Historical Control Rate Research Articles

A phase 2 single-arm trial of high-dose precision targeted radiotherapy added to immunotherapy for patients with metastatic non-small cell lung cancer.

For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS). In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%. Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis. The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease.

CTNI-16. USE OF PREDICTIVE SCORE-BASED HISTORICAL CONTROL DATA IN SINGLE-ARM TRIALS

Abstract Even though the randomized controlled trials (RCTs) are still the preferred approach to evaluate the effects of treatments, single-arm study designs have been traditionally used in Phase II oncology clinical trials. The single-arm studies using historical control or external control might be inevitable and even fatal when concurrent controls are impractical or unethical in rare and high-risk diseases. Due to recruiting difficulty, ethical and economic reasons, the single-arm trials can be a good option to test the experimental efficacy with the external control data of historical control rates for early efficacy phase 2 trials in glioblastoma. The FDA guidelines on external control data focus on the use of patient-level data from other clinical trials or real-world data (RWD), and so there is no guidance for summary-level historical control. Furthermore, there exist methodological issues to use historical data like identification of relevant data, amount of discounting (time difference and dissimilarity), prior robustness or operating characteristics. In this study, we propose a synthetic data based predictive scoring method optimally to match the historical control data with the characteristic conditions of the experimental studies. We consider both a binary (PFS on six months) and survival (median PFS) endpoints as surrogates for Phase 2 single-arm trials in newly diagnosed and recurrent glioblastoma patients. We perform meta-analysis to summarize the endpoints and the related socio-demographic, treatment and genetic factors from the summary-level historical data. Then we generate the synthetic patients based on the meta-summarized data. The generalized boosted regression models will be used to identify significant characteristics affecting the survival of GBM patients using the synthetic data. Finally the predictive score-based historical data model will be developed to provide the optimal matching with the characteristics of the experimental studies. This study will be validated using existing patient-level data as well as cross-validation methods.

ARTIA-Bladder: Daily Online Adaptive Short-Course Radiation Therapy (RT) and Concurrent Chemotherapy for Muscle-Invasive Bladder Cancer (MIBC): A Prospective Trial of an Individualized Approach for Reducing Bowel and Bladder Toxicity

Concurrent chemo-radiotherapy is commonly prescribed for muscle-invasive bladder cancer (MIBC). Post hoc analysis of two large, randomized trials found that hypofractionation improves loco-regional control (LRC) vs. standard fractionation in this population. A challenge in traditional image-guided radiotherapy of the bladder is that daily changes in bladder position and size requires large margins to ensure target coverage. This makes it difficult to spare uninvolved bladder from high-dose treatment, increases the risk of bowel toxicity, and results in historical rates of acute G3+ toxicity exceeding 20-30%. Daily online adaptive RT (ART) may enable reduced, personalized margins that maintain target coverage while reducing dose to OARs. This prospective clinical trial will test whether: 1) participants undergoing ART for MIBC have a lower rate of acute G3+ GI/GU toxicity compared with the 31% historical control rate (Stage III BC2001 trial), and 2) 2-year LRC with ART will be non-inferior to historical controls (75%). This multi-national trial will enroll 165 adult subjects with stage cT2-T4aN0M0 urothelial MIBC. Subjects will have undergone an attempt at maximal transurethral resection of bladder tumor. Patients with clinically involved nodes or G2+ GI or G3+ GU symptoms/conditions at baseline are ineligible. Concurrent with chemotherapy, participants will receive (at the discretion of the investigator) either 55 Gy in 20 fx to whole-bladder or 46 Gy in 20 fx to whole-bladder plus simultaneous in-field boost of 55 Gy in 20 fx to tumor bed. A personalized ITV will be derived for each subject based on bladder expansion, as assessed on two CT simulations separated by 30 min. Daily ART will be attempted for all subjects. The primary endpoint is acute G3+ GI/GU toxicity. Secondary endpoints are LRC; quality of life (EORTC QLQ-BLM30, EPIC 26 bowel and urinary); global function (EQ-5D-5L ); 2-year disease-free, bladder intact event-free, and overall survival; 2-year bladder cancer-specific mortality; NTCP model of acute GI toxicity for hypofractionated bladder RT; workflow feasibility of ART; improved target coverage ± reduced dose to critical OARs vs. non-ART dosimetry; acute G3+ GI/GU toxicity rate in subjects with ≥75% of their treatments as ART; and acute G3+ GI/GU toxicity in the cohort treated with partial bladder boost. Exploratory translational and correlative endpoints will also be examined. This trial opened to enrollment on Feb 2, 2023; the study duration is expected to be 4-5 years. This prospective clinical trial will provide robust clinical data to inform healthcare providers' decisions on the use of daily online ART and hypofractionation as a bladder preservation strategy for this population.

Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma.

Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in metastatic cancers remains unclear. Many patients, especially those without radiologic complete remission, develop progressive disease after ICI discontinuation. Extending DoT with ICI may potentially improve efficacy outcomes but presents major logistical and cost challenges with standard frequency dosing (SFD). Receptor occupancy data supports reduced frequency dosing (RFD) of anti-PD-1 antibodies, which may represent a more practical and economically viable option to extend DoT. We conducted a retrospective study of patients with metastatic melanoma and Merkel cell carcinoma (MCC), who received ICI at RFD administered every 3months, after initial disease control at SFD. We evaluated efficacy, safety, and cost-savings of the RFD approach in this cohort. Between 2014 and 2021, 23 patients with advanced melanoma (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT was 1.1years at SFD and 1.2years at RFD. The 3year PFS after start of RFD was 73% in melanoma and 100% in MCC patients, which compare favorably to historical control rates. In the subset of 15 patients who received at least 2years of therapy, total savings amounted to $1.1 million in drug costs and 384h saved despite the extended DoT (median 3.4years), as compared to the calculated cost of 2years at SFD. ICI administration at RFD can allow extension of treatment duration, while preserving efficacy and reducing logistical and financial burden. RFD approach deserves further exploration in prospective clinical trials.

A phase II trial of pevonedistat plus docetaxel in patients with previously treated advanced non–small-cell lung cancer (NSCLC).

e21062 Background: For patients with stage IV NSCLC, treatment options are limited after progression on immunotherapy (IO) +/- platinum-based chemotherapy. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRLs) catalyze the ubiquitylation and degradation of tumor suppressor proteins and are overactivated in NSCLC. Therefore, inhibition of CRLs has potential therapeutic value. Neddylation is required to activate CRLs; NAE (NEDD8 activating enzyme) catalyzes neddylation. In pre-clinical studies, pevonedistat, a first-in-class small molecule NAE inhibitor, exerts anti-tumor effects when combined with docetaxel. Methods: We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with stage IV NSCLC with progression on or after platinum-based chemotherapy +/- IO. Patients with tumors that had driver mutations in EGFR, ALK, ROS1, and BRAF must have also had progression on targeted inhibitors. A Simon Optimal two-stage design was utilized with 90% power and 15% type I error to detect the drug as promising when the true response rate is 25% and the historical control rate is 10%. A maximum of 37 response-evaluable (R-E) patients could be enrolled. Patients received docetaxel 75 mg/m2 on day 1 and pevonedistat 25 mg/m2 on days 1, 3 &amp; 5 of a 21-day cycle. Response was assessed every 2 cycles based on RECIST v1.1 criteria. The primary objective was overall response rate (ORR). Those who received 2 cycles or had progression prior to the end of cycle 2 were considered R-E. Patients who received any treatment on protocol were evaluable for safety (S-E). Results: From 3/5/2018 to 1/26/2021, we enrolled 31 patients and 27 were R-E with a median follow-up of 38.7 months. The trial was terminated early due to the sponsor’s decision to discontinue the development of pevonedistat. In the R-E population, 52% were female with a median age of 63 and 85% had adenocarcinoma. The median number of prior regimens was 2, and 92% of patients had previously received IO. The ORR was 22% (95%CI 8.6-42.3%) and the disease control rate (SD+CR+PR) was 66.7% (95%IC 46.0- 83.5%). The median PFS was 4.1 (2.8-5.8) months and median OS was 13.1 (6.7-24.8) months. The median duration of response was 14.5 months. The incidence of Grade 3-4 adverse events (AE) was 53% in the 30 S-E patients. The most common grade 3-4 AEs were decrease in blood counts (anemia and neutropenia) and elevation in liver transaminases. There were no Grade 5 toxicities. Conclusions: Our data suggest that the combination of docetaxel and pevonedistat is safe and may have improved anti-tumor activity compared to historical data with docetaxel alone. These results suggest that the neddylation pathway is a targetable anti-tumor pathway that should be further studied in patients with NSCLC. Clinical trial information: NCT03228186 .

DOP87 The Anti-TL1A Antibody PRA023 Demonstrated Proof-of-Concept in Crohn’s Disease: Phase 2a APOLLO-CD Study Results

Abstract Background Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases with a precision medicine approach. This Phase 2a multi-center, open-label study aimed to assess the efficacy and safety of PRA023 as induction treatment in adults with moderately to severely active Crohn’s Disease (CD). Methods Key eligibility criteria included Crohn’s disease activity index ≥220 and ≤450 with centrally read [with adjudication] Simple Endoscopic Score (SES)-CD score of ≥6 (≥4 isolated ileal disease) and a history of insufficient/loss of response and/or intolerance to conventional and/or approved biologic therapies (≤4 biologic agents from ≤3 classes). Eligible patients were treated with intravenous PRA023 1000mg on Day 1, 500mg at Weeks 2, 6, and 10. The primary endpoint was endoscopic response (reduction in SES-CD score of ≥50%) at Week 12. Study design utilized historical placebo control rate estimates as a benchmark. Exploratory endpoints include efficacy assessment in a subpopulation identified by a genetics-based companion diagnostic test (CDx). Results Of the 55 patients in the full analysis data set, 53 (96.4%) completed the 12-week Induction Period. The patient population was notable for the high rate of prior biologic exposure (70.9%) and a mean (SD) disease duration of 10.3 (9.3) years (Table 1). A significantly greater proportion of patients receiving PRA023 achieved endoscopic response (26% PRA023 vs. 12% historical placebo estimate, p=0.002) and clinical remission (CDAI &amp;lt; 150 points; 49% PRA023 vs 16% historical placebo estimate, p&amp;lt; 0.001). Efficacy was observed in biologic-exposed patients (33% endoscopic response and 38.5% clinical remission) while concurrent steroid or immunosuppressant use did not impact efficacy. Significant reductions from baseline in C-reactive protein and fecal calprotectin were observed at all timepoints (Figure 1). Although the pre-specified CDx algorithm provided only limited additional benefit in clinical responses, an alternative CD-specific algorithm (not based on clinical trial data) using the same genetic markers demonstrated enhanced performance across both clinical (12/21 [57%] remission) and endoscopic (9/20 [45%] response) outcomes. No serious/severe AEs were deemed as study drug-related. Conclusion This Phase 2a study demonstrated robust proof-of-concept for PRA023’s efficacy in moderately to severely active CD with favorable tolerability. Patient selection using prespecified genetic markers showed promising results. Placebo-controlled clinical trials will be conducted to confirm these findings.

Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review

BackgroundDue to economical and ethical reasons, the two-stage designs have been widely used for Phase 2 single-arm trials in oncology because the designs allow us to stop the trial early if the proposed treatment is likely to be ineffective. Nonetheless, none has examined the usage for published articles that had applied the two-stage designs in Phase 2 single-arm trials in brain tumor. A complete systematic review and discussions for overcoming design issues might be important to better understand why oncology trials have shown low success rates in early phase trials.MethodsWe systematically reviewed published single-arm two-stage Phase 2 trials for patients with glioblastoma and high-grade gliomas (including newly diagnosed or recurrent). We also sought to understand how these two-stage trials have been implemented and discussed potential design issues which we hope will be helpful for investigators who work with Phase 2 clinical trials in rare and high-risk cancer studies including Neuro-Oncology. The systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement. Searches were conducted using the electronic database of PubMed, Google Scholar and ClinicalTrials.gov for potentially eligible publications from inception by two independent researchers up to May 26, 2022. The followings were key words for the literature search as index terms or free-text words: “phase II trials”, “glioblastoma”, and “two-stage design”. We extracted disease type and setting, population, therapeutic drug, primary endpoint, input parameters and sample size results from two-stage designs, and historical control reference, and study termination status.ResultsAmong examined 29 trials, 12 trials (41%) appropriately provided key input parameters and sample size results from two-stage design implementation. Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. Most trials (90%) used Simon’s two-stage designs. Only three studies have been completed for both stages and two out of the three completed studies had shown the efficacy.ConclusionsRight implementation for two-stage design and sample size calculation, transparency of historical control and experimental rates, appropriate selection on primary endpoint, potential incorporation of adaptive designs, and utilization of Phase 0 paradigm might help overcoming the challenges on glioblastoma therapeutic trials in Phase 2 trials.

Optimal predictive probability designs for randomized biomarker-guided oncology trials.

Efforts to develop biomarker-targeted anti-cancer therapies have progressed rapidly in recent years. With efforts to expedite regulatory reviews of promising therapies, several targeted cancer therapies have been granted accelerated approval on the basis of evidence acquired in single-arm phase II clinical trials. And yet, in the absence of randomization, patient prognosis for progression-free survival and overall survival may not have been studied under standard of care chemotherapies for emerging biomarker subpopulations prior to the submission of an accelerated approval application. Historical control rates used to design and evaluate emerging targeted therapies often arise as population averages, lacking specificity to the targeted genetic or immunophenotypic profile. Thus, historical trial results are inherently limited for inferring the potential "comparative efficacy" of novel targeted therapies. Consequently, randomization may be unavoidable in this setting. Innovations in design methodology are needed, however, to enable efficient implementation of randomized trials for agents that target biomarker subpopulations. This article proposes three randomized designs for early phase biomarker-guided oncology clinical trials. Each design utilizes the optimal efficiency predictive probability method to monitor multiple biomarker subpopulations for futility. Only designs with type I error between 0.05 and 0.1 and power of at least 0.8 were considered when selecting an optimal efficiency design from among the candidate designs formed by different combinations of posterior and predictive threshold. A simulation study motivated by the results reported in a recent clinical trial studying atezolizumab treatment in patients with locally advanced or metastatic urothelial carcinoma is used to evaluate the operating characteristics of the various designs. Out of a maximum of 300 total patients, we find that the enrichment design has an average total sample size under the null of 101.0 and a total average sample size under the alternative of 218.0, as compared to 144.8 and 213.8 under the null and alternative, respectively, for the stratified control arm design. The pooled control arm design enrolled a total of 113.2 patients under the null and 159.6 under the alternative, out of a maximum of 200. These average sample sizes that are 23-48% smaller under the alternative and 47-64% smaller under the null, as compared to the realized sample size of 310 patients in the phase II study of atezolizumab. Our findings suggest that potentially smaller phase II trials to those used in practice can be designed using randomization and futility stopping to efficiently obtain more information about both the treatment and control groups prior to phase III study.

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium.

The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC). This single-arm, open-label, multi-center phase II study enrolled patients with RECIST measurable advanced EC. Patients could have received < 1 prior platinum-based regimen and < one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared to historical control rate of 50%. 46 patients were enrolled, and 43 were evaluable for ORR. Median age was 66 (range: 43-86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic EC. Patients received carboplatin AUC 6, paclitaxel 175mg/m2 and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles. ORR was 74.4% (32/43), higher than historic controls (p = 0.001). Median PFS was 10.6 months (95% CI 8.3-13.9 months). The most common grade 1-2 treatment related adverse event (TRAEs) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%) and neuropathy (13%), while the most common grade 3-4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T cell populations at baseline in responders. The CD8+ T cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared to non-responders. Addition of pembrolizumab to carboplatin and paclitaxel for advanced EC was tolerated and improved ORR compared to historical outcomes.

A Sampling of Highlights from the Literature

CRISPR-based screening can enhance understanding of T-cell biology (from marius walter via Wikimedia Commons)Using CRISPR-based screening, two groups have identified canonical BRG1/BRM-associated factor (cBAF) complex components as regulators of T-cell differentiation and function that are important for antitumor immunity. Guo et al. find cBAF levels influence the fate of activated CD8+ T cells: high levels promote effector T-cell differentiation and low levels promote memory T-cell differentiation. Belk et al. show cBAF complex components, including Arid1a, promote T-cell acquisition of epigenetic features of exhaustion and limit T-cell persistence. Reducing cBAF activity, either pharmacologically (Guo et al.) or genetically (Belk et al.), improves tumor control in mouse models. The two studies suggest modulating the cBAF complex may improve T cell–based cancer immunotherapy.Guo A, …, Green DR. Nature 2022 June 22;607:135–141.Belk JA, …, Satpathy AT. Cancer Cell 2022 July 11;40:768–86.E7.S. epidermis specific T-cell responses can drive skin irAEs (from NIAID via NIH Flickr)Increasing our understanding of the mechanisms underlying immune-related adverse events (irAEs) is important for optimizing the use of immune checkpoint inhibitors (ICI). Using a mouse model of skin irAEs, Hu et al. find that exposure to Staphylococcus epidermis at the time of anti-CTLA4 treatment induces an inflammatory response resembling skin irAEs in patients treated with ICIs. The response is driven by S. epidermis–specific T cells that produce IL17 and leads to the emergence of S. epidermis–specific memory T cells. Further analysis will determine whether modulating cross-talk between the host immune system and microbiota can alleviate skin irAEs.Hu ZI, …, Belkaid Y. PNAS 2022 June 21;119:e2200348119.Phase II clinical trial results testing chemoimmuno-therapy in PDAC (via Rawpixel)Immunotherapy has so far been ineffective in the treatment of pancreatic ductal adenocarcinoma (PDAC). Padrón et al. report results from a phase II clinical trial evaluating chemotherapy combined with the anti–PD-1 nivolumab or the CD40-agonist sotigalimab, or with both together. The only group of patients among whom the 1-year overall survival rate was significantly greater than a historical control rate of 35% was the group assigned nivolumab/chemotherapy. Analysis of circulating and tumor biomarkers identified distinct immune signatures of improved outcome for patients receiving nivolumab/chemotherapy or sotigalimab/chemotherapy that could be used for patient selection in future clinical trials.Padrón LJ, …, Vonderheide RH. Nat Med 2022 June 3;28:1167–77.B cells can promote or suppress tumors depending on the TME (Carsten Tolkmit via Flickr)The role of B cells in the suppression or promotion of tumors remains unclear. In colorectal cancer (CRC), Wang et al. discover a specific regulatory B-cell subset expressing leucine-tRNA-synthase-2 (LARS2) and TGFβ1 that contributes to CRC progression by altering metabolic processes in the tumor microenvironment (TME). In a second study, Sagiv-Barfi et al. demonstrate that B-cell activation and antigen presentation are key to inducing antitumor T-cell responses, and both B and T cells are needed for efficacy of combination therapy with IL12, anti-OX40, and CpG in breast cancer. The two studies highlight how B-cell responses in the TME not only depend on cancer type, but also on B-cell phenotype and regulatory function.Wang Z, …, Chu Y. Immunity 2022 June 14;55:1067–81.E8.Sagiv-Barfi I, …, Levy R. Sci Immunol 2022 May 27;7:eabn5859.Profiling the diversity of tumor antigens (Andy Mitchell via Wikimedia Commons)A greater understanding of in vivo cancer-specific patterns of peptide presentation by MHC class I complexes is needed to improve the development of antigen-specific immunotherapies. Jaeger et al. develop and use a new genetically engineered mouse model to profile the cancer immunopeptidome from autochthonous pancreatic ductal adenocarcinoma and lung adenocarcinomas. The authors find little correlation between mRNA abundance and peptide detection, suggesting significant posttranslational regulation of tumor-specific peptide presentation. Dendritic cell vaccines loaded with lung adenocarcinoma peptides uniquely identified by the assay induce antigen-specific T-cell responses ex vivo, highlighting the model’s ability to capture the cancer immunopeptidome.Jaeger AM, …, Jacks T. Nature 2022 June 15;607:149–55.A new map of human immune cell development (tzunghaor via openclipart)Understanding how and where the immune system develops can provide a better understanding of cancer origin and facilitate the development of novel immunotherapies. Through single-cell profiling and spatial transcriptomics of nine prenatal tissues, Suo et al. have generated a comprehensive atlas of the developing human immune system. Highlights of the findings include the discovery that human immune development occurs across multiple tissue sites, including sites not considered primary hematopoietic organs; the identification of a population of prenatal B1 cells; and the demonstration that unconventional T cells are selected on thymocytes. This road map provides a resource for advancing immune-based science and medicine.Suo C, …, Teichmann SA. Science 2022 May 12;376:eabo0510.

Phase 2 study of tislelizumab monotherapy in previously treated, locally advanced, unresectable or metastatic microsatellite instability-high/mismatch repair-deficient solid tumors: Gynecological cancer subgroup (127)

<b>Objectives:</b> Primary results from this Phase II study (NCT03736889) showed that tislelizumab (TIS), an anti-PD-1 antibody, was generally well tolerated and demonstrated a clinically meaningful improvement in the objective response rate (ORR) in patients (pts) with previously treated, locally advanced, unresectable or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors compared with the historical control rate (45.9% vs 10 %, respectively) [1]. Here, we report results from the updated analysis for pts with gynecologic MSI-H/dMMR tumors. <b>Methods:</b> Eligible pts received TIS 200 mg intravenously once every three weeks until disease progression, unacceptable toxicity, or withdrawal. ORR, duration of response (DoR), time to response (TTR), disease control rate (DCR), progression-free survival (PFS) (all assessed by independent committee review per RECIST v1.1), overall survival (OS), and safety were evaluated in pts with gynecologic tumors. <b>Results:</b> At the time of the latest data cut-off (July 8, 2021), 80 pts were enrolled, and 75 pts were included in the efficacy analysis set, of whom 15 had gynecologic tumors (median age: 55 years; range: 41-67 years): 13 had endometrial cancer, one had cervical cancer, and one had ovarian cancer. ORR in pts with gynecologic tumors was 53.3% (95% CI: 26.6-78.7). Three pts had complete responses (all had endometrial cancer), five pts had a partial response (three pts with endometrial cancer, one pt with cervical cancer, and one pt with ovarian cancer), one pt had stable disease (endometrial cancer), and four pts had progressive disease (endometrial cancer). At a median follow-up duration of 17.5 months, me dian OS was not reached; median PFS and median DoR were also not reached. Median TTR was 9.1 weeks, and DCR was 60.0% (95% CI: 32.3-83.7). TIS was generally well tolerated in pts with gynecologic tumors (Table 1); the most common treatment-emergent adverse events were increased alanine aminotransferase (86.7%), increased aspartate aminotransferase (46.7%), decreased white blood cell count (46.7%), and anemia (46.7%). <b>Conclusions:</b> This subgroup analysis demonstrates that TIS was clinically active in pts with gynecologic MSI-H/dMMR tumors and was generally well tolerated with no new safety signals. These data support TIS as a potential new treatment option for pts with gynecologic MSI-H/dMMR tumors and further investigation with a larger population is warranted to further confirm the clinical benefit of TIS in these pts. [1] J Li, et al. J Clin Oncol 2021;39(15_suppl):2569 <b>Acknowledgments:</b> This study is sponsored by BeiGene Ltd. Medical writing support for the development of this abstract, under the direction of the authors, was provided by Claire White, Ph.D., of Ashfield MedComms, an Ashfield Health company, and was funded by BeiGene Ltd.

Efficacy of Preoperative mFOLFIRINOX vs mFOLFIRINOX Plus Hypofractionated Radiotherapy for Borderline Resectable Adenocarcinoma of the Pancreas

National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear. To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC. This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021. Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2 over 46 hours). Each treatment arm's 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection. Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively. This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting. ClinicalTrials.gov Identifier: NCT02839343.

Evaluation of phase 2 single-arm two-stage trials in glioblastoma and brain tumor.

e14033 Background: Oncology clinical trials have shown the lowest success rate on Phase 2 and the highest median expense in a new drug to market. We aimed to assess the appropriate implementation of single-arm two-stage Phase 2 trials with other critical design issues of phase 2 single-arm trials such as selection of primary endpoint and historical control rates, and challenges of the blood-brain barrier, and to suggest guidelines to handle design issues related to single-arm Phase 2 trials in Neuro-Oncology. Methods: Two researchers searched with the key words of “phase 2 single arm two-stage design in glioblastoma” through PubMed.gov, clinicaltrials.gov, and Google Scholar to examine study designs of (i) study information, (ii) two-stage design parameters, (iii) rejection numbers and sample size for each stage. Design issues in primary endpoints, historical controls, and challenges on brain tumor trials were discussed with the effect of adaptive design on two-stage designs, and several guidelines on these issues were suggested for investigators in Phase 2 single-arm Neuro-Oncology trials. Results: Almost 50% of single-arm two-stage studies failed to provide key information related to study designs and sample size calculation, even wrong power analysis and interpretation. Response rate and progression-free survival are used as popular surrogate endpoints for overall survival. It is time to evaluate other potential endpoints like post-progress survival and hazard ratio, and usefulness of co-primary endpoint. Investigators should keep transparency of the trials by fully providing and citing historical data source. If there exist large variabilities among existing historical data, meta-analysis can be a good option to accurately estimate the historical control. Conclusions: The appropriate selection on primary endpoint(s) and historical control data, incorporation of adaptive designs if necessary, and right application of two-stage design might help overcoming the challenges on low success rates in new therapeutic oncology trials. Furthermore, the new paradigm of Phase 0 trial might be one potential tool to overcome the challenges with insufficient penetration of therapeutic agents across the blood-brain barrier and limitations in the applicability of animal models to the human condition in glioblastoma and Neuro-Oncology.

Social Vulnerability and COVID-19: Changes in Trauma Activations at a Safety-Net Hospital.

IntroductionFollowing the declaration of the COVID-19 pandemic, there were reports of decreased trauma hospitalizations, although violent crime persisted. COVID-19 has had the greatest impact on minoritized and vulnerable communities. Decreases in traumatic events may not extend to these communities, given pandemic-related socioeconomic and psychological burdens that increase the risk of exposure to trauma and violence.Materials and methodsThis was a retrospective cohort study (n = 1634) of all trauma activations presenting to our institution January 1, 2020 to May 31, 2020, and same time periods in 2018 and 2019. Census tracts and associated Social Vulnerability Index quartiles were determined from patient addresses. Changes in trauma activations pre and post Massachusetts’ state-of-emergency declaration compared to a historical control were analyzed using a difference-in-differences methodology.ResultsWeekly all-cause trauma activations fell from 26.44 to 8.25 (rate ratio = 0.36 [0.26, 0.50]) postdeclaration, with significant difference-in-differences compared to a historical control (P < 0.0001). Nonviolent trauma activations significantly decreased from 21.11 to 5.17 after the declaration (rate ratio = 0.27 [0.37, 0.91]; P < 0.0001), whereas there was no significant decrease in violent injury (5.33 to 3.08 rate ratio = 0.69 [0.39, 1.22]; P = 0.20). Stratified by vulnerability, the most vulnerable quartile had an increased proportion of all-cause trauma postdeclaration and had no decrease in violent trauma activations following the declaration compared to the historical control (rate ratio = 0.84 [0.38-1.86]; P = 0.67).ConclusionsThe state-of-emergency declaration was associated with significant decreases in overall trauma, to a greater extent in nonviolent injuries. Among those living in the most socially vulnerable communities, there was no decrease in violent trauma. These findings highlight the need for violence and injury prevention programs in vulnerable communities, particularly in times of crisis.

A Prospective, Single-Arm, Phase II, Multi-Center Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer

To measure the biochemical disease-free survival (bDFS) & the rates of acute & late gastrointestinal (GI) or genitourinary toxicity (GU) following stereotactic body radiation therapy (SBRT) for clinically localized prostate adenocarcinoma.Eligible men aged 18 years & older with NCCN low- & intermediate-risk prostate cancer & ECOG performance status 0-1 were enrolled at two institutions. Participants were simulated with a Foley catheter to visualize the prostatic urethra. All patients received MRI. Participants received 36.25 Gy in 5 fractions on non-consecutive days to the planning target volume (PTV) with a simultaneous boost of 40 Gy to the entire prostate. Treatment was performed on a linear accelerator or frameless robotic radiosurgery system. Androgen deprivation therapy & hydrogel spacer placement were not permitted. The coprimary endpoints were grade 3 or higher GI or GU toxicity as measured by CTCAE v3.0 & bDFS using the Phoenix criteria. This study was designed to test the null hypothesis that the cumulative incidence of Grade 3 or higher GI/GU toxicity rate at 2 years was less than 10%. With n = 200 eligible patients, there was 99% power of identifying an unacceptable toxicity rate if the true toxicity rate was 20% with a one-sided significance level of 0.05. Assuming a 2-year bDFS rate of 97% for SBRT, a sample size of 200 patients also provided 92% power to determine if SBRT was superior to a historical bDFS control rate of 92%. Secondary endpoints were quality of life (QoL), prostate cancer-specific mortality, & overall survival.From January 2011 to July 2020, we enrolled 163 men. The trial was stopped early due to slow accrual. Two men were deemed ineligible & one man withdrew consent leaving 160 evaluable men. Median age was 67.9 years (IQR 62.6-73.2), 60 men (37.5%) were low risk, and 100 (62.5%) were intermediate risk. Median prostate volume was 41.5 cm3 (IQR 35.0-59.2), median baseline IPSS was 7 (IQR 3-12), and median baseline SHIM was 15 (IQR 3-23). Median PTV coverage was 96.9%. With a median follow-up of 2.2 years, the worst acute GU toxicity proportions were grade 2 in 51 (31.9%) & grade 1 in 66 (41.2%) patients, and the worst acute GI toxicity proportions were grade 2 in 7 (4.3%) and grade 1 in 30 (18.8%) patients. The cumulative incidence of late GI and GU grade 2 adverse events were 3.1% and 20.6%, respectively. No acute or late grade 3 or higher GI or GU toxicities were reported, meeting the co-primary safety endpoint (P < 0.001). 2-year bDFS was 98%, significantly higher than historical control (P < 0.01). Dosimetric correlates for toxicities and QoL will be reported separately.In one of the largest prospective series to date, prostate SBRT for low- and intermediate-risk prostate cancer is efficacious and well tolerated, with high rates of early biochemical control and low rates of clinically significant toxicity. Long-term outcomes will be reported with longer follow-up.

A Phase II Study to Determine the Efficacy of Pre-Operative Stereotactic Radiosurgery Followed by Resection for Brain Metastasis

<h3>Purpose/Objective(s)</h3> Brain metastasis is a frequent cause of morbidity and mortality in stage IV cancer patients. Efforts to treat brain metastasis include surgical resection, whole brain radiation treatment (WBRT), and stereotactic radiosurgery (SRS). In contemporary times, SRS is deployed utilizing conformal, high dose radiation with rapid dose fall off to limit neurocognitive toxicity seen with WBRT. In the combined modality setting wherein surgical resection is required, post-operative SRS is utilized with excellent local control. However, several difficulties may arise from treatment in the post-operative setting. Changes to the tumor bed necessitating increased margin for uncertainty, increased treatment normal brain tissue, treatment in a hypoxic field may portend for less-than-ideal treatment. Therefore, pre-operative SRS is being explored due to potentially better-defined target, less target uncertainty, and reports of less radionecrosis and less leptomeningeal disease. Therefore, our group conducted a phase II clinical trial exploring the efficacy of the preoperative SRS approach in regard to local brain control, distant brain control, and overall survival. <h3>Materials/Methods</h3> A phase II institutional non-randomized clinical trial was initiated at UPMC Hillman Cancer Center enrolling patients with brain metastasis of any malignant histology. Lymphoma, leukemia, multiple myeloma, or germ cell tumors were excluded due to their radiosensitive nature. Patients were to receive SRS followed by surgical resection. Inclusion criteria included ≥18yo, KPS≥50 with a life expectancy of 12 weeks. Patients could have no more than four lesions measuring 1.5-4.0cm in size. Patients that had tumors < 3cm in size were required to be symptomatic to enroll on trial. Patients were subsequently selected to receive 15Gy, 18Gy, or 24Gy, based on tumor size. All patients proceeded to surgical resection within seven days of SRS. The primary endpoint was local control of ≥ 85% when compared to historical control rate of 60%. <h3>Results</h3> A total of 24 patients were enrolled on study. One patient was deemed unresectable due to risk to the peri- rolandic location. Median number of brain metastasis treated was one (range 1-3). The most common treated histology was non-small cell lung carcinoma (NSCLC) (9). Median days from consult to SRS was 3.9 days. Median SRS dose and fraction was 16.5Gy [range: 15-24Gy] in a single fraction. The median number of surveillance MRIs performed was 6 [range 1-17]. Local brain control was 90%, 90%, and 74% at 6, 12, and 24 months. Distant brain control at 6, 12, and 24 months was 66%, 60%, and 54% respectively. Progression free survival (PFS) and overall survival (OS) at 6, 12, and 24 months were as followed [46%, 38%, 29%] and [66%, 58%, 50%] respectively. <h3>Conclusion</h3> Preoperative stereotactic radiosurgery appears to have excellent local control with a 6- and 12-month local control rates of 90%. Further study is warranted in the continued exploration of preoperative radiation therapy.

A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study.

BackgroundMost patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients.MethodsWe conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population.ResultsThirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56–84%) with median RFS of 21 months (95% CI, 14–40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05–0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15–0.93, p = 0.0351, respectively).ConclusionsAdjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.

Preliminary Results from an Open-Label, Phase 2 Study of Tipifarnib in Chronic Myelomonocytic Leukemia (CMML)

BackgroundTipifarnib is a potent and selective inhibitor of farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation. KRAS and NRAS, on the other hand, can undergo an alternative pathway for prenylation, i.e. geranylgernylation, enabling these cancer cells to overcome signaling inhibition by FT inhibition alone. Oncogenic RAS pathway mutations (NRAS, KRAS, CBL and PTPN11) are seen in approximately 30% of CMML patients (Patnaik BCJ 2016) and are associated with a proliferative phenotype. Tipifarnib has previously been shown to be well tolerated and to have a 32% response rate in patients (pts) with myelodysplastic syndromes, including 3 (17%) complete responses in 17 pts with CMML (Fenaux Blood 2007). Given the known resistance mechanisms and reported clinical activity, we hypothesize that tipifarnib might have greater activity in RAS wild type CMML patients. We report the efficacy, safety and biomarker data from our ongoing Phase 2 study in CMML.MethodsThis Phase 2 study is a multi-institutional, single-arm, open-label study to determine the efficacy and safety of tipifarnib in pts with CMML (N=20). Pts aged ≥ 18 years old and with a performance status of 0-1 were eligible and retrospectively stratified based on KRAS/NRAS mutational status. At study initiation, pts received 1200 mg orally twice daily, but due to frequent myelosuppression and azotemia, the trial was amended and 900 mg twice daily on days 1-7 and 15 -21 of 28-day treatment cycles was selected as the optimal dose. The primary endpoint was overall response rate (ORR) per Myelodysplastic/Myeloproliferative International Working Group (MDS/MPN IWG) criteria (Savona Blood 2015) with the probability that the TRUE underlying ORR rate exceeds historical control rate 0.1 computed via Bayesian methodology. Secondary endpoints included safety and tolerability, duration of response (DOR) and progression free survival (PFS). Biomarker studies included, serial next-generation sequencing, gene expression profiling of pre- and on-treatment bone marrow samples by RNASeq and flow cytometry based monocyte and immune cell subsets analyses. Clinical trial information: NCT02807272.ResultsAt data cut-off (July 2017), 15 pts (11 CMML-1, 4 CMML-2) were treated with tipifarnib, with 10 pts continuing on treatment in cycles 1 - 6. Most common treatment related AEs (all grades) were thrombocytopenia (33%); diarrhea and nausea (27%); neutropenia, fatigue and vomiting (20%). 1 pt experienced tumor lysis syndrome during the first cycle of tipifarnib treatment that resolved with sequelae. Of the 7 pts evaluable for response, marrow response and symptom response have been observed in 1 pt each, 4 pts have stable disease and 1 pt progressed. Five of those pts received prior therapy with hypomethylating agents (HMA). DNA sequencing data are available for 10 pts. Most commonly observed mutations at study entry were TET2 (80%), SRSF2 (50%), ASXL1 (50%), NRAS (50%), CBL (40%), RUNX1 (40%), EZH2 (30%), and KRAS (20%). Two of the 5 pts with NRAS mutations were evaluable beyond cycle 2 and an increase in NRAS allele frequency was observed (15 to 32%, p = 0.04 and 13 to 20%, p = ns). No meaningful changes were observed in the allele frequency of other mutations. Early decreases in monocytes counts were observed in several pts with a responding patient having normalization of CD14+/CD16- classical monocytes.ConclusionIn this ongoing Phase 2 trial, preliminary data suggest that tipifarnib was generally well-tolerated and has antitumor activity in pts with CMML in a post-HMA setting. DisclosuresSallman:Celgene: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Bejar:Foundation Medicine: Honoraria, Other: Ad-hoc advisory board; Celgene: Consultancy, Honoraria, Other: DSMB, Steering Committee, Research Funding; Genoptix: Consultancy, Honoraria, Patents & Royalties; Otsuka/Astex: Honoraria, Other: Ad-hoc advisory board; AbbVie/Genetech: Honoraria, Other: Ad-hoc advisory board; Modus Outcomes: Consultancy, Honoraria. Bolognese:Kura Oncology: Consultancy. Traynor:Kura Oncology: Employment, Equity Ownership. Mishra:Kura Oncology: Employment, Equity Ownership. Wages:Kura Oncology: Consultancy. Gualberto:Kura Oncology: Employment, Equity Ownership, Other: Chief Medical Officer, Patents & Royalties. Scholz:Kura Oncology: Employment, Equity Ownership, Patents & Royalties.

Use of Direct Oral Anticoagulants in Inherited Thrombophilia

Introduction: Factor V Leiden mutation and prothrombin G20210A mutation are the most common causes of an inherited thrombophilia and together account for 50 to 60 percent of diagnoses. Traditionally, patients have been treated with oral warfarin therapy or injectable low molecular weight heparin (LMWH), which requires frequent laboratory monitoring or self-injections. The difficulty with administration and monitoring of traditional therapy has made direct oral anticoagulants (DOACs) increasingly favored for treatment of VTE. However, the efficacy and bleeding complication of DOAC use in inherited thrombophilia has not been well studied.Methods: We designed a retrospective analysis of patients with Factor V Leiden mutation and prothrombin G20210A mutation at the University of Virginia who were treated with a DOAC (rivaroxaban, apixaban, edoxaban, or dabigatran) for treatment of VTE or atrial fibrillation from January 28th, 2011 to May 30th, 2017. Adult patients with presence of either homozygous or heterozygous mutation for either Factor V Leiden mutation or prothrombin mutation were included. All patients were required to be treated for at least 48 hours with a documented follow-up of adverse events. Medical charts were reviewed for age, gender, weight, presence of Factor V Leiden mutation and/or prothrombin G20210A mutation, DOAC dose, and frequency, bleeding events, and recurrent thrombotic events. Our primary outcomes were efficacy defined as development of a recurrent VTE and safety defined as occurrence of any bleeding event. Efficacy was compared to the post-hoc sub-group analysis that was conducted on the data from the RE-MEDY trial, in which VTE/VTE-related deaths were observed to be 1.5% with patients taking dabigatran compared to 2.3% with patients taking warfarin (p=0.2277) (Skelley, et al. J Throm Thrombolysis, 2017). Major and minor events were defined per International Society of Thrombosis and Hemostasis (ISTH) anticoagulation committee guidelines.Results: Fifty eight patients were eligible for analysis. The median age was 52.7 ± 16.7 years with 39 (67.2%) females. Baseline patient characteristics, type of thrombophilia, and indication for DOAC therapy are represented in Table 1. Median length of time on a DOAC was 24 months.Four patients developed a recurrent VTE however on further analysis, 3 patients were found to be non-compliant with DOAC therapy. Excluding the noncompliant patients, the rate of a recurrent VTE was 1.7% (Table 2).Nine (15.5%) patients suffered a bleeding event, of which 4 were major and 5 were minor (Table 2). Of the 4 major bleeding events, 3 were gastrointestinal (GI). One patient bled due to arterio-venous malformations, the second patient developed a bleed at the esophagectomy site, and the third patient had biliary drainage from ischemic liver disease post liver transplant. One patient suffered an intracranial hemorrhage; this patient was concurrently taking aspirin and clopidogrel while on therapeutic apixaban. The minor bleeding events included epistaxis (n=1), hemoptysis (n=1) and GI (n=3). Hemoptysis was discovered simultaneously with the diagnosis of lung cancer. Three of the patients with minor bleeding events were taking ASA, including one who was also taking dual antiplatelet therapy with clopidogrel.Conclusion: DOACs have been shown to have similar efficacy and safety compared to warfarin in many patient populations. However, there are limited studies evaluating use of DOACs in patients with inherited thrombophilia. Substantial evidence supporting widespread DOAC use in these patients is lacking. Our study confirmed the efficacy of DOACs in this patient population with a thrombosis event of only 1.7% which is favorable compared to the warfarin historical control rate of 2.3% (Skelley, et al. J Throm Thrombolysis, 2017). There was a higher than expected rate of bleeding complications, however many patients were on dual antiplatelet therapy or had other risk factors for bleeding. It would be imprudent to attribute these bleeding events solely to DOAC use. Though this is the only study of its kind, it is limited by small numbers and retrospective design. Further studies are needed to evaluate the use of DOACs compared to warfarin and LMWH. We plan to conduct further analysis utilizing a control group of inherited thrombophilia patients on warfarin compared to those on DOACs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A phase Ib/II and pharmacokinetic study of EP0057 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer

Background: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC).Methods: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response.Results: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%).Conclusions: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words