Placebo Plus Research Articles

Tislelizumab Plus Platinum and Etoposide Versus Placebo Plus Platinum and Etoposide as First-Line Treatment for Extensive-Stage SCLC (RATIONALE-312): A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Phase 3 Clinical Trial

IntroductionExtensive-stage SCLC (ES-SCLC) prognosis remains poor. The phase 3 RATIONALE-312 study aimed to evaluate the efficacy and safety of tislelizumab plus chemotherapy as first-line treatment for ES-SCLC. MethodsRATIONALE-312 is a randomized, double-blind, placebo-controlled trial, conducted in the People's Republic of China. Eligible patients with previously untreated ES-SCLC were randomized 1:1 to receive four cycles of tislelizumab 200 mg or placebo, with etoposide plus carboplatin or cisplatin intravenously every 3 weeks, followed by tislelizumab 200 mg or placebo as maintenance. The primary end point was overall survival (OS). Secondary end points included progression-free survival and safety. ResultsBetween July 22, 2019 and April 21, 2021, 457 patients were randomized to tislelizumab (n = 227) or placebo (n = 230), plus chemotherapy. Baseline demographics were generally balanced between arms. At the data cutoff (April 19, 2023), the median study follow-up was 14.2 months (interquartile range: 8.6–25.3). Tislelizumab plus chemotherapy exhibited a statistically significant OS benefit versus placebo plus chemotherapy (stratified hazard ratio = 0.75 [95% confidence interval (CI): 0.61–0.93]; one-sided p = 0.0040; median: 15.5 [95% CI: 13.5–17.1] versus 13.5 mo [95% CI: 12.1–14.9], respectively). Progression-free survival was significantly improved in the tislelizumab versus placebo arm (stratified hazard ratio = 0.64 [95% CI: 0.52–0.78]; p < 0.0001; median: 4.7 [95% CI: 4.3–5.5] versus 4.3 mo [95% CI: 4.2–4.4], respectively). Grade greater than or equal to 3 treatment-related adverse events were reported in 86% of patients in each treatment arm and were mostly hematologic. ConclusionsTislelizumab plus chemotherapy exhibited statistically significant clinical benefit and manageable safety compared with placebo plus chemotherapy as first-line treatment in patients with advanced ES-SCLC.

Exploring Potential Molecular Mechanisms of Drug Response in FLT3-ITD Negative AML Patients Treated with Quizartinib Vs Placebo Plus Standard Chemotherapy in the Quiwi Trial

Introduction Wild-type FLT3 AML presents significant therapeutic challenges due to limited treatment options. The QUIWI trial investigated quizartinib (Quiz) combined with standard chemotherapy, showing promising results. To understand drug response and refractoriness, we conducted a correlative analysis, exploring differential expression patterns among distinct patient groups. We reasoned that the molecular fingerprints of good responders to Quiz plus chemotherapy would be different with respect to patients who respond only to standard chemotherapy, helping to elucidate critical molecular mechanisms associated with Quiz response. Our study provides a basis for personalized therapeutic strategies in FLT3-ITD negative AML. Methods We performed RNA sequencing (RNAseq) analysis on a subset of patients from the clinical trial. RNA was extracted using standard methods, followed by assessment of nucleic acid integrity (TapeStation) and quantification (Qubit). Total mRNA sequencing was performed using polyA RNAseq with TruSeq technology. A total of 206 adequate samples from bone marrow and peripheral blood were sequenced, out of which 55 cases were FLT3-ITD and were discarded for this analysis. For this analysis, only samples with a minimum of 20% blasts were considered. The sequences were aligned to the GRCh37 reference genome using the Hisat algorithm. Differential expression was assessed with the DESeq2 algorithm, using Blast proportion to adjust for disparities among the samples. P-values were adjusted for multiple testing using the FDR method. OS was defined as time from start of screening to death. Gene ontology and pathways analysis were performed using the WebGestalt portal. Results In this study, we compared the gene expression profiles of Quiz versus placebo-treated patients categorized as good responders, defined arbitrarily as those who continue alive and have a minimum follow-up of 6 months after diagnosis. Out of 82 eligible patients, we identified 100 (q-value &amp;lt; 0.05) and 172 (q-value &amp;lt; 0.1) differentially expressed genes between the Quiz and Placebo groups. Notably, 132 genes were overexpressed in the Quiz group, while 40 genes showed overexpression in the placebo group. Moreover, we observed a highly significant overexpression of ribosomal genes in the Quiz group (17 overlaps, KEGG pathways q-value &amp;lt; 2.2 x 10 -16), and a significant overexpression of genes related to the attenuation of the heat shock protein transcriptional response, which is involved in protein folding, in the placebo group (Reactome q-value, 0.008; gene ids: HSPA1A, HSPA1B and DNAJB1). Additionally, the Quiz group exhibited a significant overexpression of transmembrane receptor protein tyrosine phosphatase-related genes (Gene Ontology Molecular Function q-value, 0.02; gene ids: PTPRB, PTPRG and PTPRU). Conclusion This correlative analysis of the Quiwi trial revealed critical molecular mechanisms associated with Quiz response. The overexpression of ribosomal and transmembrane receptor protein tyrosine phosphatase-related genes in good responders within the Quiz group, along with the overexpression of the heat shock pathway genes in the placebo group, aligns with existing knowledge about the FLT3 pathway biology and the molecular determinants to tyrosine-kinase inhibitors. These findings offer potential biomarkers for personalized therapeutic approaches to improve clinical outcomes in this challenging AML population.

Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in Men with High-Risk Biochemically Recurrent Prostate Cancer and Prior Radiotherapy: EMBARK Subgroup Analysis

Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in Men with High-Risk Biochemically Recurrent Prostate Cancer and Prior Radiotherapy: EMBARK Subgroup Analysis

LBA43 Updated response data and analysis of progression free survival by mechanism of mismatch repair loss in endometrial cancer (EC) patients (pts) treated with pembrolizumab plus carboplatin/paclitaxel (CP) as compared to CP plus placebo (PBO) in the NRG GY018 trial

LBA43 Updated response data and analysis of progression free survival by mechanism of mismatch repair loss in endometrial cancer (EC) patients (pts) treated with pembrolizumab plus carboplatin/paclitaxel (CP) as compared to CP plus placebo (PBO) in the NRG GY018 trial

Tislelizumab Plus Chemotherapy Versus Placebo Plus Chemotherapy as First-Line Treatment for Chinese Patients with Advanced Esophageal Squamous Cell Carcinoma: A Cost-Effectiveness Analysis.

Advanced esophageal squamous cell carcinoma (ESCC) is a prevalent and highly malignant tumor with a poor prognosis. Recently, the RATIONALE-306 trial demonstrated that tislelizumab combined with chemotherapy provided overall survival benefits for these patients. This study aimed to assess the cost-effectiveness of this treatment approach in Chinese patients with advanced ESCC from the perspective of healthcare system. A Markov model was constructed to assess the economic and health benefits associated with tislelizumab plus chemotherapy over a 10-year lifetime horizon, utilizing data from the RATIONALE-306 trial. The analysis encompassed the calculation of several key parameters, including the incremental cost-effectiveness ratio (ICER), total cost, incremental cost, total effectiveness, and incremental effectiveness. Tislelizumab was considered cost-effective if the ICER obtained was below the willingness-to-pay (WTP) threshold of US$38,223 per quality-adjusted life-year (QALY); otherwise, it would be deemed not cost-effective. To ensure the robustness of the findings, the results were subjected to one-way sensitivity analysis and probabilistic sensitivity analysis (PSA). In the base-case analysis, the incremental effectiveness and cost associated with tislelizumab plus chemotherapy, compared to chemotherapy alone, were determined to be 0.40 QALY and US$7604, respectively. This resulted in an ICER of US$18,846 per QALY, which is below the WTP threshold of US$38,223 per QALY. Furthermore, the results from the one-way sensitivity analysis and PSA indicated robustness of the findings. Our lifetime simulation study demonstrated that, in the case of advanced ESCC, the combination of tislelizumab and chemotherapy offers increased effectiveness compared to chemotherapy alone, albeit at a higher cost. Moreover, considering the current WTP threshold in China, the addition of tislelizumab to chemotherapy is considered a cost-effective approach.

184 - A Phase 3 Double-Blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and Safety of AB-205 Plus Standard of Care (SOC) Versus Placebo Plus SOC in Adults with Lymphoma Undergoing High-Dose Therapy and Autologous Hematopoietic Cell Transplantation (E-CELERATE; NCT05181540): Trial in Progress

184 - A Phase 3 Double-Blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and Safety of AB-205 Plus Standard of Care (SOC) Versus Placebo Plus SOC in Adults with Lymphoma Undergoing High-Dose Therapy and Autologous Hematopoietic Cell Transplantation (E-CELERATE; NCT05181540): Trial in Progress

A Phase 3 Double-Blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and Safety of AB-205 Plus Standard of Care (SOC) Versus Placebo Plus Standard of Care in Adults with Lymphoma Undergoing High-Dose Therapy and Autologous Hematopoietic Cell Transplantation (E-CELERATE) (NCT05181540) - Trials in Progress

Myeloablative conditioning or high-dose therapy followed by autologous hematopoietic cell transplantation (HDT-AHCT) is a standard of care (SOC) and potentially curative consolidation therapy for eligible patients diagnosed with aggressive lymphoma. Although effective in chemosensitive patients, HDT-AHCT is associated with severe regimen-related toxicities (SRRTs) that affect quality of life and may increase mortality risk (Olivieri et al., BBMT 2018). SRRTs occur due to the off-target cytotoxicity of HDT that involves damage to the microvasculature and the vascular stem cell niches of multiple organs. SRRTs predominantly affect organs with high cell turnover causing severe complications such as diffuse gastrointestinal (GI) mucositis (oral/GI SRRT) and delayed hematopoietic recovery. Rates and severity of toxicities increase with age, relevant to the demographics of the aging lymphoma population. Importantly, patients identify oral/GI SRRT as one of the most severe adverse effects experienced with HDT-AHCT (Stiff et al., BMT 2001). Notwithstanding, there are limited treatment strategies aimed at preventing SRRTs. AB-205 is an experimental, engineered cell therapy that consists of allogeneic, human umbilical vein endothelial cells transduced with the pro-survival E4ORF1+ gene (E-CEL® cells). The proposed mechanism of action is paracrine in nature consisting of cell expression of reparative angiocrine factors which are thought to accelerate the repair injuries from off-target cytotoxicity of myeloablative conditioning. In a previously presented Phase 1/2 study [NCT03925935] in HCT-eligible patients with lymphoma, AB-205 was well tolerated and resulted in a 9% incidence of early oral/GI SRRT [defined as Grade ≥3 mucositis (M), nausea (N), vomiting (V) or diarrhea (D) in systemic lymphoma subjects conditioned with BEAM and BEAM-alternates (Phase 1/2 data is locked and analysis is in progress). This oral/GI SRRT incidence compared highly favorably to an incidence rate of 41% resulting from a contemporary, retrospective observational study conducted at two phase 1/2 sites (done concurrently during the conduct of the phase 1/2 study). Accordingly, a phase 3, randomized, double-blind, placebo-controlled multi-center study (E-CELERATE) has been initiated to further investigate the efficacy and safety of AB-205 in reducing (preventing) severe toxicities and complications related to off-target cytotoxicity of myeloablative HDT. Approximately 140 patients will be enrolled across 25 sites in the United States. Key inclusion criteria: Age ≥ 40; diagnosis of Hodgkin or non-Hodgkin lymphoma who are candidates for HDT-AHCT with one of the following myeloablative conditioning regimens: carmustine, etoposide, cytarabine, melphalan (BEAM); bendamustine, etoposide, cytarabine, melphalan (BeEAM); achieved complete response (CR) or partial response (PR) prior to planned HDT; ECOG ≤ 2; serum bilirubin ≤ 2 mg/dL; AST, ALT, and alkaline phosphatase < 3 × ULN. Key exclusion criteria: Prior HCT; primary CNS lymphoma; systemic lymphoma with secondary CNS involvement at time of relapse prior to planned HDT-AHCT; active malignancy other than the one for which the subject is undergoing HDT-AHCT; subjects with a known history of HIV. Endpoints: The primary endpoint is complete response defined as the absence of oral/GI SRRT (NCI CTCAE Grade ≥ 3 M, N, V, or D from the time of HDT through Day +21 post-HCT). Secondary endpoints include the duration of oral/GI SRRT; patient-reported symptom burden per MD Anderson Symptom Inventory; duration of febrile neutropenia; time to neutrophil engraftment; incidence of Grade ≥ 3 non-hematologic treatment emergent AEs; absence of SRRT; and survival endpoints: non-relapse mortality, progression free survival and overall survival. Eligible patients will be randomized 1:1 to receive SOC supportive care prophylaxis + AB-205 or placebo intravenously (IV) given on Day 0 within 4 hours of AHCT. 20×106 cells/kg AB-205 IV or an analogous volume of placebo IV will be administered. Randomization will be stratified by lymphoma type (HL/NHL), hematopoietic cell transplantation-comorbidity index, disease status prior to HDT (CR/PR). Daily assessments of oral/GI SRRT will occur from start of HDT to Day +21 post AHCT (Figure 1). Current status: Active recruitment and enrollment ongoing [NCT05181540]. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

AML-029 Quizartinib Prolonged Overall Survival (OS) vs Placebo Plus Intensive Induction and Consolidation Therapy Followed by Single-Agent Continuation in Patients Aged 18-75 Years With Newly Diagnosed FLT3–Internal Tandem Duplication Positive (FLT3-ITD+) Acute Myeloid Leukemia (AML)

Quizartinib is an oral, potent, selective, type II FLT3 inhibitor with prolonged OS as a single-agent in relapsed/refractory FLT3-ITD+ AML. We report results from the global, randomized, double-blind, phase 3 QuANTUM-First trial (NCT02668653), evaluating quizartinib plus standard induction and post-remission consolidation (including allogeneic hematopoietic cell transplant [allo-HCT] in first complete remission [CR1]) followed by single-agent continuation (up to 3 years) vs placebo plus chemotherapy in newly diagnosed FLT3-ITD+ AML. Patients 18-75 years with newly diagnosed FLT3-ITD+ AML received induction with cytarabine 100 or 200 mg/m2/day (days 1-7) and daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day (days 1-3). Patients were randomized to quizartinib (40 mg/day [days 8-21]) or placebo; stratified by region, age, and white blood cell count at diagnosis. Patients with CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus quizartinib (40 mg/day) or placebo and/or allo-HCT followed by continuation with quizartinib (30-60 mg/day) or placebo (up to 3 years). The primary endpoint was OS. Between September 2016 and August 2019, 539 patients were randomized (quizartinib [n=268], placebo [n=271]). Median age was 56 years (range, 20-75 years). As of August 2021 (median follow-up, 39.2 months), 58 patients remained on continuation. Median OS was significantly longer with quizartinib vs placebo (31.9 vs 15.1 months; HR, 0.776; 95% CI, 0.615-0.979; 2-sided P=.0324). CR+CRi rates were 71.6% and 64.9%, respectively. Allo-HCT in CR1 was performed in 157 patients (quizartinib, 31%; placebo, 27%). When censored for allo-HCT, OS trended longer with quizartinib vs placebo (HR, 0.752; 95% CI, 0.562-1.008; 2-sided P=.055). Relapse-free survival was longer with quizartinib vs placebo (HR, 0.733; 95% CI, 0.554-0.969). Grade ≥3 adverse events (AEs) were similar across arms. Discontinuations due to AEs occurred in 20.4% (quizartinib) and 8.6% (placebo). Fifty-six patients died from treatment-emergent AEs (quizartinib, 11.3%; placebo, 9.7%); mostly infections. Grade 3/4 electrocardiographic QT prolongation occurred in 3.0% (quizartinib) and 1.1% (placebo). Quizartinib plus standard therapy, followed by continuation, including after allo-HCT, for up to 3 years was tolerable with statistically significant and clinically meaningful OS improvements in adults ≤75 years with newly diagnosed FLT3-ITD+ AML.

Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma

Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models. To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo). CANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021. Patients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity. The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review. A total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo. In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents. ClinicalTrials.gov Identifier: NCT03428217.

Patient-Reported Outcomes from the Phase 3 Randomized, Double-Blind, KEYNOTE-826 Trial of Pembrolizumab Plus Chemotherapy Versus Placebo Plus Chemotherapy for the First-Line Treatment of Persistent, Recurrent, or Metastatic Cervical Cancer (023)

Patient-Reported Outcomes from the Phase 3 Randomized, Double-Blind, KEYNOTE-826 Trial of Pembrolizumab Plus Chemotherapy Versus Placebo Plus Chemotherapy for the First-Line Treatment of Persistent, Recurrent, or Metastatic Cervical Cancer (023)

Supplemental Protein and a Multinutrient Beverage Speed Wound Healing after Acute Sleep Restriction in Healthy Adults

BackgroundPhysiologic and psychologic stress slow healing from experimental wounds by impairing immune function. ObjectivesWe aimed to determine whether supplemental protein and multinutrient supplementation improved wound healing markers after acute stress induced by acute sleep restriction. MethodsIn this single-blind, crossover study in generally healthy young adults (18 males/2 females; mean ± SD age: 19.7 ± 2.30 y), experimental wounds were created by removing the top layer of forearm blisters induced via suction after 48 h of 72-h sleep restriction (2-h nightly sleep), a protocol previously shown to delay wound healing. Skin barrier restoration (measured by transepidermal water loss) assessed wound healing ≤10 d postblistering, and local immune responses were evaluated by serial measurement of cytokine concentrations in fluid collected at wound sites for 48 h postblistering. Participants consumed controlled, isocaloric diets with either 0.900 g · kg−1 · d−1 protein plus placebo (PLA) or 1.50 g · kg−1 · d−1 protein plus multinutrient beverage [l-arginine: 20.0 g/d; l-glutamine: 30.0 g/d; omega-3 (n–3) fatty acids: 1.00 g/d; zinc sulfate: 24.0 mg/d; cholecalciferol: 800 IU/d; and vitamin C: 400 mg/d] (NUT) during sleep restriction and for 4 d afterwards. ResultsSkin barrier restoration (primary outcome) was shorter for NUT (median: 3.98 d; IQR: 1.17 d) than for PLA (median: 5.25 d; IQR: 1.05 d) (P = 0.001). Cytokines from wound fluid (secondary outcome) increased over time (main effect of time P ≤ 0.001), except IL-13 (P = 0.07); however, no effects of treatment were observed. ConclusionsSupplemental nutrition may promote wound healing after sleep restriction in healthy adults including military personnel, the latter of which also have a high incidence of wounds and infection.This trial was registered at clinicaltrials.gov as NCT03525184.

Preventive efficacy of six monthly oral doses of Simparica Trio\xae, Heartgard\xae Plus, and Interceptor\xae Plus against a macrocyclic lactone-resistant strain (ZoeLA) of heartworm (Dirofilaria immitis) in dogs

BackgroundAdministration of four to six consecutive monthly doses of 24 µg/kg moxidectin alone shows high effectiveness in preventing the maturation of macrocyclic lactone (ML)-resistant heartworm strains, Dirofilaria immitis JYD-34 and ZoeLA. This laboratory study evaluated the efficacy of six consecutive monthly oral doses of Simparica Trio® (moxidectin/sarolaner/pyrantel) compared to six monthly doses of either Heartgard® Plus (ivermectin/pyrantel) or Interceptor® Plus (milbemycin oxime/praziquantel) against ML-resistant D. immitis ZoeLA strain.MethodsBeagle dogs were inoculated with 50 third-stage (L3) D. immitis larvae (ZoeLA) 30 days prior to the first treatment. Dogs were randomized to treatment (six animals in each group) with six monthly oral doses of placebo, Simparica Trio, Heartgard Plus, or Interceptor Plus at their respective label doses. Microfilaria (MF) and antigen tests were conducted periodically, and efficacy was evaluated by necropsy for adult heartworms approximately 9 months after L3 inoculation.ResultsAdult heartworms were recovered from all six placebo dogs, with a geometric mean of 35.5 worms (range, 23–48). Five of the six dogs treated with Simparica Trio were infected with a geometric mean of 1.0 worms (range, 0–3), and all remained MF-negative. All Heartgard Plus-treated dogs (six) were infected with a geometric mean of 32.5 worms (range, 22–38); five of these dogs were MF-positive at day 236. All Interceptor Plus-treated dogs (six) were infected with a geometric mean of 22.8 worms (range, 10–34); five of these dogs were MF-positive at day 236. The efficacy of six consecutive doses with Simparica Trio, Heartgard Plus, and Interceptor Plus against ZoeLA was 97.2, 8.5, and 35.9%, respectively. Adult worm counts for the Simparica Trio-treated group were significantly lower (P < 0.0001) than placebo control, Heartgard Plus, and Interceptor Plus-treated groups. Adult worm counts for Heartgard Plus and Interceptor Plus were not significantly different from placebo (P > 0.05).ConclusionsSimparica Trio prevented microfilaremia in all dogs and was highly effective (97.2%) and significantly better than either Heartgard Plus (8.5%) or Interceptor Plus (35.9%) in preventing the development of the ZoeLA ML-resistant heartworm strain when administered for six consecutive months in this comparative laboratory efficacy study.Graphical

POSA423 Healthcare Resource Utilization (HRU) Survey to Inform HRU Data Collection Alongside the Double-Blinded Trilynx Study Evaluating Xevinapant in Combination with Chemoradiotherapy Versus Placebo Plus Chemoradiotherapy in Patients with Previously Untreated Locally-Advanced Squamous Cell Carcinoma of the Head and Neck (LA SCCHN)

Using a healthcare resource utilization (HRU) survey to inform HRU data collection alongside the Phase 3 TrilynX study evaluating the addition of xevinapant to chemoradiotherapy (CRT) in locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

RELAY, Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients with Untreated, Epidermal Growth Factor Receptor Mutation-Positive, Metastatic Non-Small-Cell Lung Cancer: Safety Profile and Manageability.

IntroductionRELAY was a global, double-blind, placebo-controlled phase III study that demonstrated superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus placebo plus erlotinib (PBO + ERL) in the first-line treatment of patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) mutation-positive, metastatic non-small-cell lung cancer (NSCLC).ObjectiveThis article provides an in-depth analysis of the safety profile of RAM + ERL versus PBO + ERL observed in RELAY.MethodsEligible patients met these criteria: stage IV NSCLC; EGFR exon 19 deletion or exon 21 substitution (L858R) mutation; Eastern Cooperative Oncology Group performance status 0 or 1; and no central nervous system metastases. Patients were randomized (1:1) to receive erlotinib 150 mg/day orally plus either ramucirumab 10 mg/kg intravenously or matching placebo once every 2 weeks, until disease progression or unacceptable toxicity. The primary endpoint was PFS. Safety was evaluated based on reported treatment-emergent adverse events (AEs) and clinical laboratory assessments.ResultsThe safety population comprised 446 patients (221 in RAM+ERL arm; 225 in PBO + ERL arm) who received at least one dose of study drug between January 2016 and February 2018. The overall incidence of grade ≥ 3 AEs was higher with RAM + ERL than with PBO + ERL, primarily driven by grade 3 hypertension. Grade ≥ 3 dermatitis acneiform and diarrhea were also reported more frequently in the RAM + ERL arm. The increased incidence of AEs with RAM + ERL was easily detected through routine monitoring and managed through dose adjustments and appropriate supportive care.ConclusionThis in-depth safety analysis from RELAY supports that RAM + ERL, irrespective of the increased incidence of AEs, does not affect a patient’s ability to benefit from treatment.Clinical Trial Registration NumberNCT02411448.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01127-2.

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2− Advanced Breast Cancer in the MONALEESA-3 Trial

BackgroundMONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3. MethodsKaplan-Meier OS was partitioned into health states: (1) toxicity (TOX)=time spent with grade 3 –4 adverse events before progression (DP); (2) progression (PROG)=time between DP and death; and (3) time without symptoms or toxicity (TWiST)=time not in TOX or PROG. QA time was calculated by combining estimated mean time in each health state with treatment-group specific health-state utility values estimated using EQ-5D-5L questionnaire. Outcomes included QA progression-free survival (QAPFS), QAOS, and QA TWiST (Q-TWiST). Q-TWiST was calculated with health-state utility values for TOX and PROG defined relative to TWiST. ResultsMean PFS and OS were significantly greater with R+F vs. P+F (difference 0.56 and 0.19 years). Mean time in TOX and TWiST were greater with R+F; mean time in PROG was greater with P+F. QAPFS was 0.45 years (95% CI 0.27 –0.63) greater with R+F than P+F (P <.001). QAOS was numerically greater with R+F vs. P+F (0.16 years, 95% CI 0.07 –0.45, P = .0569). Q-TWiST was 0.23 years greater with R+F (95% CI 0.07 –0.45, P = .0069). In a sensitivity analysis using an estimate of disutility for PROG, the difference in QAOS was 0.23 years (95% CI 0.08 –0.41, P = .0022). ConclusionR+F in postmenopausal women with HR+/HER2- ABC improves QAPFS, resulting in clinically important improvements in Q-TWiST and may improve QAOS.

Duration of Objective Responses for Patients with Indolent Non-Hodgkin Lymphoma Discontinuing Treatment before Progression: Analysis from the Phase III Chronos-3 Trial Comparing Copanlisib Plus Rituximab with Placebo Plus Rituximab

Duration of Objective Responses for Patients with Indolent Non-Hodgkin Lymphoma Discontinuing Treatment before Progression: Analysis from the Phase III Chronos-3 Trial Comparing Copanlisib Plus Rituximab with Placebo Plus Rituximab

Subgroup Analysis by Liver Metastasis in the FRESCO Trial Comparing Fruquintinib versus Placebo Plus Best Supportive Care in Chinese Patients with Metastatic Colorectal Cancer.

ObjectiveThe aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy.MethodsOverall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups.ResultsA total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45–0.77, P<0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17–0.30; P<0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group.ConclusionFruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM.ClinicalTrials.gov IdentifierNCT02314819.

Effect of a dietary intervention with functional foods on LDL-C concentrations and lipoprotein subclasses in overweight subjects with hypercholesterolemia: Results of a controlled trial

Cardiovascular diseases (CVDs) are the leading cause of global death. Hypercholesterolemia is among the main risk factors for developing cardiovascular events, and is highly prevalent in the Mexican population. The primary objective of the present work was to assess the effect of a dietary portfolio (DP) with functional foods containing dehydrated nopal, soy protein, chia seeds, inulin, and oats in LDL-C and TC concentrations of subjects with mild hypercholesterolemia. Also, we explored the changes in the profile of the lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy (NMR). Sixty-two subjects (47 women, 15 men) with mild hypercholesterolemia (LDL-C, ≥130≤190mg/dL, TC>200mg/dL) completed the randomized, parallel, controlled study. The dietary intervention was given in two stages. First, a dietary standardization stage with a low saturated fat diet (LSFD) which matched the habitual energy intake of the volunteers for 2-weeks, followed by 2.5 months of dietary intervention with a LSFD plus placebo (PL) or DP. Subjects who consumed the LSFD+DP interventions had a significantly higher reduction of LDL-C (-18.05%, P=0.003) and TC (-17.08%, P=0.02) compared to volunteers who consumed an LSFD for the same period. Furthermore, the lipoprotein subclass profiling showed that the small low-density-lipoproteins, and the small high-density-lipoproteins significantly decreased (P=0.04, P<0.001, respectively), conveying a less atherogenic state. At the end of the study, 78% of the subjects who consumed LSFD+DP reduced their LDL-C below 160mg/dL, and of these, 47% reduced it below 130mg/dL. Based on the results obtained from this study, the inclusion of functional foods as part of the lifestyle modifications is recommended to treat mild hypercholesterolemia and reduce cardiovascular risk. Registered under ClinicalTrials.gov Identifier no. NCT04148976.

2: Acute and Subacute Gastrointestinal and Genitourinary Toxicity Profiles of Metformin Versus Placebo Plus Prostate and Pelvic Radiotherapy for the Management of High Risk Prostate Cancer: Interim Toxicity Results of a Double-Blinded, Multicentre, Phase Ii Randomized Controlled Trial

2: Acute and Subacute Gastrointestinal and Genitourinary Toxicity Profiles of Metformin Versus Placebo Plus Prostate and Pelvic Radiotherapy for the Management of High Risk Prostate Cancer: Interim Toxicity Results of a Double-Blinded, Multicentre, Phase Ii Randomized Controlled Trial

Supplemental Protein and Multi-Nutrient Beverage Improve Skin Barrier Restoration of an Experimental Wound Site During 72-h Sleep Restriction

Abstract Objectives Acute bouts of sleep restriction (SR) are unavoidable in certain populations (e.g., military personnel and first responders), and impairs immune function as evidenced by delays in skin barrier recovery of experimental wounds by ∼1 day. To what extent this impairment can be mitigated by nutritional supplementation is less clear. We tested the efficacy of a multi-nutrient beverage and additional protein on wound healing in response to acute SR. Methods In this single-blind, cross-over study, wounds were created in healthy adults by removing the top layer of ≤ 8 forearm blisters (∼30 mm2) induced via suction on Day 2 of 72-h SR (lab monitored, 2-h nightly sleep). A controlled, isocaloric diet was provided during SR with either 0.9 g · kg−1 · d−1 protein plus placebo (PLA) or 1.5 g · kg−1 · d−1 protein plus multi-nutrient beverage (NUT; L-arginine: 20 g · d−1, L-glutamine: 30 g · d−1, omega-3 fatty acids: 1 g · d−1, zinc sulfate: 24 mg · d−1, vitamin D3: 800 IU · d−1 and vitamin C: 400 mg · d−1). For 4 days following SR, participants were instructed to continue with the respective PLA or NUT treatment. Protein prescription and beverage components were based on data from clinical settings that have shown benefits related to postsurgical infectious complications and wound healing disorders. Skin barrier restoration was assessed by transepidermal water loss, measured daily until values were within 90% of unbroken skin. Results Twenty participants completed PLA and NUT (18 M/2F; 19.7 ± 2.3 years [mean ± SD]), Body weight change was not different during PLA and NUT (–0.06 ± 0.88 kg and −0.12 ± 1.54 kg, respectively, P = 0.90) and dietary protein intake during and after SR was 1.08 ± 0.28 g · kg−1 · d−1 and 1.44 ± 0.27 g · kg−1 · d−1, respectively. Compliance with study beverages was ∼95%. Skin barrier recovery time was shorter for NUT (4.29 ± 1.17 days) compared to PLA (5.48 ± 1.30 days) (P = 0.001). Conclusions Supplemental nutrition may be beneficial for mitigating delays in wound closure consequent to SR. Findings are of practical importance for affected populations, since the potential for infection is heightened when the skin barrier is perturbed. Funding Sources US Army MMRDC. Authors’ views do not reflect official DoD or Army policy.