A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer

OBJECTIVES: Berzosertib (formerly M6620, VX-970) is an intravenous, highly potent and selective, first-in-class ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. We assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of berzosertib plus gemcitabine in an expansion cohort of patients with advanced non-small cell lung cancer (NSCLC). The association of efficacy with TP53 status and other tumor markers was also explored. MATERIALS AND METHODS: Adult patients with advanced histologically confirmed NSCLC received berzosertib 210 mg/m2 (days 2 and 9) and gemcitabine 1000 mg/m2 (days 1 and 8) at the recommended phase 2 dose established in the dose escalation part of the study. RESULTS: Thirty-eight patients received at least one dose of study treatment. The most common treatment-emergent adverse events were fatigue (55.3%), anemia (52.6%), and nausea (39.5%). Gemcitabine had no apparent effect on the PK of berzosertib. The objective response rate (ORR) was 10.5% (4/38, 90% confidence interval [CI]: 3.7–22.5%). In the exploratory analysis, the ORR was 30.0% (3/10, 90% CI: 9.0–61.0%) in patients with high loss of heterozygosity (LOH) and 11.0% (1/9, 90% CI: 1.0–43.0%) in patients with low LOH. The ORR was 33.0% (2/6, 90% CI: 6.0–73.0%) in patients with high tumor mutational burden (TMB), 12.5% (2/16, 90% CI: 2.0–34.0%) in patients with intermediate TMB, and 0% (0/3, 90% CI: 0.0–53.6%) in patients with low TMB. CONCLUSIONS: Berzosertib plus gemcitabine was well tolerated in patients with advanced, pre-treated NSCLC. Based on the observed clinical efficacy, future clinical trials should involve genomically selected patients

Experiential learning and the acquisition of managerial tacit knowledge

Tacit knowledge is believed to be one factor that distinguishes successful managers from others. We sought to determine whether levels of accumulated managerial tacit knowledge (LAMTK) were associated with managers' dominant learning styles. Instruments used in the study, involving 356 Malaysian public sector employees, included Sternberg et al.'s (2000) Tacit Knowledge Inventory for Managers and a normative version of Kolb's (1999a) Learning Styles Inventory (LSI-Ill). Findings suggest that LAMTK is independent of the length of subjects' general work experience, but positively related to the amount of time spent working in a management context. Learning styles also had a significant relationship. Subjects who spent most of their time performing management functions and whose dominant learning styles were accommodating had significantly higher LAMTK than those with different learning styles. We also found support for the belief that learners with a strong preference for all four different abilities defined in Kolb's learning theory may be critical for effective experiential learning

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months

SEA-BCMA, an Investigational Nonfucosylated Monoclonal Antibody: Ongoing Results of a Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma (SGNBCMA-001)

Abstract Background Patients (pts) with relapsed/triple-class refractory (R/R; refractory to a proteasome inhibitor, immunomodulatory drug or anti-CD38 antibody) multiple myeloma (MM) have limited treatment options. A need remains for novel combination therapies with manageable toxicity and non-cross-resistant mechanisms of action. B-cell maturation antigen (BCMA) is expressed in most MM pt tumors. SEA-BCMA is an investigational, humanized, nonfucosylated IgG1 monoclonal anti-BCMA antibody. Proposed mechanisms of action of SEA-BCMA include blocking of BCMA-mediated pro-survival and proliferative signaling, mediating antibody-dependent cellular phagocytosis, and displaying enhanced antibody-dependent cellular cytotoxicity. Preclinical data demonstrate promising antitumor activity and versatile combinability. Here, we present preliminary data from the first-in-human Phase 1 clinical trial. Methods SGNBCMA-001 (NCT03582033) is an ongoing phase 1, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability and antitumor activity of SEA-BCMA in adults with R/R MM not previously exposed to any other BCMA-directed therapy. Part A tested monotherapy safety and tolerability with dose escalation (100-1600 mg flat dosing once every 2 weeks [Q2W] by intravenous infusion), and dose expansion at the highest tolerated dose. Parts B and C aim to optimize efficacy by testing intensified dosing (Part B; weekly [Q1W] induction dosing of SEA BCMA for 8 weeks is followed by Q2W maintenance dosing) and dexamethasone (DEX) combination therapy (Part C) in pts who have received ≥3 prior lines of therapy for MM and are triple-class refractory. Responses are assessed per the 2016 International Myeloma Working Group criteria. Results As of June 15, 2021, Part A completed enrollment. A total of 55 pts received SEA-BCMA (see Table 1 for pt characteristics). SEA-BCMA was generally well tolerated, and the maximum tolerated dose was not reached in the 5 dose levels tested in Part A (100, 200, 400, 800, or 1600 mg Q2W; n=2, 2, 2, 7, and 7, respectively). At 800 mg, 1 of 7 pts reported a Grade 3 infusion-related reaction (IRR), which met dose-limiting toxicity (DLT) criteria by lasting >24 hours despite supportive care. This constituted the single DLT observed during dose escalation. Subsequently, dose expansion (n=15) proceeded at 1600 mg Q2W. The most common treatment-emergent adverse events (TEAEs) observed with 1600 mg Q2W (n=22) were fatigue (32%), pyrexia (23%), IRR (23%), and hypertension (23%) for non-hematological events, and anemia (14%) for hematologic events. The most common ≥Grade 3 TEAEs with 1600 mg Q2W were anemia and syncope (9% each). Following a safety monitoring review, premedication with acetaminophen + antihistamine was introduced to mitigate IRRs in expansion cohorts. Parts B and C completed parallel safety run-ins (n=6 each) at the 1600 mg dose with no DLTs observed and with similar tolerability. Pharmacokinetic (PK) analyses indicate serum SEA-BCMA exposures increased proportionally with increasing dose with a half-life of approximately 10 days. Preliminary analyses suggest the PK profile of SEA-BCMA in combination therapy with DEX (n=5) is comparable to monotherapy and is unaltered with a change in schedule from Q2W to Q1W. Three of 22 pts who received 1600 mg SEA-BCMA Q2W monotherapy (Part A) achieved a confirmed objective response (OR; OR rate: 14% [95% confidence interval: 2.91, 34.91]; 2 partial responses [PR], 1 very good PR [VGPR]). To date, 3 pts remain on treatment (2 PRs and 1 stable disease). The median duration of treatment was 12 weeks (Figure 1; range 4-88). In Parts B and C, 2 of 8 (2 PR) and 2 of 12 (1 VGPR, 1 PR) pts reported a confirmed OR; 3 of the 4 responding pts remain on treatment in cycle 7, 8, and 9, respectively. Conclusions Preliminary results for SGNBCMA-001 suggest a favorable safety profile and combination potential. SEA-BCMA also showed encouraging duration on treatment and initial antitumor activity in a heavily pre-treated late-line R/R MM pt population. Expansion cohorts testing intensified SEA-BCMA dosing and the addition of DEX are underway to further assess the safety, tolerability, and estimate of SEA-BCMA activity in the context of these treatment approaches. An additional expansion cohort (Part D), testing the combination of SEA-BCMA with pomalidomide and DEX in pts who have received ≥2 prior lines of therapy, is now enrolling. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Liedtke: Pfizer: Honoraria; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Niesvizky: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; GSK: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Tomasson: Pfizer, Inc.: Research Funding; Rafael Pharmaceuticals: Research Funding; syros Pharmaceuticals: Research Funding; Janssen R&D: Research Funding; Seagen, Inc.: Research Funding. Yasenchak: Seagen Inc.: Research Funding. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Li: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Wang: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company. Ho: Seagen Inc.: Current Employment, Current equity holder in publicly-traded company