tbuckley/cabot-search huggingface dataset:
Combination chemotherapy of nafamostat mesilate with gemcitabine targeting NFκB for advanced pancreatic cancer: Phase I pilot study
Authors: T. Uwagawa, T. Misawa, T. Gocho, S. Hirohara, S. Sadaoka, K. Yanaga
Journal: Journal of Clinical Oncology (2008)

15642 Background: Gemcitabine (GEM) currently remains the best chemotherapeutic agent available for the treatment of unresectable pancreatic cancer. However the chemoresistance caused by GEM-induced nuclear factor kappa B (NF-κB) activation results in unsatisfactory outcome. We reported that synthetic serine protease inhibitor nafamostat mesilate (NAM), an agent for pancreatitis or disseminated intravascular coagulation in Japan, acts as a NF-κB inhibitor as well as an apoptosis inducer in pancreatic cancer cells. Phase I combination chemotherapy of NAM with GEM targeting NF-κB was conducted through translational research. Since intravenous injection of NAM with clinical maximum dose is insufficient to accomplish NF-κB inhibition of pancreatic cancer cells, NAM was infused intraarterially. Methods: Study treatment was: GEM 1,000 mg/m2 on d 8, 15 and 22 plus NAM 2.4∼4.8 mg/kg on d 8, 15 and 22. NAM was administered intraarterially by continuous regional infusion for 24 hours via an intraarterial infusion port system one hour before administration of GEM. Results: Currently 4 patients with unresectable pancreatic cancer were included in this study. Pts characteristics: male/female: 4/0, median age 60.0 (range 38–65) yrs, median Karnofsky PS 80% (range 70–90%), stage III/IV: 0/4. None developed gr 3/4 adverse effect after 1 cycle. One pt had gr 3 neutrocytopenia, 2 pt had gr 2 leucopenia, and 1pt had gr 1 hyperkalemia after 2 cycles. Currently no dose limiting toxicities has been reported. All patients are alive. One pt achieved partial remission and 3 pts had stable disease. Furthermore, 2 pts could become off oral morphine sulfate for pain and 2 pts gained weight. Median survival was 8.0 months. Conclusions: The combination of NAM with GEM is well tolerated and MTD has not been reached. The initial clinical outcome of this trial has been encouraging. No significant financial relationships to disclose.
Phase I study of imatinib in combination with gemcitabine and capecitabine
Authors: R. C. Ramaekers, J. Elkahwaji, E. Reed, A. Ganti, J. Wang, J. Grem, J. Baranowska-Kortylewicz, R. Hauke
Journal: Journal of Clinical Oncology (2009)

e13523 Background: Imatinib-mediated inhibition of platelet-derived growth factor receptor lowers tumor interstitial pressure allowing for improved intratumoral antineoplastic drug concentration. A phase I study of imatinib (Im) with the synergistic combination of gemcitabine (Gem) and capecitabine (Cape) was undertaken. Methods: Eligibility requirements included refractory solid tumors, ECOG 0/1 and adequate organ function. A 3-week treatment cycle was used with the dose levels (DL) 0 and -1 as outlined in the table. Dose limiting toxicity (DLT) was defined as occurring within the first 2 cycles of therapy. Patients remained on therapy unless DLT occurred or disease progression. Results: Twelve patients with a median age of 59.5 (range 44 - 77) were evaluable. Baseline characteristics included ECOG PS 0/1: 6/6; prior systemic therapies: median 3 (range 1–6); tumor types: renal (4), melanoma (2), prostate, esophageal, pancreatic, small cell lung, breast, unknown primary. At DL 0, 2 of 6 patients experienced DLT (gr. 3 thrombocytopenia; gr. 4 leucopenia). At DL -1, 1 of 6 patients experienced DLT (gr. 3 thrombocytopenia). No patient missed a dose; one patient in DL -1 completed only 1 cycle. Median cycles administered was 2 (range, 1 - 19). At cycle 2 evaluation, 7 pts had stable disease, 4 had progressive disease and 1 was not evaluable. Grade 3 or 4 toxicity included thrombocytopenia, leucopenia, hyperglycemia and weakness. All hematologic grade 3/4 toxicity was seen in patients having received ≥3 cytotoxic regimens previously. Most common grade 1/2 toxicities included anemia, nausea/emesis and fatigue. One patient with renal cell had stable disease (SD) for 15 cycles and one patient with melanoma had SD for 19 cycles. Conclusions: Im in combination with Gem and Cape is well tolerated in patients without extensive exposure to cytotoxic therapy. Activity is seen in various tumor types particularly melanoma and renal cell. The suggested dose for phase II studies is Im 400 mg/d, Gem 400 mg/m 2 and Cape 400 mg/m 2 in the dose schedule as described above. [Table: see text] [Table: see text]
Preliminary results of a randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (CapeOx) vs. oxaliplatin and 5-fluorouracil in continuous infusion (5-FU CI) as first line treatment in advanced or metastatic colorectal cancer (CRC)
Authors: J. Sastre, B. Massuti, J. M. Tabernero, M. Chaves, J. J. Reina, J. Aparicio, B. Queralt, J. Maurel, E. Díaz-Rubio, E. Aranda
Journal: Journal of Clinical Oncology (2005)

3524 Background: Ox plus CI 5-FU is one of the standard chemotherapy regimens for first-line treatment in patients (p) with advanced CRC. Phase II trials have shown CapeOx as a convenient combination, with a high activity and a favourable safety profile. This study is a phase III trial comparing both schedules. Methods: The study is designed to include 348 p with histological or cytological confirmation of advanced/metastatic CRC adenocarcinoma, measurable disease, PS≥70% and adequate bone marrow, renal and hepatic function. Previous adjuvant chemotherapy was allowed. Treatment: P were randomly assigned to receive either Arm A: oral Cape 1000 mg/m2 twice daily from day 1 to day 15, plus Ox 130 mg/m2, iv, 2h, on day 1 (in 3-week treatment cycles) or Arm B: biweekly 85 mg/m2, Ox, iv, 2h, plus weekly CI 5-FU 2250 mg/m2, in 48h (TTD schedule). Treatment was continued, until progressive disease, unacceptable toxicity or consent withdrawal. Results: 268 p have been included in the interim analysis over 348 enrolled, (M/F, 61%/39%), median age: 65.9 years (32.3–81.6), PS 90–100%: 62%. Primary tumour sites were colon (66.3%), rectum (27.7%) and both (6.1%). Median number of lesion sites was 1 (1 site 68.1%), located in liver (76.1%), lung (31.5%), and lymph nodes (12.0%) mainly. Previous treatment included surgery (82.0%), adjuvant chemotherapy (21.8%) and radiotherapy (12.0%). Median relative dose intensity was 94% for Cape and 95% for Ox in arm A and 83% for Ox and 81% for 5-FU in arm B. Efficacy: over 98/97 evaluable patients, overall response rate in each arm (A/B) was 46.9/53.6%, with (6.1/4.1%) CR, (40.8/49.5%) PR, (38.8/26.8%) SD and (14.3/19.6%) PD. Grade 3–4 toxicity per p in each arm (A/B) was: paresthesia (13.4/9.0%), asthenia (10.4/17.2%), diarrhea (11.2/17.1%), neutropenia (3.7/6.7%), vomiting (5.2/6.0%) and febrile neutropenia (1.5/0.7%). Conclusions: Preliminary efficacy and safety results suggest a very similar toxicity profile and response rate for both regimens. No significant financial relationships to disclose.
Geriatric assessment of older adults with cancer: Baseline data from a 500 patient multicenter study
Authors: A. Hurria, S. Mohile, S. Lichtman, C. Owusu, H. Klepin, C. Gross, K. Hansen, S. Klapper, K. Togawa, W. Tew
Journal: Journal of Clinical Oncology (2009)

9546 Background: As the cancer population ages, a brief, comprehensive measure is needed to characterize the “functional age” of a patient, in order to optimize treatment decisions and evaluate outcomes based on factors other than chronological age. A geriatric assessment (GA) evaluates factors other than age that predict morbidity and mortality in older adults. The goals of this study are to describe the results of a GA performed in 500 older adults with cancer from 7 participating institutions and to evaluate the feasibility of completing this assessment in oncology practice. Methods: The GA is comprised of validated measures of functional status, comorbidity, cognition, psychological status, social functioning and support, and nutritional status (Hurria et al, Cancer 2005). The GA was completed prior to the start of a new chemotherapy regimen in patients age ≥ 65 with a solid tumor or lymphoma. Results: 500 patients (mean age 73; range 65–91) completed the GA. The most common tumor types were lung (29%), GI (29%) and breast/gyn (22%) cancer; 57% had stage IV disease. The GA revealed that 41% of patients needed assistance with instrumental activities of daily living despite a mean physician-reported KPS of 85 (range 50–100), 92% had ≥1 comorbid medical conditions (mean 2.5; range 0–9), 95% took ≥ 1 medications (mean 5; range 0–23), 16% had ≥ 1 falls in the past 6 months, 6% had gross cognitive impairment on the Blessed Orientation-Memory-Concentration Test, and 39% had &gt; 5% weight loss in the past 6 months. The mean time to complete the GA was 27 minutes (range 10–80); 94% were satisfied with the GA length and 70% were able to complete the GA without assistance. Multivariate logistic regression identified the following sociodemiographic and disease variables predict the need for assistance with completion of the GA: age ≥ 80 (p=0.02), high school education or less (p&lt;0.01), non-white race (p&lt;0.01), and the presence of metastatic disease (p=0.01). Conclusions: This brief GA is largely self-administered, can be completed by the majority of older patients without assistance, and identifies important deficits and problems that may impact morbidity and mortality. Prospective data are being acquired to identify factors in the GA that predict chemotherapy toxicity in older adults with cancer. No significant financial relationships to disclose.
Five year outcomes of clinically localized prostate cancer in patients with Human Immunodeficiency Virus
Authors: A. W. Levinson, V. M. Santillo, A. Hansen, F. C. Lowe
Journal: Journal of Clinical Oncology (2008)

16095 Background: The advent of highly active antiretroviral therapy (HAART) has prolonged the survival of HIV positive men (HIVPM). As HIV evolves into a chronic disease, asymptomatic HIVPM are more frequently being screened for and subsequently diagnosed with clinically relevant prostate cancer (PCa). Little is known about their outcomes. We explored the cancer and HIV specific outcomes of a cohort of HIVPM with localized PCa. Methods: We reviewed the HIV and PCa outcomes of 14 HIVPM who presented with elevated prostate specific antigen (PSA) levels and were subsequently diagnosed with clinically localized PCa (≤cT2b). For patients who elected radical prostatectomy (RP), biochemical recurrence was strictly defined as no PSA ≥ 0.2ng/ml. Results: At PCa diagnosis, our cohort had a mean age of 54.7y, time since HIV diagnosis of 9.5y (median 9.0), CD4 count of 443 (median 415, range 76–1070), viral load of 9741 [median 0 (undetectable), range 0–106000], PSA of 8.8ng/ml (range 4.1–19.9), and Gleason score of 6.2. At PCa diagnosis, 13/14 (93%) patients were receiving HAART. PCa treatment was as follows: RP in 4 (3 open; 1 lap), primary androgen deprivation therapy (ADT) in 1, cryosurgery in 1, brachytherapy in 3 (one with ADT), external beam radiotherapy in 4 (2 with ADT), and expectant management in 1. Mean follow-up 4.7y (median 5.1). At last follow up, no patient had progressed to AIDS, and no patient had clinical or biochemical progression of their HIV [mean/median CD4 count 538/300, mean/median viral load 810/0 (12/14 patients undetectable)]. For patients electing therapy with curative intent for PCa the mean PSA at follow up was 0.5mg/ml (median undetectable, range undetectable to 3.6). None of the RP patients had a detectable PSA. All PSA values at follow up represented appropriate responses to individual therapies. Neither the patient who elected expectant management nor the primary ADT patient has progressed clinically, though the primary ADT patient does have a slowly rising PSA. He continues to decline further therapy. Conclusions: HIVPM with localized PCa appear to respond appropriately to all forms of PCa therapy. Asymptomatic HIVPM with life expectancies greater than 10y should be screened for PCa, and offered the same therapeutic options as patients without HIV. No significant financial relationships to disclose.
FDA accelerated approval of anticancer agents.
Authors: Y. M. Ning, J. R. Johnson, A. T. Farrell, V. E. Maher, R. L. Justice, R. Pazdur
Journal: Journal of Clinical Oncology (2010)

6065 Background: The Subpart H NDA regulations allow accelerated approval (AA) of agents for serious or life-threatening diseases. Approval is based on surrogate endpoints reasonably likely to predict clinical benefit. Postmarketing trials are required to confirm clinical benefit. Methods: Databases and approval letters were searched to identify anticancer agents that received AA, verify the surrogate endpoint used and verify if confirmatory trials were completed. AAs of anticancer agents approved from 1/1/95 to 1/1/10 are reviewed. Results: AA was granted for 43 new indications for 34 anticancer agents. Post-marketing trials established clinical benefit and resulted in conversion to full approval (FA) of 24 indications. The time interval between AA and FA was median 3.4 years, mean 4.5 years and range 0.8 to 12.6 years, demonstrating substantial time saved in availability to patients. Nineteen AA indications remain without establishment of clinical benefit with the five longest for 10, 9, 5, 5 and 5 years since AA. For these 19 indications, post-marketing trials failed to confirm clinical benefit for 2 indications. One indication was withdrawn by the Applicant and the other limited to restricted distribution by the FDA. Of the 23 AAs during 1995-2003, 19 were converted to FA. Of the 20 AAs during 2004-2009, 5 were converted to FA. Trial designs for the AAs were randomized comparative for 18 indications and single arm for 25. The surrogate endpoints for AA were objective response rate and duration (32), time-to-event (9) and improved safety (2). Conclusions: Since implementation of the Subpart H AA regulations, the FDA has granted AA for 43 new indications for 34 anticancer agents. The time interval between AA and FA was median 3.4 years and mean 4.5 years, demonstrating substantial time saved in making anticancer agents available to patients. No significant financial relationships to disclose.
The Tolerability of Combination Therapy with Thalidomide and 5-Azacitidine in Patients with Advanced Myelodysplastic Syndromes (MDS).
Authors: Melita K Kenealy, John F Seymour, Cowan Linda, Alvin Milner, Pratyush Giri, Shir-Jing Ho, Warwick Benson, Andrew Nicol, Philip Campbell, Ian Prosser, Craig Underhill, Ilona Cunningham, Anthony K. Mills, Jeffrey Szer, Peter Presgrave, Robin Filshie
Journal: Blood (2009)
The pharmacokinetics (PK) and pharmacodynamics (PD) of ABT-751 in children with recurrent neuroblastoma or other solid tumors
Authors: E. Fox, B. C. Widemann, J. M. Maris, S. L. Cohn, H. Xiong, A. P. Krivoshik, A. E. Hagey, P. C. Adamson, F. M. Balis
Journal: Journal of Clinical Oncology (2007)

9557 Background: ABT-751 is an orally administered agent that binds to the colchicine site on β-tubulin and blocks microtubule formation. We studied the PK and PD of ABT-751 and its sulfate and glucuronide conjugates in children enrolled on a phase 1 trial in solid tumors and a pilot study in neuroblastoma. Methods: Seventy-two children (2–18 yrs) received ABT-751 on a once, daily × 7d or daily × 21d schedule. Sixty had PK plasma sampling (53 sets analyzed), and 41 had a 24h urine collection after the first dose. Drug concentrations were quantified with a LC/MS/MS assay. Results: Median (range) plasma PK parameters are shown in the table . ABT-751 was rapidly absorbed (T max , 2h), and the C max and AUC 0- 8 increased in proportion to dose. The median molar ratio of the sulfate plasma AUC 0- 8 to glucuronide plasma AUC 0- 8 was 1.5. The median (range) percent of the administered dose excreted in urine as ABT-751, glucuronide, or sulfate conjugates was 0.09 (0–0.4)%, 10.2 (1.0–38.5)%, and 12.6 (2.3–50.9)%, respectively. The median ABT-751 AUC 0- 8 was higher in patients with dose-limiting toxicity (DLT) compared to those without DLT on the 7d (118 vs. 74.5 μg·h/mL; P=0.014) and 21d (73.8 vs 49.3 μg·h/mL; P=0.049) schedules. In 28 patients with neuroblastoma, the AUC 0- 8 did not correlate with time to progression. Apparent clearance (CL/F) did not correlate with age or gender. Conclusions: PK samples were obtained from 83% (60/72) of children enrolled. The ABT-751 AUC 0- 8 was dose proportional; inter- and intra-patient variability was low. Patients who experienced DLT had higher ABT-751 AUC 0- 8 . The mean CL/F of ABT-751 was similar to that observed in adults (40 mL/min/m 2 ) but did not correlate with age or gender. The sulfate conjugate was the primary metabolite in plasma and urine. Urinary excretion was not a major route of elimination of the parent drug. [Table: see text] No significant financial relationships to disclose.
Incidence of febrile neutropenia in lymphoma patients receiving CHOP with Day 1 or 2 pegfilgrastim.
Authors: M. A. Woods, T. Lopez, S. P. Thomas, H. Harwood, S. M. Kettler
Journal: Journal of Clinical Oncology (2010)

e18562 Background: Febrile neutropenia is a rare, but serious consequence of chemotherapy that can be fatal. The current guidelines set forth by the American Society of Clinical Oncology (ASCO) recommend prophylactic use of granulocyte colony stimulating factors in patients being treated with chemotherapy regimens associated with a greater than 20% risk of developing febrile neutropenia. Pegfilgrastim is indicated to decrease the incidence of infection as manifested by febrile neutropenia. Some oncologists have employed the practice of administering pegfilgratim on the same day as chemotherapy in order to help patients avoid returning for a single treatment on a day when patients may be experiencing some of the most unpleasant adverse effects of chemotherapy. This project was undertaken in an attempt to determine whether same day pegfilgrastim does or does not lead to an increase in febrile neutropenia. Methods: A retrospective data review of patients receiving chemotherapy consisting of CHOP with Day 1 and Day 2 pegfilgrastim administration for lymphoma malignancy was collected. Data was collected from the Illinois CancerCare electronic database in Peoria, Illinois. Illinois CancerCare is a large community-based medical oncology practice. Data was collected for patients between January 2004 and January 31, 2009. All eligible patients had received a single dose of pegfilgrastim, 6 mg subcutaneously, on either Day 1 or Day 2 of chemotherapy administration. A statistical analysis was performed using a chi-square test, Fisher's Exact test, and a student's T-test. A p value of 0.01 was considered statistically significant. Results: A total of 13 episodes of febrile neutropenia were reported. 6% (10) of the Day 1 cohort (N=162), and 10% (3) of the Day 2 cohort (N=31) developed febrile neutropenia (p=0.4). There were 52 (8.1%) episodes of grade 4 neutropenia with D1 administration compared to 14 (11%) with D2 (p=0.4). Conclusions: In this setting there was no difference in incidence of febrile neutropenia between Day 1 and Day 2 pegfilgrastim administration. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen
Evaluation of the effect of intravenous calcium and magnesium (CaMg) on chronic and acute neurotoxicity associated with oxaliplatin: Results from a placebo-controlled phase III trial
Authors: A. Grothey, D. A. Nikcevich, J. A. Sloan, J. W. Kugler, P. T. Silberstein, T. Dentchev, D. B. Wender, H. E. Windschilt, X. Zhao, C. L. Loprinzi
Journal: Journal of Clinical Oncology (2009)

4025 Background: Cumulative sNT is the dose-limiting toxicity of oxaliplatin which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant setting. We recently demonstrated the protective effect of CaMg against oxaliplatin-induced sNT as assessed by NCI-CTC (Nikcevich ASCO 2008). It is unclear, though, if CaMg reduced acute and/or chronic, cumulative sNT. Methods: 104 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to IV CaMg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo (PL) in a double-blinded manner. NCI-CTC, an oxaliplatin-specific sNT scale and patient-reported outcome (PRO) questionnaires were used to differentially assess the effect of CaMg on acute (effect on sNT on days 1–4 after oxaliplatin) and chronic sNT (area between curves over whole course of therapy). Results: A total of 102 pts (50 CaMg, 52 PL; 96 mFOLFOX6, 6 FOLFOX4) were available for analysis. Apart from a strong reduction in muscle cramps with CaMg (p=0.002), no difference was found between CaMg and PL in PRO with regard to items reflecting acute sNT (e.g. sensitivity to cold, swallowing of cold liquids, throat discomfort) on days 1–4 after oxaliplatin of any treatment cycle. In contrast, CaMg was able to significantly reduce cumulative sNT in form of numbness in fingers (p=0.02), impaired ability to button shirts (p=0.05), tingling in fingers (p=0.06), and muscle cramps over the course of therapy (p=0.01). Conclusions: In our phase III, placebo-controlled trial, CaMg was able to significantly reduce chronic, cumulative sNT related to oxaliplatin as evaluated by specific PRO questionnaires. No effect was noted on phenomena associated with acute sNT. CaMg can be recommended as neuroprotectant against oxaliplatin-related chronic sNT, oxaliplatin's dose-limiting toxicity. [Table: see text]
Presentation trends of breast cancer patients at a single cancer institute in India
Authors: S. Goyle, S. Karmarkar, I. Ambulkar, A. Borker, G. Ingle, S. H. Advani
Journal: Journal of Clinical Oncology (2008)

11571 Background: Evidence suggests that breast cancer patients with ER/PR/HER2 negative disease present in a more advanced and aggressive manner. The purpose of this study was to assess the presentation trends of breast cancer patients with regards to ER/PR/HER2 status in our Indian population. Methods: We analysed retrospective data of 131 breast cancer patients presenting to our institute between January and December 2007. The patients were staged according to AJCC criteria and were divided into 3 categories: stage I/II, stage III and stage IV. ER, PR and HER2 status was then compared for the 3 categories. Results: Of the 131 breast cancer patients, 77 (59%) presented with stage I/II disease, 45 (34%) with stage III disease and 9 (7%) with stage IV disease. 28 (36%) patients with stage I/II disease were ER/PR/HER2 negative, 11 (25%) with stage III disease were ER/PR/HER2 negative and 2 (22%) with stage IV disease were ER/PR/HER2 negative. Overall 41 (31%) patients were found to be ER/PR/HER2 negative, of which 28 (68%) belonged to stage I/II, 11 (27%) to stage III and 2 (5%) to stage IV disease. Conclusions: From our data we conclude that presence of ER/PR/HER2 negativity does not necessarily correlate with more advanced disease at presentation in our Indian population. No significant financial relationships to disclose.