tbuckley/cabot-search huggingface dataset:
Sirolimus in advanced hemangioendothelioma.
Authors: Silvia Stacchiotti, Elena Palassini, Michela Libertini, Andrea Marrari, Rossella Bertulli, Carlo Morosi, Antonella Messina, Flavio Crippa, Gianpaolo Dagrada, Angelo Paolo Dei Tos, Alessandro Gronchi, Silvana Pilotti, Paolo Giovanni Casali
Journal: Journal of Clinical Oncology (2013)

10565 Background: Haemangioendothelioma (HE) is a very rare vascular tumor. The epithelioid variant is characterized by a specific t(1;3)(p36.3;q25) translocation, resulting in the WWTR1-CAMTA1 fusion product. We retrospectively reviewed patients with HE treated with sirolimus, an mTOR inhibitor, at our institution. Methods: We identified 12 patients (M/F: 4/8 – mean age: 46 years – epithelioid HE/ retiform HE: 10/2 – locally advanced/multifocal: 1/11 – pretreated: 6) with advanced HE who were treated with sirolimus, as a single agent, 5 mg/day, from 2005 on. They had evidence of progression in the 3 months before starting treatment. The daily dose of sirolimus was adjusted according to drug blood levels (range 10-20 ng/dl). Response was evaluated with CT/MRI/PET scans after 4-6 weeks of treatment, then every 3 months, by RECIST and Choi criteria. WWTR1 gene rearrangement was evaluated by FISH, and the histochemical expression of mTOR effectors, S6 and 4BP1, is ongoing. Results: 10 patients are evaluable for response (2 pts are too early). Sirolimus daily dose ranged from 3 to 6 mg/day. Best response by RECIST was PR = 1, SD = 6 (all &gt;6 months, range 6-48+), PD = 3 cases. In 3 cases, a Choi response could be detected. PET response was observed in 6/6 evaluated case. Median PFS (range) was 24 (3-48) months. Two patients with evidence of tumor stabilization while under sirolimus stopped their treatment after 12 and 24 months of therapy, respectively, with evidence of interval progression in both. A new disease stabilization was obtained after restoring sirolimus. Conclusions: HE is known for its potentially long-lasting course, even in typical cases with multicentric/multifocal disease. Progressive HE may require a medical therapy, but is insensitive to cytotoxic chemotherapy, while mainly andecdotal responses were reported to interferon, bevacizumab and thalidomide. In this retrospective series, sirolimus resulted in a high proportion of mainly non-dimensional, possibly long-lasting, tumor responses.
A phase II study of NGR-hTNF, a novel vascular targeting agent (VTA), administered as single agent at low dose in patients (pts) with colorectal cancer (CRC) refractory to standard regimens
Authors: A. Santoro, V. Andretta, V. Gregorc, L. Rimassa, E. Bennicelli, F. Sclafani, F. Caprioni, F. Caligaris-Cappio, A. Lambiase, C. Bordignon
Journal: Journal of Clinical Oncology (2008)

4110 Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13 highly expressed on tumour blood vessels. NGR-hTNF combines activity on tumour vascular permeability and direct anticancer activity. In preclinical models, NGR-hTNF showed antitumor activity at both low and high doses. Methods: Pts with CRC refractory to standard treatments, including biological agents, were enrolled to evaluate a low dose of NGR-hTNF given at 0.8 mcg/m2 as 1-hour intravenous infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and 27 pts to be enrolled in stage 1 and 2, respectively. Progression-free survival (PFS) was the primary end point and reassessment was performed q6w. Results: 32 pts (16 M/16 F; PS 0/1 26/6; median age: 65 years, range 53–79) received 111 cycles (median 2, range 1–10) and 13 pts (41%) were treated with ≥4 doses. The median number of prior regimens was 3 (range: 2–5), with 8 pts (25%) pre-treated with ≥4 lines. In the first stage, one pt (6%) achieved a confirmed partial response lasting 5 months and 9/16 pts (56%) had a stable disease (SD). The median and 3-month PFS were 2.9 months (95% CI 1.9–3.9) and 47% (95% CI 21–71%), respectively. After completion of the second stage, a total of 4 pts were progression-free at 4.5 months, with one pt still on treatment after 7 months. Neither grade 3–4 treatment-related adverse events nor toxicity- related death were observed. Main grade 1–2 toxicities per patient were infusion-related chills (41%) and transient blood pressure increase (9%). The study is currently recruiting patients into a subsequent cohort of 12 patients treated with a weekly schedule of administration. Conclusions: Based on the favourable and manageable toxicity profile and preliminary evidence of activity in heavily pretreated CRC patients, NGR-hTNF will be further developed both as single agent and in combination with standard chemotherapeutics. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Molmed
Exploratory evaluation of pharmacodynamic biomarkers and pharmacokinetics (PK) of ziv-aflibercept (Z) + FOLFIRI in a phase II study of Japanese patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Takayuki Yoshino, Naotoshi Sugimoto, Kentaro Yamazaki, Takeshi Kajiwara, Yoshito Komatsu, Toru Sasaki, Marielle Chiron, Samira Ziti-Ljajic, Claire Brillac, Tetsuya Hamaguchi
Journal: Journal of Clinical Oncology (2017)

799 Background: Z + 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a 2 nd -line treatment for mCRC. There are no established biomarkers that predict response to this treatment. This study aimed to identify such biomarkers. Methods: 62 pts with mCRC received Z (4 mg/kg) + FOLFIRI every 2 weeks. 78 potential protein biomarkers (e.g., cytokines) were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and pre-dose 3 (Day 1 of Cycle 3) were measured in all pts by enzyme-linked immunosorbent assays. Relationships between these levels and efficacy endpoints were assessed. PK data were calculated. Results: 10 potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P &lt; .001); the greatest changes were in placental growth factor (median: 4,716%) and vascular endothelial growth factor receptor 1 (2,171%). Baseline levels of 8 potential biomarkers correlated with overall survival (OS; see table) in a univariate Cox regression analysis; none correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Conclusions: Preliminary data show that these 8 biomarkers could be associated with OS. No significant drug interactions were found. Clinical trial information: NCT01882868. [Table: see text]
Pretreatment Whole Blood Epstein-Barr Viremia Is a Prognostic Factor in Peripheral T-Cell Lymphoma
Authors: Yu Ri Kim, Soo-Jeong Kim, June-Won Cheong, Hyewon Lee, Haerim Chung, Jung Yeon Lee, Ji Eun Jang, Yundeok Kim, Woo-Ick Yang, Yoo-Hong Min, Jin Seok Kim
Journal: Blood (2016)
Factors affecting in-hospital mortality in primary malignant brain tumor patients with grand mal status epilepticus.
Authors: Sonam Puri, Tapan Mehta, Parshva Patel, Khushboo Sheth, Jitesh Joshi, James J. Vredenburgh
Journal: Journal of Clinical Oncology (2015)

e13002 Background: Primary malignant brain tumors (PMBT) are the second leading cause of death among individuals less than 34 years of age. Seizures are relatively common in these patients and may be the initial manifestation or occur late during the course of disease. In this nationwide study, we investigated the factors affecting mortality in PMBT patients with grand mal status epilepticus. Methods: We queried the Nationwide Inpatient Sample (NIS) database between 2002 and 2011 and separated the hospitalizations due to or with PMBT using respective ICD 9 diagnostic codes. We investigated status epilepticus related mortality in PMBT population using multivariate logistic regression. The regression model included demographics (age, sex, and race) and clinically relevant covariates (hypertension, ischemic stroke, intracranial bleed, craniotomy, radiation therapy, hyponatremia, intracranial infections, brain neoplasms other than PMBT, and alcohol use. Using SAS 9.2, survey procedures were used to identify multivariate predictors of inpatient mortality in PMBT population with grand mal status epilepticus. Results: A total of 633,356 hospitalizations with PMBT were available for analysis, of which 5,112 had grand mal status epilepticus. Mean age of PMBT patients with grand mal status epilepticus was 49.3 years with 57.7% males. The odds ratio for grand mal status epilepticus (1.867 with 95% Confidence interval [CI] 1.482-2.352, p < 0.0001) and seizure related mortality (1.483 with 95% CI 1.322-1.665, p < 0.0001) was significantly higher in the African American population. Additionally, compared to other areas of the brain, the odds ratio for seizure related mortality in patients with temporal and occipital lesions was significantly lower at 0.711 (95% CI 0.593-0.852, p = 0.002) and 0.675 (95% CI 0.518-0.881, p = 0.0039) respectively. Conclusions: African American race is an independent predictor of grand mal status epilepticus and mortality related to it in patients with PMBT. Moreover, temporal and occipital disease was found to have decreased seizure related mortality compared to other areas of the brain in these patients.
Patient attitudes toward cancer care financial burden.
Authors: Barry R. Meisenberg, Stephen Ebner, Erin M Ellis, John Moxley, Erika Siegrist, David Edward Weng, Ashley Varner
Journal: Journal of Clinical Oncology (2015)

e17805 Background: The high costs of cancer care are now recognized as major concerns for pts. High financial burden is associated with stress, anxiety, and poor QOL, a phenomenon known as “Financial Toxicity.” Surveys indicate1/2-2/3 of cancer pts have moderate or high financial stress related to finances. Pts express a desire to learn more about their costs but more nuanced pt. attitudes and beliefs remain unaddressed. Methods: Convenience sample of pts visiting infusion or radiation clinics completed a survey that included the Personal Financial Wellness Scale™ (PFWS) and supplemental questions. Results: 132 returned surveys (94% response rate). M:F ratio = 30:70, median age = 64 51% diagnosed w/in 6 months Rx: 92% IV/oral chemo; 58% surgery; 46% radiation; 13% hormone Rx. All pts. were insured: 73% commercial; 42% Medicare; median income: $75,000. Financial stress level (PFWS): high: 47%, moderate: 15%, low: 38%. Even among those with the highest financial stress, 81% do not want their personal costs considered in treatment planning. However, 28% of high-stress pts. are willing to receive the less expensive treatment if they are of equivalent efficacy. Conclusions: These preliminary data have implications for efforts to address the high costs of cancer care. Given that most pts – even those with high financial stress – are reluctant to discuss costs with their oncologists or have costs impact their Rx. regimen, it will be hard to modify prescribing practices of oncologists based upon concerns over financial toxicity. Further research is examining why pts are reluctant to discuss costs with their oncologists and how they perceive chemotherapy choices (e.g., Do pts. equate costs with efficacy?) Patient attitudes about considering cost in treatment decisions. Question Strongly agree or agree (%) Neutral (%) Strongly disagree or disagree (%) “Information on costs should come from my oncologist” 20 34 46 “My personal financial situation should be a major factor in deciding among treatment options” 11 11 77 “Overall costs to society should be a major factor in deciding among treatment options” 10 18 72 “If there were more than one equivalent treatment plan, I would want the less costly one” 31 25 44
A double blind, parallel, placebo controlled, dose ranging study on efficacy and safety of oral clodronate in cancer induced osteolysis measured by biochemical markers of bone resorption
Authors: J. E. Brown, E. McCloskey, J. A. Dewar, J.-J. Body, D. A. Cameron, O. P.-K. Purohit, A. Harnett, R. Tahtela, M. Kurkilahti, R. E. Coleman
Journal: Journal of Clinical Oncology (2004)

8056 Background: The bisphosphonate clodronate is effective in the treatment of osteolytic bone metastases at an oral dose of 1600 mg per day. However other doses such as 2400 mg and 3200 mg have also been used. Using bone markers as surrogate biomarkers for osteolysis, the purpose of the study was to investigate the efficacy of oral clodronate (BONEFOS®) across a range of doses in patients with tumour induced osteolysis. Methods: 125 patients with metastatic bone disease (87 breast, 33 prostate and 5 other tumour types) were randomized to oral clodronate (800, 1600, 2400 and 3200 mg) or placebo in a phase II double blind, dose ranging, multicentre study with ethical approval. During 6 weeks of treatment, bone markers were assessed weekly. Results: Doses of 1600 mg or above were all effective in producing a mean fall in both urinary N-telopeptide (NTX, see table for breast data) and C-telopeptide of over 40 % from baseline values. Moreover, effects of clodronate were seen by 1 week. The 800mg dose gave a smaller effect and placebo gave no effect. The number of adverse events in the treatment arms was not significantly different from the placebo arm, except for the 3200 mg dose, where a higher number of patients had significant diarrhoea. Conclusions: This is the first such dose-ranging study with clodronate, where bone markers have been used as the primary end-point to assess efficacy. The data are consistent with the known clinical use of 1600 mg daily, but suggest that 2400 mg may also be used without increased toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering OY Schering OY Schering OY Schering OY
The vascular endothelial growth factor as a predictive and prognostic factor in patients with advanced gastric cancer treated with docetaxel, cisplatin, and 5-florouracil (DCF) regimen.
Authors: Sedef H. Aktas, Hakan Akbulut, Ozan Yazici, Nurullah Zengin, Nalan Akgun, Zeki Ustuner, Fikri Icli
Journal: Journal of Clinical Oncology (2013)

e15191 Background: Vascular endothelial growth factor (VEGF) is a key element stimulating the angiogenesis in solid tumors. In the current study, we aimed to assess the role of plasma VEGF levels as a prognostic and predictive marker for advanced gastric cancer patients treated with a modified docetaxel, cisplatinum and 5-florouracil (DCF) regimen. Methods: Thirty consecutive patients treated with a modified DCF regimen were included in the study. The plasma VEGF levels of the patients before treatment and following two cycles of chemotherapy were assayed. Results: The modified DCF regimen was well tolerated and yielded a median overall survival (OS) time of 9,0 months and 2-year OS rate of 20%. Good performance status, lower pre-treatment VEGF levels,and decrease in VEGF levels following chemotherapy were found to be independent prognostic factors for OS. Conclusions: The results of the current study suggest that the corrected plasma levels of VEGF could be used as a prognostic factor for advanced gastric cancer patients and a decrease in VEGF levels following 2 cycles of chemotherapy as a predictive marker for patients receiving DCF chemotherapy regimen.
Phase 1 study of BPM 31510 (Ubidecarenone) in patients with advanced solid tumors (ST): Use of multiomics platform to evaluate reversal of Warburg effect.
Authors: Ralph Zinner, Peter Paul Yu, Niven R. Narain, Rangaprasad Sarangarajan, Michael Kiebish, Vivek Vishnudas, Yezhou Sun, Leonardo Rodrigues, Viacheslav R Akmaev, Susan Brouwer, Janice Stevens, Ely Benaim, Manish A. Shah
Journal: Journal of Clinical Oncology (2015)

2539 Background: BPM 31510 is a small molecule that targets the metabolic machinery of the cancer microenvironment to create a hallmark shift from lactate dependency towards mitochondrial oxidative phosphorylation, reversing the Warburg effect. Preclinical data indicate BPM 31510 causes this shift resulting in tumor regression and enhances the antitumor activity in combination with chemotherapy agents in a priming schedule. This is the first clinical study to evaluate BPM 31510 at a 4-days (d) continuous infusion in four arms; as a single agent, and in combination with Gemcitabine, 5-FU or Docetaxel. Methods: Eligible patients (pts) (aged ≥ 18 y) had previously treated relapsed/refractory ST. Pts in the monotherapy arm received IV BPM 31510 for 4 d in continuous infusion in 28-d cycles. Pts in the combination arms were primed for 3 wks and then started in a weekly dosing (either gemcitabine, 5-FU or docetaxel) after the BPM 31510 infusion in a 6-wk cycle. Doses were escalated in a 3+3 schema. Phase I endpoints were safety, PK and Multi-Omics based pharmacodynamics. Tumor response is evaluated at wk 2 and every 4 -6 wks. Results: As of 01 Dec 2014, 56 pts have been enrolled. Pts have been treated at 3 dose levels up to 137 mg/kg. No DLTs or treatment‐related SAEs have been reported. MTD has not yet been established. Most frequently reported related AEs in all 4 arms were grade 1-2 INR prolongation that resolved after Vitamin K administration. No bleeding reported. Grade 1-2 thrombocytopenia has been seen in the Gemcitabine arm requiring dose modification. PK data indicated linear distribution. 12/25 pts (48%) that are evaluable for efficacy after cycle 2 showed various responses including: tumor reductions, decrease FDG, arrested tumor progression, stable disease, decrease in tumor markers, QOL improvements. Integrated multi-omics technology showed reversal of the Warburg effect in selected pts. Conclusions: Emerging data from this study suggest that BPM 31510 is well tolerated in monotherapy or in combination with chemotherapy agents. Early anti-tumor activity is seen. Dose-escalation on a 6-day infusion schedule is ongoing to determine the recommended phase II dose Clinical trial information: NCT01957735.
Special protocol assessments: 10 years of experience in FDA’s Office of Hematology and Oncology Products.
Authors: Virginia Ellen Maher, Alice Kacuba, Yangmin M. Ning, Anthony J. Murgo, Amna Ibrahim, Ann T. Farrell, Patricia Keegan, Robert L. Justice, Richard Pazdur
Journal: Journal of Clinical Oncology (2014)

e17511 Background: A special protocol assessment (SPAs) for a clinical trial evaluates the suitability of the protocol and its statistical analysis plan to support a regulatory submission and potential approval of a drug or licensure of a biologic product. The SPA outcome is either agreement or disagreement. If there is disagreement on the original SPA request, the package can be revised and resubmitted for a second or subsequent SPA. Even if an SPA agreement is reached, it does not mean that achieving statistical significance will necessarily result in approval as the outcome should also be clinically significant and the benefit to risk assessment must be favorable. Methods: We reviewed all submissions to the Office of Hematology and Oncology Products (OHOP) between January 2003 and January 2013 labeled as an SPA in our electronic filing system and for which a communication was sent to the sponsor. Submissions were categorized as original requests or as resubmissions. Results: There were 532 SPAs submitted during the 10-year period examined. These included 344 original submissions and 188 resubmissions. Protocols and their statistical analysis plans were revised and resubmitted up to four times. Agreement was reached on 132 submissions (25%). Among the 132 SPA agreements, 30 (23%) have been submitted (28) or will be submitted (2) as a New Drug Application (NDA) or a Biologics License Application (BLA). Among the remaining 102 SPA agreements, 44 (33%) of trials did not demonstrate a benefit for the study drug, 26 (20%) are continuing to recruit patients, 16 (12%) were not conducted, 11 (8%) have completed accrual and are awaiting results, and in 5 (4%) the status is unknown. Conclusions: Over the 10-year period examined, OHOP received a large number of SPA submissions. A minority of these submissions resulted in agreements, and 23% of SPA agreements resulted in the submission of an NDA/BLA.
Outcome and prognostic factors in metastatic primitive neuroectodermal tumors with uniform chemotherapy protocol: A single center experience of 150 patients.
Authors: Sameer Bakhshi, Bivas Biswas, B. K. Mohanti, N. K. Shukla, Shishir Rastogi, Sandeep Agarwala, S. V. S. Deo, Dayanand Sharma, Shah Alam Khan, Sanjay Thulkar, Sreenivas Vishnubhatla
Journal: Journal of Clinical Oncology (2013)

e21522 Background: Data on metastatic primitive neuroectodermal tumor (PNET) with uniform protocol is minimal. Methods: This is single institutional patient review treated between June 2003-Nov 2011, and evaluated on intent-to-treat analysis. All patients received uniform chemotherapy (VAC/IE) as follows: neoadjuvant chemotherapy (NACT), surgery and/or radiotherapy as local treatment followed by ACT. Local treatment was offered if patient achieved CR and/or PR at both primary and metastatic site. Results: 150/374 (40%) PNET patients were metastatic with median age 15 years (range: 2–50); tumor diameter 10 cm (range: 1.8-26) and symptom duration 4 months (range: 0.1-30). Most common tumor region was pelvis 34 (23%), thorax 26 (17%) and femur in 26 (17%). Most common metastatic sites were lung only 53 (35%), bone only 35 (23%), combined bone/lung 25(17%), and bone marrow 37 (25%). Post-NACT, 9 (6%) achieved CR and 79 (53%) PR (53%) with ORR 59%. Twenty patients underwent surgery; 55 patients received radical radiotherapy following NACT. At median follow-up of 20.8 months (range: 1.6–95), 5-year EFS, OS and local control rate (LCR) were 7.6%, 15% and 37.6%, respectively. Multivariate analysis of prognostic factors in entire group and lung only metastases group is shown in the Table. Conclusions: This is the largest study of metastatic PNET from Asia and has identified unique prognostic factors. Hypoalbuminemia had inferior EFS; radical radiotherapy had inferior LCR. In group with only lung metastases, age ≤15 years and number of metastases &gt;3 had lower EFS. In view of dismal prognosis with conventional chemotherapy in metastatic PNET, metronomic therapy may be a potential therapeutic alternative for subgroup of metastatic patients with hypoalbuminemia. [Table: see text]