Phase III randomized clinical trials global distribution and funding: Trends and disparities.

e18563 Background: Phase III clinical trials (PIIICT) constitute the cornerstone of the progress and development of new therapeutic strategies. However, their complexity and costs in a scenario of limited funding sources impose important limitations in their scope and reach. Methods: We searched in clinicaltrials.gov to identify PIIICT evaluating pharmacological interventions in adjuvant, neoadjuvant and metastatic settings between 2010-2020 in breast, cervix, colorectal cancer (CRC), lung, melanoma, prostate and penile cancer. Trials identified were categorized according to disease site, funding source and world region/country (R/C). Case incidence in 2020 was collected from the IARC website. Results: Of 825 clinical trials, 72.7% were industry-sponsored (IS). Trials by R/C, not including multicentric studies (61.8%): (A) USA 76 trials, 53.9% non-industry sponsored (NIS); (B) Europe/UK 112, 59.8% NIS; (C) Asia (excluding China) 62, 27.4% NIS and (D) China 183, 43.7% NIS. There was a statistically significant association between location and funding source (p= 0.0003). NIS source was detected in higher proportion of trials ongoing in regions A and B (59%). IS was statistically less frequent in uterine cervix/penis (42.8%) and CRC (49.6%) IS was significantly higher in lung and prostate trials (both 81%) (p<0.0001). Table summarizes our results by tumor sites. We also found a statistically significant association between the incidence of malignancies in the selected primary sites and the amount of registered clinical trials, overall (p<0.0001) and IS as well (p<0.0001). The database is under expansion to include other disease sites as well as other geographic areas separately (Africa, Russia, South America, India, and Oceania). Cervix and penile results were combined given their biological and epidemiological similarities. Conclusions: There is a significant disparity between the number of clinical trials and tumor prevalences as well as among the distribution of IS trials funding.[Table: see text]

Keyboard: An R Package Suite for Early Phase Dose-finding Designs

Background: Phase I and/or I/II oncology trials are conducted to find the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) of a new drug or treatment. In these trials, for cytotoxic agents, the primary aim of the single-agent or drug-combination is to find the MTD with a certain target toxicity rate, while for the cytostatic agents, a more appropriate target is the OBD, which is often defined by consideration of toxicity and efficacy simultaneously. However, there still lacks accessible software packages to achieve both yet. Results: Objective of this work is to develop a software package that can provide tools for both MTD- and OBD-finding trials, which implements the Keyboard design for single-agent MTD-finding trials by Yan et al., the Keyboard design for drug-combination MTD-finding trials by Pan et al., and phase I/II OBD-finding method by Li et al., in a single R package, called Keyboard. For each of the designs, the Keyboard package provides corresponding functions that begins with get.boundary( . . . ) to determine the optimal dose escalation and de-escalation boundaries, that begins with select.mtd( . . . ) to select the MTD when the trial is completed, that begins with select.obd( . . . ) to select the OBD at the end of a trial, and that begins with get.oc( . . . ) to generate the operating characteristics. Conclusions: The developed Keyboard R package provides convenient tools for designing, conducting and analyzing single-agent, drug-combination and phase I/II dose-finding trials, which supports Bayesian designs of innovative dose-finding studies.

Phase Angle as a Bioelectrical Marker to Identify Sarcopenia

Background: Phase angle (PhA) has been suggested as an indicator of cellular death and nutritional status. We aimed to evaluate the performance of phase angle as a sarcopenia marker among 50 years older and determine the optimal cut-off values. Materials and Methods: A cross section of 4500 with ≥50 years were assessed in terms of sarcopenia with bioelectrical indices. Phase angle can be determined through bioelectrical impedance analysis (In Body 770). Muscle strength and physical function were measured using hand grip and 4 m walking speed. Significant determinants of sarcopenia were further analyzed with multivariate logistic regression analysis. Results: 869 patients (19.31%) were diagnosed with sarcopenia. The average PhA was 5.03 ± 0.64° (Male: 5.31 ± 0.66°; Female: 4.87 ± 0.57°). After adjusting age, gender, race, occupation, BMI, marital status, smoking, drinking, exercise, chronic disease and ADL, phase angle was still independent associated factors with sarcopenia: phase angle (OR=0.25, 95% CI: 0.203-0.308, P &lt; 0.001). Receiver operating characteristic analysis revealed that the optimal phase angle cutoff value to detect sarcopenia was ≤4.9º (AUC=0.768). Conclusions: Bioelectrical phase angle can be an useful bioelectrical marker to identify sarcopenia.

Reimbursement recommendations for cancer drugs supported by phase II evidence in Canada

Background Phase ii data are increasingly being used as primary evidence for public reimbursement for oncologic drugs. We compared the frequency of reimbursement recommendations for phase ii and phase iii submissions and assessed for variables associated with a positive or conditional recommendation. Methods We identified submissions made to the pan-Canadian Oncology Drug Review’s Expert Review Commit­tee (perc), of the Canadian Agency for Drugs and Technologies in Health, July 2011 to July 2019, that were supported only by phase ii data. We identified variables within the perc’s deliberative framework, including clinical and eco­nomic factors, associated with the final reimbursement recommendation. We conducted a multivariable analysis with logistic regression for these variables: feasibility of phase iii study, hematologic indication, and unmet need. Results We identified 139 submissions with a perc final recommendation. In 27 instances (19%), the submission had only phase ii evidence, and a positive recommendation was issued for 63% of them (the positive recommendation rate was 82% for submissions with phase iii evidence). Clinical benefit (p < 0.001), unmet need (p = 0.047), and patient alignment (p = 0.015) were associated with a positive recommendation. If a future phase iii study was deemed feasible for submissions with only phase ii evidence, then in univariable (p = 0.040) and multivariable analysis (p = 0.024), the perc was less likely to recommend reimbursement (odds ratio: 0.132). Conclusions Although more than half the oncologic submissions with phase ii data were recommended for pub­lic reimbursement, compared with submissions having phase iii data, they were less likely to be recommended. A positive or conditional recommendation was more likely if clinical benefit and alignment with patient values was demonstrated. The perc was less likely to recommend reimbursement for submissions with phase ii evidence if a phase iii trial was deemed possible.

Early pulmonary function changes associated with brigatinib initiation.

9538 Background: Phase I-III studies reported symptomatic pulmonary toxicity within the first week of initiating brigatinib in 6% patients post-crizotinib and 3% in TKI naive patients with standard dosing (90mg QD for 7 days then 180mg QD as tolerated). A prospective observational study of pulmonary function testing (PFT) on initiating brigatinib was conducted. Methods: Patients PS≤2, with resting O2 sats on RA ≥90% and Hg ≥10 g/dL, without significant heart/lung disease or steroid use initiating brigatinib 90 mg QD were eligible. PFT with DLCO, Borg dyspnea and 6-minute walk tests were performed at baseline (prior to brigatinib), and on day 2 (D2), 8 (D8), and 15 (D15) of brigatinib. D15 analyses were initially as clinically indicated but became mandatory if DLCO had not returned to baseline by D8. Peripheral blood was collected at baseline, D2 and D8 for CyTOF analysis. The primary endpoint was the incidence of Early Onset Pulmonary Events (EOPEs), defined as a DLCO reduction of ≥ 20% from baseline. An interim analysis was performed on the first 10 patients due to a higher than expected incidence of DLCO reduction. Results: D2 and D8 measurements were captured in all 10 patients, D15 in 7 patients. Ninety percent (9/10) of patients experienced DLCO reduction with nadir occurring on D2 in 4/9 and on D8 in 5/9 patients. Median DLCO nadir was −13.33% from baseline (range: −34.44 to −5.00). Three patients (30%) met EOPE criteria, all on D8, all without symptoms. Brigatinib was not held and all 10 patients escalated to 180mg on D8. Despite continued dosing, 4/9 patients recovered DLCO to baseline or above by D15 (2/3 EOPEs cases), 2/9 recovered above nadir but below baseline by D15 (1/3 EOPE case), and 3/9 did not have improvement from nadir values but no D15 assessment was performed. Dyspnea and 6-minute walk test did not correlate with DLCO changes. Patients who experienced an EOPE had significantly higher levels of activated neutrophils (pERKhi) at baseline. On the day of the EOPE event, patients who met EOPE criteria had significantly higher levels of activated neutrophils and fewer activated CD4+ effector memory T cells. Conclusions: Modest DLCO reduction occurred in 90% (9/10) patients during the first 8 days of brigatinib-dosing without associated symptoms. When rechecked on D15, DLCO improved in 100% patients (6/6) despite continued dosing and standard dose escalation at D8. Patients unlikely to tolerate even this modest, short-lived change should consider shallower step-up dosing or alternative drugs. CyTOF analysis suggests levels of pretreatment neutrophils may be a biomarker for developing EOPEs. Clinical trial information: NCT03389399 .

Stationary tissue background correction increases the precision of clinical evaluation of intra-cardiac shunts by cardiovascular magnetic resonance

We aimed to evaluate the clinical utility of stationary tissue background phase correction for affecting precision in the measurement of Qp/Qs by cardiovascular magnetic resonance (CMR). We enrolled consecutive patients (n = 91) referred for CMR at 1.5T without suspicion of cardiac shunt, and patients (n = 10) with verified cardiac shunts in this retrospective study. All patients underwent phase contrast flow quantification in the ascending aorta and pulmonary trunk. Flow was quantified using two semi-automatic software platforms (SyngoVia VA30, Vendor 1; Segment 2.0R4534, Vendor 2). Measurements were performed both uncorrected and corrected for linear (Vendor 1 and Vendor 2) or quadratic (Vendor 2) background phase. The proportion of patients outside the normal range of Qp/Qs was compared using the McNemar’s test. Compared to uncorrected measurements, there were fewer patients with a Qp/Qs outside the normal range following linear correction using Vendor 1 (10% vs 18%, p < 0.001), and Vendor 2 (10% vs 18%, p < 0.001), and following quadratic correction using Vendor 2 (7% vs 18%, p < 0.001). No patient with known shunt was reclassified as normal following stationary background correction. Therefore, we conclude that stationary tissue background correction reduces the number of patients with a Qp/Qs ratio outside the normal range in a consecutive clinical population, while simultaneously not reclassifying any patient with known cardiac shunts as having a normal Qp/Qs. Stationary tissue background correction may be used in clinical patients to increase diagnostic precision.