatment regimens. The risk-benefit profile of IMO-8400 to date merits further clinical testing for genetically defined B-cell malignancies, as monotherapy and in combination with other agents. Based on the accumulated preclinical data, clinical safety, and demonstrated mechanism of action of IMO-8400, Phase 1/2 clinical trials of IMO-8400 are being conducted in both relapsed/refractory patients with WM and in patients with DLBCL and the MYD88 L265P mutation. Disclosures Brenner: Idera Pharmaceuticals : Employment, Equity Ownership. Arbeit:Idera Pharmaceuticals: Employment. Sullivan:Idera Pharmaceuticals: Employment.

scholarly journals A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies

2021 ◽  
pp. 1-12
Author(s):  
Graham P. Collins ◽  
Tracy N. Clevenger ◽  
Kathleen A. Burke ◽  
Buyue Yang ◽  
Alex MacDonald ◽  
...  
Keyword(s):  
B Cell ◽  
Phase 1 ◽  
B Cell Malignancies

Trial in progress: A phase 1, multicenter, open-label, dose-exploration and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG650 in subjects with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5600-TPS5600
Author(s):  
Ramaswamy Govindan ◽  
Amanda Rose Townsend ◽  
Kathy D. Miller ◽  
Inderjit Mehmi ◽  
Yasutoshi Kuboki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Solid Tumors ◽  
Triple Negative ◽  
Phase 1 ◽  
Locally Advanced ◽  
Maximum Plasma ◽  
High Grade ◽  
Serous Ovarian Cancer

TPS5600 Background: KIF18A is a mitotic kinesin motor protein that regulates chromosome positioning during cell division and is overexpressed in a subset of human cancers. TP53 mutant unstable aneuploid cancer cells with chromosomal instability (CIN) features are dependent on KIF18A motor activity to prevent lethal multipolar cell division. Preclinical data demonstrate that treatment with AMG 650; an oral, first in class, selective small molecule inhibitor of KIF18A may be safe and tolerable. We are conducting a first-in-human phase 1 study with AMG 650 in adult subjects with locally advanced or metastatic solid tumors with TP53MUT, triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC) or serous like endometrial cancers and other solid tumors. Methods: In this phase 1, multicentric, dose escalation and dose expansion study we evaluate the safety and tolerability of AMG 650 monotherapy in patients with advanced/metastatic solid tumors (NCT04293094). The main objective is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) based on emerging safety, efficacy, and pharmacodynamics (PD) data prior to reaching the MTD. Key inclusion criteria include the presence of measurable disease and diagnosis of advanced/metastatic triple negative breast cancer (TNBC), high-grade serous ovarian cancer (HGSOC), serous-like endometrial cancer or other solid tumors with documented TP53 mutations. In the dose expansion phase, participants with locally advanced or metastatic TNBC or HGSOC will be treated with the preliminary RP2D identified from the dose exploration part of the study. Primary endpoints include the incidence of Dose Limiting Toxicities (DLTs),Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment-related Adverse Events and the evaluation of the number of participants who experience a clinically significant change from baseline in vital signs, electrocardiogram and laboratory tests parameters. Secondary endpoints include Objective Response Rate, Duration of Response, Progression-free Survival, Clinical Benefit Rate, Time to Response, Time to Progression, Overall Survival (OS), Maximum Plasma Concentration (Cmax) of AMG 650, Time to Maximum Plasma Concentration (Tmax) of AMG 650 as well as Area Under the Plasma Concentration-time Curve (AUC) Over the Dosing Interval for AMG 650. Continuous monitoring of toxicity is conducted. The study began enrolling pts in March 2020 and is ongoing. For more information, please contact Amgen Medical Information: [email protected] Clinical trial information: NCT04293094.

scholarly journals The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL

Blood ◽  
2018 ◽  
Vol 132 (23) ◽  
pp. 2446-2455 ◽  
Author(s):  
Ian W. Flinn ◽  
Peter Hillmen ◽  
Marco Montillo ◽  
Zsolt Nagy ◽  
Árpád Illés ◽  
...  
Keyword(s):  
B Cell ◽  
Phase 1 ◽  
Randomized Study ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Primary Study ◽  
Effective Treatment Option ◽  
Phase 3 ◽  
Dual Inhibitor

Abstract Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.

scholarly journals Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL

Blood ◽  
2019 ◽  
Vol 134 (11) ◽  
pp. 851-859 ◽  
Author(s):  
Constantine S. Tam ◽  
Judith Trotman ◽  
Stephen Opat ◽  
Jan A. Burger ◽  
Gavin Cull ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Phase 1 Study ◽  
End Points ◽  
Once Daily ◽  
Grade 3

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Sign in / Sign up

Export Citation Format

Share Document