Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

A Randomized Phase II Study of Anti-CSF1 Monoclonal Antibody Lacnotuzumab (MCS110) Combined with Gemcitabine and Carboplatin in Advanced Triple-Negative Breast Cancer.

PURPOSE: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient. RESULTS: Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47-8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45-7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand. CONCLUSIONS: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1-CSF1 receptor pathway in TNBC.

Association of Very Early Serum Levels of S100B, Glial Fibrillary Acidic Protein, Ubiquitin C-Terminal Hydrolase-L1, and Spectrin Breakdown Product with Outcome in ProTECT III.

Rapid risk-stratification of patients with acute traumatic brain injury (TBI) would inform management decisions and prognostication. The objective of this serum biomarker study (Biomarkers of Injury and Outcome [BIO]-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment [ProTECT]) was to test the hypothesis that serum biomarkers of structural brain injury, measured at a single, very early time-point, add value beyond relevant clinical covariates when predicting unfavorable outcome 6 months after moderate-to-severe acute TBI. BIO-ProTECT utilized prospectively collected samples obtained from subjects with moderate-to-severe TBI enrolled in the ProTECT III clinical trial of progesterone. Serum samples were obtained within 4 h after injury. Glial fibrillary acidic protein (GFAP), S100B, αII-spectrin breakdown product of molecular weight 150 (SBDP150), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) were measured. The association between log-transformed biomarker levels and poor outcome, defined by a Glasgow Outcome Scale-Extended (GOS-E) score of 1-4 at 6 months post-injury, were estimated via logistic regression. Prognostic models and a biomarker risk score were developed using bootstrapping techniques. Of 882 ProTECT III subjects, samples were available for 566. Each biomarker was associated with 6-month GOS-E (p < 0.001). Compared with a model containing baseline patient variables/characteristics, inclusion of S100B and GFAP significantly improved prognostic capacity (p ≤ 0.05 both comparisons); conversely, UCH-L1 and SBDP did not. A final predictive model incorporating baseline patient variables/characteristics and biomarker data (S100B and GFAP) had the best prognostic capability (area under the curve [AUC] = 0.85, 95% confidence interval [CI]: CI 0.81-0.89). Very early measurements of brain-specific biomarkers are independently associated with 6-month outcome after moderate-to-severe TBI and enhance outcome prediction.

Visceral fat area, not body mass index, predicts postoperative 30-day morbidity in patients undergoing colon resection for cancer.

PURPOSE: Colectomy for cancer in obese patients is technically challenging and may be associated with worse outcomes. Whether visceral obesity, as measured on computed tomography, is a better predictor of complication than body mass index (BMI) or determines long-term oncologic outcomes has not been well characterized. This study examines the association between derived anthropometrics and postoperative complication and long-term oncologic outcomes. METHODS: Retrospective review of patients undergoing elective colectomy for cancer at a single tertiary-care center from 2010 to 2016. Adipose tissue distribution measurements, including visceral fat area (VFA), were determined from preoperative imaging. The primary outcome was 30-day postoperative complication; secondary outcomes included overall and disease-free survival. Multivariable logistic regression was performed to determine association between obesity metrics and outcome. RESULTS: Two hundred and sixty-four patients underwent 266 primary resections of colon cancer. Twenty-eight patients (10.5%) developed major morbidity (Clavien-Dindo grade ≥ III). VFA but not BMI was significantly associated with morbidity in multivariate analysis (p = 0.004, odds ratio 1.99, 95% confidence interval 1.25-3.19). No other imaging-derived anthropometric was associated with increased morbidity. In receiver operating characteristic analysis, VFA was predictive of major morbidity (area under curve 0.660). A cutoff value of VFA ≥ 191 cm2 was associated with 50% sensitivity and 76% specificity for predicting major morbidity. Patients with VFA ≥ 191cm2 had 19.4% risk of morbidity, whereas those with < 191 cm2 had 7.2% risk (relative risk ratio 2.69, unadjusted p = 0.004). Neither VFA nor BMI was associated with overall or disease-free survival. CONCLUSION: VFA but not BMI predicts morbidity following elective surgery for colon cancer.

The influence of advanced age on venous-arterial extracorporeal membrane oxygenation outcomes.

OBJECTIVES: Ethical and health care economic concerns surround the use of venous-arterial extracorporeal membrane oxygenation (VA-ECMO) in elderly patients. Patients requiring VA-ECMO are often in critical condition and the decision to cannulate is time-sensitive. We investigated the relationship between age and VA-ECMO outcomes to better inform this decision. METHODS: This is a retrospective study of 355 patients placed on VA-ECMO between March 2007 and August 2016 at our institution. Using piecewise modelling, age became associated with in-hospital mortality after 63 years. Based on further analysis with the χ2 statistic maximization, patients were divided into 2 age groups: ≤72 years old [Group Y (Young), n = 310] and >72 years old [Group O (Old), n = 45]. Multivariable logistic regression was performed to identify preoperative predictors of in-hospital mortality. RESULTS: Patients over the age of 72 had a significantly higher prevalence of comorbidities, including coronary disease, previous strokes and chronic kidney disease. Weaning from ECMO was achieved in 76% of Group Y and 47% of Group O (P < 0.001). In-hospital mortality was 52% among Group Y and 69% among Group O (P = 0.037). Multivariable logistic regression using preoperative risk factors identified coronary artery disease, acute decompensated heart failure and an age >72 years as independent predictors of mortality (age >72 years: odds ratio 2.71, 95% confidence interval 1.22-6.00; P = 0.01). CONCLUSIONS: VA-ECMO in-hospital mortality is considerable across all age groups. However, age only becomes associated with mortality after 63 years and rises dramatically after 72 years. This study provides useful insight into these time-sensitive decisions for the development of possible practice guidelines.

The impact of covariate misclassification using generalized linear regression under covariate-adaptive randomization.

Under covariate adaptive randomization, the covariate is tied to both randomization and analysis. Misclassification of such covariate will impact the intended treatment assignment; further, it is unclear what the appropriate analysis strategy should be. We explore the impact of such misclassification on the trial's statistical operating characteristics. Simulation scenarios were created based on the misclassification rate and the covariate effect on the outcome. Models including unadjusted, adjusted for the misclassified, or adjusted for the corrected covariate were compared using logistic regression for a binary outcome and Poisson regression for a count outcome. For the binary outcome using logistic regression, type I error can be maintained in the adjusted model, but the test is conservative using an unadjusted model. Power decreased with both increasing covariate effect on the outcome as well as the misclassification rate. Treatment effect estimates were biased towards the null for both the misclassified and unadjusted models. For the count outcome using a Poisson model, covariate misclassification led to inflated type I error probabilities and reduced power in the misclassified and the unadjusted model. The impact of covariate misclassification under covariate-adaptive randomization differs depending on the underlying distribution of the outcome.

Endovascular Therapy Demonstrates Benefit over Intravenous Recombinant Tissue Plasminogen Activator Based on Repeatedly Measured National Institutes of Health Stroke Scale.

BACKGROUND AND PURPOSE: The Interventional Management of Stroke (IMS) III trial was a randomized controlled trial designed to compare the effect of endovascular therapy after intravenous recombinant tissue plasminogen activator (i.v. rt-PA) as compared to i.v. rt-PA alone. The primary outcome was modified Rankin Scale at 90 days. Secondary outcomes included National Institutes of Health Stroke Scale (NIHSS), which was assessed repeatedly through 90 days. The objective of this analysis is to evaluate the treatment effect of endovascular therapy over time on NIHSS. METHODS: 656 subjects were enrolled in the IMS III trial, including 434 subjects randomized to endovascular therapy and 222 to i.v. rt-PA only. NIHSS scores evaluated at 40 min, 24 h, Day 5, and Day 90 were included in the analysis. A covariance structure model was used to investigate the treatment effect on NIHSS over time, adjusting for relevant covariates including baseline stroke severity. Model assumptions were valid. RESULTS: Based on the covariance structure model, after adjusting for relevant baseline covariates, a significant time-by-treatment interaction effect (p = 0.0137) was observed. Only NIHSS at Day 90 showed a significant treatment effect (p = 0.0473), with subjects in the endovascular arm having a lower NIHSS (less neurologic deficit) compared to the i.v. rt-PA arm. CONCLUSIONS: The IMS III trial demonstrated an endovascular treatment effect based on the secondary outcome of NIHSS. However, the magnitude of this treatment effect varied by the time of assessment. It was only at Day 90 that the endovascular arm had a significantly lower NIHSS compared to that in the i.v. rt-PA arm.

Early reperfusion and clinical outcomes in patients with M2 occlusion: pooled analysis of the PROACT II, IMS, and IMS II studies.

OBJECT: The role of endovascular therapy in patients with acute ischemic stroke and a solitary M2 occlusion remains unclear. Through a pooled analysis of 3 interventional stroke trials, the authors sought to analyze the impact of successful early reperfusion of M2 occlusions on patient outcome. METHODS: Patients with a solitary M2 occlusion were identified from the Prolyse in Acute Cerebral Thromboembolism (PROACT) II, Interventional Management of Stroke (IMS), and IMS II trial databases and were divided into 2 groups: successful reperfusion (thrombolysis in cerebral infarction [TICI] 2-3) at 2 hours and failed reperfusion (TICI 0-1) at 2 hours. Baseline characteristics and clinical outcomes were compared. RESULTS: Sixty-three patients, 40 from PROACT II and 23 from IMS and IMS II, were identified. Successful early angiographic reperfusion (TICI 2-3) was observed in 31 patients (49.2%). No statistically significant difference in the rates of intracerebral hemorrhage (60.9% vs 47.6%, p = 0.55) or mortality (19.4% vs 15.6%, p = 0.75) was observed. However, there was a trend toward higher incidence of symptomatic hemorrhage in the TICI 2-3 group (17.4% vs 0%, p = 0.11). There was also a trend toward higher baseline glucose levels in this group (151.5 mg/dl vs 129.6 mg/ dl, p = 0.09). Despite these differences, the rate of functional independence (modified Rankin Scale Score 0-2) at 3 months was similar (TICI 2-3, 58.1% vs TICI 0-1, 53.1%; p = 0.80). CONCLUSIONS: A positive correlation between successful early reperfusion and clinical outcome could not be demonstrated for patients with M2 occlusion. Irrespective of reperfusion status, such patients have better outcomes than those with more proximal occlusions, with more than 50% achieving functional independence at 3 months.

Evaluation of interval times from onset to reperfusion in patients undergoing endovascular therapy in the Interventional Management of Stroke III trial.

BACKGROUND: Meaningful delays occurred in the Interventional Management of Stroke (IMS) III trial. Analysis of the work flow will identify factors contributing to the in-hospital delays. METHODS AND RESULTS: In the endovascular arm of the IMS III trial, the following time intervals were calculated: stroke onset to emergency department arrival; emergency department to computed tomography (CT); CT to intravenous tissue plasminogen activator start; intravenous tissue plasminogen activator start to randomization; randomization to groin puncture; groin puncture to thrombus identification; thrombus identification to start of endovascular therapy; and start of endovascular therapy to reperfusion. The effects of enrollment time, CT angiography use, interhospital transfers, and intubation on work flow were evaluated. Delays occurred notably in the time intervals from intravenous tissue plasminogen activator initiation to groin puncture (median 84 minutes) and start of endovascular therapy to reperfusion (median 85 minutes). The CT to groin puncture time was significantly shorter during working hours than after. Times from emergency department to reperfusion and groin puncture to reperfusion decreased over the trial period. Patients with CT angiography had shorter emergency department to reperfusion and onset to reperfusion times. Transfer of patients resulted in a longer onset to reperfusion time compared with those treated in the same center. Age, sex, National Institutes of Health Stroke Scale score, and intubation did not affect delays. CONCLUSIONS: Important delays were identified before reperfusion in the IMS III trial. Delays decreased as the trial progressed. Use of CT angiography and endovascular treatment in the same center were associated with time savings. These data may help in optimizing work flow in current and future endovascular trials. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424.