tbuckley/cabot-search huggingface dataset:
Phase I/II study of E7050 (golvantinib) in combination with sorafenib in patients (pts) with advanced hepatocellular carcinoma (HCC): Phase I results.
Authors: Bert H. O'Neil, Johanna C. Bendell, Manuel R. Modiano, Jean-Pascal H. Machiels, Melissa Jo Versola, Jeff Paul Hodge, Karen Sawarna, Nielson Tse
Journal: Journal of Clinical Oncology (2013)

294 Background: Golvatinib (G) is highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. G plus sorafenib (S) had an additive cell killing effect in a HepG2 hepatocellular cell viability assay, thus warranting further evaluation of the combination in HCC. Methods: The study is an ongoing open-label phase I/II study. Eligible pts have advanced HCC, Child-Pugh (CP) A or B, up to 2 prior regimens, including S. A 3+3 dose escalation design was used to determine the maximum tolerated dose (MTD) with planned doses of G (200 mg, 300 mg, 400 mg) PO qd each in combination with S 400 mg bid in 28 day cycles.The dose limiting toxicity (DLT) evaluation period was the first 28 days. Treatment continued until disease progression or development of unmanageable toxicities. Response was assessed by RECIST 1.1. Phase I is complete and preliminary data are presented. Results: 13 pts (med age: 60; M/F: 83%/17%, CP A/B: 92%/8%) were enrolled in 2 cohorts and the MTD was declared as G 200 mg qd and S 400 mg bid. Median treatment duration, 112 days. Confirmed partial responses (PRs) were observed in 2/12 (17%) pts and durable SD was observed in 4/13 (31%) pts based on investigator assessment. Conclusions: G in combination with S appeared to demonstrate manageable toxicity in advanced HCC pts. The PRs and durable SD observed in this pretreated pt population appear favourable and support continued evaluation in phase II. Clinical trial information: NCT01271504. [Table: see text]
Multi-institutional evaluation of multiparametric MRI and fusion-guided prostate biopsy in a biopsy-naive population.
Authors: Meet Kadakia, Arvin Koruthu George, Minhaj Siddiqui, Soroush Rais-Bahrami, Ardeshir Rastinehad, Srinivas Vourganti, Michele Fascelli, Michael Kongnyuy, Akhil Muthigi, Abhinav Sidana, Thomas P Frye, Amichai Kilchevsky, Jeffrey Nix, Vidhush K. Yarlagadda, Daniel Su, Maria J Merino, Bradford J. Wood, Peter L. Choyke, Ismail B. Turkbey, Peter A. Pinto
Journal: Journal of Clinical Oncology (2016)

60 Background: Multiparametric MRI (mpMRI) and fusion biopsy (FB) has proven beneficial in men with a prior negative systematic biopsy (SB) or diagnosis of prostate cancer (CaP). The aim of the study was to evaluate mpMRI and FB in a biopsy-naive population. Methods: A multi-institutional review was performed on patients with no prior biopsy history who underwent mpMRI followed by concurrent FB and SB. Imaging protocol was standardized across institutions. Gleason score (GS) distribution/risk classifications were recorded. Univariate analysis was performed to compare FB versus SB. Results: A total of 361 biopsy-naive men were identified from 4 institutions. GS distribution/risk classification for FB and SB are presented in the table. Overall cancer detection rate (CDR) was 65.4%. In biopsy-naive men, FB detected a greater absolute number of high grade disease with 13% more high risk CaP than SB (78 vs 69). Additionally, FB detected 21% fewer cases of GS 6 CaP (57 vs 69). The CDR for FB alone was 57.3% with only 3 intermediate-risk and 1 high-risk patient not identified. The addition of SB to FB resulted in diagnosing 25 added cases of low-risk disease for each high risk CaP detected. The CDR of SB alone was 59.6%, however, 2 intermediate- and 4 high-risk CaP were missed. The addition of FB to SB alone resulted in only 4 added cases of low-risk CaP for each high-risk CaP detected. Conclusions: In biopsy-naive men, mpMRI and fusion biopsy detects a greater number of patients with high-risk disease while decreasing the detection of low-risk CaP. Additional studies with greater power will be required to validate the potential benefit of mpMRI and FB in patients with no prior biopsy history. [Table: see text]
A phase I trial of pemetrexed and vinflunine (VFL)
Authors: U. Shah, H. K. Sanoff, B. H. O’Neil, T. E. Stinchcombe, K. Keller, D. Carrizosa, C. M. Walko, L. Buie, W. Chiu, E. C. Dees
Journal: Journal of Clinical Oncology (2008)

13508 Background: VFL is a novel vinca alkaloid microtubule inhibitor with enhanced antitumor activity. We performed a phase I trial of VFL in combination with pemetrexed, a multi-targeted folate antagonist that has shown at least additive activity in combination with other vincas. Methods: A standard dose escalation scheme was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of VFL in combination with pemetrexed in patients with refractory solid tumors. Pemetrexed 500mg/m2 was administered intravenously (IV) over 10 minutes followed by VFL at 280mg/m2 (cohort 1), 300mg/m2 (cohort 2) or 320mg/m2 (cohort 3) IV over 20 minutes on day 1 of a 21-day cycle. Results: 19 patients (pts) (10 men, 9 women) with a median age of 58 years (range 32–77) participated. 3 pts had breast cancer, 9 colorectal cancer, 2 non-small cell lung cancer, 2 pancreatic adenocarcinoma, 2 cholangiocarcinoma and 1 sarcoma. The median number of prior therapies in the metastatic setting was 3 (range 1–6). Pts had good performance status (18 ECOG 0–1). Total cycles administered were 72. The grade 3/4 adverse events were neutropenia (7), leukopenia (5), febrile neutropenia (FN) (5), cardiac arrythmia (1), hypotension (1), abdominal pain (1), hyponatremia (1), hypokalemia(1), transaminitis (1), thrombocytopenia (1), hyperbilirubinemia (1), dyspnea (1), fatigue(1). DLTs were noted in 1 of 6 pts in cohort 1 (platelets), 2 of 10 pts in cohort 2 (FN and fistula; FN and fatigue), and 2 of 3 pts in cohort 3 (FN and hypokalemia; FN and myalgia). 1 pt in cohort 2 died prior to completion of cycle 1 likely from disease progression. No objective responses were seen, 2 pts (breast and lung) continue on treatment with stable disease for 20 and 10 cycles. Conclusions: The combination of pemetrexed and VFL is a manageable regimen with hematologic toxicity being the most prominent. In this heavily pretreated population, the MTD recommended for future studies is VFL 300 mg/m2 and pemetrexed 500 mg/m2. Correlation of CYP3A4 activity with toxicity and VFL plasma clearance is planned. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb, Lilly Oncology
Self-reported compliance compared to biomarker levels of vitamin E in breast cancer patients participating in a CoQ10 clinical trial.
Authors: M. Vitolins, G. J. Lesser, L. D. Case, S. K. Williford, J. K. Giguere, A. Garino, M. J. Naughton, M. Lively, S. A. Melin, E. G. Shaw
Journal: Journal of Clinical Oncology (2010)

e19524 Background: Participant compliance in clinical trials is crucial as noncompliance leads to underestimation of treatment effect and loss of statistical power. Compliance is frequently assessed using diaries and pill counts and less frequently using biomarker measurements. This report compares self-reported and serum biomarker measures of compliance in one clinical trial. Methods: A randomized, double-blind, placebo-controlled trial of CoQ10 (CoQ) was conducted to assess the supplement's effect on fatigue. Women with newly diagnosed breast cancer who had planned adjuvant chemotherapy were randomized to receive oral supplements of either 300mg CoQ per day or placebo, each with 300 IU Vitamin E (Vit E) to support absorption of CoQ, split into three daily doses over 24 weeks. Patients completed pill diaries. Blood samples were drawn at baseline, 8, 16, and 24 weeks. Patients were categorized into quartiles according to reported compliance and changes in serum levels of VitE. Crosstabs and correlations were used to determine the concordance between the two measures. Results: Women (N = 236) ages 28- 85 were enrolled between 8/2004 and 3/2009. 113 Patients had complete sets of serum Vit E. Mean baseline and 24 week Vit E levels increased from 14.2 to 23.3, respectively; 14% had increases less than 1 ug/mL. Self-reported compliance in this subset was 88% (range: 29%-100%). Association between measures was weak (r = .15, p = .12); 7 participants in the lowest quartile of self-reported compliance were in the highest quartile of serum Vit E and 5 in the highest quartile of self-reported compliance were in the lowest quartile of Vit E. Conclusions: Self-reported compliance was not strongly related to patient's biomarker levels, supporting the notion that self- reported compliance is overestimated. The addition of biomarker methods to self-report may assist in improving interpretation of this and other intervention studies. Supported by NCI grant 3 U10 CA081851. No significant financial relationships to disclose.
Gene Therapeutic Reversal of Peripheral Olfactory Impairment in Bardet-Biedl Syndrome
Authors: Corey L. Williams, Cedric R. Uytingco, Warren W. Green, Jeremy C. McIntyre, Kirill Ukhanov, Arthur D. Zimmerman, Dana T. Shively, Lian Zhang, Darryl Y. Nishimura, Val C. Sheffield, Jeffrey R. Martens
Journal: Molecular Therapy (2017)

Olfactory dysfunction is a pervasive but underappreciated health concern that affects personal safety and quality of life. Patients with olfactory dysfunctions have limited therapeutic options, particularly those involving congenital diseases. Bardet-Biedl syndrome (BBS) is one such disorder, where olfactory loss and other symptoms manifest from defective cilium morphology and/or function in various cell types/tissues. Olfactory sensory neurons (OSNs) of BBS mutant mice lack the capacity to build/maintain cilia, rendering the cells incapable of odor detection. Here we examined OSN cilium defects in Bbs1 mutant mice and assessed the utility of gene therapy to restore ciliation and function in young and adult mice. Bbs1 mutant mice possessed short residual OSN cilia in which BBSome protein trafficking and odorant detection were defective. Gene therapy with an adenovirus-delivered wild-type Bbs1 gene restored OSN ciliation, corrected BBSome cilium trafficking defects, and returned acute odor responses. Finally, using clinically approved AAV serotypes, we demonstrate, for the first time, the capacity of AAVs to restore ciliation and odor detection in OSNs of Bbs1 mutants. Together, our data demonstrate that OSN ciliogenesis can be promoted in differentiated cells of young and adult Bbs1 mutants and highlight the potential of gene therapy as a viable restorative treatment for congenital olfactory disorders.
The role of NKTR-102 in women with platinum resistant/refractory ovarian cancer and failure on pegylated liposomal doxorubicin (PLD).
Authors: A. A. Garcia, I. B. Vergote, J. P. Micha, C. H. Pippitt, G. G. Rao, D. L. Spitz, N. Reed, G. G. Dark, E. N. Ibrahim, V. A. Armenio, L. R. Duska, C. J. Poole, C. Gennigens, L. Y. Dirix, J. West, C. Zhao, A. C. Leung, L. K. Masuoka, G. J. S. Rustin
Journal: Journal of Clinical Oncology (2011)

5047 Background: NKTR-102, a topoisomerase-I inhibitor-polymer conjugate with markedly reduced peak concentrations and a continuous concentration profile, demonstrated broad antitumor activity per RECIST in a phase I study. The original phase 2 study in platinum-resistant/refractory ovarian cancer showed a 21% confirmed objective response rate (ORR) (RECIST; Vergote, ASCO 2010). Methods: 71 pts with platinum resistant/refractory ovarian cancer (PROC) were originally randomized to NKTR-102 IV at a dose of 145 mg/m2 q14d vs. q21d. In addition to being resistant/refractory to platinum, 33 pts in this analysis (16/q14d; 17/q21d) had also progressed on prior PLD. 6 of these 33 pts were platinum-refractory (progression within 28 days of last platinum dose). Eligible pts had ECOG PS 0-1, adequate renal, hepatic, and marrow function. The primary endpoint was ORR per RECIST; secondary endpoints included PFS, OS and safety. Results: For the 33 PROC pts pre-treated with PLD, median age was 59; ECOG PS 0/1 was 46%/54%; median number of prior cancer treatments was 4, with 2 of the treatments being platin-based. All but 2 pts received prior taxanes. 58% had received prior gemcitabine. Median platinum-free interval after prior platin-based regimen was 2.9 months. Confirmed ORR equaled 20%, 21%, and 21% for the q14d, q21d, and all pts combined, respectively. For all pts combined, median PFS was 5.5 months and median OS was 14.0 months. Common related Grade ≥ 3 toxicities (q14d/q21d) were diarrhea (31%/18%), nausea (31%/6%), hypokalemia (38%/0%), dehydration (19%/6%), fatigue (6%/18%) and vomiting (25%/0%). In contrast to other commonly used agents in PROC, NKTR-102 did not show clinically significant myelosuppression, neuropathy or alopecia. Conclusions: NKTR-102 demonstrated clinically significant activity (confirmed ORR by RECIST of 21%) as a single agent in pts with heavily pretreated PROC who have also failed prior PLD. This study is being expanded to enroll an additional 50 pts with PROC having progressed on prior PLD. All pts are now receiving NKTR-102 on the q21d regimen due to the better toxicity profile.(Vergote, ASCO 2010).
Use of self-reporting outcomes to inform patient care.
Authors: Brandon Bosch, Diane Denny, Maurie Markman
Journal: Journal of Clinical Oncology (2014)

176 Background: Cancer Treatment Centers of America, Inc (CTCA) is a national network of hospitals that specialize in the treatment of patients fighting complex or advanced-stage cancer. The Symptom Inventory Tool (SIT) is an assessment tool that captures the patients’ perceived symptom burden for real-time clinical intervention, from the point of no intervention (baseline) and every 21 days or greater. The SIT is comprised of 27 questions utilizing the MD Anderson Symptom Inventory tool, a validated assessment instrument with eight questions added and a free text box by CTCA. The SIT became an integral part of patient care at CTCA beginning in 2012. Methods: Non-clinical stakeholders administer the SIT via an electronic tablet. Upon completion of the assessment, a trending graph known as Symptoms-at-a-Glance (SAG) report is auto populated and available to clinicians in the EHR or may be printed at the point of care. The SAG provides run graphs for each symptom including arrows identifying clinically relevant changes in score. An accompanying e-mail notification system was created for physicians to review specific symptoms of interest at a threshold of their choosing, and refer patients to other specialties deemed integral for the patient’s treatment plan. Results: The SIT assessment is utilized by the nurse as a starting point from which they can initiate a more pointed conversation with the patient including the need for appropriate intervention including follow-up with the oncologist and/or referral to a member of the extended integrative care team. The percentage of new and returning patients completing an assessment is at 94.94% and 84.81%, respectively, for patients (1/1/14-6/9/14) across CTCA suggesting this process is useful for both patient and clinicians. Patients comment that the time for self-reflection is a healthy exercise enabled by the user-friendly tablet. Clinicians value both the ease of administration/use as well as the ability to create a large data set for quality improvement. Conclusions: With a majority of new and returning patients participating in the SIT, the SAG report fully implemented into the EHR along with the use of an e-mail functionality, clinicians and physicians can now better manage symptom burden real time
CD93 Is a Novel Biomarker of Leukemia Stem Cells in Chronic Myeloid Leukemia
Authors: Ross Kinstrie, Gillian A. Horne, Heather Morrison, Hothri A. Moka, Jennifer Cassels, Karen Dunn, Pawel Herzyk, David A. Irvine, Mhairi Copland
Journal: Blood (2015)
A novel modified CpG inhibits EGF receptor signalling and synergistically enhances antitumor activity of cetuximab and irinotecan in colon cancer xenografts
Authors: G. Tortora, R. Bianco, S. de Placido, F. D’Armiento, D. Melisi, G. Daniele, S. Agrawal, A. R. Bianco, F. Ciardiello, V. Damiano
Journal: Journal of Clinical Oncology (2005)

3191 Background: CpG dinucleotides, that act as agonists of TLR9 inducing potent Th1-type immune responses, exhibit antitumor activity and ability to increase the effect of cytotoxic drugs and to enhance the antibody-dependent cellular cytotoxicity (ADCC). We have hypothesized that CpG oligos may interfere with EGFR-related signalling and, on this basis, may specifically enhance the activity of anti-EGFR antibody Cetuximab. Materials and Methods: We have used a novel modified CpG linked to an immunomodulatory sequence (IMO), that has recently completed a phase I study in cancer patients, studying its effect, alone and in combination with Cetuximab, on the growth, the expression of signalling proteins and the angiogenesis of human colon cancer xenografts in nude mice. Results: IMO exhibited significant antitumor activity accompanied by a potent inhibitory effect on the expression of EGFR, pMAPK and pAkt, bcl-2, COX-2 and VEGF. IMO in combination with Cetuximab produced a potent and long lasting antitumor effect on tumor xenografts, together with a marked inhibition of the analyzed signalling proteins and of microvessels formation. Combination of IMO with Cetuximab plus the cytotoxic agent irinotecan, a regimen shown active in colorectal cancer patients, produced a dramatic effect, eradicating the tumors in over 90% of mice. Conclusions: These results demonstrate for the first time an interference of TLR9 agonist IMO with EGFR-related signalling and a potent cooperative effect with Cetuximab and irinotecan, providing a strong rationale for the translation of this therapeutic strategy in a clinical setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hybridon
Pilot study of clinical targeted next generation sequencing for prostate cancer: Consequences for treatment and genetic counseling.
Authors: Heather H. Cheng, Nola Klemfuss, Robert B. Montgomery, Celestia S. Higano, Michael Thomas Schweizer, Elahe A. Mostaghel, Evan Y. Yu, Peter Nelson, Colin C. Pritchard
Journal: Journal of Clinical Oncology (2016)

251 Background: Targeted next generation sequencing (NGS) panels for identification of actionable mutations are increasingly used in oncology for therapeutic decision-making, but have yet to be widely used for prostate cancer.To determine the utility of applying a targeted next generation sequencing to prostate cancer management, we conducted a pilot study using the clinical molecular diagnostic assay, UW-OncoPlex, on primary and metastatic tumors from patients with prostate cancer. Methods: Patients receiving treatment for prostate cancer by a medical oncologist were eligible. After providing informed consent, tumor DNA was extracted from formalin-fixed, paraffin-embedded (FFPE)primary tumors and/or metastatic biopsies. Extracted DNA was analyzed using UW-OncoPlex, a targeted NGS panel designed to assess genomic alterations in 234 cancer-associated genes (PMID: 24189654). Results were discussed at a monthly multidisciplinary precision tumor board prior to communicating results to patients. Results: Forty patients consented to the study and 31 (78%) had reportable results. Findings included frequently observed prostate cancer genomic aberrations, including: TMPRSS2-ERG fusions and copy-number alterations of PTEN, TP53, FOXA1, AR, and SPOP. We also observed potentially actionable alterations in BRAF, MAP2K1 (MEK1), PIK3R1, MET, FGFR1, and FGFR3, which inform future treatment and clinical trial considerations. Notably, 8/31 (25%) patients had suspected high penetrance germline mutations, including in BRCA2 (N = 3), TP53 (N = 2), ATM (N = 1), and CHEK2 (N = 2). These 8 individuals were referred to medical genetics and 7 of 8 mutations were confirmed to be germline. One patient was found to have a hypermutated phenotype associated with bi-allelic MSH6 mutation and microsatellite instability. Conclusions: Targeted NGS panel testing may be useful in informing future treatment approaches and clinical trial selection for patients with prostate cancer. In addition, we observed a high proportion of cases with suspected high-penetrance germline mutations and immediate actionability through referral to medical genetics.
Safety and activity of the multikinase inhibitor sorafenib in heavily pretreated patients with refractory/relapsed malignant lymphomas: Final results of a phase II study.
Authors: A. Guidetti, C. Carlo-Stella, S. Viviani, L. Devizzi, S. Locatelli, P. Matteucci, A. Marchianò, R. Lanocita, M. Magni, A. Dodero, C. Tarella, M. A. Di Nicola, P. Corradini, A. M. Gianni
Journal: Journal of Clinical Oncology (2011)

e13593 Background: Sorafenib might have a role in the treatment of malignant lymphomas by overcoming the cytoprotective effects of Bcl-XL, ERK, and Mcl-1 and eventually targeting additional signalling pathways relevant to lymphomagenesis. This Phase II study was aimed to determine safety and activity of Sorafenib in patients (pts) with refractory/relapsed malignant lymphomas. Methods: Between March 2008 and July 2010, 30 pts (M/F: 19/11; median age, 61 years; range, 18-74) with relapsed (n = 6) or refractory (n = 24) aggressive non-Hodgkin lymphoma (NHL) (n = 14), indolent NHL (n = 7), chronic lymphocytic leukemia (n = 2), peripheral T cell NHL (n = 1) and Hodgkin Lymphoma (n = 6) were enrolled in this study. Prior to study entry, pts received a median of 4 (range, 1-8) lines of treatment with autografting performed in 67% and an additional allografting in 17% of cases. Sorafenib 400 mg BID was administered continuously until disease progression or appearance of clinical significant toxicity. Tumor response was assessed according to the revised response criteria for malignant lymphoma. Results: Pts received a median of 4 months (mos) (range, 1 – 10) of therapy. Common grade 1-2 adverse events (AE) were diarrhea (27%), hand-foot skin reaction (HFSR) (23%), fatigue (23%), weight loss (17%), thrombocytopenia (36%) and anemia (10%); grade 3-4 AE included HFSR (20%), infection (12%), neutropenia (20%) and thrombocytopenia (14%). The overall response rate was 13%, 2 pts achieved complete remission, 2 pts partial remission; response duration (DR) was 7, 5, 7 and 3 mos. Stable disease (SD) was observed in 15 pts, progression disease (PD) in 11. 37% of pts with at least a SD had a DR > 5 mos. Median progression free survival was 4 mos (range, 1-9), median survival was 16 mos (range, 1-34). Analysis of phosphorylation of ERK (pERK) in peripheral blood lymphocytes showed significant difference in pre- and post-treatment values between responding and non responding pts. Conclusions: Sorafenib in lymphoma pts was well tolerated. Although objective reponse was limited, results suggest an antilymphoma activity that warrants further researches focused on combination therapy.