scholarly journals Results from a First-in-Human, Proof-of-Concept Phase 1 Trial in Pretreated B-Cell Malignancies for Loxo-305, a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 501-501 ◽  
Author(s):  
Anthony R. Mato ◽  
Ian W. Flinn ◽  
John M. Pagel ◽  
Jennifer R. Brown ◽  
Chan Y. Cheah ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Phase 1 ◽  
Acquired Resistance ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Proof Of Concept ◽  
Wild Type ◽  
B Cell Malignancies

Introduction: Bruton Tyrosine Kinase inhibitors (BTKis) have transformed the treatment of patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies by inducing durable responses, improving quality of life and prolonging overall survival. Prolonged use of BTKi in the real-world setting is limited by toxicity and acquired resistance. Discontinuation rates for BTKis may be as high as 40% in relapsed/refractory CLL, with BTK C481-mediated resistance evident in many progressing patients. Alternative therapies such as venetoclax are associated with on-target (BCL2) acquired resistance. We hypothesized that a selective, non-covalent BTKi would benefit patients with B-cell malignancies in the setting of acquired resistance and/ or unacceptable toxicities following an irreversible BTKi. LOXO-305 is a next-generation, highly selective, oral, non-covalent BTKi that inhibits wild-type and C481-mutated BTK preclinically. Here, we report results from a first-in-human, proof-of-concept phase 1 trial in patients with B-cell malignancies. Methods: This multicenter phase 1/2 trial (NCT 03740529) enrolled patients with advanced B-cell malignancies who had failed or were intolerant to > 2 prior therapies. LOXO-305 was dosed orally in 28-day cycles, using a standard 3+3 dose-escalation design with a primary endpoint of MTD/RP2D identification. Results: As of 26 July 2019, 13 patients (9 CLL and 4 MCL) were enrolled to 3 dose levels: 25mg (n=5), 50mg (n=5) and 100mg (n=3) QD. Median age was 65 (range 51-79) years and the median number of prior therapies was 3 (range 2-6). 12 patients (8 CLL, 4 MCL) received prior chemotherapy + anti-CD20 antibody; 2 MCL patients underwent prior autologous stem cell transplantation; 5 CLL patients received prior umbralisib; 10 patients (7 CLL, 3 MCL) received prior ibrutinib (5 intolerant, 5 relapsed), including 1 who had also received venetoclax. 6 CLL patients displayed high-risk genetic features, including unmutated IGHV (4), complex karyotype (4) and del17p (3). Molecular characterization was available in 7 patients (6 CLL, 1 MCL) and revealed: BTK C481S mutations (in 2 CLL patients post-ibrutinib), a BCL2 G101V mutation (in a CLL patient post-venetoclax), and a TP53 mutation (in an MCL patient post-ibrutinib). At doses ≥50 mg QD, LOXO-305 exposure exceeded the calculated IC90 for wild-type and C481S mutated BTK. No DLTs were reported and all TEAEs are grade 1-2. Clinical activity was noted within the first cycle of therapy and at the first dose level of 25mg QD. The first eight patients were evaluable for initial response and 7 tumor responses (87.5%) were observed (by disease-defined criteria): 5/5 CLL patients (1 PR and 4 PR-L including one with BTK C481S mutation after ibrutinib and one with BCL2 G101V mutation after venetoclax) and 2/3 MCL patients (2 PR and 1 PD with a preexisting TP53 mutation). 2 additional CLL patients were awaiting initial radiologic assessment but had already demonstrated treatment-induced lymphocytosis. 12/13 patients remain on therapy, the longest 5+ months. Conclusion: Phase 1 data with LOXO-305 demonstrate a favorable safety profile and provide proof-of-concept evidence of efficacy in heavily pretreated CLL and MCL patients, including patients with acquired resistance to available BTKis and venetoclax. Disclosures Mato: DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Brown:Teva: Honoraria; Janssen: Honoraria; Sunesis: Consultancy; Juno/Celgene: Consultancy; Gilead: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Loxo: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Octapharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Acerta Pharma: Consultancy; Invectys: Other: Data safety monitoring board; Morphosys: Other: Data safety monitoring board; AbbVie: Consultancy. Cheah:Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, Roche, Abbvie: Research Funding; Roche: Other: Travel expenses. Coombs:Medscape: Honoraria; Covance: Consultancy; Cowen & Co.: Consultancy; H3 Biomedicine: Honoraria; Dedham Group: Consultancy; Loxo: Honoraria; Abbvie: Consultancy; Octopharma: Honoraria; Pharmacyclics: Honoraria. Rothenberg:LOXO Oncology Inc.: Employment. Tsai:Eli Lilly and Company: Employment. Ku:Eli Lilly and Company: Employment. Wang:BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Dava Oncology: Honoraria; Aviara: Research Funding.

Safety Profile and Clinical Response To MEDI-551, a Humanized Monoclonal Anti-CD19, In a Phase 1/2 Study In Adults With Relapsed Or Refractory Advanced B-Cell Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1810-1810 ◽  
Author(s):  
Andres Forero-Torres ◽  
Mehdi Hamadani ◽  
Michelle A. Fanale ◽  
Celeste M. Bello ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
B Cell ◽  
Dose Escalation ◽  
Safety Profile ◽  
Stock Options ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Phase 2 ◽  
B Cell Malignancies

Abstract Background MEDI-551 is an affinity-optimized and afucosylated humanized IgG kappa monoclonal antibody directed against CD19 and induces malignant clone destruction by antibody-dependent cellular cytotoxicity. This study evaluates the safety profile and clinical activity of MEDI-551 in patients with relapsed/refractory B-cell malignancies. These include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma (MM). Objectives Determine the safety profile and maximum tolerated dose (MTD) of MEDI-551 in patients with relapsed/refractory B-cell malignancies. Secondary objectives include clinical activity of MEDI-551. Methods In this phase 1/2 open-label multicenter, global dose-escalation and expansion study, patients with relapsed or refractory CLL, DLBCL, FL, or MM received MEDI-551 (at 0.5, 1, 2, 4, 8, or 12 mg/kg) by intravenous infusion administered over 28-day cycles using standard 3+3 dose escalation. Dose escalation continued to the maximum dose ≤12 mg/kg or until MTD was reached. Therapy continued for 2 cycles beyond complete response (CR), or until unacceptable toxicity or disease progression. Dose-limiting toxicity was defined as a MEDI-551-related adverse event (AE) that prevented completion of a full first cycle of MEDI-551, or as a ≥grade 3 toxicity (excluding hematologic toxicity) that could not be ascribed to another cause. Results Of 91 patients who received ≥1 dose of MEDI-551, 25 patients (CLL [3], DLBCL [6], FL [12], MM [4]) were enrolled in the phase 1 escalation portion (Jun 2010–Aug 2011). No MTD was achieved. The phase 2 expansion phase included 66 patients (CLL [23], DLBCL [20], FL [22], MM [1]) as of 14Jul2013. Three patients were re-treated with MEDI-551 upon relapse. Median age of patients treated was 66 years; median lines of prior therapy was 6. The median number of treatment cycles was 5 with a maximum of 28 cycles. There were 14 deaths due to AEs (none were drug-related) and 15 subjects discontinued treatment. One subject each discontinued due to drug-related neutropenia and infusion reaction. Most AEs were grade 1/2 with dose-independent frequency and severity (Table). Of 91 patients, 5 (5.5%) patients had grade 4 TEAEs (2 with drug-related neutropenia) and 9 (9.9%) had grade 5 events, none were drug related. Of 19 patients with 38 serious AEs (SAE), 2 patients had 3 events that were considered drug-related; pneumonia and sepsis in 1 patient and infusion related reaction in the other. Of 83 patients in the efficacy evaluable population (includes all patients who received any treatment of MEDI-551 and completed at least 1 post-baseline disease assessment), 9 had CR, 12 had partial responses (PR) and 42 had stable disease (SD; Figure 1). ORR to single-agent MEDI-551 was 24%, 24%, or 31% respectively in heavily pre-treated patients with CLL, DLBCL, or FL. Median progression-free survival was ≈9 months (Figure 2). Conclusions MEDI-551 has an acceptable safety profile warranting further study. Anti-tumor activity was achieved in a heavily pre-treated population of DLBCL, CLL, and FL patients respectively in this single-agent study. Phase 2 studies of MEDI-551 in combination with chemotherapy in DLBCL and CLL are ongoing. Funding Source This study was sponsored by MedImmune. Disclosures: Forero-Torres: MedImmune: Research Funding. Hamadani:MedImmune: Research Funding. Fanale:MedImmune: Research Funding. Bello:MedImmune: Research Funding. Kipps:MedImmune: Research Funding. Offner:MedImmune: Research Funding. Verhoef:MedImmune: Research Funding. Federico:MedImmune: Research Funding. Gregory:MedImmune: Research Funding. Sonet:MedImmune: Research Funding. Assouline:MedImmune: Research Funding. Pérez de Oteyza:MedImmune: Research Funding. Tomas:MedImmune: Research Funding. Cuneo:MedImmune: Research Funding. Elgeioushi:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Goswami:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Ibrahim:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Herbst:MedImmune: Employment, Stock/stock options from AstraZeneca Other. Cheson:MedImmune: Research Funding.

The Btk Inhibitor, PCI-32765, Induces Durable Responses with Minimal Toxicity In Patients with Relapsed/Refractory B-Cell Malignancies: Results From a Phase I Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 964-964 ◽  
Author(s):  
Nathan Fowler ◽  
Jeff Porte Sharman ◽  
Sonali M Smith ◽  
Thomas Boyd ◽  
Barbara Grant ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Study Drug ◽  
B Cell Malignancies ◽  
Btk Inhibitor ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 964 Introduction: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor signaling. PCI-32765 is a potent, selective, irreversible and orally bioavailable small molecule inhibitor of Btk. We have previously reported initial efficacy and safety data with this agent in various B-cell malignancies (ASCO 2010 abstract # 8012). We now report updated efficacy and safety of PCI-32765 in patients (pts) with long-term dosing. Pts and Methods: Pts on the Phase 1 study were treated with escalating doses over 6 cohorts. Cohort 1 was dosed at 1.25 mg/kg/day with subsequent dose escalation (2.5, 5.0, 8.3, 8.3 continuous dosing, and 12.5 mg/kg/day) based on safety evaluation. Pts were analyzed according to histology, pretreatment clinical and laboratory characteristics, PCI-32765 dose levels, overall response (OR), and response duration. Results: Responses and time on study (≥ 6 months) are summarized in Table 1. Of 47 pts enrolled in the Phase 1 study, 20 pts (43%) achieved an OR including 3 complete remissions (CR) and 17 partial remissions (PR). Fourteen of 47 pts have been on study ≥ 6 months; of these 8 pts demonstrated a PR or better and 6 pts maintained stable disease (SD). Responses were observed irrespective of pretreatment risk factors such as performance status, lactate dehydrogenase (LDH) levels, or disease burden. Durable responses were seen at all dose levels and across various histologic subtypes (Table 1) and currently 9 of 14 pts with treatment ≥ 6 months are still on study. Study-drug related Grade ≥ 3 toxicities were reported in 9/47 pts (19%). Five of 47 pts discontinued study drug due to adverse events: neutropenia (Grade 3) lasting > 7 days, hypersensitivity reaction (Grade 3), small bowel obstruction (Grade 3), anemia (Grade 2), and exacerbation of chronic obstructive pulmonary disease (Grade 3). No evidence of cumulative hematologic toxicity or long-term safety signals have been observed. No treatment-related deaths have been reported. Conclusion: PCI-32765 is a novel oral Btk inhibitor that induces durable objective responses in various relapsed or refractory B-cell malignancies. The favorable safety profile and lack of cumulative hematologic toxicities support further studies of both monotherapy and combination treatment with PCI-32765. Disclosures: Fowler: Pharmacyclics: Consultancy, Research Funding. Off Label Use: This phase I trial describes the results of a first in human Phase I trial. This drug is not FDA approved for the treatment of malignancy. Sharman:Pharmacyclics, Inc: Honoraria, PI grant. Smith:pharmacyclics: Research Funding. Boyd:pharmacyclics: Research Funding. Grant:pharmacyclics: Research Funding. Kolibaba:pharmacyclics: Research Funding. Furman:Pharmacyclics, Inc: Research Funding. Buggy:pharmacyclics: Employment. Loury:Pharmacyclics: Employment, Equity Ownership. Hamdy:pharmacyclics: Employment. Advani:Pharmacyclics, Inc: Honoraria, PI grant.

An Ongoing Open-Label Phase 1/2 Study of INCB050465, a Selective PI3Kδ Inhibitor, in Patients with Previously Treated B-Cell Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4195-4195 ◽  
Author(s):  
Tycel Phillips ◽  
Rod Ramchandren ◽  
Michael S Wertheim ◽  
Martin E Gutierrez ◽  
William J Edenfield ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Linear Pharmacokinetics ◽  
B Cell Malignancies ◽  
Once Daily ◽  
Food And Beverage ◽  
Grade 3

Abstract Background: Signaling of PI3Kd has been implicated in proliferation, migration, and function of B cells. PI3Kd inhibitors have demonstrated clinical activity in a number of lymphoid tumor types. INCB050465 is a novel, potent, and highly specific inhibitor of PI3Kd (≥19,000-fold more selective for the d vs other isoforms) with no hepatotoxicity in preclinical evaluation at clinically relevant exposures. Here we report the emerging safety, pharmacokinetics, and efficacy results of INCB050465 monotherapy in B-cell malignancies. Methods: This phase 1/2 study (NCT02018861) enrolled patients aged ≥18 years with relapsed/refractory B-cell malignancies. After an initial single-patient cohort of oral INCB050465 5 mg once daily, a 3+3 dose escalation was conducted with doses ranging from 10 to 45 mg once daily; the dose-limiting toxicity observation period was 21 days. The 20 mg and 30 mg once daily doses were selected for monotherapy expansion. Efficacy was assessed every 9 weeks by Lugano Classification or International Working Group on Chronic Lymphocytic Leukemia (CLL) criteria. Results: As of the data cutoff (May 20, 2016), 39 patients had been enrolled and treated with INCB050465 monotherapy. The median age was 63 and 62% were men. Subtypes included diffuse large B-cell lymphoma (n=13); Hodgkin lymphoma (HL; n=8); follicular lymphoma (FL; n=6); CLL (n=5); marginal zone lymphoma (MZL; n=4); and mantle cell lymphoma (n=3). At baseline, the median number of prior systemic regimens was 3, and the median time since diagnosis was 4.9 years. INCB050465 demonstrated low oral clearance and linear pharmacokinetics, with a terminal half-life that supports once-daily dosing. The steady-state Cavg was 15-fold greater than the whole blood IC90 at the 30-mg dose. Pharmacodynamic analysis indicated maximal inhibition of the target throughout the dosing interval at all doses tested. Patients received INCB050465 for a median duration of 82 days (range: 4+ to 382+ days); no DLTs were observed. Treatment was discontinued in 16 patients due to disease progression (n=12), adverse events (AEs; n=3), or loss to follow-up (n=1). Dose interruption occurred in 6 patients (15%) and dose reduction in 1 (3%). The most common nonhematologic AEs were nausea (33%), pyrexia (21%), and cough (18%), all of which were grade 1 or 2. All observed alanine aminotransferase (15%) and aspartate aminotransferase elevations (15%) were grade 1. Nine patients (23%) experienced 16 grade ≥3 nonhematologic AEs, 3 of which were considered treatment-related by the investigator. New or worsening grade ≥3 anemia, thrombocytopenia, and neutropenia occurred in 8%, 10%, and 15% of patients, respectively. There was 1 instance (3%) each of colitis (grade 3) and pneumonitis (grade 2). Thirteen patients (33%) experienced a serious AE (SAE); SAEs occurring in more than 1 patient included diarrhea, exfoliative dermatitis, and hypotension (n=2 each). Among efficacy-evaluable patients (n=35), the objective response rate (ORR) was 57% and varied by disease subtype (Table 1). The ORRs for non-Hodgkin lymphoma (NHL) and HL were 66% (19/29) and 17% (1/6), respectively. Objective responses were observed in both transformed and non-transformed DLBCL, and both germinal center B-cell (GCB) and non-GCB subtypes. Objective responses were observed for all 10 patients with FL or MZL. Ninety percent of objective responses were observed at the first response assessment, and responses occurred at all but the 5-mg dose. Conclusion: The linear pharmacokinetics and absence of DLTs allow INCB050465 to achieve higher levels of target inhibition at the recommended phase 2 dose (30 mg once daily) than have been reported for other PI3Kd inhibitors. INCB050465 monotherapy was well tolerated at all doses tested with no significant transaminase elevations or early-onset diarrhea, and no cases of Pneumocystis jirovecii pneumonia. Objective responses, including complete responses, were observed in both aggressive and indolent NHL. Enrollment is ongoing at the 30 mg once daily dose level. Disclosures Gutierrez: Bayer Health Care Pharmaceuticals, Inc.: Other: Traveling and Lodging- Food and Beverage; Pfizer Inc: Consultancy; Merck Sharp & Dohme Corporation: Consultancy, Other: Travel and Lodging; Pharmacyclics LLC, An AbbVie Company: Other: Food and Beverage; Incyte Corporation: Consultancy; E.R. Squibb & Sons, LLC (Bristol Myers Squibb): Consultancy, Other: Travel and Lodging. Edenfield:Astellas/Medivation: Speakers Bureau; Novartis: Speakers Bureau; Greenville Health System Cancer Institute: Employment. Dawkins:Incyte Corporation: Employment, Other: Stocks. DeMarini:Incyte Corporation: Employment, Other: Stocks. Zhou:Incyte Corporation: Employment, Other: Stocks. Yeleswaram:Incyte Corporation: Employment, Other: Stocks. Newton:Incyte Corporation: Employment, Other: Stocks. Chen:Incyte Corporation: Employment, Other: Stocks. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding.

Target Engagement, Pathway Inhibition, and Efficacy Of The Bruton’s Tyrosine Kinase (Btk) Inhibitor CC-292

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4169-4169 ◽  
Author(s):  
Daniel W Pierce ◽  
Sabine Ponader ◽  
Kumudha Balakrishnan ◽  
Varsha Gandhi ◽  
William G. Wierda ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Clinical Activity ◽  
B Cell Malignancies ◽  
Employment Equity ◽  
Post Dose ◽  
Equity Ownership

Abstract Introduction The B-cell receptor (BCR) and its downstream effectors have emerged as important therapeutic targets in B-cell malignancies. CC-292 is a novel, potent, covalent, and highly selective inhibitor of Btk (IC50apparent of 0.5 nM, kinact/KI ratio of 7.69 × 104 M-1s-1), that does not appreciably inhibit other kinases involved in BCR signaling (eg, IC50 Lyn kinase, 4401 nM) (Evans et al., J Pharmacol Exp Ther. 2013). Here, we report preclinical characterization and clinical data in CLL from a single-agent phase 1 dose-escalation trial of CC-292 in B-cell malignancies, with a focus on how target engagement and downstream events correlate with clinical activity. Results Pharmacodynamic effects of Btk inhibition by CC-292 can be monitored by occupancy of the Btk catalytic site, Btk autophosphorylation on Y223, and downstream phosphorylation of Plc-γ2 and Erk. We developed a sensitive (10 pg/mL lower limit of quantification) and quantitative assay to measure covalent binding of CC-292 to Btk (Evans et al., J Pharmacol Exp Ther. 2013), as well as Western and novel phos-flow assays to probe downstream signal transduction. These methods showed that CC-292 treatment blocks Btk autophosphorylation and downstream pathway activation in both tumor cells and human peripheral blood mononuclear cells (PBMCs). The extent of CC-292 binding to Btk correlated with its in vitro and in vivo effects. The occupancy assay demonstrated that CC-292 effectively targets Btk in tumor cell lines, PBMCs, spleen, and lymph nodes (LNs) in animal models, and in PBMC and lymph node samples from clinical trial subjects. In rats and non-human primates treated with CC-292, Btk occupancy in spleen and LNs was dose-dependent. Measured occupancy in rat spleen and axillary, mesenteric, and superficial cervical LNs was 94%, 92%, 90%, and 76% respectively, 4 hours (hrs) after a single 30-mg/kg dose. Interim data from the phase 1 CLL trial showed that PBMC Btk was completely occupied in the majority of subjects 4 hrs post-dose with both QD and BID dosing. Twenty-four hrs post-dose at 750 and 1000 mg QD, CC-292 exhibited 83% ± 17% Btk occupancy, whereas with BID dosing at 375 and 500 mg, occupancy was 94% ± 16% at the corresponding time point (12 hrs after the second dose). Thus, while both schedules achieved extensive and sustained Btk occupancy, residual free Btk levels were lower with the BID schedule, offering a rationale for an early trend towards more rapid nodal responses, lymphocytosis, and partial responses on the BID schedule observed to date in the phase 1 study. In the 10 clinical LN biopsies tested to date, no measurable levels of unoccupied Btk have been detected, although Btk protein was present as determined by Western blotting, showing that CC-292 was able to penetrate LNs and inhibit Btk in human subjects as it did in preclinical models. For monitoring downstream signal transduction, we developed reagents and assays including a phos-flow assay based on a novel rabbit monoclonal antibody to detect Btk pY223 levels in PBMC subsets. CC-292 effectively inhibited constitutive and induced phosphorylation of Btk and Plc-γ2 at low nanomolar concentrations. CC-292 also inhibited BCR activation and nurse-like cell–supported survival of CLL cells. Furthermore, CC-292 reduced CLL cell migration and actin polymerization in response to chemokines (CXCL12, CXCL13) and inhibited secretion of the chemokines CCL3 and CCL4 by CLL cells. These chemokines are essential for migration and retention of normal and neoplastic B cells in the marrow and secondary lymphatic tissues. Consistent with this preclinical data, CC-292 treatment resulted in rapid reductions in circulating CCL3 and CCL4 levels. In subjects treated at the 750 mg QD, 1000 mg QD, 375 mg BID, and 500 mg BID dose levels, plasma CCL3 was reduced from 99 ± 16 pg/ml before treatment to 28 ± 5 pg/ml (N = 48, mean ± SEM) at 24 hrs after the first dose, while CCL4 was reduced from 235 ± 59 pg/ml to 74 ± 16 pg/ml (N = 51). Conclusions These data demonstrate that CC-292 achieves significant and durable occupancy of Btk in vitro and in vivo, inhibits Btk-mediated downstream signaling events and chemokine production, and that these preclinical activities have translated into the clinic. Taken together, these results argue that Btk inhibition is necessary and sufficient for clinical activity in CLL. These emerging data support continued development of CC-292 for the treatment of B-cell malignancies. Disclosures: Pierce: Celgene: Employment, Equity Ownership. O'Brien:Genentech: Consultancy, Research Funding; Emergent: Consultancy, Research Funding; CLL Global Research Foundation: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; MorphoSys: Research Funding; Pharmacyclics: Consultancy, Research Funding; Talon: Consultancy, Research Funding; Teva/Cephalon: Consultancy. Heise:Celgene: Employment, Equity Ownership. Nacht:Celgene: Employment, Equity Ownership. Aslanian:Celgene: Employment, Equity Ownership. Liu:Celgene: Employment, Equity Ownership. Hong:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Zavodovskaya:Celgene: Employment, Equity Ownership. Marine:Celgene: Employment, Equity Ownership. Barnett:Celgene: Employment, Equity Ownership. Nava-Parada:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Chopra:Celgene: Employment, Equity Ownership. Burger:Pharmacyclics: Research Funding; Gilead: Research Funding. Singh:Celgene: Employment, Equity Ownership.

MEDI-551, a Humanized Monoclonal Anti-CD19, in Adults with Relapsed or Refractory Advanced B-Cell Malignancies: Results From a Phase 1/2 Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3677-3677 ◽  
Author(s):  
Andres Forero ◽  
Mehdi Hamadani ◽  
Michelle A. Fanale ◽  
Celeste M. Bello ◽  
Thomas J Kipps ◽  
...  
Keyword(s):  
B Cell ◽  
Disease Progression ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Disease Assessment ◽  
Hematologic Toxicity ◽  
B Cell Malignancies

Abstract Abstract 3677 Background: MEDI-551 is an affinity-optimized and afucosylated humanized IgG kappa monoclonal antibody directed against CD19 and induces malignant clone destruction by antibody-dependent cellular cytotoxicity. This study evaluates the safety and preliminary efficacy profile of MEDI-551 in patients with relapsed/refractory B-cell malignancies. These include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma (MM). Objectives: To determine the safety profile and maximum tolerated dose (MTD) or optimal biological dose of MEDI-551 in patients with relapsed/refractory B-cell malignancies. Secondary objectives include pharmacokinetics, immunogenicity, and clinical activity of MEDI-551. Methods: In this phase 1/2 open-label multicenter, global dose-escalation and expansion study, patients with relapsed or refractory CLL, DLBCL, FL, or MM received MEDI-551 (at 0.5, 1, 2, 4, 8, or 12 mg/kg) by intravenous infusion administered over 28-day cycles using standard 3+3 dose escalation. Dose escalation continued until the MTD (≤12 mg/kg) was reached. Therapy continued for 2 cycles beyond complete response (CR), or until unacceptable toxicity or disease progression. Dose-limiting toxicity was defined as a MEDI-551-related adverse event (AE) that prevented completion of a full first cycle of MEDI-551, or as a grade 3 or higher toxicity (excluding hematologic toxicity) that could not be ascribed to another cause, such as disease progression or accident. Results: Of the 63 patients (CLL [12], DLBCL [23], FL [23], MM [5]) who received ≥1 dose of MEDI-551, 25 patients (CLL [3], DLBCL [6], FL [12], MM [4]) were enrolled in the phase 1 escalation portion (Jun 2010–Aug 2011). No MTD was achieved. The phase 2 expansion phase is ongoing. Median age of patients treated was 62 years. The median of completed treatment cycles was 4.0 with a maximum of 15 cycles. Dose intensity was approximately 98%. There were 6 deaths due to AEs (none were drug-related) and 9 subjects discontinued treatment (2 [neutropenia and infusion site reaction] were nonserious drug-related AEs). Most AEs were grade 1/2 with dose-independent frequency and severity (Table). 13 patients had serious treatment-emergent adverse events (TEAEs); pneumonia, sepsis, and bacteremia in 1 patient were considered drug-related. 7 patients had grade 4 TEAEs (2 with neutropenia were drug-related) and 7 had grade 5 events, none related to drug. Of 43 patients in the evaluable for efficacy population (includes all patients who received any treatment of MEDI-551 and completed at least 1 post-baseline disease assessment), 5 had CR, 6 had partial responses (PR) and 21 had stable disease (SD; Figure 1). Median progression-free survival was ≈6 months (Figure 2). Conclusions: MEDI-551 demonstrated a safety profile warranting further study and no MTD was identified at the highest dose studied. The responses (CR: 11.6%; PR: 14.0%, objective response of 25.6% and SD of 48.8%) achieved in this single-agent study in heavily pretreated patients provide encouraging evidence of antitumor activity. Disclosures: Fanale: MedImmune: Research Funding. Kipps:MedImmune: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gregory:MedImmune (ALLRESEARCH FINDING PROCEEDS GO TO RUSH UVERSITY MEDICAL CENTER, NOT TOT ME PERSONALLY: Honoraria, Research Funding. Zhang:MedImmune: Employment. Goswami:MedImmune: Employment; AstraZeneca: Stocks, Stocks Other. Ibrahim:MedImmune: Employment; AstraZeneca: Stocks, Stocks Other. Yao:MedImmune: Employment. Herbst:MedImmune: Employment.

Design Of a Phase 1/2 Study Of Moxetumomab Pasudotox In Adult Patients With Relapsed and/Or Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5021-5021
Author(s):  
Farhad Ravandi ◽  
Hagop M. Kantarjian ◽  
Trishna Goswami ◽  
Fujun Wang ◽  
Ramy Ibrahim
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase 1 ◽  
Adult Patients ◽  
Clinical Activity ◽  
Multiple Time ◽  
Phase 2 ◽  
B Cell Malignancies ◽  
Term Survival ◽  
Primary Endpoints

Abstract Background Adult ALL encompasses a heterogeneous group of lymphoid malignancies. Long-term survival in adults is currently only 35% to 45%; the predominant reason for this is disease recurrence. Current outcomes of salvage chemotherapy for ALL are poor, with complete response rates of 20% to 30% depending on prior therapy and duration of first remission. Older patients with ALL who relapse have a very poor prognosis and very limited options. Thus, adults with relapsed/refractory ALL are a population with significant unmet needs, requiring effective salvage therapies that maintain durable remissions. CD22 is expressed on most B-lineage ALL blasts; thus, it is an ideal target for eliminating leukemic cells. Moxetumomab pasudotox (MP) is a recombinant immunoconjugate composed of an anti-CD22 immunoglobulin variable domain genetically fused to a truncated form of Pseudomonasexotoxin, PE38. MP has been clinically tested and showed antitumor activity in other B-cell malignancies including relapsed hairy cell leukemia (Kreitman RJ, et al. J Clin Onc. 2012;30:1822-28) and pediatric ALL (Shah NN, et al. 2nd International Workshop on the Biology, Prevention, and Treatment of Relapse After HSCT Program and Abstract Book; Bethesda, MD. 2012. P-49). Study Design This is a single-arm, open-label, phase 1/2, single-institution study of MP in relapsed and/or refractory adult patients with ALL. The phase 1 portion will determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the regimen. The phase 2 portion will evaluate the clinical activity of the regimen as well as the tolerability and safety profile. The primary endpoints of the phase 1 are MTD and DLTs. In the phase 2, the primary endpoints are overall response, including complete remission (CR), CR without recovery of counts, and partial remission; the secondary endpoints are event-free survival (time from enrollment to relapse or death, or the last known follow-up) and overall survival at 2 years. MP will be administered intravenously over 30 minutes. The phase 1 will start with a 30 µg/kg dose every other day x 6 doses in a 21-day cycle; it will use a standard 3+3 dose escalation. Additional dose regimens may be investigated. The phase 2 starting dose will be the MTD from phase 1. Dosing will be discontinued upon disease progression, development of unacceptable toxicity, recommendation for alternate therapy, or patient noncompliance. Minimal residual disease at multiple time points and immunogenicity will be assessed. Enrollment will include a maximum of 60 patients. Conclusion This study will provide new insights into the treatment of adults with relapsed/refractory ALL as well as expand upon the clinical activity of MP previously demonstrated in B-cell malignancies. This study is sponsored by MD Anderson Cancer Center. Collaborator: MedImmune. ClinicalTrials.gov Identifier: NCT01891981 Disclosures: Ravandi: MedImmune: Research Funding. Kantarjian:MedImmune: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Bristol Myers-Squibb: Research Funding; Ariad: Research Funding. Goswami:MedImmune: Employment. Wang:MedImmune: Employment. Ibrahim:MedImmune: Employment.

177lu-Satetraxetan-Lilotomab in the Treatment of Patients with Indolent Non-Hodgkin B-Cell Lymphoma (NHL), Phase 1/2 Safety and Efficacy Data from Four Different Pre-Dosing Regimens

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1780-1780 ◽  
Author(s):  
Arne Kolstad ◽  
Ulf Madsbu ◽  
Matthew Beasley ◽  
Michael Bayne ◽  
Tim Illidge ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Marginal Zone ◽  
Phase 1 ◽  
Phase 2 ◽  
Dosing Regimen ◽  
B Cell Malignancies ◽  
Dosing Regimens ◽  
Equity Ownership ◽  
Pre Treatment

Abstract 177Lu-Satetraxetan-lilotomab (Betalutin®) is a novel CD37-binding IgG1 antibody labelled with the beta-emitter lutetium-177, in a ready-to-use formulation currently in Phase 1/2 clinical development for the treatment of Non-Hodgkins lymphoma. CD37 is an internalizing transmembrane antigen highly expressed on most B-cell malignancies, and is a promising therapeutic target. The optimisation of the pre-dosing regimen prior to administration of 177Lu-Satetraxetan-lilotomab may result in an improved safety and efficacy profile. The phase 1 stage of this study is designed with 4 arms to test different pre-dosing regimens (no pre-dosing, rituximab and two doses of lilotomab) on the effect of 177Lu-Satetraxetan-lilotomab. Methods: Patients with relapsed incurable NHL of follicular grade I-IIIA, marginal zone, mantle cell, lymphoplasmacytic and small lymphocytic subtypes and with platelet counts ≥ 150 x109/l were eligible for inclusion in the study. All patients received pre-treatment with rituximab (375 mg/m2) to deplete peripheral B cells and improve biodistribution of the labelled antibody. Pre-dosing with lilotomab (cold anti-CD37 antibody) was given in arms 1 and 4 or rituximab in arm 3, within 4 hours of 177Lu-Satetraxetan-lilotomab to block binding in the non-tumour tissue. The pre-treatment and pre-dosing regimen used in each arm is summarised below: Arm 1: rituximab day1 and 8, lilotomab (40 mg) plus Betalutin day 29 Arm 2: rituximab day 1 and 8, Betalutin day 29 Arm 3: rituximab day 1, rituximab plus Betalutin day 15 Arm 4: rituximab day 1, lilotomab (100 mg/m2) plus Betalutin day 15 The starting dose for Arm 1 was10 MBq/kg and was 15 MBq/kg for arm 2, 3 and 4 and in phase 2. Response was assessed by FDG PET/CT scans at 3 and 6 months post-treatment and then by CT scan up to 5 years after treatment. The results of the protocol specified interim analysis will be presented. Results: A total of36 patients have been enrolled into study, of which 24 are currently evaluable. Patients enrolled into the study had either follicular (n=20), mantel cell (n=2) or marginal zone (n=2) lymphoma. The number of prior therapies ranged from 1 to 8. The efficacy and safety results from patients enrolled into Arms 3 and 4 and treated with two different pre-dosing regimens will be presented for the first time. The most common toxicities observed were hematologic with all dose limiting toxicities (DLTs) being reversible and manageable and related to thrombocytopenia and neutropenia. At a dose of 15 MBq/kg, pre-dosing with 40 mg of lilotomab (Arm 1 and phase 2) reduced the incidence of hematological DLTs to 14% (2/14 patients) compared with 100% (2/2 patients) with no pre-dosing in Arm 2. No DLTs have been reported at 10 MBq/kg in either Arm 1 or 2. Fourteen serious adverse events (SAEs) were reported by 8 patients: Atrial fibrillation (n=2) and platelet count decreased (n=2) were the only SAEs reported by more than one patient. There have been no deaths and no secondary malignancies or other long-term safety events. The overall tumor response rate observed in 23 patients evaluable for efficacy was 57%, comprising 7/23 complete responses, 6/23 partial responses, 5/23 stable disease and 5/23 with progressive disease. In addition, one patient had a confirmed transformed lymphoma at 3 months. One patient is still in remission more than 3 years after treatment and two further patients are still in remission more than 2 years after treatment. Conclusions: Betalutin has the potential to be a novel, safe and effective therapy for B-cell malignancies with durable responses. Betalutin, a single dose, ready-to-use formulation, has a predictable and manageable safety profile which is improved by pre-dosing. Most AEs were haematological, all transient and reversible. Disclosures Kolstad: Nordic Nanovector: Other: Membership of Scientific Advisory Board. Illidge:Nordic Nanovector: Consultancy. Dahle:Nordic Nanovector ASA: Employment, Equity Ownership. Baylor Curtis:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment. Turner:Nordic Nanovector: Employment. Hartvig Larsen:Nordic nanovector: Equity Ownership. Holte:Mundipharma: Research Funding; Amgen: Research Funding.

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 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

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.

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