tbuckley/cabot-search huggingface dataset:
Phase I dose escalation study of the first-in-class selective PTEFb inhibitor BAY 1251152 in patients with advanced cancer: Novel target validation and early evidence of clinical activity.
Authors: Jennifer Robinson Diamond, Victor Moreno, Emerson A. Lim, Raul Cordoba, Charles Cai, Stuart James Ince, John T. Lettieri, Claudia Merz, Ray Valencia, Valentina Boni
Journal: Journal of Clinical Oncology (2018)

2507 Background: PTEFb/CDK9 mediated transcription of short-lived anti-apoptotic survival proteins and oncogenes like MYC and MCL-1 plays a critical role in a variety of cancers. We present findings from a phase I study of BAY 1251152 in pts with solid tumors and aggressive NHL. Methods: Patients with advanced or metastatic solid tumors or aggressive NHL and refractory to available therapies were eligible. BAY 1251152 was administered once weekly as a 30-minute IV infusion on Days 1, 8 and 15 of a 21-day cycle. Tumor response was assessed according to RECIST v1.1 and the revised Cheson criteria (2007). Results: A total of 31 pts were enrolled and evaluable for safety, including subjects with breast cancer (n = 6), pancreatic adenocarcionoma (5), ovarian cancer (4), and colorectal cancer (3). No DLTs were reported in the first 3 cohorts (5 mg, 10 mg and 15 mg). There was one DLT in the 22.5 mg cohort (grade 4 [G4] neutropenia), which was then expanded to 6 pts without subsequent DLTs. At 30 mg, neutropenia became the most prominent AE, with one G3 febrile neutropenia and two G4 neutropenia's reported as DLTs in 9 evaluable pts. Three additional pts were enrolled in the 22.5 mg cohort, with one DLT (G3 neutropenia) but no other G3 or G4 drug-related AEs. The 30 mg dose was deemed the MTD. There were 4 deaths on study, none of which was attributed to study drug. Pharmacodynamic biomarker analysis showed significant dose-dependent reduction of MYC, PCNA, and MCL-1 RNA. PK was generally linear over the dose range. Antitumor activity consisted of stable disease (SD) in 9 subjects and durable SD in 3 pts: one relapsed pancreatic adenocarcinoma pt treated for 15 cycles, one double-hit DLBCL (GCB subtype, 2 prior lines) pt was treated > 22 cycles with a 40% reduction in tumor size and complete metabolic response, and a salivary gland carcinoma pt treated for > 24 cycles with a 21% reduction in tumor size; the latter 2 pts remain on treatment. Conclusions: PTEFb inhibitor BAY 1251152 had a manageable safety profile, apparent dose-proportional PK, on-target pharmacodynamic activity and signs of antitumor activity. Clinical trial information: NCT02635672.
A phase 1/2 study with birinapant in combination with pembrolizumab.
Authors: Russell J. Schilder, Mark Albertella, James Strauss, Malin Sydvander, Santosh M. Nair, Kingsley Urakpo, Stefan Norin, John Öhd
Journal: Journal of Clinical Oncology (2018)

TPS3131 Background: Birinapant is a bivalent SMAC mimetic with activity against multiple members of the inhibitor of apoptosis protein (IAP) family including cIAP1 and has demonstrated tolerability with robust and durable target engagement in advanced cancers. Synergistic effects of combining birinapant with immune checkpoint inhibitors have been demonstrated in preclinical models, consistent with the reported role of cIAP1 in tumor cells and immune cells (Beug et al., 2017). Based on these observations, a phase 1/2 trial with birinapant and pembrolizumab has been initiated (NCT02587962). Methods: In the dose escalation part of this multi-center phase 1/2 study, patients > 18 years with advanced solid tumors without further suitable standard therapeutic options are eligible for inclusion. The primary objective is to determine the safety and tolerability of the recommended phase 2 dose (RP2D) of birinapant in combination with pembrolizumab using a standard 3+3 design. The secondary objective is to assess efficacy by RECIST 1.1. The doses of birinapant to be evaluated are 5.6, 11, 17 and 22 mg/m2 IV on day 1 and 8 in addition to pembrolizumab 200 mg on day 1 in a 21-day cycle. RP2D will be proposed by the safety review committee. The phase 2 part plans to include 111 patients. The primary objective is to assess the clinical activity of birinapant and pembrolizumab, measured as ORR by RECIST in separate cohorts of microsatellite stable colorectal (N = 28), ovarian (N = 27) and cervical cancer (N = 26). Simon's two-stage design yields a type I error rate of 0.05 and statistical power of 0.80 for each of the three cohorts using a one-sided test based on true response rates of 20% (colorectal cancer), 25% (ovarian cancer) and 30% (cervical cancer). The study will also evaluate an exploratory cohort consisting of five patients each with small cell lung cancer, cholangiocarcinoma, gastroesophageal carcinoma, mesothelioma, head and neck squamous cell carcinoma (check-point inhibitor-naïve and experienced). The phase 2 secondary objectives are safety and tolerability, tumor response, progression-free and overall survival. Exploratory objectives will assess tumor response by iRECIST, pharmacokinetics, pharmacodynamics and predictive biomarkers. Clinical trial information: NCT02587962.
A next-generation statistical tool for phase I dose finding trials.
Authors: Yuan Ji
Journal: Journal of Clinical Oncology (2016)

e14037 Background: There are no consensus results for assessing different statistical designs for phase I dose finding trials. Despite previous findings in the literature that recommend against the use of the 3+3 design [Storer, Biometrics, 1990], it remains the standard method in the clinical community. Methods: Powered by big and crowd-sourcing data [Yang et al., Contemporary Clinical Trials, 2015], we present massive comparison of main-stream statistical designs for phase I dose-finding in oncology. The data (Table), summarized across more than 100 independent users worldwide, using computer simulations for over 4 million simulated trials, provide objective assessment of various statistical designs. Results: The crowd-sourcing data challenge the current standard use of the 3+3 design in the clinical community, as 3+3 is shown to be less safe and less effective in identifying the true maximum tolerated dose (MTD). Also, the data confirm the superiority of the mTPI design over 3+3 reported in the literature [Ji and Wang, JCO, 2013]. To facilitate the implementation of various designs in practice, we introduce a next-generation dose-finding tool, called NextGen-DF [Yang et al., CCT, 2015] that allows investigators to construct, compare, and calibrate multiple designs via internet, in real time, and independent of computer operating systems. As such, a phase I study can be fully designed on an iPad or a smart phone, as long as the device is connected to the internet. Conclusions: NextGen-DF allows for direct comparison of different designs via ultrafast and transparent web computing, thereby promoting the use of the safest and most powerful design. NextGen-DF is available at www.compgenome.org/NGDF and currently used by major industrial and academic institutions. NextGen-DF will be demoed in real time to the audience. Crowd-sourcing data comparing the 3+3, mTPI and CRM designs. mTPI CRM 3+3 Safety 0.848 (0.300) 0.836 (0.309) 0.829 (0.305) Reliability 0.518 (0.265) 0.500 (0.265) 0.375 (0.263) Safety = percentage of patients treated at doses at or below the true MTD. Reliability = percentage of simulated trials selecting the true MTD. Entries are median(sd) over 4,000,000 computer simulated trials.
TCT-790 Efficacy and Safety of the Ultrathin Bioresorbable Polymer Sirolimus-Eluting Stents versus Thin Durable Polymer Everolimus-Eluting Stents for Treatment of Patients With Diabetes Mellitus
Authors: Ron Waksman, Stephan Windecker, Jacques J. Koolen, David Kandzari, Shigeru Saito, Paul Kolm, Rebecca Torguson
Journal: Journal of the American College of Cardiology (2018)
Novel prognostic markers for epithelioid malignant pleural mesothelioma.
Authors: Rossella Bruno, Anello Marcello Poma, Greta Alì, Riccardo Giannini, Gianfranco Puppo, Franca Melfi, Marco Lucchi, Alfredo Mussi, Alfredo Falcone, Antonio Chella, Gabriella Fontanini
Journal: Journal of Clinical Oncology (2017)

e20028 Background: Malignant pleural mesothelioma (MPM) is a deadly asbestos related tumour. The median survival is about 12 months and MPM patients are usually offered with a multimodality approach. With regard to chemotherapy the treatment of choice is the antifolate pemetrexed in combination with cisplatin or carboplatin. The high variability in the survival of patients with similar characteristics make it challenging to identify reliable prognostic markers. In this study we sought novel prognostic markers for epithelioid MPM, by investigating the expression levels of 117 genes involved in cancer. Methods: Gene expression analysis was evaluated on RNA from 15 epithelioid MPM patients undergoing pleurectomy (fomalin-fixed paraffin-embedded tissue) using a custom panel on nanoString platform. All patients were treated with cisplatin plus pemetrexed chemotherapy. Patients were divided in two groups for each gene (high and low expression level) on the basis of median. The correlation between gene expression, overall survival (OS) and progression free survival (PFS) was carried out by Log-rank test (Kaplan Meier). Results: A poorer OS was associated with a higher expression of 3 genes: MCM2 (p-value 0.005), PLK1 (p-value 0.005) and CCNB2 (p-value 0.01). These findings were in agreement with TCGA data ( PROGgeneV2: enhancements on the existing database. BMC Cancer 2014). Moreover, PLK1 showed a significant correlation also with PFS (p-value 0.01). Conclusions: Several biomarkers have been suggested as MPM prognostic factors, but sensitive and specific ones for the clinical practice are still missing. Despite the relatively small number of tissue samples, related to the rarity of this tumour, we identified 3 genes as potential prognostic markers. MCM2 is involved in the initiation of genome replication, PLK1 and CCNB2 regulate cell cycle by promoting mitosis. All these genes proved to be not only useful prognostic indicators but also promising therapeutic targets as reported in functional studies on different cancer models. The validation of these new markers, particularly of PLK1 which is correlated also with PFS, may improve the prognostic stratification at diagnosis, providing information valuable in the management of MPM patients.
A randomized phase II study assessing an optimized schedule of oregovomab (O) anti-CA125 vaccination with carboplatin paclitaxel (CP) relative to CP alone in front-line treatment of optimally cytoreduced stage III/IV ovarian cancer (EOC).
Authors: Gabriella Ferrandina, Patricia S. Braly, Corrado Terranova, Vanda Salutari, Caterina Ricci, Francesco Raspagliesi, Domenica Lorusso, Pierluigi Benedetti Panici, Paolo Scollo, Francesco Plotti, Molly Brewer, Michael W. Method, Robert W. Holloway, Madi Madiyalakan, Christopher F. Nicodemus, Sergio L. Pecorelli, Giovanni Scambia, Roberto Angioli
Journal: Journal of Clinical Oncology (2017)

5536 Background: In a phase II study of vaccination schedule in front-line combinatorial treatment of EOC (Braly JIT 2009), simultaneous day infusion dramatically enhanced the magnitude of induced immunity relative to a one week delayed schedule &amp; other schedules historically evaluated. The current study is exploring the clinical &amp; biological effects of the optimized 4 vaccine schedule relative to CP alone. Methods: Stage III/IV EOC patients (pts) optimally debulked to &lt;1cm residual disease with CA125 &gt;2x ULN were randomized to CP+O (cycle 1,3,5, &amp; C5 +12 weeks) vs CP and followed for clinical outcomes and immune reponse. A total of at least 80 evaluable pts were required for 80% power to detect a difference of 45% vs 15% for a primary comparative analysis of induced CA125 specific T cell immunity using an IFN-γ ELISpot. Clinical evaluations and safety were considered secondary endpoints. Results: 97 pts (47 OV+SOC &amp; 50 SOC) were accrued at 13 centers in US &amp; Italy. Analysis of immune markers and long term clinical outcomes is ongoing. The median duration of follow up at time of this analysis was 26 months (m). There was no difference in safety outcomes between the treatment groups. Grade 3-4 toxicity was observed in 24 (52%) CP+O vs 28 (58%) C-P pts. Toxicities were typical of standard IV C-P chemotherapy. K-M Analysis of recurrence free survival (RFS) showed median RFS not estimable for CP+O [95% CI: 21.3, NE] vs 15.4 m [10.9,19.3] for CP (p=0.0009 log rank). In the interim analysis of survival (OS), 4 deaths have been observed in CP+O vs 16 in CP (log rank p=0.0025). Cox proportional hazard analysis finds consistent results across centers, and no imbalance in identified risk factors explanatory for the emerging outcome Conclusions: This study suggests simultaneous day vaccination with O on alternate cycles of front line CP leverages CP associated temporal change in the tumor microenvironment permitting an immune treatment effect to enhance the outcomes achievable with CP alone. This observation will be further characterized in ongoing translational studies and confirmed in a future phase III study. Clinical trial information: NCT01616303.
PCPs knowledge and self-efficacy for caring for breast and colon cancer survivors.
Authors: Niharika Dixit, Nancy Burke, Gladys Rodriguez, Urmimala Sarkar, Judy Quan, Joana Devore, Barbara Cicerelli, Anna Napoles
Journal: Journal of Clinical Oncology (2018)

10083 Background: The role of primary care providers (PCPs) in caring for cancer survivors is critical, as care shifts from active cancer treatment to managing late and long-term effects of treatment and health maintenance. Safety net providers often need to provide cancer survivorship care in limited resource settings. This study assessed PCPs’ knowledge, attitudes, and self-efficacy related to caring for breast and colon cancer survivors in a public hospital setting. Methods: A modified National Cancer Institute Survey of Physician Attitudes Regarding the Care of Cancer Survivors was sent electronically to 220 PCPs in 12 primary care clinics in the San Francisco Health Network affiliated with Zuckerberg San Francisco General Hospital. The response rate was 50% (110/220). Results: About half of PCPs strongly/somewhat agreed (vs. strongly/somewhat disagreed) that PCPs have the knowledge needed to provide follow-up care related to breast (49%) and colon cancer (53%). Providers were more likely to report feeling somewhat/very confident (vs. not at all confident) in providing appropriate surveillance testing to detect recurrent colon than breast cancer (73.6% vs. 65.3%). Most providers (92%) correctly reported recommended frequency of mammography, however, frequency of blood tests and other imaging surveillance were not as well recognized for breast or colon cancer. Recognition of long-term side effects of chemotherapy drugs was low (highest = 44% for Adriamycin). Lack of knowledge (76.3%) and unclear delineation of roles between PCP and oncologists (70.7%) were the most commonly reported barriers to providing high quality cancer survivorship care. Only 33% of providers reported receiving any survivorship training on late and long-term effects of treatment. The most preferred model for survivorship care was shared care (40.2%) and least preferred was one in which PCPs have primary responsibility (47.6%). Conclusions: PCPs feel they lack the appropriate knowledge, training, and confidence to assume primary responsibility for the care of breast and colon cancer survivors. A shared care model was most preferred, indicating an opportunity to improve survivorship care through effective oncologist-PCP-patient partnerships.
Single-agent dose-finding cohort of a phase 1/2 study of lenvatinib (LEN) in children and adolescents with refractory or relapsed solid tumors.
Authors: Nathalie Gaspar, Maria Soledad Gallego Melcon, Rajkumar Venkatramani, Stefan S. Bielack, Michela Casanova, Franco Locatelli, Estelle Thebaud, Charlotte Rigaud, Samuel Abbou, Marion Gambart, Bruce Morland, Isabelle Aerts, Silvija Kraljevic, Di Li, Hina Maniar, Seiichi Hayato, Corina E Dutcus, Quentin Campbell Hewson
Journal: Journal of Clinical Oncology (2017)

10544 Background: LEN is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet-derived growth factor receptor α, RET, and KIT. LEN is approved in adults for radioiodine-refractory differentiated thyroid cancer (DTC) and in combination with everolimus in patients (pts) with advanced renal cell carcinoma. We show results from the single-agent LEN dose-finding part of a phase 1/2 study in children and adolescents with solid tumors. Methods: Pts had any relapsed or refractory solid tumor, evaluable or measurable disease, were aged 2 to ≤18 years, had &lt; 2 prior VEGF-targeted therapies, and adequate organ function. A starting dose of LEN 11 mg/m 2 was escalated with a time-to-event continual reassessment method. The primary endpoint was to determine the LEN recommended dose (RD). Secondary objectives included best overall response (BOR), objective response rate, safety, and pharmacokinetics (PK). Results: 23 pts enrolled (11 mg/m 2 : n = 5, 14 mg/m 2 : n = 11, 17 mg/m 2 : n = 7). The most common tumors were rhabdomyosarcoma (n = 5), Ewing sarcoma (n = 4), and neuroblastoma (n = 3). 3 Dose-limiting toxicities occurred in cycle 1 at 14 mg/m 2 (increased alanine aminotransferase: 1; hypertension: 2). All pts had any-grade treatment-emergent adverse events (TEAEs; grade 3/4: 65%). Most common any-grade TEAEs were vomiting (52%), abdominal pain (48%), decreased appetite (48%), diarrhea (44%), and hypothyroidism (44%). 1 Pt discontinued LEN due to a LEN-related TEAE (hypertension). BOR was stable disease (n = 10). Effect of age on oral clearance and central volume of distribution was not significant. Exposure was similar to that in adults. LEN 14 mg/m 2 /day was therefore identified as the RD. Updated cohort 1 data will be shown. Conclusions: The LEN RD in children and adolescents was similar to the adult dose and showed a reasonable safety profile. PK in these pts did not differ significantly from that in adults. The phase 1b dose-finding study of LEN in combination with chemotherapy in osteosarcoma (OS) and phase 2 LEN monotherapy (RD 14 mg/m 2 ) parts in DTC and OS are ongoing. Clinical trial information: NCT02432274.
Estimated Costs of Pivotal Trials for Novel Therapeutic Agents Approved by the US Food and Drug Administration, 2015-2016
Authors: Thomas J. Moore, Hanzhe Zhang, Gerard Anderson, G. Caleb Alexander
Journal: JAMA Internal Medicine (2018)

A critical question in health care is the extent of scientific evidence that should be required to establish that a new therapeutic agent has benefits that outweigh its risks. Estimating the costs of this evidence of efficacy provides an important perspective.To estimate costs and assess scientific characteristics of pivotal efficacy trials that supported the approval of new therapeutic agents by the US Food and Drug Administration (FDA) from 2015 to 2016.This study identified 59 novel therapeutic drugs using the annual summary reports from the FDA Center for Drug Evaluation and Research. ClinicalTrials.gov, FDA reviews, and peer-reviewed publications that were publicly available in 2017 were used to identify 52 characteristics of each efficacy trial. Costs were calculated with a global clinical trial cost assessment tool available to contract research organizations and pharmaceutical sponsors.Estimated mean cost and 95% CIs based on industry benchmark data from 60 countries. Measures of trials' scientific characteristics included trial design (no control group, placebo, and active drug), end point (surrogate outcome, clinical scale, and clinical outcome), patient enrollment, and treatment duration.A total of 138 pivotal clinical trials provided the basis for approval of 59 new therapeutic agents by the FDA from 2015 to 2016, with a median estimated cost of $19.0 million (interquartile range, $12.2 million-$33.1 million). Estimated costs ranged from less than $5 million for trials without a control group for 3 orphan drugs with fewer than 15 patients each to $346.8 million (95% CI, $252.0 million-$441.5 million) for a noninferiority trial with end points assessing clinical benefit. Twenty-six of 138 trials (18.8%) were uncontrolled, with a mean estimated cost of $13.5 million (95% CI, $10.1 million-$16.9 million). Trials designed with placebo or active drug comparators had an estimated mean cost of $35.1 million (95% CI, $25.4 million-$44.8 million). Costs also varied by trial end point, treatment duration, patient enrollment, and therapeutic area.The highest-cost trials were those in which the new agent had to be proved to be noninferior with clinical benefit end points compared with an agent already available or those that required larger patient populations to achieve statistical power to document smaller treatment effects or accrue infrequently occurring end points.
Treatment and outcomes of small cell neuroendocrine carcinoma of the cervix (SCCC).
Authors: Brooke Schlappe, Emmet Jordan, Qin Zhou, Alexia Iasonos, Mario M. Leitao, Kay J. Park, Kaled M. Alektiar, Oliver Zivanovic, Paul Sabbatini, Carol Aghajanian, Roisin Eilish O'Cearbhaill
Journal: Journal of Clinical Oncology (2017)

5531 Background: Extrapulmonary small cell carcinoma is rare. SCCC represent 2% of cervical cancers and can portend a poor prognosis. Treatment standardization is challenging given its rarity. We describe management of limited stage (LS; disease could be encompassed within one radiation port) at a large tertiary referral center and the characteristics and outcomes in a cohort of patients (pts) with LS and extensive stage (ES) SCCC. Methods: Pts with SCCC diagnosed from 1/1990-1/2016 were identified following IRB approval. Clinicopathologic, treatment, and follow-up data were recorded. Descriptive statistics were provided. Median PFS/OS or PFS/OS rate were estimated using Kaplan-Meier method. Results: 39 pts were identified, 29 with LS. Select characteristics are shown in table. Tumor molecular profiling revealed MYC amplifications, TP53 mutations, PIK3CA mutation among the small subset of pts who had this performed. LS SCCC was treated with whole pelvic radiation therapy (RT) (4500-5040cGy) and concurrent IV cisplatin (60mg/m 2 ) on day 1 and etoposide (120mg/m 2 ) on days 1, 3, and 5 during RT and days 1-3 post RT to complete a total of 4 cycles. 26 pts, all had LS, underwent initial surgical management. No pt had prophylactic cranial RT. 3 pts (8%), all had LS, developed brain metastases. Median follow-up was 59.5 months (1.9-234.1). Median PFS (95%CI) for LS pts was 39.2 months (15.1-not estimable) vs 2.9 months (0.9-4.6) for ES. Median OS(95%CI) was 31.8 months (16.3-56.0) for the whole cohort, 52.8 months (31.8-not estimable) for LS and 5.9 months(1.8-16.3) for ES. Conclusions: In the LS SCCC cohort treated with concurrent cisplatin/etoposide chemo/RT and outback cis/etoposide +/- post initial radical hysterectomy the 5-year PFS (95%CI) was 37.5% (19.2-55.9%). Clinicopathologic characteristics and risk factors for SCCC appear distinct to cervical cancers and lung small cell cancers. Further investigation of molecular alterations and treatment of this rare tumor is needed to improve pt outcomes. [Table: see text]