tbuckley/cabot-search huggingface dataset:
Reassessing the Role of Surrogate End Points in Drug Development for Heart Failure
Authors: Stephen J. Greene, Robert J. Mentz, Mona Fiuzat, Javed Butler, Scott D. Solomon, Andrew P. Ambrosy, Cyrus Mehta, John R. Teerlink, Faiez Zannad, Christopher M. O’Connor
Journal: Circulation (2018)

With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.
Disparities in Neurotoxicity Risk and Outcomes among Pediatric Acute Lymphoblastic Leukemia Patients
Authors: Olga A. Taylor, Austin L. Brown, Julienne Brackett, ZoAnn E. Dreyer, Ida Ki Moore, Pauline Mitby, Mary C. Hooke, Marilyn J. Hockenberry, Philip J. Lupo, Michael E. Scheurer
Journal: Clinical Cancer Research (2018)

Purpose: Methotrexate chemotherapy can be associated with neurologic complications during therapy and long-term neurologic deficits. This study evaluated demographic and clinical factors associated with incidence of methotrexate neurotoxicity and described the impact of neurotoxicity on acute lymphoblastic leukemia (ALL) therapy in pediatric patients.Experimental Design: Patients were enrolled between 2012 and 2017 from three pediatric cancer treatment centers in the United States. Medical records for suspected cases of methotrexate neurotoxicity, defined as an acute neurologic event following methotrexate therapy, were reviewed. Cox proportional hazards models were used to estimate the association between race/ethnicity and methotrexate neurotoxicity. Multivariable linear regression models compared treatment outcomes between patients with and without methotrexate neurotoxicity.Results: Of the 280 newly diagnosed patients enrolled, 39 patients (13.9%) experienced methotrexate neurotoxicity. Compared with non-Hispanic whites, Hispanic patients experienced the greatest risk of methotrexate neurotoxicity (adjusted HR, 2.43; 95% CI, 1.06-5.58) after accounting for sex, age at diagnosis, BMI Z-score at diagnosis, and ALL risk stratification. Patients who experienced a neurotoxic event received an average of 2.25 fewer doses of intrathecal methotrexate. Six of the 39 cases of neurotoxicity (15.4%) experienced relapse during the study period, compared with 13 of the 241 (2.1%) patients without neurotoxicity (P = 0.0038).Conclusions: Hispanic ethnicity was associated with increased risk of methotrexate neurotoxicity, which was associated with treatment modifications and relapse. Understanding the mechanism and predictors of methotrexate neurotoxicity is important to improving treatment outcomes in pediatric ALL. Clin Cancer Res; 24(20); 5012-7. ©2018 AACR.
Hematological toxicity with adjuvant FOLFOX in colon cancer.
Authors: Jean Alfred Maroun, Horia Marginean
Journal: Journal of Clinical Oncology (2016)

e15062 Background: The curability of colon cancer (CC) has improved with the introduction of FOLFOX adjuvant chemotherapy. Better understanding of FOLFOX hematologic toxic profile has to be defined in order to achieve improved delivery of chemotherapy. Methods: We review consecutive charts of CC patients (pts) treated at TOHCC that received ≥ 1 cycle of adjuvant FOLFOX from January 1st 2007. We assessed the incidence of chemo-induced neutropenia (CIN) and thrombocytopenia (CIT), defined as the threshold where according to the TOHCC practice FOLFOX adjustment is considered: CIN ≤ 1.3 x109/L, CIT ≤ 100 x109/L. G-CSF secondary prophylaxis was used according to clinicians’ decision. The specific survival rate was calculated using the Kaplan-Meier method and competing risks survival analysis. Results: 302 pts were enrolled: median age 60 years, 59% female, 94%/6% ECOG PS 0/1, 55% proximal location, 88% stage III. After a median follow-up of 29 months, pts that received adjuvant mFOLFOX6, experienced 10% FOLFOX related admissions, 2% febrile neutropenia, 26% recurrence, 92% survival. Of the 164 (54%) of pts that developed CIN, 48% received G-CSF (38% after the 1st event). Median time to 1st CIN was 4.3 months. The risk to develop CIN is 84% lower for young ( < 65 yo), obese (BMI ≥ 30 kg/m2) men with high ANC ( > 4.3). The competing risks effect of FOLFOX discontinuation without CIN was not important. CIN recurred in 54% of pts after a median of 2.5 months. After the 1st CIN occurrence, the ability to complete 12 cycle, the number of cycles completed or attrition rate does not differ with use of G-CSF secondary prophylaxis. FOLFOX relative dose intensity (RDI) was 91% for pts without CIN, while the ones with CIN had 85% RDI without secondary G-CSF and 81% if secondary prophylaxis was required. 49% pts experienced CIT after median time of 5.3 months. While obese pts (BMI ≥ 30 kg/m2) experienced lower rates of CIT, the risk was higher in pts with proximal tumour location and low platelets at baseline. Conclusions: CIN and CIT are common, expected hematologic adverse events that occur each in half of pts receiving adjuvant FOLFOX treatment for CC. Recurrent CIN occurs in half of pts despite dose adjustments. Use of G-CSF secondary prophylaxis ensured equivalent FOLFOX exposure and RDI.
Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) study (NRG- GI004/SWOG-S1610): A randomized phase III study of mFOLFOX6/bevacizumab combination chemotherapy with or without atezolizumab or atezolizumab monotherapy in the first-line treatment of patients with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer.
Authors: James J. Lee, Greg Yothers, Samuel A. Jacobs, Hanna Kelly Sanoff, Deirdre Jill Cohen, Katherine A Guthrie, Norah Lynn Henry, Patricia A. Ganz, Scott Kopetz, Peter C. Lucas, Carmen Joseph Allegra, Charles David Blanke, Norman Wolmark, Howard S. Hochster, Thomas J. George, Michael J. Overman
Journal: Journal of Clinical Oncology (2018)

TPS3615 Background: DNA mismatch repair defect (dMMR) colorectal cancer (CRC) cells are highly immunogenic. Preclinical data showed that oxaliplatin-containing chemotherapy in combination with anti-VEGF enhances the antitumor activity of programmed cell death-1 (PD-1) pathway blockade in murine CRC models. Prior phase I study showed that mFOLFOX6/bevacizumab (bev) plus atezolizumab was well tolerated and enhanced intratumoral infiltration of CD8+ T cells. We hypothesize that the dMMR subset of CRC may be effectively targeted with the combination of PD-1 pathway blockade and mFOLFOX6/bev to promote tumor regression. Methods: This is a prospective randomized phase III open-label trial. Patients (pts) (N=347) with metastatic dMMR CRC will be randomized to 3 trial arms (1:1:1): mFOLFOX6/bev; atezolizumab monotherapy; or mFOLFOX6/bev plus atezolizumab. Stratification factors include BRAF status, metastatic site, and prior adjuvant therapy for CRC. Primary objective is to evaluate the efficacy of mFOLFOX6/bev/atezolizumab and atezolizumab monotherapy as compared to mFOLFOX6/bev. Primary endpoint is progression-free survival (PFS) assessed by study investigator. Secondary endpoints include overall survival, objective response rate, safety profile, surgical conversion rate, disease control rate, duration of response, and PFS by retrospective central review. Exploratory objective includes health-related quality of life. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: Metastatic CRC without prior chemotherapy for metastatic disease; Tumor determined to be dMMR by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2); Availability of archived tumor tissue for central confirmation of dMMR status; and measurable disease per RECIST. Activated as of Nov 7, 2017, the 1st of the planned 347 pts has been enrolled. Clinical trial #: NCT02997228. SUPPORT: U10CA180868, -180822, UGICA189867, U24CA196067 Clinical trial information: NCT02997228.
The TCGA malignant pleural mesothelioma (MPM) project: VISTA expression and delineation of a novel clinical-molecular subtype of MPM.
Authors: Marc Ladanyi, Bruce WS Robinson, Peter J. Campbell
Journal: Journal of Clinical Oncology (2018)

8516 Background: To expand the understanding of MPM biology and pave the way for novel therapeutic strategies, The Cancer Genome Atlas (TCGA) Research Network conducted a comprehensive integrated genomic study of MPM. Methods: We performed whole exome, mRNA, miRNA, and non-coding RNA sequencing, copy number analysis, DNA methylation and reverse-phase protein array profiling on 74 rigorously reviewed and annotated MPM cases with no prior radio- or chemotherapy, followed by integrated data analyses. Findings were extended or validated using additional external datasets. Results: Three key findings emerged from the analyses of this comprehensive integrated genomic dataset. First, we defined a novel subtype of MPM characterized by extensive loss of heterozygosity, (genomic near-haploidization), and inactivating mutations in TP53 and SETDB1, which encodes a histone methyltransferase involved in epigenetic gene silencing. SETDB1 mutations appear specific to this novel subset of MPM, which accounts for approximately 3% of MPM patients, is more frequently found in younger and female patients and shows little or no linkage to asbestos exposure. Secondly, we detected strong expression of the immune checkpoint molecule VISTA [a.k.a. PD1-H (PD1 homolog) or B7-H5] in MPM, particularly in the more differentiated epithelioid subtype, where it is higher than in any other cancer type studied by TCGA. Immunohistochemistry confirmed that VISTA is present in epithelioid MPM tumor cells and in normal and reactive mesothelium, suggesting that its expression in epithelioid MPM may reflect retention of mesothelial cell antigen presenting properties. Thirdly, through the most comprehensive analysis of BAP1 status in MPM to date, we found the overall prevalence of BAP1 alterations to be 57%, and defined their downstream effects in terms of gene expression, transcriptional networks, and immune cell reactivity. Conclusions: Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. In particular, our findings provide both a rationale and a biomarker for clinical trials of emerging anti-VISTA immunotherapies in this highly lethal cancer.
DREAM: A phase II study of durvalumab with first line chemotherapy in mesothelioma—First results.
Authors: Anna K. Nowak, Willem Joost Lesterhuis, Brett Gordon Maxwell Hughes, Chris Brown, Peey Sei Kok, Kenneth John O'Byrne, Tom John, Nick Pavlakis, Steven Chuan-Hao Kao, Sonia Yip, Deme John Karikios, Wei-Sen Lam, Ailsa Langford, Martin R. Stockler
Journal: Journal of Clinical Oncology (2018)

8503 Background: DREAM is an open-label, single arm, multi-centre, phase II trial with a safety run in designed to determine the activity, safety and tolerability of durvalumab combined with cisplatin and pemetrexed as first line therapy in malignant pleural mesothelioma (MPM). ANZ Clinical trial registry number: ACTRN12616001170415. Methods: Chemotherapy-naïve patients with MPM of all histological subtypes, planned for first-line cisplatin and pemetrexed who had not received prior radiotherapy and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 were eligible. Patients received durvalumab (1125mg), cisplatin (75mg/m2) and pemetrexed (500mg/m2) 3-weekly for a maximum of 6 cycles, followed by durvalumab alone (1125 mg 3-weekly) until progression or to 12 months total therapy. Primary endpoint was progression-free survival at 6 months (PFS6). The design provides >90% power if the true PFS6 rate is 65%, with 5% type I error using an expected PFS6 from standard treatment of 45%. Matching tissue and bloods were collected for translational research. Results: Between Dec 2016 to Sep 2017 54 participants were recruited. The median age was 68 (42-82) with 82% male and 60% ECOG 0. They received a median of 6 cycles of chemotherapy (range 1-6) and 7 of durvalumab (given with and without chemotherapy) (range 1-18). The 6-patient safety run in confirmed the tolerability of chemoimmunotherapy. In the first 31 evaluable patients (pre-specified primary interim analysis), PFS6 based on modified RECIST (mRECIST) for MPM was 71%. The objective response rate (ORR) was 61% using mRECIST and 53% using iRECIST. Thirty-one patients (57%) experienced adverse events (AEs) that were grade ≥3. Nineteen patients (35%) had immune-related (ir) AEs including 2 grade 3 irAEs. Conclusions: In MPM, adding durvalumab to first line treatment with cisplatin and pemetrexed had higher rates of PFS6 and ORR than expected for chemotherapy alone, with acceptable tolerability. The final result of PFS6 for all 54 patients will be reported in late 2018. Clinical trial information: ACTRN12616001170415.
Current trends and in-patient outcomes of venous thromboembolism-related admissions in patients with Philadelphia-negative myeloproliferative neoplasms: A Nationwide Inpatient Sample Database analysis.
Authors: Xavier Alberto Andrade Gonzalez, Harry Eduardo Fuentes Bayne, Andres Mendez Hernandez, Hashim Mann, Alfonso Javier Tafur, Roberto Antonio Leon-Ferre
Journal: Journal of Clinical Oncology (2018)

e19030 Background: Patients with Philadelphia-negative myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (MF), have a significant risk of venous thromboembolism (VTE). Despite risk-adapted therapy, VTE remains a leading cause of hospitalization and healthcare expenditure. We aim to determine the trends in annual rates of VTE-related admissions, associated cost, length of stay (LOS), and in-hospital mortality in patients with MPN. Methods: We identified patients with PV, ET and MF from the Nationwide Inpatient Sample database from 2006 - 2014 using ICD-9CM coding. Hospitalizations where VTE was among the top-three diagnoses were considered VTE-related. We compared in-hospital outcomes between VTE and non-VTE hospitalizations using Chi-square and Mann-Whitney U-test and used linear regression for trend analysis. Results: We identified 1,046,666 admissions with a diagnosis of PV, ET and MF. Patients were predominantly white (65.6%) female (52.7%), with a median age of 66 years (range 18-108).The predominant MPN was ET (54%) followed by PV (29.8%). A total of 37,702 (3.6%) were VTE-related admissions. There was no difference in in-hospital mortality between groups (VTE: 3.4% vs Non-VTE: 3.2% p = 0.12), however VTE admissions had a longer LOS (median 6 days vs 5 days p < 0.01) and higher cost (median: VTE US$32,239 vs US$28,403 p = < 0.01). The annual rate of VTE admissions decreased over time (2006:3.94% vs 2014:2.43% p = < 0.01), however admissions for pulmonary embolism (PE) increased over the study period (2006:1.1% vs 2014:1.49%, p < 0.01) and were associated with higher likelihood of mortality (OR:2.02; CI 95% 1.88- 2.18; p < 0.01) compared with non-VTE-related admissions. Conclusions: In patients with Philadelphia-negative MPN, annual rates of VTE-related admissions have decreased over time but are associated with a higher cost and LOS. Admissions for PE have increased over time and are associated with a higher mortality. Newer risk assessment tools for PE may assist in preventing mortality and optimize resource utilization.
A prospective multicenter observational study of bevacizumab for the treatment of metastatic colorectal cancer in Chinese patients (Obtain study).
Authors: Fenghua Wang, Guanghai Dai, Yanhong Deng, Yong Tang, Wei Wang, Zuoxing Niu, Feng Bi, Liangjun Zhu, Zengqing Guo, Jin Yan, Bing Hu, Min Tao, Shujun Yang, Suzhan Zhang, Lu Wen, Ruihua Xu
Journal: Journal of Clinical Oncology (2018)

e15560 Background: Bevacizumab (BV) was approved in China seven years ago. Safety data from multicenter observational study was limited. To understand practical use of BV and confirm the correlation of prognostic factors with outcomes in Chinese patients (Pts) with mCRC, we have studied safety and efficacy of BV combined with 5-FU based chemotherapy (CT) in Pts with mCRC. Various subgroup analysis were considered in this study. Methods: The current study is a multicenter, prospective observational study. Pts were treated with BV plus 5-FU based CT for mCRC. The primary objective was to investigate the safety profile of the treatment. In the subgroup analysis, age, KRAS mutational status, peritoneal metastasis, primary tumor resection, metastatic status and blood pressure increasing were analyzed. Results: From Sep 2013 to Nov 2016, 613 Pts were accrued from 25 Chinese cites (median age 55 years (46–64); ECOG PS 0-1: 95.3%). Total 151 (24.63%) Pts experienced grade ≥ 3 AEs. AEs related to BV were reported in 46.98% of Pts. AESIs in this study were hypertension (1.96%), proteinuria (0.49%), bleeding (0.98%), GI perforation (0.33%), venous TE (0.16%) and fistula/abscess (1.14%). The median OS of all mCRC Pts was 18 months (95% CI, 16.99–20.07), (1st line 18 months (95% CI, 17.08–21.82); 2nd line 17.45 months (95% CI, 14.72–20.07)). The median PFS were 10.05 months (95% CI, 9.2%–11.37%), (1st line 11.04 months (95% CI, 9.66–13.34); 2nd line 8.74 months (95% CI, 7.49–10.58)). In the multivariate analysis of 1st line Pts and 2nd line Pts, peritoneal metastasis and blood pressure increasing were associated with OS, respectively. Age, KRAS mutation status, primary tumor location, primary tumor resection and metastatic status were not associated with OS in this population. Conclusions: The safety profile, such as BV-related AEs in this study seemed comparable with those reported from other pivotal studies or Chinese registration studies (ARTIST and REACT). BV combined with standard CT is effective. However, OS in1st line Pts was shorter than those studies. We will discuss this in future presentation and manuscript. Clinical trial information: NCT01912443.
Early integration of palliative care in Ontario cancer settings.
Authors: Frances Catriona Wright
Journal: Journal of Clinical Oncology (2017)

e18234 Background: Introducing palliative care early in the cancer journey results in a better life quality, less aggressive care and possibly longer survival compared to patients receiving standard care. The INTEGRATE project aimed to identify and manage patients who may benefit from palliative care earlier in their cancer treatment. This pilot project assessed whether multidisciplinary forums (Multidisciplinary Cancer Conferences, Clinics and Diagnostic Assessment Programs ) could be used to identify patients using the UK Gold Standards Framework Surprise Question (SQ) “Would you be surprised if this person died within the next year?” Methods: Cancer centres volunteered to pilot test the efficacy of the SQ at multidisciplinary forums and implement a palliative model of care. A survey was completed at 3 different points during the project to measure provider comfort in providing palliative care. All sites received primary level palliative care education. Patient and caregiver experience were assessed using interviews and a validated survey. Identified patients received Advance Care Planning (ACP), symptom management, referrals and standardized reporting to primary care. Patient level data was collected. Results: 3 academic and 1 non-academic cancer centres used the SQ in multidisciplinary forums to identify patients in the Lung, Gastrointestinal and Central Nervous System disease sites between February '15-August '16. A baseline survey showed over 50% of providers had no palliative care training. 157 providers received education and at the end of the project providers had increased comfort &amp; confidence in delivering palliative care. Analyses show that 933 patients were identified using the SQ, from which 78% had ACP initiated and 83% are receiving community palliative care services Conclusions: Multidisciplinary forums appear to be excellent for identifying patients who may benefit from a palliative approach to care. Inter-professional provider education and organized approaches to linking patients to community resources, had a positive impact on provider willingness to address end-of-life and palliative issues. Patients &amp; caregivers report positive experiences of care, but different levels of ‘readiness’ to have the ACP discussions.
Clinical correlates of response to anti-PD-1 (aPD1)-based therapy in patients (pts) with metastatic melanoma (MM).
Authors: Elizabeth J. Davis, Shilin Zhao, Fei Ye, Katherine Rappazzo, Jeffrey Alan Sosman, Douglas Buckner Johnson
Journal: Journal of Clinical Oncology (2017)

e21000 Background: aPD1, alone or in combination with ipilimumab (IPI), produces durable responses in a subset of MM. Tumor features that correlate with treatment response, including size, number, and location of metastases (mets) are not well defined. Methods: We collected clinical data from mm pts treated at one center who received aPD1 (n = 185) or aPD1 + IPI (n = 42). We correlated number of mets, size of largest tumor, and organ involvement with response rate (RR), progression-free survival (PFS) and overall survival (OS). Results: Among all pts, RR was 67% for aPD1 + IPI and 41% for aPD1 alone. In univariate analyses, responders to aPD1 had lower diameter of largest tumor (4cm vs. 5.5cm; p = 0.02) whereas aPD1 + IPI had equivalent largest tumor diameters (p = 0.65). Regarding sites of mets, liver mets were associated with lower RR in aPD1 treated pts (26% vs. 46%), lower PFS (median 138 vs. 326 days, p = 0.02), and lower OS (median 334 vs. 1080 days, p &lt; 0.01). No associations with RR, PFS, or OS were observed with liver mets in aPD1 + IPI treated pts. We also did not observe any differences between pts who did or did not have lung, lymph node, or brain mets for either aPD1 or aPD1 + IPI. Interestingly, superior RR to aPD1 + IPI was observed in pts with bone mets compared to those without bone mets (91% vs. 58%, p = 0.048). Regarding number of sites, RR to aPD1 was greater in pts with ≤10 mets compared with those with &gt; 10 (46% vs. 28%, p = 0.02), although no consistent relationship was observed at lower cutoffs. In multivariable analyses, diameter of largest tumor (tumor bulk) was independently associated with PFS (OR, 1.11, p &lt; 0.001) and OS (OR 1.08, p &lt; 0.001) whereas AJCC stage, lactate dehydrogenase, liver mets, ECOG performance status, number of mets, and prior therapies were not significant. Tumor bulk and other risk factors were not associated with PFS or OS in aPD1 + IPI. Conclusions: Tumor bulk was strongly and independently associated with clinical outcomes in aPD1 but not IPI + aPD1. Other associations with disease sites (liver and bone) need further validation. In conjunction with molecular biomarkers, clinical predictors may help guide selection of aPD1 or aPD1 + IPI.