tbuckley/cabot-search huggingface dataset:
Phase II study of PX-866 in recurrent glioblastoma.
Authors: Marshall W. Pitz, Mary Valeria MacNeil, David R. Macdonald, Ankineedu Saranya Kakumanu, Brian Thiessen, Ming Sound Tsao, Suzanne Kamel-Reid, Jeremy Squire, Joana Sederias, Wendy Walsh, Elizabeth A. Eisenhauer, Warren P. Mason
Journal: Journal of Clinical Oncology (2012)

2051 Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. The majority of GBM have genetic changes that increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway, critical for cell motility, proliferation, and survival. We present the interim results of PX-866, an oral PI3K inhibitor, in patients (pts) with recurrent GBM. Methods: Pts with histologically confirmed GBM at first recurrence after treatment with chemoradiation and adjuvant temozolomide are given PX-866 8 mg daily on this single-arm phase II study. MRI and clinical exam are done every 8 weeks to determine treatment response. The trial has a 2-stage design with dual endpoints of objective response and early progression (within 8 weeks). In Stage I, 15 pts are evaluated and if 0 responses and 10 or more early progressions are seen, enrolment will stop. Otherwise, Stage II will enrol another 15 pts for efficacy analysis. Tumour tissue is collected for analysis of potential markers of PI3K inhibitory activity (PTEN, EGFRvIII, PIK3CA mutations). Results: Seventeen pts have been enroled to date: 14 evaluable for response and 15 for toxicity. Median age was 54 years (range 35-70), with 7 females and 10 males. No pts had received treatment for recurrent GBM, and median time between initial diagnosis and study enrolment was 300 days (range: 113-447 days). Pts have received a median of one 8-week cycle of PX-866 (range: 1-4). Twelve pts have discontinued therapy, 9 due to disease progression and 3 due to grade 3/4 liver enzyme abnormalities. Other adverse effects have included fatigue (10 pts/1 grade 3), diarrhea (6 pts/3 grade 3), nausea (7 pts/0 grade 3), vomiting (6 pts/0 grade 3), lymphopenia (14 pts/3 grade 3). Stage I response data are premature; it is not yet known if the trial will continue to Stage II. Archival tissue is available on all patients and is undergoing analysis. Conclusions: This is one of the first trials of a PI3K inhibitor in pts with recurrent GBM. PX-866 has been relatively well tolerated. Stage I response data are premature; while it is not yet known if the criteria will be met to continue to Stage II, prolonged SD has been observed in some pts. The correlative biomarker assays underway will be important to understand this observation.
Updated safety result of a large Italian early access program (EAP) with cabazitaxel plus prednisone (CbzP) in metastatic castration-resistant prostate cancer (mCRPC) patients who progressed during or after docetaxel (D) therapy.
Authors: Sergio Bracarda, Giuseppe Di Lorenzo, Donatello Gasparro, Paolo Marchetti, Francesco Boccardo, Andrea Martoni, Giacomo Carteni, Giuseppe Fornarini, Valentina Baldazzi, Luigi Dogliotti, Caterina Messina, Michele Sisani
Journal: Journal of Clinical Oncology (2012)

e15185 Background: A significant percentage of mCRPC pts, who have progressed on D therapy, have a long life expectancy and are candidates for additional treatments. In TROPIC trial pts who progressed during or after D had a statistically significant OS advantage and clinical benefit with CbzP in respect to mitoxantrone plus prednisone (MP). Benefits observed in the TROPIC study supported a global EAP, to allow pts with mCRPC to have an early access to CbzP and provide confirmatory data in daily clinical practice Methods: We report the safety results of the first 90 pts entered into EAP and treated with CbzP, out of 232 pts enrolled by 25 Italian centers between Jan and Aug 2011 Results: Pts characteristics were median age 70 years (≥ 75 years 22.2%); ECOG PS 0-1, 97.8%; median N. of previous D cycles 8 (median cumulative D 675mg/m 2 ); 14.1% received 675 ÷ 900 mg and 40.0% ≥ 900 mg of D. Median time from last D dose to first CbzP dose was 5.29 months including any other chemotherapy treatment.At the time of this analysis 50% of pts had received 4 cycles of CbzP. 33 pts discontinued CbzP mainly due to PD (42.4%), AEs (related/not related, 27.3%), investigator’s (3.0 %) / pts decision (18.2%) and others (9.1%). AEs resulting in CbzP discontinuation (10.0%) are mainly fatigue, pyrexia and haematological disorders. A total of 57 pts were still on treatment. In the 33 discontinued pts, CbzP has been delayed in 24.2% while a dose reduction occurred in 21.2% of pts. AEs of any grade were observed in 81/90 pts. Most common G 3/4 AEs were leukopenia (25.6%), neutropenia (48.9%), anaemia (6.7%), diarrhoea (1.1%), asthenia (3.3%) and fatigue (5.6%). One death occurred during the study period in a heavily pretreated pt who received 33 cycles of D Conclusions: This preliminary safety analysis suggests the good tolerability of cabazitaxel, in terms of haematological as well as non-haematological AEs even in heavily pretreated pts according to the previous experience of Italian Centers in theTROPIC trial. This is remarkable because of the increased similarity of the patient’ populations treated in the EAP and daily clinical practice
SWOG S1505: A randomized phase II study of perioperative mFOLFIRINOX vs. gemcitabine/nab-paclitaxel as therapy for resectable pancreatic adenocarcinom.
Authors: Davendra Sohal, Shannon L McDonough, Syed A. Ahmad, Namita Gandhi, Muhammad Shaalan Beg, Andrea Wang-Gillam, Katherine A Guthrie, Andrew M. Lowy, Philip Agop Philip, Howard S. Hochster
Journal: Journal of Clinical Oncology (2017)

TPS508 Background: Clinical outcomes after curative therapy for resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. Series show that 70-85% of patients die of systemic recurrence. Improved overall survival (OS) in the metastatic setting with the use of multi-agent chemotherapy regimens (FOLFIRINOX, gemcitabine/nab-paclitaxel) holds the promise of progress in the curative setting as well. However, aggressive systemic therapy is usually not feasible after major pancreatic surgery. Therefore, early control of systemic disease by increased preoperative chemotherapy may improve outcomes. Furthermore, the perioperative platform facilitates early identification of patients with chemotherapy-resistant tumors and allows prospective biomarker studies in the future. Methods: This is a randomized phase II study intended to choose the most promising perioperative regimen to test in a larger trial. Eligibility requirements include patients with an ECOG PS of 0 or 1, a confirmed histopathologic diagnosis of PDA, and resectable disease as confirmed by central radiology review: no involvement of the celiac, common hepatic, or superior mesenteric arteries (and, if present, variants); no involvement, or &lt; 180° interface between tumor and vessel wall, of the portal or superior mesenteric veins; patent portal vein/splenic vein confluence; no metastases. Treatment includes 12 weeks [either mFOLFIRINOX (5-fluorouracil infusion (no bolus), irinotecan, oxaliplatin), or gemcitabine/nab-paclitaxel] of preoperative chemotherapy, followed by surgical resection and 12 weeks of identical postoperative chemotherapy. Primary outcome is 2-year OS, using a “pick the winner” design with minimum activity requirements. Assuming a historical 2-year OS of 40% and a 58% alternative hypothesis, 88% power, a 1-sided α of 0.05, and 100 eligible patients, the design provides a 90% probability of selecting the better regimen. The study opened through the National Clinical Trials Network (NCT02562716), and is supported by NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180833. Clinical trial information: NCT02562716.
Novel oncogenic function of ATDC in bladder cancer.
Authors: Phillip Lee Palmbos, Lidong Wang, Huibin Yang, Taylor Detzler, Gina Ney, Yair Lotan, Patrick N. Healy, Stephanie Daignault-Newton, Priya Kunju, Chandan Kumar, Mats Ljungman, Monica Liebert, Diane M. Simeone
Journal: Journal of Clinical Oncology (2012)

4591 Background: Bladder cancer is a common and deadly disease, but the molecular events leading to its initiation and progression are incompletely understood. We recently identified Ataxia-Telangiectasia Group D Associated (ATDC) as a novel oncogene which drives tumor proliferation and invasion in pancreatic carcinoma (Cancer Cell, 2009). In this study, we describe the role of ATDC as an oncogene in bladder cancer. Methods: To further determine the oncogenic role of ATDC, we generated ATDC transgenic (tg) mice in which ATDC expression was driven by a CMV promoter and characterized the resulting tumors. Results: Interestingly, the dominant phenotype in these mice was the development of both non-invasive and invasive urothelial carcinomas (9% and 20% respectively, average age of onset 10-12 months of age). Histologically, these tumors were indistinguishable from human urothelial carcinomas. Gene expression profiling of invasive tumors derived from ATDC tg mice demonstrated a marked overlap with gene signatures of human invasive bladder cancers. ATDC was the 11th most highly up-regulated gene in bladder cancers represented in the Oncomine gene expression database. Analysis of a human bladder cancer tissue microarray (311 samples) by IHC showed elevated expression in 70% (173/252) of muscle-invasive carcinomas, 22% (5/23) of papillary tumors and little or no expression in normal bladder urothelium. ATDC tg mouse bladder tumors demonstrated loss of p53 signaling and down-regulation of PTEN expression, which correlated with ATDC induced methylation of the PTEN promoter by DNMT3A. Furthermore, ATDC knock-down in invasive cancer cell lines resulted in decreased proliferation, invasion and reactivation of p53-mediated signaling and PTEN expression. Conclusions: ATDC is a novel oncogene that is highly expressed in human bladder cancers and is sufficient to drive the development of invasive bladder tumors in tg mice. The mechanism by which ATDC drives bladder cancer formation involves alterations in p53 and PTEN pathways known to be important in bladder tumorigenesis.
U.S. Intergroup phase II trial (SWOG 1108) of alisertib, an investigational aurora A kinase (AAK) inhibitor, in patients with peripheral T-cell lymphoma (PTCL; NCT01466881).
Authors: Paul M. Barr, Hongli Li, Catherine M Spier, Daruka Mahadevan, Jonathan W. Friedberg, Michael Leo LeBlanc, Mansoor Ul Haq, Christopher Flowers, Nina D. Wagner-Johnston, Bruce D. Cheson, Steven M. Horwitz, Thomas P. Miller, Richard I. Fisher
Journal: Journal of Clinical Oncology (2014)

8523 Background: AAK is a serine/threonine kinase that regulates the G2-M transition and centrosome separation during mitosis. Alisertib (MLN8237) is an oral AAK inhibitor active in aggressive lymphoma, with 4 of 8 T cell lymphoma pts responding in a phase II trial (Friedberg JCO 2013). This phase II study was conducted to further investigate the efficacy of alisertib in PTCL. Methods: Eligible pts with histologically confirmed relapsed/refractory PTCL had normal organ function, ANC ≥1500/mm3 and platelets ≥75,000/mm3. Pts received alisertib 50mg BID for 7d on 21d cycles. Tumors were evaluated for expression levels of AAK, ABK, Myc, Bcl2, PI3Kδ, and Notch1 and quantified by image analysis. Results: Of 42 pts accrued, 37 eligible pts had a median age of 62 (range 22-86). Histologies included PTCL not otherwise specified (NOS)(13), angioimmunoblastic (AITL)(9), transformed mycosis fungoides (MF) (7), adult T-cell lymphoma (ATLL) (4), anaplastic large cell (ALCL) (2) and extranodal NK/T-cell (NK/T) (2). With a median number of 3 (range 1-18) prior therapies, 3 pts had undergone a prior stem cell transplant and 20 were refractory to prior therapy. Grade 3 and 4 AEs in ≥ 5% of pts included neutropenia (30%), anemia (27%), thrombocytopenia (24%), febrile neutropenia (14%), mucositis (11%) and rash (5%). 6 pts discontinued therapy and 9 were dose reduced due to AEs. Treatment was discontinued most commonly for PTCL progression. 2 complete responses and 7 partial responses were observed for a response rate (ORR) of 24% (95%CI: 12-41%). Among the most common subtypes, (PTCL NOS, AITL and ALCL), the ORR was 33% (95%CI: 16-55%). Of 27 pts with available biopsies, 0 and 6 expressed AAK and ABK respectively. Conclusions: Alisertib has antitumor activity in PTCL, including heavily pretreated pts. Toxicities to date were manageable and reversible. An international randomized phase III trial is comparing alisertib to investigator’s choice in PTCL. Support: NIH/NCI Cooperative Group Grants CA32102 and CA38926; CA21115; CA21946; and Takeda Pharmaceuticals. Clinical trial information: NCT01466881. Histology PTCL NOS AITL Transformed MF ATLL ALCL NK/T N 13 9 7 4 2 2 CR/PR 1/3 0/3 0/0 1/0 0/1 0/0 SD 1 2 2 0 1 1 PD 8 4 5 3 0 1
Screening for depression in community-based radiation oncology settings: Results from RTOG 0841.
Authors: Lynne I. Wagner, Stephanie L. Pugh, William Small, Jeffrey J. Kirshner, Kulbir Sidhu, Martin Joseph Bury, Albert S. DeNittis, Tracy E. Alpert, Binh N. Tran, Beatrice Bloom, Julie Mai, Deborah Bruner
Journal: Journal of Clinical Oncology (2013)

9527 Background: Depression screening is recommended in routine cancer care. Brief tools are needed to identify depressed patients in radiation oncology treatment settings. Methods: Patients starting radiotherapy for first diagnosis of any tumor were eligible. Screening measures administered prior to or within the first 2 weeks of radiation therapy included: Hopkins Symptom Checklist (HSCL-25), Patient Health Questionnaire (PHQ-9; PHQ-2), and the National Comprehensive Cancer Network-Distress Thermometer (NCCN-DT). Patients exceeding validated cutoff scores on the HSCL-25, PHQ-9 or PHQ-2, and a systematic sample of patients who screened negative, completed telephone-based administration of the Structured Clinical Interview for DSM-IV (SCID) Mood Disorder modules. Results: 463 patients from 35 community-based and 2 academic radiation oncology sites were accrued. The majority were women (n=298, 66%). Participants had breast (45%), GI (11%), lung (10%), gynecologic (6%), or other (27%) cancers. All 454 eligible patients completed the screening questionnaires and 100% of questionnaire items were completed. 75 (16%) screened positive for depressive symptoms. A total of 70 SCID interviews were administered to 37 patients who screened positive and 33 who screened negative. Among those who screened positive, 14 (20%) met SCID criteria for major depression. One participant who screened negative met depression criteria (1.4%). Results indicate the prevalence of depression is 3%. The PHQ-2 demonstrated good psychometric properties for identifying current major depressive episode, using a cut-off score &gt; 3 (ROC area under the curve=0.839). The PHQ-9 &gt; 9 was comparable (AUC=0.837). The NCCN-DT &gt; 4 did not adequately detect depression (AUC=0.64). Conclusions: The prevalence of depression was low (3%) among this community-based sample of adults receiving radiotherapy. The PHQ-2 demonstrated excellent psychometric properties to detect depression, which were equivalent to the PHQ-9 and superior to the NCCN-DT. Our findings support using the PHQ-2 to identify patients in need of further assessment and treatment for depression, a low prevalence but clinically significant comorbidity.
Evaluation of molecular testing patterns in metastatic non-small cell lung cancer at a large U.S. health plan.
Authors: Elizabeth A. MacLean, Anthony M. Louder, Kimberly R. Saverno, Gregory Smith, Jack Mardekian, Cari Bruins, Melea Ward, Robert William Sweetman, Margaret K. Pasquale
Journal: Journal of Clinical Oncology (2014)

e19075 Background: Identification of oncogene mutations and gene rearrangements in individuals with non-small cell lung cancer (NSCLC) can help identify candidates for targeted therapy. The objective of this study was to determine the extent to which clinicians are testing metastatic NSCLC (mNSCLC) patients for oncogene mutations and the timing of testing relative to the start of therapy. Methods: A retrospective analysis of claims data from a large US health plan was conducted. Patients were included in the study if they had medical claims associated with lung cancer (≥2 claims with an ICD-9-CM diagnosis code 162.xx) and metastatic disease (≥1 claim with an ICD9-CM code of 196.xx - 198.xx) between 1/1/2010—12/31/2012, were continuously enrolled in a fully insured plan 180 days prior to the index date (date of first claim with an ICD9-CM code indicative of metastasis), and were 18-89 years of age. Patients were excluded if they had history of a chemotherapy used primarily in small cell lung cancer or a medical claim associated with an unrelated malignancy. Current Procedural Terminology (CPT) codes were used to identify the occurrence of mutation testing. The timing of mutation testing was compared to the start of chemotherapy and targeted therapy, if any. Descriptive statistics were used to summarize characteristics of the study population and the frequency and timing of mutation testing. Results: A total of 2,623 patients (mean (SD) age 72.5 (8.2) years), 52.5% male) presumed to have mNSCLC were included in the analysis. A total of 1597 (60.9%) patients had a CPT code associated with mutation testing at any time in their claims history. Of the 733 patients with both mutation testing and pharmacotherapy in their claims history, mutation testing occurred prior to systemic therapy initiation in 651 (88.8%, 95% CI 86.1%-90.9%) patients. The median time between mutation testing and therapy initiation was 38 days (interquartile range [IQR] 23 – 69). Conclusions: Analysis of claims data from a large US health plan suggests that when providers assess mutation status in mNSCLC, it routinely occurs prior to initiation of treatment. Additional research should attempt to validate these findings using data from patient medical records.
Primary malignant brain tumours (PMBT) in phase I studies: Barriers to treatment and patient outcomes.
Authors: Scheryll Paula Alken, Karim Rihawi, Vasiliki Michalarea, Andrea Zivi, Shankar Bodla, Kathy Greenwood, Stanley B. Kaye, Udai Banerji, Johann Sebastian De Bono, Frank Saran, L Rhoda Molife
Journal: Journal of Clinical Oncology (2014)

2024 Background: Primary malignant brain tumours (PMBT) are a rare tumour group with a poor outcome and limited options at relapse. Despite recent incremental gains from multimodal therapy and an emerging understanding of underlying genetic alterations, patients (pts) with PMBT have traditionally been excluded from phase I trials due to a number of concerns including blood-brain barrier penetration; it is recognised that such concerns are less relevant in the molecular era. We examined the outcomes of and barriers to participation of these pts on phase I studies. Methods: We reviewed the case records of pts with PMBT referred to the Neuro Oncology and Clinical Pharmacology Units of the Royal Marsden Hospital between 2004 and 2013 for consideration of a phase I study. Pt characteristics including demographics and details of prior treatment were examined. Kaplan-Meier estimator and Cox regression were used to evaluate progression free survival (PFS) and overall survival (OS). All tests performed were two-sided with an alpha of 0.05, and a power of 80% was used. Surviving patients were censored at date of last follow-up. Results: Seventy three pts with PMBT were identified. Of these, 50 (68.5%) were allocated to a phase I trial and 38 (52%) of these patients received at least one dose of the study drug. 9 pts (18%) failed screening, 3 pts (6%) withdrew consent. 11 pts (15%) were not allocated to a study due to a lack of suitable trials, 9 (12%) were not allocated due to poor performance status (PS). Factors influencing enrolment were examined; only Karnofsky PS (KPS) was statistically significant (HR 1.09, 95% CI 1.04 – 1.15, p=0.001). The median PFS of pts dosed was 7.3 months. The median OS of these pts was 7.9 months versus 4.2 months in those not dosed (p=0.024). Grade 3 drug related toxicities were seen in 9.6% of patients. Conclusions: Patients with PMBT can be safely treated in phase I trials. A lack of suitable trials remains the main barrier to enrolment, as does KPS, which is similar to other rare malignancies. Based on our results these patients tolerate investigational agents similar to other groups. This study adds to the growing body of evidence encouraging investigators to enrol such patients.
Inpatient Palliative Care After Hematopoietic Stem Cell Transplantation
Authors: Srishti Chhabra, Zhuangming Marc Lai
Journal: JAMA (2017)

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Outcomes of ipilimumab treatment-related adverse events in patients with metastatic melanoma (MM) who received systemic corticosteroids in a phase III trial.
Authors: Jean-Francois Baurain, Michael Smylie, Paolo Antonio Ascierto, Laslo Roman, Stephen Houston, Cyril Konto, Kevin M. Chin, Tai-Tsang Chen, Stephen Francis, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2012)

8539 Background: Ipilimumab (ipi) is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses. In a phase III trial, ipi at 10 mg/kg plus dacarbazine (DTIC) improved overall survival in previously untreated patients (pts) with MM. In ipi studies, the most common drug-related adverse events (AEs) were immune-related, which were generally reversible using treatment guidelines involving prompt recognition, intervention (corticosteroids, and rarely, alternative immunosuppressive agents), and possible discontinuation of therapy. The purpose of this analysis is to evaluate outcomes of ipi treatment-related AEs with use of systemic corticosteroids. Methods: AEs were reported from the first ipi dose up to 70 days after the last dose. Immune-mediated adverse reactions (imARs) were used to characterize inflammatory AEs in previously untreated pts with MM who received ipi plus DTIC in a phase III trial. This analysis includes the imAR categories of hepatitis, dermatitis, enterocolitis, and endocrinopathies. Results: More than 70% of pts who received corticosteroids had complete resolution of the imAR, ie, last reported Grade (Gr) of 0 (Table). In pts for whom a high-grade imAR had not completely resolved at the last report, ≥50% had improved to Gr 1. Conclusions: In the majority of pts treated with ipi at 10 mg/kg plus DTIC who received corticosteroids for the management of imARs, as recommended per treatment guidelines, the most common imARs had completely resolved or improved to Gr 1. [Table: see text]