Low Accrual Research Articles

Phase I Study of Bortezomib, Fludarabine, and Melphalan, with or without Total Marrow Irradiation as Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk or Relapsed/Refractory Multiple Myeloma

Though outcomes of patients with multiple myeloma (MM) have improved, cure remains elusive. Allogeneic hematopoietic stem cell transplantation (allo-sCT) is associated with a lower relapse rate, but its role is hindered due to toxicities. We hypothesized that targeted total body irradiation in the form of total marrow irradiation (TMI) could safely facilitate allo-SCT via an improved toxicity profile. Therefore, we conducted a phase I study to investigate the safety and feasibility of a bortezomib (BTZ), fludarabine (FLU), and melphalan (MEL), with or without TMI, prior to allo-SCT for patients with high-risk (HR) or relapsed/refractory (R/R) MM. Between 2012 and 2018 this study enrolled patients with HR or R/R MM on one of two strata, each comprising BTZ dose-escalation cohorts. Patients aged 18-60 with no prior radiation (RT) received TMI at 900 cGy (in 6 fractions delivered twice-daily), FLU, and MEL conditioning, with BTZ added in the second cohort (stratum I). Patients aged 18-70 with prior RT received FLU, MEL, and BTZ, without TMI (stratum II). The primary endpoint was feasibility of escalating doses of BTZ, with or without TMI, defined using a 3+3 design. Dose-limiting toxicity (DLT) was defined as any Grade 3+ Bearman toxicity or prolonged CTCAE v4.0 Grade 4+ neutropenia. Secondary endpoints included treatment response, time to neutrophil and platelet engraftment, incidence of acute (a) and chronic (c) graft-versus-host disease (GVHD), progression-free-survival (PFS), and overall survival (OS). Eight patients were enrolled on stratum I. One of three patients in the first cohort of stratum I experienced DLT, which led to expansion to three more patients with no DLT. Cohort 2 enrolled only 2 patients due to low accrual, with BTZ added at 0.5 mg/m2; neither experienced DLT. Nine patients were enrolled on stratum II. Three patients were enrolled on cohort 1 (BTZ 0.5 mg/m2) and none experienced DLT. Three were enrolled on cohort 2 (bortezomib 0.7 mg/m2), and one experienced DLT. Therefore, the cohort expanded to three more patients. One more patient experienced DLT and 0.5 mg/m2 was considered the maximum tolerated dose. There were no primary or secondary graft failures. Complete response was achieved in 7 and 4 patients in strata I and II, respectively. Median follow-up for all patients was 30.7 months (mos) and was 99.8 mos for surviving patients. Median overall survival (OS) on strata I and II were 44.5 mos and 21.6 mos, respectively. Median PFS on strata I and II were 18.1 mos and 8.9 mos, respectively. In strata I, 5 patients developed Grade 2+ aGVHD and 8 developed extensive cGVHD. In strata II, 4 patients developed Grade 2+ aGVHD and 6 developed extensive cGVHD. The TMI 900 cGy, FLU, and MEL conditioning regimen is considered safe as conditioning for allo-SCT and may warrant further investigation due to favorable response rates and survival; the conditioning regimen of FLU, MEL, and BTZ (0.7 mg/m2) is associated with unacceptable toxicities.

Preoperative Carbon Ion Radiotherapy (CIRT) with Chemotherapy in Resectable and Borderline Resectable Pancreatic Adenocarcinoma (PCa): A Multicenter Prospective Phase II Clinical Study (Pioppo Study NCT 03822936)

Preoperative chemoradiation and surgery may improve survival for resectable (Re) or borderline resectable (BRe) PCa. However, there is a lack of evidence regarding the feasibility of combined chemotherapy (CT) and CIRT in the neoadjuvant setting for Re/BRe PCa, especially in the Caucasian population. To assess the safety and efficacy of this challenging combination, we designed a prospective multicentric single-arm phase II trial MATERIALS/METHODS: PIOPPO trial was opened in September 2014. We prospectively treated patients with Re/BRe Pca with a neoadjuvant CT (3 cycles of FOLFIRINOX) and a short-course of CIRT (38.4 GyRBE, 8 fractions, 4 fractions per week) planned with 4D-imaging and delivered with breath-gating and rescanning. Four-6 weeks after CIRT patients (pts) received surgery followed by adjuvant-CT (FOLFIRINOX for 9 or gemcitabine for 6 cycles). After each step patients underwent a re-staging. The primary endpoint was Local Progression Free Survival (LPFS). Fourteen (47%) of the foreseen 30 pts were evaluated for enrollment. There were 4 screening failures for duodenum infiltration. Ten Caucasian pts (M = 7; 70%; F = 3;30%) with a median age of 65.5 (range:46-76) started the treatment. There were four (40%) Re and 6 (60%) BRe Pca. 100% of the Re and 50% of BRe PCa completed the planned combined treatment for a total of 7 (70%) pts. Three (30%) pts developed systemic progression after CT and underwent palliative care (2 cases) or a second line of CT (1 case). With regards to toxicities, we recorded 2 (28.6%) cases of neutropenia during CT, none acute CIRT toxicity and one (14%) case of intra-operative ulceration of the gastro-enteric anastomosis. Moreover, we reported one (14%) case of fatal liver failure due to portal vein stenosis due to the combo approach (CT+CIRT+surgery). Six (86%) pts experienced Tumor Regression Grade (TRG) = 2 according to the College of American Pathologists (CAP) and 1 (14%) a TRG = 3. At the last follow-up, among pts who completed the scheme, 2 (28%) are currently alive and disease-free at 57 and 49 months, respectively. With a median follow-up of 13 months, the median LPFS was 9.4 months (range:4.9-57), with 1 case (14%) of systemic progression and 3 cases (43%) of local recurrence + systemic progression. The study was early closed due to low accrual in August 2022. Although the small sample size limits the interpretation of the endpoints, a neoadjuvant approach combining CT and a short course of CIRT for resectable/borderline Pca seems feasible. Liver toxicity was similar to the Japanese series and needs to deepen investigation on the vascular dose constraints and surgical techniques. Considering the worse outcomes, a better selection of patients to treat also with a centralized imaging interpretation is mandatory.

Impact of COVID-19 pandemic mitigation strategies on industry and NCI cancer treatment trials.

1565 Background: The onset of the COVID-19 pandemic resulted in major disruptions in enrollment and conduct of cancer clinical trials. In response, regulators allowed modifications to traditional trial processes to enable clinical research and care to continue. The American Society of Clinical Oncology and Friends of Cancer Research established a task force to evaluate how sponsors perceived the impact of these mitigation strategies on data quality and overall trial conduct. Methods: The study used a survey and live interviews of industry and National Cancer Institute (NCI) cooperative group sponsors of cancer treatment trials. Sponsors with trials active in the United States from January 2015-May 2022 were eligible. We assessed perceived impacts of the pandemic on protocol deviations, types of mitigation strategies, trial closures, dropouts, adverse events (AEs), and data integrity. Descriptive statistics were used for survey data summaries. Key findings from semi-structured interviews were described by theme. Results: Of forty-one eligible sponsors, 20 (49%; 15/36 industry and 5/5 cooperative group) completed the survey; eleven (55%; 7/15 industry and 4/5 cooperative group) were interviewed. Sixty percent of sponsors reported large portfolios (>10 trials) of phase II and/or phase III trials. The most widely adopted mitigation strategies were remote distribution of oral anticancer therapies (70%), remote consenting (65%), and remote symptom monitoring for AEs (65%). The proportion of sponsors reporting a “substantial” increase in protocol deviations compared to the pre-pandemic period dropped from 42% in the initial wave (March-April 2020) to 16% thereafter. Sponsors primarily reported “no change” in trial drop-out rates (77%), the number of trials closed due to low accrual (90%), or rates of AEs (81%) at any point during the pandemic. Overall, most (83%) respondents reported the pandemic had “minimal” (14) or “no” impact (1) on data integrity. In interviews, many sponsors reported persistent time delays in data entry related to labor shortages at sites. Conclusions: This study represents the first systematic evaluation of clinical trial sponsors about the impact of the COVID-19 pandemic on the conduct of cancer clinical trials. Remote clinical trial conduct mitigation strategies were broadly adopted. Despite an observed increase in protocol deviations, most sponsors reported the pandemic had minimal or no impact on data integrity. The COVID-19 pandemic impacted how cancer clinical trials were performed and has likely accelerated a trend towards greater flexibility in trial conduct that was already emerging, with potential benefits of reduced burden and improved access for patients and sites . Future work is planned to further quantify the impact of the pandemic and trial mitigation strategies on the quality of trial data both overall and for historically underrepresented patient groups.

A framework for setting enrollment goals to ensure participant diversity in sponsored clinical trials in the United States

BackgroundDiversity in clinical trials (CTs) has the potential to improve health equity and close health disparities. Underrepresentation of historically underserved groups compromises the generalizability of trial findings to the target population, hinders innovation, and contributes to low accrual. The aim of this study was to establish a transparent and reproducible process for setting trial diversity enrollment goals informed by the disease epidemiology. MethodAn advisory board of epidemiologists with expertise in health disparities, equity, diversity, and social determinants of health was convened to evaluate and strengthen the initial goal-setting framework. Data sources used were the epidemiologic literature, US Census, and real-world data (RWD); limitations were considered and addressed where appropriate. A framework was designed to safeguard against the underrepresentation of historically medically underserved groups. A stepwise approach was created with Y/N decisions based on empirical data. ResultsWe compared race and ethnicity distributions in the RWD of six diseases from Pfizer's portfolio chosen to represent different therapeutic areas (multiple myeloma, fungal infections, Crohn's disease, Gaucher disease, COVID-19, and Lyme disease) to the distributions in the US Census and established trial enrollment goals. Enrollment goals for potential CTs were based on RWD for multiple myeloma, Gaucher disease, and COVID-19; enrollment goals were based on the Census for fungal infections, Crohn's disease, and Lyme disease. ConclusionsWe developed a transparent and reproducible framework for setting CT diversity enrollment goals. We note how limitations due to data sources can be mitigated and consider several ethical decisions in setting equitable enrollment goals.

Phase 2 open label study of durvalumab with neoadjuvant chemotherapy in variant histology bladder cancer.

524 Background: The immune-responsive nature of bladder cancer has made it an active area of interest for novel applications of immune checkpoint inhibitors (ICIs), with multiple ICI agents approved in the metastatic setting and ongoing perioperative trials. Variant histology urothelial carcinoma is a rare, heterogenous, and aggressive disease category associated with poor prognosis and response to standard therapies. This investigator-initiated phase 2 trial explored the addition of durvalumab to neoadjuvant chemotherapy (NAC) in the setting of variant histology MIBC. Methods: Patients with cT2-T4a, N0-N1, M0 histologically-confirmed bladder cancer of variant histology who were candidates for platinum-based NAC and radical cystectomy were eligible for the study. Enrolled patients received durvalumab with each cycle of investigator’s choice of platinum NAC (ddMVAC, cisplatin/gemcitabine, or carboplatin/gemcitabine). The primary objective was to determine the safety and tolerability of each study treatment as assessed by the total number of adverse events of grade 3 or higher, judged by the investigator as probably or definitely related to durvalumab. Secondary objective was to determine the percent of subjects post neoadjuvant chemo immunotherapy who achieve tumor stage of pT2N0M0 or better at cystectomy. Target accrual was 24 patients. Results: Six patients were enrolled (the study closed early due to low accrual). Median age was 72 years, 17% were women, 67% were white, 33% were Asian. 50% received ddMVAC and 50% received carboplatin/gemcitabine. All patients completed the planned cycles of NAC and durvalumab (4 cycles) and 5/6 proceeded to radical cystectomy (one patient declined cystectomy). Three patients experienced a Grade 3 AE that was assessed by the investigator to be related to treatment (table). One patient with sarcomatoid and glandular histology had pathological complete response and one patient with papillary and 10% squamous had pT2N0 at cystectomy. Conclusions: The addition of durvalumab to platinum NAC for patients with variant-histology muscle invasive bladder cancer demonstrates a reasonable safety and tolerability profile. Further investigation into this combination is warranted in larger scale trials. Clinical trial information: NCT03912818 . [Table: see text]

Outcomes of achieving lupus low disease activity state and damage accrual in childhood-onset systemic lupus erythematosus.

At present, the treat-to-target approach has been proposed with the lupus low disease activity state (LLDAS) as an achievable target. To determine damage accrual and baseline clinical characteristics associated with achieving LLDAS within 12months of treatment in patients with childhood-onset systemic lupus erythematosus (c-SLE). This retrospective cohort study was conducted at the largest university-based tertiary referral center in Thailand. Data of c-SLE patients (≤ 18years) at diagnosis who were followed ≥ 12months during January 2009 to December 2019 were collected. SLE disease status was categorized into LLDAS and non-optimally controlled state. SLEDAI-2K score was used to assess disease activity. Damage accrual was assessed by a pediatric version of the SLICC/ACR damage index. A total of 232 c-SLE patients (85.8% female) were included. At 12months of treatment, 109 (47%) patients achieved LLDAS. Damage accrual was observed in 93 (40.1%) patients at the mean follow-up time of 6.2 ± 3.7years. Damage accrual was significantly lower in patients who achieved LLDAS within 12months than in those non-optimally controlled (p = 0.002). The median time to achieving LLDAS was 12.6months (95%CI: 11.19-13.97). The median time to achieving LLDAS was significantly shorter in those without renal involvement (10.8months, 95%CI: 9.62-12.00 vs. 15.6months, 95%CI: 13.76-17.52, respectively; p = 0.044). Multivariable logistic regression analysis revealed absence of renal involvement as the predictor of achieving LLDAS within 12months of treatment (aOR: 2.430, 95%CI: 1.420-4.158; p = 0.001). Achieving LLDAS within 12months of treatment was associated with lower damage accrual. Absence of renal involvement was the predictor of achieving LLDAS within 12months of treatment. Key Points • LLDAS is a promising and achievable treatment target in c-SLE. • Achieving LLDAS within 12 months of treatment is associated with lower damage accrual. • Absence of renal involvement is the predictor of achieving LLDAS within 12 months of treatment.

A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613.

140 Background: HER2 ( ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibody-based (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio > 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (>5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 – 7.6) months in TP group and 3.7 (95%CI: 1.6 – 6.7) months in CETIRI group (p = 0.35). Grade ≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of 31%. Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy. Clinical trial information: NCT03365882 . [Table: see text]

The Evolving Landscape of Leptomeningeal Cancer from Solid Tumors: A Systematic Review of Clinical Trials.

Leptomeningeal carcinomatosis (LMC) is a fatal but uncommon complication occurring in 5-15% of patients with stage IV cancer. Current treatment options are ineffective at managing leptomeningeal spread, with a median overall survival (mOS) of 2-6 months. We aimed to conduct a systematic review of the literature to identify past and future therapies for LMC from solid tumors. Forty-three clinical trials (CTs) published between 1982-2022 were identified. Of these, 35 (81.4%) were non-randomized CTs and 8 (18.6%) were randomized CTs. The majority consisted of phase I (16.3%) and phase II CTs (65.1%). Trials enrolled patients with LMC from various primary histology (n = 23, 57.5%), with one CT evaluating LCM from melanoma (2.4%). A total of 21 trials evaluated a single modality treatment. Among CTs, 23.7% closed due to low accrual. Intraventricular (ITV)/intrathecal (IT) drug delivery was the most common route of administration (n = 22, 51.2%) vs. systemic drug delivery (n = 13, 30.3%). Two clinical trials evaluated the use of craniospinal irradiation for LMC with favorable results. LMC continues to carry a dismal prognosis, and over the years, increments in survival have remained stagnant. A paradigm shift towards targeted systemic therapy with continued standardization of efficacy endpoints will help to shed light on promising treatments.

Growth in eligibility criteria content and failure to accrue among National Cancer Institute (NCI)-affiliated clinical trials.

Cancer trial accrual is a national priority, yet up to 20% of trials fail to accrue. Trial eligibility criteria growth may be associated with accrual failure. We sought to quantify eligibility criteria growth within National Cancer Institute (NCI)-affiliated trials and determine impact on accrual. Utilizing the Aggregated Analysis of ClinicalTrials.gov, we analyzed phase II/III interventional NCI-affiliated trials initiated between 2008 and 2018. Eligibility criteria growth was assessed via number of unique content words within combined inclusion and exclusion criteria. Association between unique word count and accrual failure was evaluated with multivariable logistic regression, adjusting for known predictors of failure. Medical terms associated with accrual failure were identified via natural language processing and categorized. Of 1197 trials, 231 (19.3%) failed due to low accrual. Accrual failure rate increased with eligibility criteria growth, from 11.8% in the lowest decile (12-112 words) to 29.4% in the highest decile (445-750 words). Median eligibility criteria increased over time, from 214 (IQR [23, 282]) unique content words in 2008 to 417 (IQR [289, 514]) in 2018 (r2 =0.73, P < 0.001). Eligibility criteria growth was independently associated with accrual failure (OR: 1.09 per decile, 95% CI [1.03-1.15], p=0.004). Eighteen exclusion criteria categories were significantly associated with accrual failure, including renal, pulmonary, and diabetic, among others (Bonferroni-corrected p < 0.001). Eligibility criteria content growth is increasing dramatically among NCI-affiliated trials and is strongly associated with accrual failure. These findings support national initiatives to simplify eligibility criteria and suggest that further efforts are warranted to improve cancer trial accrual.

Optimizing Shared Decision Making about Hydroxyurea in Young Children with Sickle Cell Anemia

Introduction: The National Heart, Lung, and Blood Institute (NHLBI) recommends hydroxyurea (HU) be offered to all children with sickle cell anemia (SCA) age >9 months via shared decision-making (SDM). However, HU remains underutilized, largely due to parental concerns about safety and potential long-term effects. SDM was recommended because it can decrease parental uncertainty as families clarify their values/preferences and understand scientific evidence about HU. Funded by the Patient-Centered Outcomes Research Institute (PCORI), the Engage HU study (NCT03442114) compared two methods for optimizing SDM for HU in young children with SCA: the American Society of Hematology's (ASH) HU clinician pocket guide (usual care condition) and a HU SDM toolkit (toolkit condition) created by the research team. This study aimed to compare the impact of these on caregiver decisional uncertainty and caregiver perception of clinician use of SDM. Methods: Engage HU was a prospective, multi-site intervention trial with a unidirectional crossover design in which each clinic began enrolling in the usual care condition and then one-by-one crossed over to the toolkit condition. Inclusion criteria included children ages 0-5 years followed at 12 SCA centers in the US who were candidates for HU and whose caregivers had not decided about HU therapy within 3 months prior to enrollment. After receiving a flyer/letter, eligible caregivers were approached in clinic or by phone. Caregivers completed an e-consent form. Study visits were conducted in-person or via telehealth. Primary endpoints were caregiver decisional uncertainty (Decisional Conflict Scale-DCS) and caregiver perception of clinician use of SDM (Dyadic OPTION scale-OPTION). Lower scores on the DCS indicate less decisional uncertainty and higher scores on the OPTION indicate that the clinician demonstrated more SDM behaviors (e.g., asked about caregiver preferences/values). All survey data were collected using paper surveys or electronically via REDCap™. Data were analyzed using linear regression models in Stata version 17 for each main outcome of interest (DCS and OPTION Total Scores). Our primary predictor was group (toolkit versus usual care). The model was estimated using full information maximum likelihood estimation on the full analysis sample (N=132) to account for missing data. We also accounted for site-level variation, when the sites crossed from usual care to toolkit (i.e., the cluster), when data were collected (0=pre-COVID, 1=during COVID), and the impact of COVID-19 on caregivers (assessed using the COVID-19 Exposure and Family Impact Survey [CEFIS]). Results: A total of 176 caregivers of eligible children consented. Twelve SCA clinical sites participated; however, four sites were terminated early due to staff turnover or low accrual. Mean caregiver age was 30.19 (SD=6.97); most identified as female (93.1%), Black/African American (89.3%), or Mixed race (6.1%), and mothers (90.8%). Most children had HbSS (94.7%). Preliminary analyses were conducted on 132 caregivers with complete data (n=85 Usual Care; n=47 Toolkit). Regression analyses showed that participants in the toolkit condition had significantly lower DCS Total scores (i.e., lower decisional conflict) than those in usual care condition (b=-7.33, 95% CI=-13.3 to 1.31, p=.017). In addition, significant differences were found on the DCS subscales (see Table 1). Similarly, participants in the toolkit condition had significantly higher OPTION Total scores (i.e., parents reported that the clinician exhibited more SDM behaviors) than those in usual care (b=2.38, 95% CI=0.44 to 4.34, p=.016). Conclusions: Use of the HU toolkit compared to the usual care approach significantly improved SDM between providers and caregivers of children with SCA; however, given site team turnover, lower than expected accrual, and study interruption due to the COVID-19 pandemic, additional research is needed to confirm these preliminary findings. Future studies should also seek to identify context-specific factors (e.g., clinic processes) that are key to successful implementation of SDM with both younger and older children with SCA. This project was supported by an award fromPCORI contract number CDR-1609-36055 (PI: Crosby).Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The adjusted Global Anti-Phospholipid Syndrome Score as predictor of damage accrual measured by Damage Index for APS: a longitudinal study.

To analyse the association between the average 'adjusted' Global APS Score (aGAPSS) over time, as a surrogate of disease activity, and change in Damage Index for APS (DIAPS) during follow-up in patients with thrombotic and non-thrombotic APS. Two hundred APS patients (138 primary, 62 associated to other autoimmune diseases) were included. DIAPS change was calculated as the difference between basal DIAPS and DIAPS at the end of follow-up. The aGAPSS was calculated for each patient at baseline and on a yearly basis for up to 6 years (minimum 3 years). The average score per patient was computed and considered the reference aGAPSS. Linear regression models were designed to analyse the association between mean aGAPSS and DIAPS change. Moreover, factors associated to high (increase of DIAPS ≥1 during follow-up) vs low (increase of DIAPS <1 during follow-up) damage accrual were assessed. A higher mean aGAPSS value was associated to a DIAPS increase during follow-up (b = 0.04, P < 0.001) in the multivariate analysis. Higher mean aGAPSS values were found in patients with a DIAPS increase ≥1 during follow-up compared with patients with an increase of <1 point [9.22 (95% CI 7.58, 10.86) vs 6.72 (95% CI 6.0, 7.43), P = 0.003]. aGAPSS increased the odds a DIAPS increment of ≥1 point during follow-up [OR = 1.12 (95% CI 1.04, 1.21), P = 0.003]. Our data support the utility of longitudinal assessing of the aGAPSS score in predicting damage accrual, measured by DIAPS, in APS.

Disease-Free Survival of Patients with Muscle Invasive Bladder Cancer Treated by Radical Cystectomy vs. Bladder-Sparing Therapy at a Nationwide Level

<h3>Purpose/Objective(s)</h3> Organ-sparing treatment has become the standard of curative cancer treatment for many tumor types. For patients with muscle invasive bladder cancer (MIBC), radical cystectomy (RC) is still the recommended treatment according to both the American Urological Association and the European Association of Urology guidelines. An attempted RCT between RC and bladder sparing therapy (BST) failed due to low accrual and noncompliance. A large prospective comparative study is the best alternative to compare outcomes between modalities. We hypothesized that the two-year disease-free survival (DFS) with BST is equal to the DFS with RC in selected patients with non-metastasized MIBC. <h3>Materials/Methods</h3> All patients diagnosed with MIBC between November 2017 and November 2019 were identified via the population-based Netherlands Cancer Registry. Detailed clinical data was retrieved by consulting medical files. Only patients treated with BST or RC were included. BST was defined as patients treated with concurrent chemoradiation (CRT) or external beam radiation followed by brachytherapy (BT). The primary endpoint was DFS, defined as free from muscle invasive locoregional recurrence, distant metastasis or death. Secondary endpoint was overall survival (OS). Two-year follow-up (FU) data were collected Survival was analyzed with a Cox proportional hazards model, we present the crude results in this abstract. Time was defined from treatment start to first event. Patients were censored at end of FU if alive or at last contact if lost to follow-up. <h3>Results</h3> A total of 1429 patients were included, 1100 underwent RC, 283 concurrent CRT and 44 BT. Median follow-up was 22 months (range: 1-43 months). Patients treated by RC and BST had similar DFS with a crude HR 0.96 (95%CI 0.78-1.16). The 2-year DFS for patients treated by RC, concurrent CRT or BT was 56% (95%CI 53-60%), 56% (95%CI 50-63%) and 67% (95%CI 52-82%) respectively. After a median time of 15.8 months, salvage cystectomy was performed in 21 patients (6,4%) of which 17 in the CRT and 4 in the BT group. The 2-year OS for patients treated with RC, concurrent CRT or BT was 63.8% (95%CI 61-67%), 68.3% (95%CI 62-74%) and 85.9% (95%CI 75-96%) respectively. The crude HR for OS was 0.84, 95%CI 0.66-1.05, (p=0.14) for RC vs CRT and 0.40 95%CI 0.17-0.77(p=0.015) for RC vs BT. Our study is limited by the inherent biases of observational data. <h3>Conclusion</h3> At two years, DFS did not significantly differ between patients treated with BST and RC. We conclude that after appropriate selection BST leads to similar DFS rates compared to RC. Nevertheless, these results should be interpreted with care, as the treatment groups were not yet matched for case-mix variables. The results of this study can be used to aid patients and physicians to choose the modality best tailored to their individual preferences.

238 (PB118) - Phase II study of sunitinib in tumors with c-KIT mutations: results from the NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocol V

Background: KIT mutations are common in gastrointestinal stromal tumors (GISTs) but are also found to a lesser degree in other tumor types such as mucosal melanomas, testicular seminomas or dysgerminomas. The NCI-MATCH study is a tumor agnostic platform trial enrolling patients to targeted therapies based on genomic alterations. Subprotocol V of the NCI-MATCH platform trial investigated sunitinib in patients with tumors harboring c-KIT mutations. Material & Methods: EAY131-V, is an open-label, single arm, phase 2 study. Eligible patients were those with a somatic c-KIT mutation on exons 9, 11, 13, and 14. Exclusions were mutations on exons 17, 18 which are reported to have resistance to sunitinib. Excluded tumor types were GIST, renal cell carcinoma, and pancreatic neuroendocrine tumors which have a known response to sunitinib. Patients received sunitinib 50 mg orally daily for 4 weeks with 2-week rest, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival (PFS) at 6 months, PFS, and toxicities. Results: Between November 1, 2016, and May 21, 2020, 10 patients were enrolled, 9 were analyzable. Median age was 62 years (range 30–76), 77.8% received 2 lines of systemic therapy, while 22.2% received >3 lines. The most common tumor type was melanoma (44%), followed by squamous cell carcinoma of the lung or thymus (33%). There were 2 partial responses (PRs), both in squamous cell carcinomas, with an ORR of 22.2% (90% CI 4.1%–55%) and stable disease in 44%. Estimated 6-month PFS was 33.3% (90% CI 15.4%–72.4%). The 2 PRs had a PFS of 8 months and 10.8 months, respectively. Grade 3–4 toxicities at least possibly related to treatment occurred in 5 patients and included a thromboembolic event (n = 1), skin infections (n = 2), and lymphopenia (n = 2). This arm of the study was closed in 2022 based on low accrual, despite an amendment for additional actionable mutations. Prevalence of eligible c-KIT mutations after screening 5540 patients was estimated at 0.13%. Conclusions: In this study, sunitinib monotherapy for c-KIT mutations did not meet the primary endpoint for response, but in this small sample size a potential signal cannot be ruled out. Estimated rates of c-KIT mutations was lower than expected, impacting accrual to this arm. This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers: U10CA180820, U10CA180794, UG1CA233302, UG1CA233180, UG1CA233341, and UG1CA189869. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. No conflict of interest.

Diversity, equity, and inclusion in cancer clinical trial enrollment: Laying the groundwork for a cancer center collaborative intervention through key informant interviews.

98 Background: Clinical trial (CT) participation rates in the US are about 8% overall. Although, Black, Indigenous and People of Color (BIPOC) are as willing to join CTs as Whites, they remain underrepresented. We will implement a multi-level intervention across 3 cancer centers in New York City by creating a collaborative pool of CTs for breast, prostate, and liver cancer, thereby increasing availability of trials for all, especially BIPOC populations. To lay the groundwork, we conducted a formative evaluation to identify constructs that can influence implementation of this intervention. Methods: We designed a semi-structured interview guide for key informants to ascertain barriers and facilitators of enrollment at 1 cancer center and its 2 community affiliates. 23 key informants including oncologists, research staff, informatics, nurses, and cancer center leadership were identified using a targeted approach, followed by snowball sampling. Interviews were recorded, transcribed, and analyzed using thematic analysis approach. Results: Facilitators of accrual include patient referrals from physician-investigators and their teams, and oncologists’ knowledge of open trials through tumor boards, disease focus groups, and research meetings. Major barriers to CT enrollment are gaps in trial portfolio, inadequate infrastructure (e.g., staffing, space, and time), and incentives (e.g., RVU-based reimbursements). Informants felt that for patients, financial toxicity, medical mistrust, inadequate health literacy, comorbidities, poor performance status, and language are reasons for low accrual. Physicians emphasized their willingness to refer patients out-of-institution for CTs but lacked knowledge of outside trials. Care coordination across sites and loss of revenue for home institution are system-level barriers to referral. Additionally, informants believed that patients’ willingness to seek trials at other institutions is influenced by their commute, unfamiliarity with a new system, insurance coverage, rapport with oncologist, and motivation. Conclusions: Involving key stakeholders, increasing physician awareness of open CTs, educating patients and addressing their concerns about CTs, improving access to bilingual materials and interpreters, standardizing care coordination and ensuring similar rates of referrals across institutions are key facilitators to implement a multi-level intervention to increase CT enrollment across a cancer center collaboration.

Accrual-Monitoring Practices for Various Disease Trials among AACI Member Cancer Centers.

Progress in the management of rare diseases, including rare cancers, is dependent upon clinical trials; however, as many as 32% of rare-disease trials go uncompleted or unpublished due to insufficient accrual. Monitoring practices may differ between institutions. We sought to survey the regulatory standards for various trial types among major U.S. cancer centers. A 10-question survey was designed using Qualtrics assessment software. The survey was sent via email to an internal server of member institutions of the Association of American Cancer Institutes (AACI). Of 103 AACI centers, 31% completed the survey (n = 32). Respondents differed in their definitions of a rare disease, minimum expectations for rare tumor studies, and frequency of accrual monitoring by their institutional Protocol Review and Monitoring Committee. Seventy-three percent of respondents did not close trials based on low accrual. Strategies to optimize accrual included investigator incentives for high accrual and penalties for low accrual in 37% and 13% of respondents, respectively.

Creating and Implementing a Principal Investigator Tool Kit for Enhancing Accrual to Late Phase Clinical Trials: Development and Usability Study.

BackgroundAccrual to oncology clinical trials remains a challenge, particularly during the COVID-19 pandemic. For late phase clinical trials funded by the National Cancer Institute, the development of these research protocols is a resource-intensive process; however, mechanisms to optimize patient accrual after trial activation are underdeveloped across the National Clinical Trial Network (NCTN). Low patient accrual can lead to the premature closure of clinical trials and can ultimately delay the availability of new, potentially life-saving therapies in oncology.ObjectiveThe purpose of this study is to formally create an easily implemented tool kit of resources for investigators of oncology clinical trials within the NCTN, specifically the NRG Oncology cooperative group, in order to optimize patient accrual.MethodsNRG Oncology sought to formally develop a tool kit of resources to use at specific time points during the lifetime of NRG Oncology clinical trials. The tools are clearly described and involve the facilitation of engagement of the study principal investigator with the scientific and patient advocate community during the planning, activation, and accrual periods. Social media tools are also leveraged to enhance such engagement. The principal investigator (PI) tool kit was created in 2019 and thereafter piloted with the NRG Oncology/Alliance NRG-LU005 phase II or III trial in small-cell lung cancer. The PI tool kit was developed by the NRG Oncology Protocol Operations Management committee and was tested with the NRG/Alliance LU005 randomized trial within the NCTN.ResultsNRG Oncology/Alliance NRG-LU005 has seen robust enrollment, currently 127% of the projected accrual. Importantly, many of the tool kit elements are already being used in ongoing NRG Oncology trials, with 56% of active NRG trials using at least one element of the PI tool kit and all in-development trials offered the resource. This underscores the feasibility and potential benefits of deploying the PI tool kit across all NRG Oncology trials moving forward.ConclusionsWhile clinical trial accrual can be challenging, the PI tool kit has been shown to augment accrual in a low-cost and easily implementable fashion. It could be widely and consistently deployed across the NCTN to improve accrual in oncology clinical trials.Trial RegistrationClinicalTrials.gov NCT03811002; https://clinicaltrials.gov/ct2/show/NCT03811002

A phase II trial of gemcitabine and erlotinib followed by ChemoProton therapy plus capecitabine and oxaliplatin for locally advanced pancreatic cancer.

BackgroundEpidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer. EGFR expression plays a potentially important role in modulation of tumor sensitivity to either chemotherapy or radiotherapy. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR/HER1. A phase II trial was conducted to explore the efficacy of a regimen utilizing erlotinib and proton therapy.MethodsPatients with unresectable or borderline resectable non-metastatic adenocarcinoma of the pancreas were included. Patients received 8-week systemic treatment with gemcitabine 1,000 mg/m2 and erlotinib 100 mg (GE). If there was no evidence of metastatic disease after GE, then patients preceded with proton therapy to 50.4 Gy in 28 fractions with concurrent capecitabine 825 mg/m2 (CPT). This was followed with oxaliplatin 130 mg/m2 and capecitabine 1,000 mg/m2 (CapOx) for 4 cycles. The primary study objective was 1-year overall survival (OS). The benchmark was 43% 1-year survival as demonstrated in RTOG/NRG 98-12. The Kaplan-Meier method was used to estimate the one-year OS and the median OS and progression-free survival (PFS).ResultsThe study enrolled 9 patients ages 47–81 years old (median 62) between January 2013 and March 2016, when the trial was closed due to low patient accrual. The 1-year OS rate was 55.6% (95% CI: 31% to 99%). The median OS was 14.1 months (95% CI: 11.4–NE) and the median PFS was 10.8 months (95% CI: 7.44–NE). A majority of patients completed CPT and GE, but only 33.3% completed the four cycles of CapOx. A third of patients experienced grade 3 toxicities, which were all hepatic along with one patient who also had grade 3 diarrhea. There were no grade 4 or 5 toxicities. Four patients were enrolled with borderline resectable disease, three of which were eligible for pancreaticoduodenectomy after GE and CPT treatment. One of two patients who underwent resection had a negative margin.ConclusionsThis regimen for locally advanced pancreatic cancer (LAPC) exceeded the pre-specified benchmark and was safe and well tolerated. Additional investigations utilizing more current systemic treatment regimens with proton therapy are warranted.Trial RegistrationClinicalTrials.gov identifier (NCTNCT01683422).

Clinical Trials in Hepatopancreatobiliary Surgery: Assessing Trial Characteristics, Early Discontinuation, Result Reporting, and Publication

BackgroundHepatopancreaticobiliary (HPB) diseases carry high morbidity despite efforts aimed at their reduction. An assessment of their trial characteristics is paramount to determine trial design adequacy and highlight areas for improvement. As such, the aim of this study is to assess HPB surgery trial characteristics, summarize logistic, financial, and practical reasons behind early discontinuation, and propose potential interventions to prevent this in the future. MethodsAll clinical trials investigating HPB surgery registered on ClinicalTrials.gov from October 1st, 2007 (inclusive), to April 20th, 2021 (inclusive), were examined. Trial characteristics were collected including, but not limited to, study phase, duration, patient enrollment size, location, and study design. Peer-reviewed publications associated with the selected trials were also assessed to determine outcome reporting. ResultsA total of 1776 clinical trials conducted in 43 countries were identified, the majority of which were conducted in the USA. Of these trials, 32% were reported as “completed” whereas 12% were “discontinued.” The most common cause of trial discontinuation was low accrual, which was reported in 37% of terminated studies. These resulted in 413 published studies. Most trials had multiple assignment, randomized, or open-label designs. Treatment was the most common study objective (73%) with pharmacological therapy being the most commonly studied intervention. ConclusionsThe main reasons for early discontinuation of clinical trials in HPB surgery are poor patient recruitment and inadequate funding. Improved trial design, recruitment strategies and increased funding are needed to prevent trial discontinuation and increase publication rates of HPB surgery clinical trials.

A phase I/II trial of concurrent immunotherapy with chemoradiation in locally advanced larynx cancer.

ObjectivesCisplatin‐based chemoradiation is an established organ‐preserving strategy for locally advanced laryngeal cancer, but long‐term survival remains suboptimal. Immunotherapy has been studied in the metastatic and unresectable recurrent settings. However, additional data are needed to assess its role in organ preservation for locally advanced laryngeal cancer.MethodsThis trial was an open‐label, single‐arm, multi‐institutional study with a Phase I run‐in portion followed by a planned Phase II component, which closed early due to low accrual. Study patients had Stage III or IV (T2–3; N0–3; M0) laryngeal squamous cell carcinoma and were candidates for larynx preservation. Pembrolizumab was given 2–3 weeks prior to chemoradiation and then, q21 days concurrently with high‐dose cisplatin and radiation prescribed to a total dose of 70 Gy. The primary endpoint of the trial was organ‐preservation rate (OPR) at 18 months.ResultsA total of nine patients were enrolled with a median follow‐up of 30.1 months. No patient required laryngectomy, resulting in 100% OPR at 18 months. The 12‐month overall survival (OS) rate was 77.8% and the median duration of OS was not reached. All acute Grade 4 (n = 3) toxicities occurred in a single patient with poorly controlled diabetes at baseline. One patient had late Grade 4 laryngeal edema requiring tracheostomy 8 months after chemoradiation, which self‐resolved.ConclusionUCCI‐HN‐15‐02 demonstrated the safety of the addition of immunotherapy to definitive chemoradiation and the patient outcomes suggest the potential for improving long‐term survival while minimizing negative impact from treatment. While results from this trial were promising, a randomized study with a larger number of patients and longer follow‐up is warranted to verify this treatment approach prior to wider adoption. NCT #: NCT02759575.Level of evidence: 2b

Serum PTH, PTH1R/ATF4 pathway, and the sRANKL/OPG system in bone as a new link between bone growth, cross-sectional geometry, and strength in young rats with experimental chronic kidney disease.

The progression of chronic kidney disease (CKD) in children is associated with deregulated parathyroid hormone (PTH), growth retardation, and low bone accrual. PTH can cause both catabolic and anabolic impact on bone, and the activating transcription factor 4 (ATF4), a downstream target gene of PTH, is related to its anabolic effect. Osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANKL) are PTH-dependent cytokines, which may play an important role in the regulation of bone remodeling. This study aimed to evaluate the impact of endogenous PTH and the bone RANKL/OPG system on bone growth, cross-sectional geometry and strength utilizing young, nephrectomized rats. The parameters of cross-sectional geometry were significantly elevated in rats with CKD during the three-month experimental period compared with the controls, and they were strongly associated with serum PTH levels and the expression of parathyroid hormone 1 receptor (PTH1R)/ATF4 genes in bone. Low bone soluble RANKL (sRANKL) levels and sRANKL/OPG ratios were also positively correlated with cross-sectional bone geometry and femoral length. Moreover, the analyzed geometric parameters were strongly related to the biomechanical properties of femoral diaphysis. In summary, the mild increase in endogenous PTH, its anabolic PTH1R/ATF4 axis and PTH-dependent alterations in the bone RANKL/OPG system may be one of the possible mechanisms responsible for the favorable impact on bone growth, cross-sectional geometry and strength in young rats with experimental CKD.