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BACKGROUND Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment.

Introduction: Rilzabrutinib is an oral, reversible, covalent inhibitor of Bruton tyrosine kinase (BTK) that targets underlying disease mechanisms of platelet destruction without inhibiting platelet aggregation (common with ibrutinib). The mechanisms of BTK inhibition provide a new approach for treating patients with immune thrombocytopenia (ITP). Completion of dose-escalation study phase determined that the minimally-effective dose was rilzabrutinib 400 mg given twice daily (BID; Kuter. ASH 2019). Methods: This open-label phase I/II study evaluated rilzabrutinib in adults with relapsed ITP who had at least two platelet counts Results: As of May 5, 2020, 32 patients initiated treatment with rilzabrutinib 400 mg BID. The median baseline age was 50 years (range, 21-74) and 97% were classified as having primary ITP. Patients had a median baseline platelet count of 13×109/L, had ITP for a median duration of 7.3 y (range, 0.4-52.5), and were heavily pretreated with a median of 6 prior therapies (range, 1-53; 28% prior splenectomy). Median duration of rilzabrutinib 400 mg BID treatment was 18.0 wk (range, 1.4-24.6). Overall, 14/32 patients (44%) achieved the primary endpoint, and responders maintained platelet counts ≥50×109/L for a median of 71% (range, 33%-100%) of weekly counts. Primary endpoint responses were achieved despite prior splenectomy or lack of response to prior ITP therapies (Table). Independent of the primary response, 67% of all patients were able to achieve clinically meaningful benefit of platelet counts ≥30×109/L. Nine patients continued rilzabrutinib 400 mg BID into the LTE period for an additional median of 20 wk (range, 4-36) of treatment. Four of these LTE patients were on rilzabrutinib monotherapy and 5 on rilzabrutinib with concomitant ITP therapy (n=3 corticosteroids, n=2 romiplostim). Baseline characteristics for the 9 LTE patients were a median duration of ITP of 2.6 y (1.2-14.3) and a median of 5 prior therapies (range, 1-8; 1 patient had a prior splenectomy). Platelet counts of ≥50×109/L in the LTE period were maintained for a median of 100% (range, 36%-100%) of weekly counts (Figure). Treatment-related, treatment-emergent adverse events (TEAEs) were all grade 1/2 in patients initiating rilzabrutinib 400 mg BID; 1 patient each experienced grade 1 diarrhea and grade 1 hypophosphatemia in the LTE period. Conclusions: Oral rilzabrutinib treatment achieved clinically significant platelet responses (≥50×109/L) in patients with heavily pretreated ITP irrespective of splenectomy or lack of response to prior ITP therapy, and maintained responses for the majority of time. In addition, most patients (67%) achieved a clinically meaningful response (platelet counts ≥30×109/L). In patients treated beyond 6 months in the LTE, responses remained consistently reliable (median 100% of weeks). Rilzabrutinib was well tolerated with only grade 1/2 treatment-related TEAEs overall, with only 2 related grade 1 events observed in the LTE period. Continued study is warranted to further demonstrate the magnitude and durability of rilzabrutinib's clinical benefit. Disclosures Kuter: Zafgen: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Protalix Biotherapeutics: Consultancy; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Principia: Consultancy, Research Funding; Momenta: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria. Efraim:UMHAT"ST.MARINA": Consultancy, Current Employment, Current equity holder in private company. Mayer:AbbVie: Research Funding; Principia Biopharma: Research Funding. McDonald:Bayer: Consultancy, Honoraria; Rigel: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Consultancy, Honoraria, Other: Travel Expenses. Bird:Sanofi: Consultancy, Other: (pls note personal honoraria declined for ad board); Principia Biopharma: Other: investigator in clinical studies; Amgen: Consultancy, Other: (pls note personal honoraria declined for all), Speakers Bureau; Novartis: Consultancy, Other: (pls note personal honoraria declined for all), Speakers Bureau; Rigel: Other: investigator in clinical studies; CSL-Behring: Other: investigator in clinical studies; Bristol-Myers Squibb Company: Other: investigator in clinical studies; Ablynx: Other: investigator in clinical studies. Regenbogen:Roche: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Garg:Takeda: Consultancy. Kaplan:Celgene: Honoraria; Novartis: Honoraria. Bandman:Principia Biopharma: Current Employment. Burns:Principia Biopharma: Current Employment. Neale:Principia Biopharma: Current Employment. Thomas:Principia Biopharma: Current Employment, Current equity holder in publicly-traded company. Cooper:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Principia: Consultancy, Honoraria. OffLabel Disclosure: Rilzabrutinib is an investigational therapy being evaluated in a clinical study for the treatment of patients with immune thrombocytopenia.

IntroductionClinical research in non–small-cell lung cancer (NSCLC) is a rapidly evolving field. In an effort to identify the current trends in lung cancer clinical research, we reviewed ongoing clinical trials in NSCLC listed in the ClinicalTrials.gov registry in 2012, and we also compared this data to a similar survey conducted by us in 2009.MethodsThe Web site's advanced search function was used to search for the term “non-small cell lung cancer.” The search was further refined by using the following options from the search page drop-down menu, “open studies” and “interventional.” Studies with non-NSCLC tumor histologies and pediatric studies were excluded.ResultsOf the 477 trials included in the analysis, 105 (22.0%) were phase I, 223 phase II (46.8%), and 63 phase III trials (13.2%). When compared with data from 2009, university-sponsored trials decreased in number (45.4%–34.2%; p < 0.001) whereas industry-sponsored trials remained almost the same. There was a significant increase in trials conducted exclusively outside of the United States (35.9%–48.8%; p = 0.001). The number of studies with locations in China (61, 12.8%) was second only to that in the United States (244, 51.2%). Studies reporting biomarker analysis increased significantly from 37.5% to 49.1% in 2012 (p < 0.001). Biomarker-based patient selection also increased significantly from 7.9% to 25.8% (p < 0.001). Targeted therapies were evaluated in 70.6% of phase I/II and II trials, and the most common class of targeted agent studied was epidermal growth factor receptor tyrosine kinase inhibitors (38.0%). Prespecified accrual times were observed to increase when compared with data reported in 2009, especially among industry-sponsored studies.ConclusionsOur survey identified major changes in lung cancer clinical research since 2009. Almost half of all studies registered at the ClinicalTrials.gov Web site are being conducted outside the United States, and several novel molecularly targeted agents are being evaluated in the treatment of patients with NSCLC. More importantly, we identified a threefold increase in the number of studies that perform biomarker testing to determine patient selection over the last 3 years.

Introduction Several new agents are being tested in clinical trials for patients with non-small cell lung cancer (NSCLC). A survey of ongoing clinical trials in NSCLC in the ClinicalTrials.gov website would help identify areas that require further attention in the future. Methods We conducted a survey of ongoing clinical trials on NSCLC registered in the ClinicalTrials.gov website. The advanced search option was applied using the terms "non small cell lung cancer," "open studies," "interventional," and "adults 18 years or older." Results Of the 493 eligible trials, 77 (15.6%) were phase III, 92 (18.7%) were phase I, and 240 (48.7%) were phase II trials. Universities were listed as the primary sponsor for 224 (45.4%) trials and pharmaceutical industry for 166 (33.7%) trials. Majority of the trials were multicenter studies (56.8%) and were being conducted exclusively within the United States (51.3%). A large proportion of phase II and III clinical trials (77.2%) were focused on patients with advanced-stage disease. The most frequently used end points were progression-free survival (27.1%) followed by tumor response rate (22.9%) and overall survival (16.6%). Although biomarker analysis was included in 185 (37.5%) trials, only 39 (7.9%) trials used biomarkers for patient selection. Conclusions Progression-free survival is the end point most commonly used to assess the effectiveness of experimental regimens, and biomarker-based patient selection is rarely used in ongoing clinical trials for NSCLC.