Sarah Cannon Research Institute (SCRI) is a research organization focusing on therapies for patients which include drugs that are in development. With corporate headquarters in Nashville, Tennessee, United States, it conducts community-based clinical trials in oncology, cardiology, gastroenterology, and other therapeutic areas. The current CEO is Dee Anna Smith.SCRI accrued more than 2,500 patients to cancer trials in 2009, including more than 500 to Phase I investigational studies. Non-oncology trials accounted for nearly 1,500 additional patients for a total of almost 4,000.Its drug development program has conducted 400+ "first-in-human" trials. SCRI has been involved in the testing and development of about 10 drugs that have been approved since 1999.SCRI employs over 350 people and was No. 4 on NashvillePost magazine's 2010 list of the Best Employers in Middle Tennessee. In 2009 and 2010, SCRI was awarded a spot on Modern Healthcare's list of the 100 Best Places to Work in Healthcare.
Although the tissue-agnostic FDA approval of pembrolizumab for tumor mutational burden (TMB)-high tumors has provided meaningful clinical benefit to patients, there remains a need to optimize TMB assessment. In this cohort study, we investigated the discordance between whole-exome sequencing (WES) and panel-based methods and evaluated their relative clinical utility in identifying patients likely to benefit from pembrolizumab. Molecularly-profiled tumors from patients treated with pembrolizumab were analyzed (N = 26,756). TMB was calculated using WES data or panels of genes (324, 523, and 648) from commercially available assays (TMB-High ≥ 10 mutations/Mb). Pembrolizumab-specific overall survival (OS) was calculated from insurance claims data (treatment start to last contact). Targeted gene panels tended to overestimate TMB and demonstrated 10–15
BACKGROUND:Sickle cell disease is characterized by chronic hemolytic anemia and recurrent severe vaso-occlusive crises. Ristoglogene autogetemcel (risto-cel) includes autologous CD34+ hematopoietic stem and progenitor cells that have been base-edited to target the HBG1 and HBG2 promoters and inhibit BCL11A binding without altering BCL11A expression, yielding a switch in hemoglobin production from sickle hemoglobin (HbS) to antisickling fetal hemoglobin (HbF). METHODS:In this phase 1-2 study, we enrolled patients 12 to 35 years of age with sickle cell disease who had had at least four severe vaso-occlusive crises in the 2 years before enrollment. After myeloablative conditioning with pharmacokinetically guided administration of busulfan, patients received a single infusion of risto-cel (at a dose of ≥3.0×106 viable CD34+ cells per kilogram of body weight). The primary efficacy end point was freedom from severe vaso-occlusive crises for 12 consecutive months, starting later than 60 days after the last red-cell transfusion. This interim analysis was unplanned; here, we describe safety, editing, engraftment, and hemoglobin production and the number of severe vaso-occlusive crises starting later than 60 days after the last red-cell transfusion. RESULTS:A total of 31 patients received risto-cel and were followed for a mean of 6.6 months (range, 0.3 to 20.4). A median of one cycle (range, one to five) was required for stem-cell collection. Neutrophil engraftment occurred at a median of 17.5 days, and platelet engraftment at a median of 19 days. One patient died from idiopathic pneumonia syndrome. All 31 patients had at least one adverse event, 27 (87%) had an adverse event of grade 3 or higher, and 12 (39%) had a serious adverse event. At 6 months, the mean fraction of on-target edited alleles in peripheral blood was 67.4%, the mean HbF as a fraction of total hemoglobin was more than 60%, and the HbS as a fraction of total hemoglobin was less than 40% (among 13 patients); these levels were maintained throughout follow-up. No investigator-reported severe vaso-occlusive crises occurred later than 60 days after the last red-cell transfusion. CONCLUSIONS:Treatment with risto-cel was followed by rapid engraftment and durable expression of HbF and reduction in HbS. These data support further investigation of risto-cel to treat sickle cell disease. (Funded by Beam Therapeutics; BEACON ClinicalTrials.gov number, NCT05456880.).
BACKGROUND:Renizgamglogene autogedtemcel (reni-cel) is an investigational clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a gene-edited autologous hematopoietic stem-cell therapy. The therapy was designed to disrupt the BCL11A binding sites in the HBG1 and HBG2 promoters to reactivate fetal hemoglobin production for the treatment of sickle cell disease. METHODS:We conducted a phase 1-2, multicenter, open-label, single-group study involving patients with severe sickle cell disease who were 12 to 50 years of age and had had at least two severe vaso-occlusive events per year in the previous 2 years. The patients received a single infusion of reni-cel after myeloablative conditioning with busulfan. The patients were monitored for engraftment, hemoglobin-related measures, allelic editing levels, vaso-occlusive events, and adverse events over a 24-month period. The study was terminated early on the basis of the sponsor's reassessment of clinical development priorities. Results of an analysis that was not prespecified are reported. RESULTS:As of October 29, 2024, a total of 28 patients with severe sickle cell disease had been treated with reni-cel. The median duration of follow-up was 9.5 months (range, 0.7 to 25.2). Among 27 patients who had neutrophil and platelet engraftment by the data-cutoff date, neutrophil engraftment occurred after a median of 23 days (range, 14 to 29), and platelet engraftment occurred after a median of 25 days (range, 17 to 51). At month 6, among 18 patients with at least 6 months of available data, the mean (±SD) total hemoglobin level (9.8±1.7 g per deciliter at baseline) had increased to 13.8±1.9 g per deciliter, and the mean percentage of fetal hemoglobin (2.5±2.5% at baseline) had increased to 48.1±3.2%; both measures were maintained at or above these values thereafter. One patient had two severe vaso-occlusive events after infusion. Adverse events were consistent with those that occur after myeloablative busulfan-based conditioning and autologous hematopoietic stem-cell transplantation. CONCLUSIONS:Treatment with reni-cel led to normalization of the total hemoglobin level and an increase in the percentage of fetal hemoglobin, with no vaso-occlusive events occurring in 27 of 28 patients after infusion. These results support further investigation of this gene-editing approach in the treatment of severe sickle cell disease. (Funded by Editas Medicine; RUBY ClinicalTrials.gov number, NCT04853576.).
BACKGROUND:Current therapies for patients with pancreatic ductal adenocarcinoma (PDAC) provide modest benefit. Activating RAS mutations occur in more than 90% of PDAC tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS. METHODS:In this phase 1-2 study, we evaluated daraxonrasib in patients with advanced solid tumors with activating RAS mutations. Patients received 10 to 400 mg of daraxonrasib orally once daily; 300 mg was selected as the phase 3 dose. The primary end point was safety. Pharmacokinetics and antitumor activity were secondary end points. This report focuses on the 168 study patients with previously treated RAS-mutated PDAC. RESULTS:Among the 168 patients with PDAC who received daraxonrasib at a dose of 300 mg or less, treatment-related adverse events of any grade were reported in 96%; such events of grade 3 or higher were reported in 30%. Treatment-related adverse events that occurred in at least 10% of the patients included rash, diarrhea, nausea, stomatitis or mucositis, vomiting, and fatigue. In a subgroup of 26 patients with RAS G12 mutations who were treated with second-line daraxonrasib at a dose of 300 mg, an objective response to therapy was reported in 35% (95% confidence interval [CI], 17 to 56). The median duration of response was 8.2 months (95% CI, 3.8 to not evaluable), with median values of 8.5 months for progression-free survival and 13.1 months for overall survival. Among the 38 patients with RAS G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival. CONCLUSIONS:Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).
Although immune checkpoint inhibitor therapies have revolutionized oncology, many cancers are unresponsive or develop resistance that involves transforming growth factor-β1 (TGFβ1). This multicenter, open-label, phase 1 study (DRAGON trial, SRK-181-001) evaluated safety, pharmacokinetics, pharmacodynamics, predictive biomarkers and efficacy of linavonkibart, a first-in-class fully human selective anti-latent TGFβ1 antibody with anti-programmed cell death protein 1 (PD-1) therapy. The DRAGON trial was divided into three treatment parts: part A1 (dose-escalation cohorts with single-agent linavonkibart), part A2 (dose-escalation cohorts with the combination treatment of linavonkibart and pembrolizumab) and part B (dose-expansion cohorts with the combination treatment). The primary objective of the study was to determine the safety and tolerability of linavonkibart alone and in combination with pembrolizumab. Secondary objectives included evaluation of linavonkibart pharmacokinetics for each treatment paradigm, assessment of anti-linavonkibart antibody development (parts A and B) and measurement of antitumor activity (part B) after treatment. All primary and secondary objectives were met in the study. Overall, linavonkibart had a manageable safety profile, and combined therapy with pembrolizumab was generally consistent with that of pembrolizumab monotherapy. Dermatological reactions were the only additional risk identified. Neither cytokine release syndrome nor infusion interruption was observed in any patient enrolled in DRAGON. In part A (n = 34), no dose-limiting toxicities or grade 4 or 5 treatment-related adverse events occurred (linavonkibart; ≤3,000 mg once every 3 weeks (Q3W) and 2,000 mg once every 2 weeks (Q2W)). In part B (n = 78), patients progressing on prior anti-PD-1 therapy received linavonkibart (1,500 mg Q3W/1,000 mg Q2W) with pembrolizumab (200 mg Q3W). This combination demonstrated confirmed objective response rates of 20.0%, 18.2%, 9.1% and 9.1% in anti-PD-1-resistant patients with clear cell renal cell cancer (ccRCC), melanoma, head and neck squamous cell cancer and urothelial cancer, respectively. Biomarker data provide proof of mechanism and a potential ccRCC patient selection strategy. ClinicalTrials.gov identifier: NCT04291079 .
