Early-phase Trials Research Articles

Drug approval delays in hematologic malignancies between Europe and the US and between Japan and the US: a clinical perspective.

Since novel therapeutic agents for malignancies are developed rapidly mainly in the US, the interval of approval timing between the US and other countries is an important issue. Among them, drugs for hematologic malignancies tended to have a particularly long delays in Japan, but its characteristics have not been fully understood. This study assessed the approval delays in drugs for hematologic malignancies in Japan compared with that in Europe. Using the public database of Europe, Japan and the US, we analyzed the differences in drug approval delays between Europe and the US and between Japan and US according to disease. New molecular entity drugs for hematologic malignancies that were already approved in the US and were approved from April 2010 to March 2022 in Europe or Japan were identified. The results showed the longer drug approval delays in Japan compared with that in Europe (29vs. 9.4months, median), presumably due to the lower proportion of participation in global clinical trials (37 vs. 94%). Notably, the participation rate in global clinical trials varied widely by disease in Japan, resulting in a greater difference in drug approval delays by disease. In contrast, when focusing on early phase trials, Japanese participation was uniformly very limited regardless of the disease. The current study provided data that can be used as a basis for discussion on how to improve drug approval delays in drugs for hematologic malignancies.

Review article: Externally derived control arms-An opportunity for clinical trials in inflammatory bowel disease?

One of the greatest challenges in the current IBD clinical trial landscape is, perhaps, the recruitment and retention of eligible participants. Seamless testing of promising investigational compounds is paramount to address unmet needs, but this is hindered by a number of barriers, particularly patient concerns of placebo assignment. To review the use of novel trial designs leveraging externally derived data to synthetically create control groups or augment existing ones, and to summarise the regulatory position on the use of external controls for market authorisation. We conducted a PubMed literature search without restriction using search terms such as 'external controls' and 'historical controls' to identify relevant articles. External controls are increasingly being used outside the context of cancer and rare diseases, including IBD, and increasingly recognised by regulatory bodies. Such designs, particularly in earlier phase trials, can inform key nodes in drug development and permit evaluating efficacy of interventions without combating the ethical and numerical enrolment challenges described. However, the lack of randomisation and blinding subjects them to significant bias. Groups require robust statistical and computational approaches to ensure patient-level data across groups are adequately balanced. While this approach has several pitfalls, and is not robust enough to replace traditional randomised, placebo-controlled trials, it may offer a compromise to address key research questions at a more rapid pace, with fewer patients, and lower cost.

Effect of distance to tertiary centre on enrolment of paediatric patients with relapsed or refractory cancer on early phase clinical trials in British Columbia.

Access to early phase trials for children with relapsed, refractory or progressive (RRPD) cancer is limited in Canada. Patients and families face barriers to access trials, which are poorly understood. The aims of this study were to assess availability of early phase trials and examine the impact of distance from home to study centre on trial enrolment among paediatric oncology patients with RRPD. Oncology patients ≤18 years at diagnosis who later had RRPD were identified retrospectively via registry at the only quaternary paediatric oncology centre in British Columbia (BC). We determined if distance to home, as calculated using geocoding software, was predictive of trial offer or enrolment. Between January 2015 and July 2021, 266 patients experienced 396 RRPD events. Seventy-five patients (28.2%) were eligible for an early phase trial at least once. At first eligible event, 61 patients (22.9%) were offered trial (median age 11.8 years; 69.0% male; 46.0% with CNS tumour) and thirty patients (11.3%) enrolled. Distance was not associated with odds of offer (OR 1.01, CI 0.98 to 1.05) or enrolment (OR 0.99, CI 0.95 to 1.03) on univariate or multivariable analysis adjusted for sex and disease (OR 0.93, CI 0.86 to 1.00). For offered patients, 2-year event-free survival (EFS) and overall survival (OS) were 39.1% (CI 28.0% to 54.8%) and 51.8% (CI 39.9% to 67.2%), respectively. EFS/OS did not differ with distance or enrolment, but varied by disease (EFS P = 0.002, OS P < 0.0001). Children in BC with cancer and RRPD have limited access to early phase trials. Distance was not predictive of enrolment, suggesting that families travel to access therapy.

How to expedite clinical development of oncology agents: overcoming complexities of early-phase oncology trials for ATMPs

How to expedite clinical development of oncology agents: overcoming complexities of early-phase oncology trials for ATMPs

A pan-cancer clinical platform to predict immunotherapy outcomes and prioritize immuno-oncology combinations in early-phase trials

Immunotherapy is effective, but current biomarkers forpatient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing. We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types. VIGex was developed as a continuous variable, with cutoffs selected to detect three main categories (hot, intermediate-cold and cold) based on the different inflammatory status of the tumor microenvironment. Hot tumors had the highest VIGex scores and exhibited an increased abundance of tumor-infiltrating lymphocytes as compared with the intermediate-cold and cold. VIGex scores varied depending on tumor origin and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. The predictive power of VIGex-Hot was observed in a cohort of 98 refractory solid tumor from patients treated in early-phase immunotherapy trials and its clinical performance was confirmed through an extensive metanalysis across 13 clinically annotated gene expression datasets from 877 patients treated with immunotherapy agents. Last, we generated a pan-cancer biomarker platform that integrates VIGex categories with the expression levels of immunotherapy targets under development in early-phase clinical trials. Our results support the clinical utility of VIGex as a tool toaid clinicians for patient selection and personalized immunotherapy interventions. BBVA Foundation; 202-2021 Division of Medical Oncology and Hematology Fellowship award; Princess Margaret Cancer Center.

Item response theory in early phase clinical trials: Utilization of a reference model to analyze the Montgomery-Åsberg Depression Rating Scale.

In clinical trials, Montgomery-Åsberg Depression Rating Scale (MADRS) questionnaire data are added up to total scores before analysis, assuming equal contribution of each separate question. Item Response Theory (IRT)-based analysis avoids this by using individual question responses to determine the latent variable (ψ), which represents a measure of depression severity. However, utilization of IRT in early phase trials remains difficult, because large datasets are needed to develop IRT models. Therefore, we aimed to evaluate the application and assumptions of a reference IRT model for analysis of an early phase trial. A cross-over, placebo-controlled study investigating the effect of intravenous racemic ketamine on MADRS scores in patients with treatment-resistant major depressive disorder was used as a case study. One hundred forty-seven MADRS responses were measured in 17 patients at five timepoints (predose to 2 weeks after dosing). Two reference IRT models based on different patient populations were selected from literature and used to determine ψ, while testing multiple approaches regarding assumed data distribution. Use of ψ versus total score to determine treatment effect was compared through linear mixed model analysis. Results showed that determined ψ values did not differ significantly between assumed distributions, but were significantly different when changing reference IRT model. Estimated treatment effect size was not significantly affected by chosen approach nor reference population. Finally, increased precision to determine treatment effect was achieved by using IRT versus total scores. This demonstrates the usefulness of reference IRT model application for analysis of questionnaire data in early phase clinical trials.

Immunotherapy and Transarterial Radioembolization Combination Treatment for Advanced Hepatocellular Carcinoma.

The efficacy and safety of combined immunotherapy and transarterial radioembolization (TARE) were suggested in preclinical and early-phase trials, but these were limited by small sample sizes. We sought to compare the efficacy of combined therapy and immunotherapy alone in patients with advanced hepatocellular carcinoma (HCC). The National Cancer Database was used to identify patients with advanced HCC diagnosed between January 1, 2017, and December 31, 2019. We included patients who received combined therapy or immunotherapy alone as first-line treatment. Multivariable logistic regression was conducted to determine predictors of combined therapy. Kaplan-Meier and Cox regression approaches were used to identify predictors of overall survival and to compare hazards of mortality between the patients who received combined therapy and immunotherapy alone. Of 1,664 eligible patients with advanced-stage HCC, 142 received combined TARE/immunotherapy and 1,522 received immunotherapy alone. Receipt of combination therapy was associated with care at an academic center and inversely associated with racial/ethnic minority status (Hispanic and Black individuals). The median overall survival was significantly higher in the combination group than in the immunotherapy alone group (19.8 vs 9.5 months). In multivariable analysis, combined therapy was independently associated with reduced mortality (adjusted hazard ratio 0.50, 95% confidence interval: 0.36-0.68, P < 0.001). Results were consistent across subgroups and in sensitivity analyses using propensity score matching and inverse probability of treatment weighting. The combination of TARE and immunotherapy was associated with improved survival compared with immunotherapy alone in patients with advanced-stage HCC. Our findings underly the importance of large clinical trials evaluating combination therapy in these patients.

Neoadjuvant Immunotherapy for Localized Pancreatic Cancer: Challenges and Early Results.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease due to its late presentation and tendency to recur early even after optimal surgical resection. Currently, there are limited options for effective systemic therapy. In addition, PDAC typically generates an immune-suppressive tumor microenvironment; trials of immunotherapy in metastatic PDAC have yielded disappointing results. There is considerable interest in using immunotherapy approaches in the neoadjuvant setting in order to prime the immune system to detect and prevent micrometastatic disease and recurrence. A scoping review was conducted to identify published and ongoing trials utilizing preoperative immunotherapy. In total, 9 published trials and 27 ongoing trials were identified. The published trials included neoadjuvant immune checkpoint inhibitors, cancer vaccines, and other immune-modulating agents that target mechanisms distinct from that of immune checkpoint inhibition. Most of these are early phase trials which suggest improvements in disease-free and overall survival when combined with standard neoadjuvant therapy. Ongoing trials are exploring various combinations of these agents with each other and with chemotherapy and/or radiation. Rational combination immunotherapy in addition to standard neoadjuvant therapy has the potential to improve outcomes in PDAC, but further clinical trials are needed, particularly those which utilize an adaptive trial design.

Circulating tumour DNA (ctDNA) burden quantified through low-pass whole genome sequencing as an early pharmacodynamic biomarker of therapeutic response in patients enrolled on phase 1 trials.

23 Background: Early phase trials are conducted to determine the recommended dose and safety of an investigational therapy. Targeted therapies and immunotherapy may not always have dose-dependent toxicities. Therefore, dose finding is increasingly reliant on optimal biological dosing. Pharmacodynamic biomarkers are increasingly important to demonstrate proof of concept. Using ctDNA allows for dynamic and early tumour assessments compared to imaging. We sought to evaluate ctDNA as an early pharmacodynamic biomarker of therapeutic response. Methods: Patients (pts) enrolled on phase 1 trials at the National Cancer Centre Singapore were prospectively consented to collect serial blood samples at defined timepoints (pre-treatment, mid-cycle 1, end of cycle 1, and with subsequent imaging evaluations). ctDNA burden was quantified using low pass whole genome sequencing (lpWGS) with both established (ichorCNA) and novel (cell-free DNA degradation) bioinformatic analyses of ctDNA burden, and targeted panel sequencing. Early kinetics of ctDNA burden prior to imaging evaluation was evaluated as response (reduction in ctDNA burden) versus progression (increase in ctDNA burden). Results: Between May 2021 to Oct 2022, 68 plasma samples (median 3, range 2-5) were collected from 22 pts. Median age was 56 years (range 37-77) and 73% were male. Pts were enrolled on trials of targeted therapy (55%), immunotherapy (40%) or combinations of both (5%). Common tumour types were lung (36%), colorectal (23%) and pancreatic (9%) cancer. Best response on phase 1 trial as per imaging and RECIST v1.1 was partial response (PR) in 9%, stable disease (SD) in 45%, progressive disease (PD) in 27% and not evaluable (NE; taken off trial early due to toxicity) in 18%. Quantification of ctDNA burden using cell-free DNA fragment length pattern demonstrated enhanced limit of detection in detecting baseline ctDNA compared to cell-free DNA copy number profile based ichorCNA method (100% vs 59%). For pts on targeted therapies, early kinetics of ctDNA burden indicated ctDNA response in 9/13 pts, with subsequent imaging showing PR (n=2), SD (n=2), PD (n=2) or NE (n=3). In the remaining 4/13 pts on targeted therapies with early ctDNA progression, subsequent imaging showed SD (n=3) or NE (n=1). For pts on immunotherapy, early ctDNA progression was seen in 8/10 pts, with subsequent imaging showing SD (n=5) and PD (n=3). Patient enrolment and sample analysis is ongoing to further validate these initial findings and updated data will be presented. Conclusions: Early ctDNA evaluation via lpWGS may represent an early pharmacodynamic biomarker of therapeutic response. ctDNA has the potential to provide early proof of concept, particularly for targeted therapies, that may influence subsequent decisions for dose determination.

Safety analysis of pemigatinib leveraging the US Food and Drug administration adverse event reporting system.

Background: Cholangiocarcinoma (CCA) is a highly lethal and aggressive epithelial tumor of the hepatobiliary system. A poor prognosis, propensity for relapse, low chance of cure and survival are some of its hallmarks. Pemigatinib, the first targeted treatment for CCA in the United States, has been demonstrated to have a significant response rate and encouraging survival data in early-phase trials. The adverse events (AEs) of pemigatinib must also be determined. Objective: To understand more deeply the safety of pemigatinib in the real world through data-mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: Disproportionality analysis was employed in a retrospective pharmacovigilance investigation to identify the AEs linked to pemigatinib use as signals. Data were collected between 1 January 2020 to 30 June 2022. Four data-mining methods (proportional reporting odds ratio; proportional reporting ratio; Bayesian confidence propagation neural networks of information components; empirical Bayes geometric means) were used to calculate disproportionality. Results: A total of 203 cases using pemigatinib as the prime-suspect medication were found in our search, which involved 99 preferred terms (PTs). Thirteen signals of pemigatinib-induced AEs in seven System Organ Classes were detected after confirming the four algorithms simultaneously. Nephrolithiasis was an unexpected significant AE not listed on the drug label found in our data-mining. Comparison of the differences between pemigatinib and platinum drugs in terms of 33PTs revealed that 13PTs also met the criteria of the four algorithms. Ten of these PTs were identical to those compared with all other drugs, in which (excluding a reduction in phosphorus in blood) other PT signal values were higher than those of all other drugs tested. However, comparison of the differences between pemigatinib and infigratinib in terms of the 33PTs revealed no significant signals in each algorithm method. Conclusion: Some significant signals were detected between pemigatinib use and AEs. PTs with apparently strong signals and PTs not mentioned in the label should be taken seriously.

PubPredict: Prediction of progression and survival in oncology leveraging publications and early efficacy data.

In oncology/hematology early phase clinical trials, efficacies were often observed in terms of response rate, depth, timing, and duration. However, the true clinical benefits that eventually support registrational purpose are progression-free survival (PFS) and/or overall survival (OS), the follow-up of which are typically not long enough in early phase trials. This gap imposes challenges in strategies for late phase drug development. In this article, we tackle the question by leveraging published study to establish a quantitative link between early efficacy outcomes and late phase efficacy endpoints. We used solid tumor cancer as disease model. We modeled the disease course of a RECISTv1.1 assessed solid tumor with a continuous Markov chain (CMC) model. We parameterize the transition intensity matrix of a CMC model based on published aggregate-level summary statistics, and then simulate subject-level time-to-event data. The simulated data is shown to have good approximation to published studies. PFS and/or OS could be predicted with the transition intensity matrix modified given clinical knowledge to reflect various assumptions on response rate, depth, timing, and duration. The authors have built a R shiny application named PubPredict, the tool implements the algorithm described above and allows customized features including multiple response levels, treatment crossover and varying follow-up duration. This toolset has been applied to advise phase 3 trial design when only early efficacy data are available from phase 1 or 2 studies.

Clinical outcome assessment trends in clinical trials-Contrasting oncology and non-oncology trials.

Clinical outcome assessments (COAs) are key to patient-centered evaluation of novel interventions and supportive care. COAs are particularly informative in oncology where a focus on how patients feel and function is paramount, but their incorporation in trial outcomes have lagged that of traditional survival and tumor responses. To understand the trends of COA use in oncology and the impact of landmark efforts to promote COA use, we computationally surveyed oncology clinical trials in ClinicalTrials.gov comparing them to the rest of the clinical research landscape. Oncology trials were identified using medical subject heading neoplasm terms. Trials were searched for COA instrument names obtained from PROQOLID. Regression analyses assessed chronological and design-related trends. Eighteen percent of oncology interventional trials initiated 1985-2020 (N = 35,415) reported using one or more of 655 COA instruments. Eighty-four percent of the COA-using trials utilized patient-reported outcomes, with other COA categories used in 4-27% of these trials. Likelihood of COA use increased with progressing trial phase (OR = 1.30, p < 0.001), randomization (OR = 2.32, p < 0.001), use of data monitoring committees (OR = 1.26, p < 0.001), study of non-FDA-regulated interventions (OR = 1.23, p = 0.001), and in supportive care versus treatment-focused trials (OR = 2.94, p < 0.001). Twenty-six percent of non-oncology trials initiated 1985-2020 (N = 244,440) reported COA use; they had similar COA-use predictive factors as oncology trials. COA use increased linearly over time (R = 0.98, p < 0.001), with significant increases following several individual regulatory events. While COA use across clinical research has increased over time, there remains a need to further promote COA use particularly in early phase and treatment-focused oncology trials.

A Multi-Arm Two-Stage (MATS) design for proof-of-concept and dose optimization in early-phase oncology trials

The Project Optimus initiative by the FDA's Oncology Center of Excellence is widely viewed as a groundbreaking effort to change the status quo of conventional dose-finding strategies in oncology. Unlike in other therapeutic areas where multiple doses are evaluated thoroughly in dose ranging studies, early-phase oncology dose-finding studies are characterized by the practice of identifying a single dose, such as the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D). Following the spirit of Project Optimus, we propose an Multi-Arm Two-Stage (MATS) design for proof-of-concept (PoC) and dose optimization that allows the evaluation of two selected doses from a dose-escalation trial. The design assesses the higher dose first across multiple indications in the first stage, and adaptively enters the second stage for an indication if the higher dose exhibits promising anti-tumor activities. In the second stage, a randomized comparison between the higher and lower doses is conducted to achieve PoC and dose optimization. A Bayesian hierarchical model governs the statistical inference and decision making by borrowing information across doses, indications, and stages. Our simulation studies show that the proposed MATS design yield desirable performance. An R Shiny application has been developed and made available at https://matsdesign.shinyapps.io/mats/.

Identifying patient-valued outcomes for use in early phase trials of ocular surface disease interventions

BackgroundPatient-reported outcomes (PROs) can be used to evaluate the impact of dry eye symptoms (DES) on daily life. Early-phase clinical trials provide an opportunity to evaluate PRO strategies. Existing measures identified through systematic review omitted important concepts that mattered to patients. The aim of our work was to develop a conceptual map of DES and assess the relative importance of identified concepts. MethodsWeb-based group concept mapping software was used to develop a conceptual map. This semi-quantitative mixed-methods approach consists of three stages 1) statement generation, 2) thematic sorting, 3) rating of statements for importance [1 (not important), 2 (important), 3 (very important)] and relevance [1 (not my experience), 2 (sometimes my experience); 3 (definitely my experience)]. Thirty-nine participants were recruited from two UK-based patient support groups (British Sjögren's Syndrome Association, PemFriends). Three withdrew, two for health reasons and one struggled with the web-based format. Results125 statements and six thematic clusters were generated. The Environmental Impacts cluster scored highest for importance (2.45), followed by Pain and Discomfort (2.35), Eye Treatments (2.32), Daily Impact (2.07), Psychosocial Issues (1.78) and Miscellaneous (1.78). Mapping statements against existing PRO measures confirmed a number of important missing issues including the impact of ‘UV levels’ (2.50), hot dry weather (2.33), the temporal aspects of pain (2.64), and issues with night-driving (2.59). ConclusionsGroup concept mapping identified important issues for people living with DES not currently captured by existing PROs, highlighting the need for additional PRO items to be considered for use in clinical trials.

Pattern recognition receptor agonists in pathogen vaccines mediate antitumor T-cell cross-priming

BackgroundCancer immunotherapies are generally effective in patients whose tumors contain a priori primed T-cells reactive to tumor antigens (TA). One approach to prime TA-reactive T-cells is to administer immunostimulatory molecules,...

Looking ahead in early-phase trial design to improve the drug development process: examples in oncology

BackgroundClinical trial design must consider the specific resource constraints and overall goals of the drug development process (DDP); for example, in designing a phase I trial to evaluate the safety of a drug and recommend a dose for a subsequent phase II trial. Here, we focus on design considerations that involve the sequence of clinical trials, from early phase I to late phase III, that constitute the DDP.MethodsWe discuss how stylized simulation models of clinical trials in an oncology DDP can quantify important relationships between early-phase trial designs and their consequences for the remaining phases of development. Simulations for three illustrative settings are presented, using stylized models of the DDP that mimic trial designs and decisions, such as the potential discontinuation of the DDP.ResultsWe describe: (1) the relationship between a phase II single-arm trial sample size and the likelihood of a positive result in a subsequent phase III confirmatory trial; (2) the impact of a phase I dose-finding design on the likelihood that the DDP will produce evidence of a safe and effective therapy; and (3) the impact of a phase II enrichment trial design on the operating characteristics of a subsequent phase III confirmatory trial.ConclusionsStylized models of the DDP can support key decisions, such as the sample size, in the design of early-phase trials. Simulation models can be used to estimate performance metrics of the DDP under realistic scenarios; for example, the duration and the total number of patients enrolled. These estimates complement the evaluation of the operating characteristics of early-phase trial design, such as power or accuracy in selecting safe and effective dose levels.

Optimizing the Design of Clinical Trials to Evaluate the Efficacy of Function-Promoting Therapies.

Several candidate molecules that may have application in treating physical limitations associated with aging and chronic diseases are in development. Challenges in the framing of indications, eligibility criteria, and endpoints and the lack of regulatory guidance have hindered the development of function-promoting therapies. Experts from academia, pharmaceutical industry, National Institutes of Health (NIH), and Food and Drug Administration (FDA) discussed optimization of trial design including the framing of indications, eligibility criteria, and endpoints. Mobility disability associated with aging and chronic diseases is an attractive indication because it is recognized by geriatricians as a common condition associated with adverse outcomes, and it can be ascertained reliably. Other conditions associated with functional limitation in older adults include hospitalization for acute illnesses, cancer cachexia, and fall injuries. Efforts are underway to harmonize definitions of sarcopenia and frailty. Eligibility criteria should reconcile the goals of selecting participants with the condition and ensuring generalizability and ease of recruitment. An accurate measure of muscle mass (eg, D3 creatine dilution) could be a good biomarker in early-phase trials. Performance-based and patient-reported measures of physical function are needed to demonstrate whether treatment improves how a person lives, functions, or feels. Multicomponent functional training that integrates training in balance, stability, strength, and functional tasks with cognitive and behavioral strategies may be needed to translate drug-induced muscle mass gains into functional improvements. Collaborations among academic investigators, NIH, FDA, pharmaceutical industry, patients, and professional societies are needed to conduct well-designed trials of function-promoting pharmacological agents with and without multicomponent functional training.

Evaluation of hyperprogression in patients with sarcoma treated with targeted therapy and/or immunotherapy in early-phase clinical trials.

11560 Background: Hyper-progressive disease (HPD) is an adverse outcome with acceleration of tumor growth, often accompanied by clinical deterioration. This phenomenon is described with immunotherapy (IT) but its incidence in sarcoma and/or in the context of targeted therapy (TT) remains unknown. Tumor growth rate (TGR) allows for dynamic evaluation of tumor volume change over time and may complement RECIST. We evaluated HPD in sarcoma patients (pts) treated in early-phase trials by assessing TGR and describing their subsequent clinical outcomes. Methods: We retrospectively reviewed medical records from advanced soft tissue sarcoma (STS) pts enrolled in early phase trials at the Princess Margaret Cancer Centre between January 2012 and December 2022. TGR was calculated based on tumor measurements taken at pre-baseline, baseline, and on-treatment CT scans. We used the Champiat formula (Clin Cancer Res 2017) to calculate TGR ratio. Primary objective was to describe the incidence of HPD, defined as a TGR ratio of &gt; 50%. Secondary objective was to investigate the correlation between HPD with progression-free survival (PFS) and overall survival (OS). Results: We identified a total of 192 pts involved in STS early phase trials from 2012-2022. Most common histology was leiomyosarcoma seen in 72 pts. Eighty-four pts (43.8%) received TT, 75 (39%) pts received IT-based, and the rest had combined TT/IT regimens (n = 33, 17.2%). The incidence of HPD was 6.8% (n = 13), including IT-based (n = 9) and non-IT-based (n = 4) regimens. HPD was associated with a worse PFS, and OS compared to non-HPD pts (median PFS 1.6m vs 4.6m HR: 5.5, 95%CI 2.8-10.6, P &lt; 0.001; median OS 5.5 vs 16.1 months; HR: 3.7, 95%CI: 2.0-7.1, P &lt; 0.001). On multivariable analysis, only IT was significantly associated with HPD (OR 3.9, 95%CI: 1.1-13, P = 0.021). There was no association between HPD and new lesions or sarcoma histology subtype. Conclusions: HPD occurs in a small subset of sarcoma patients undergoing clinical trials with TT or IT. Exploring TGR provides clinically meaningful data as it pertains to HPD as it predicts OS and PFS in sarcoma patients undergoing early-phase clinical trials.

Examining clinical trial eligibility for oncology patients with human immunodeficiency virus (HIV): A global cross-sectional analysis.

6554 Background: People Living with HIV (PLWH) are at higher risk of developing cancer, and malignancy is the most common cause of death in PLWH in the USA . In 2017 a joint research statement by the American Society of Clinical Oncology and Friends of Cancer Research (ASCO-FCR) examined trial inclusivity, stating PLWH should not be excluded from clinical trials due to HIV positivity alone without justification. It also provided guidance for designing trial inclusion criteria using CD4 count, use of antiretroviral therapy (ART), ART-related drug interactions and HIV-associated complications. To review incorporation of ASCO-FCR recommended wording and current compliance, we examined global eligibility for PLWH in clinical trials. Methods: Clinicaltrials.gov was searched on 15 Nov 2022 for open and recruiting trials worldwide, using terms ‘advanced cancer’ and ‘interventional’. Trials lacking systemic treatment were deemed non-evaluable. Evaluable studies’ eligibility criteria were manually reviewed for specific criterion excluding PLWH or diagnosis/history of immunodeficiency (outright exclusion). Therapy type and study phase were captured and their relationships to outright exclusion were significance tested using odds ratios (OR) with 95% confidence intervals (CI). Results: The search rendered 2388 evaluable clinical trials. Eligibility criteria outrightly excluded PLWH in 1194 (50%) , of which 1113 (93%) were early phase trials (Phase 0-2). 206 evaluable trials (8.6%) permitted inclusion of PLWH aligned with ASCO-FCR guidance, including 3 (0.1%) with a cohort for PLWH. AIDS-defining illness was an exclusion criterion in 27 trials (1%), and specific interactions to ART in 10 (0.4%). Early phase trials had a significantly higher likelihood of outright exclusion of PLWH when compared with late phase trials (OR 2.98; 95% CI 2.16-4.11, p&lt;0.0001). Trials investigating immunomodulatory agents were more likely to outrightly exclude PLWH than those investigating other drug classes (OR 1.60; 95% CI 1.36-1.88, p&lt;0.0001). Criteria which may implicitly exclude PLWH were identified, including 204 (8.5%) citing active/chronic/severe infection, 189 (7.9%) listing CYP and P-gp interaction criteria and 3 (0.1%) "immunodeficiency". Conclusions: Despite adequate time to incorporate, most currently recruiting oncology clinical trials do not use ASCO-FCR guidance for including PLWH. Half of evaluated trials excluded PLWH without reason. Early phase and immunotherapy trials were significantly more likely to exclude PLWH without exception, despite data to support immunotherapy use for PLWH. Covert inclusionary barriers exist in criteria that lack HIV-specific guidance, and this may further exclude PLWH. Consideration of recommendations and guidance in eligibility criteria for oncology trials is critical to address current inequities in care for PLWH and cancer.

Baseline symptom, health status, and health utilities in patients in early-phase clinical trials combining immune checkpoint blockade with other anticancer therapies.

12117 Background: The overall goal of our prospective and longitudinal study (NCI R01CA242565) is to examine the use of patient report to evaluate symptomatic adverse events associated with combination treatment including at least one immune checkpoint inhibitor in early-stage clinical trials. We present here the baseline symptom, health status and utilities in patients prior to trial start, and their association with clinical factors. Methods: Patients scheduled to start an early-phase trial of combination treatment with at least one immune checkpoint inhibitor and who had not received clinical trial-related treatment completed the validated MD Anderson Symptom Inventory - Immunotherapy (0-10, higher scores = worse severity) and the validated EuroQoL-5 dimensions questionnaire including a visual analog scale (EQ5D VAS) (0-100, higher scores = better health status) and health utility items (e.g., self-care, mobility). Clinical data were extracted from the EMR. Statistical tests included Spearman’s correlation coefficients. Results: At baseline prior to start of trial-related treatment, 38% of patients (N = 164; median age = 60 y; 52% male; 85% White; 17% ECOG PS 0, 89% ECOG PS 1, 3% ECOG PS 2) experienced at least 1 severe symptom (≥7 on 0-10 scale). The most frequent severe baseline symptoms were pain (21% of patients), fatigue (17%), disturbed sleep (15%), drowsiness (12%), lack of appetite (10%), distress (10%), and pain in the abdomen (10%). Less than 2% of pts experienced severe immunotherapy-specific symptoms of rash, fever/chills and swelling of the hands and feet at baseline. Moderate-severe symptom-related interference (≥4 on 0-10 scale) was worst for activity (40% of patients), work (38%), and enjoyment of life (30%). For the EQ5D health utility dimensions, patients reported the most problems with pain or discomfort (75%) and fewest problems with self-care (10%). Worse composite symptom severity (P = 0.013) and worse problems with activity (P = 0.001) and pain (P = 0.012) were associated with worse and higher ECOG PS. Worse symptom severity (-0.54, P &lt; 0.001), symptom interference with activity- (-0.57, P &lt; 0.001) and mood- (-0.42, P &lt; 0.001) related functioning were associated inversely with superior health status. Worse symptom interference with activity-related functioning was linked with lower concurrent lymphocyte counts (P = 0.01), hemoglobin (P = 0.01) and serum albumin (P = 0.004) levels and higher platelet (P = 0.02) counts. Conclusions: Patients in early-phase trials that combine immunotherapy with other anti-cancer therapies may experience severe symptom burden and symptom interference with functioning, even at baseline prior to treatment start. Thus, it is important to baseline symptoms to fully understand the impact of combination treatments including checkpoint inhibitors in early-stage clinical trials.