tbuckley/cabot-search huggingface dataset:
A phase II randomized trial of three loading doses of epoetin alfa followed by every three-week (q3w) dosing in cancer patients receiving chemotherapy
Authors: J. Chang, L. Phippard, D. Sharma, C. Y. Lau
Journal: Journal of Clinical Oncology (2005)

8219 Early rise in hemoglobin (Hb) correlates with improvement in quality of life (QOL) in a phase II randomized trial of 3 loading doses of epoetin alfa followed by every three-week (q3w) dosing in cancer patients receiving chemotherapy. Background Weekly dosing of 40,000 IU epoetin alfa is an effective dose in increasing Hb, reducing transfusion and improving QOL. A loading dose to allow hb to reach 12 g/dL followed by q3w dosing was proven to be effective. Method & Results This study evaluates the effectiveness of three loading doses (30,000 IU 2X/wk, 40,000 IU 2X/wk and, 60,000 QW) given for 4 weeks followed by two different Q3W doses (80,000 IU or 120,000 IU) in maintaining Hb levels and improving QOL (Fact-F). At trial entry (week 0) patients were randomized to one of the three loading doses. An interim analysis after 18 patients enrolled showed ≥ 1 g/dL increase in Hb for all 3 groups (p=0.002) after 4 weeks of dosing and a trend towards significant improvement in QOL (p = 0.052). Patients also maintained their Hb levels after being switched to both q3w regimens for 12 weeks. QOL Data The FACT-F results at baseline (n=17), week 4 (n=16), and week 11 (n=6) were 27.4, 32.6, and 33.3 respectively. The FACT-F baseline to week 4 (n=16) and, baseline to week 11 analysis were 5.1 (p=0.051), and 3.5 respectively. Conclusion This preliminary look indicated that patients on epoetin alfa can be maintained with q3w dosing and significant increase in Hb and improvement in QOL was obtained at week 4 after treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho-Biotech, Ortho-Biotech Canada Ortho-Biotech Ortho-Biotech Canada
Safety and tolerability of vorinostat—Experience from the vorinostat clinical trial program
Authors: D. S. Siegel, M. A. Hussein, C. P. Belani, F. Robert, S. Rizvi, J. Wigginton, S. Randolph, R. Crane, R. Ganesan, J. Garcia-Vargas
Journal: Journal of Clinical Oncology (2008)

14580 Background: Vorinostat is a histone deacetylase inhibitor with anticancer properties when used alone or in combination. Here we present an overview of safety and tolerability data from patients who received vorinostat as monotherapy or in combination with other systemic therapies. Methods: Safety data from all patients who participated in the vorinostat clinical trial program were collated (cut-off date December 2007). Results: Data from 476 patients were included: 341 received vorinostat as monotherapy and 135 in combination with other systemic therapies. The most commonly reported adverse events (AEs) associated with monotherapy were fatigue (68.3%), nausea (60.1%), diarrhea (55.4%), and anorexia (49.9%). Grade 3–5 AEs included thrombocytopenia (15.2%), fatigue (13.5%), dehydration (8.5%), and anemia (7.9%). Of 156 patients who received vorinostat monotherapy at 400 mg q.d. (the current FDA approved dose in CTCL patients), 13 (8.3%) discontinued due to AEs (predominantly anorexia [1.3%], pulmonary embolism [0.6%], and weight decrease [0.6%]), and 24 (15.4%) required dose modifications (commonly due to thrombocytopenia [5.8%], diarrhea [1.9%], and nausea [1.9%]). In combination, the most commonly reported AEs were nausea (52.6%), diarrhea (43.0%), and fatigue (41.5%), and the most common Grade 3–5 AEs were fatigue (16.3%), diarrhea (5.9%), dehydration (5.2%), and nausea (5.2%). Discontinuation due to AEs occurred in 25 (18.5%) patients, commonly due to fatigue (3.0%), dehydration and nausea (both 2.2%), and 23 (17%) required dose modification, commonly due to fatigue (5.9%), diarrhea (1.5%), and hypertriglyceridemia (1.5%). Conclusions: Data from the vorinostat clinical trial program demonstrate that vorinostat has an acceptable safety and tolerability profile when used either as monotherapy, or in combination with other systemic therapies in cancer patients. Dose modifications were not required in the majority of patients who received vorinostat as monotherapy or in combination therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck
New approach for assessment of potential ethnic differences in parallel phase l/ll studies in the United States and Asia.
Authors: T. Doi, D. Oh, Y. Bang, S. Y. Rha, H. C. Chung, N. Sakamoto, K. Schlienger, D. A. Bergstrom, W. J. Grossman, A. Ohtsu
Journal: Journal of Clinical Oncology (2010)

2549 Background: Potential ethnic differences such as drug metabolism between Asian and U.S. patients has been considered one of the major obstacles for simultaneous drug development. To evaluate this, two parallel phase I studies thatincluded pharmacokinetics (PK) assessment were conducted in Korea/Japan (K/J) and the United States using a cMET inhibitor, MK-2461. K/J study has started 3 months after U.S. study. Methods: The phase I designs were essentially identical between the K/J and U.S. studies. They included dose-escalation parts (Parts A/B) with a starting dose at 60mg/day as dose level 1 with a 3+3 design to determine a maximum tolerated dose (MTD) and evaluate safety, efficacy, PK profile, and pharmacodynamics (PD). In Part-C, safety, PK, and PD are confirmed with up to 14 patients at the MTD. PD responses were evaluated in all patients treated at pharmacologically relevant doses. The K/J study also included a phase II portion in which MTD was tested in an enriched population of gastric carcinoma patients. In K/J study, clinical information including safety, enrollment plan, and the status of U.S. study was shared in biweekly teleconference among investigators and the sponsor. Results: The drug was found to be generally well tolerated in both studies and the MTD was not reached up to dose levels 7 and 5 in the K/J and U.S. studies, respectively. Part-C was not conducted due to early study discontinuation. There were no observed differences in the PK profile and safety between K/J and U.S. patients up to dose levels 5 (300 mg BID). In the patient recruitment of K/J study, 26 patients were enrolled in Part-A/B with 3-7 patients each at dose levels 1 to 7 for 15 months while in U.S. study, 23 patients were enrolled at dose levels 1 to 5 for 19 months. On average, enrollment for each dose level cohort was achieved within 2 weeks under effective collaboration and frequent communication with investigators in K/J. Conclusions: Performing an interstudy PK comparison of parallel phase I studies in Asia and the United States may be one option to evaluate the potential for ethnic differences in oncology drug development since PK profile and the other parameters can be compared at each dose level. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Banyu Pharmaceutical, Merck Merck Merck Merck
Final results of a phase I clinical trial of the bioreductive drug RH1
Authors: S. Danson, P. Johnson, T. Ward, M. Dawson, O. Denneny, A. Watson, D. Jowle, P. Sharpe, C. Dive, M. Ranson
Journal: Journal of Clinical Oncology (2007)

2514 Background: RH1 (2,5-diaziridinyl-3-[hydroxymethyl]-6-methyl-1,4-benoquinone) is a novel bioreductive drug which is activated by the two electron reductase, DT-diaphorase (DTD) (NAD(P)H:quinone oxidoreductase). DTD is over-expressed in many tumors relative to normal tissue, especially lung, breast and colorectal tumors, so it is hoped that RH1 is selectively activated in such tumours with minimal normal tissue toxicity. Methods: Under the auspices of the CR-UK Drug Development Office, a dose escalation phase I trial of RH1 was performed at two centres. The primary objective was to establish the maximum tolerated dose (MTD) of RH1 given as a 10–30 minute infusion for 5 days every 3 weeks. Toxicity was assessed according to NCI CTC V2.0 criteria. Secondary objectives were to determine RH1 pharmacokinetics (PK), DNA cross-linking in peripheral blood lymphocytes and tumour cells, DTD activity in tumour, NQO1 polymorphism status and document any anti-tumour activity. Results: Eighteen patients of WHO performance status 0–1 with advanced refractory solid malignancies were enrolled. 14 patients were male and eight patients had colorectal adenocarcinoma. The MTD was 1,430 mcg/m2/day and the dose-limiting toxicity (DLT) was bone marrow suppression. DLT occurred in both patients treated at 1,905 mcg/m2/day: one developed grade 3 thrombocytopenia with haemorrhage and grade 3 anaemia; the other died from neutropenic sepsis. Other clinically significant drug-related toxicities included moderate phlebitis and fatigue. Plasma PK analysis on days 1 and 5 in cycle 1 showed rapid plasma clearance of RH1 (t1/2=12.3 mins) with AUC increasing proportionately with dose. The comet-X assay showed increases in DNA inter-stand cross-linking in peripheral blood lymphocytes treated at 200 mcg/m2/day or above. These cross-links were detectable within one hour of commencement of dosing and reached a maximum of 30%. DNA cross-linking after RH1 was seen in tumour samples, even with low levels of DTD. One patient was homozygous for the NQO1 polymorphism. No objective tumour responses were recorded. Conclusions: The MTD of 1,430 mcg/m2/day is the dose recommended for phase II clinical trials. Tested doses were associated with DNA cross-linking in both peripheral blood lymphocytes and tumour cells. No significant financial relationships to disclose.
Relationship of induction of apoptosis by caffeine and the cAMP, PTEN, Akt-inhibition signaling pathway in sarcoma cells.
Authors: S. Miwa, N. Sugimoto, H. Tsuchiya, T. Shirai, K. Hayashi, H. Nishida, A. Takeuchi, K. Tomita
Journal: Journal of Clinical Oncology (2010)

e20500 Background: Caffeine is a radio- and chemo-sensitizing agent acting by inhibiting ATM/ATR kinases-which regulate cell cycle checkpoints. We found that caffeine also prevents proliferation of osteosarcoma and fibrosarcoma cells. Akt exerts a strong anti-apoptotic effect through the phosphorylation and inhibition of key pro-apoptotic proteins. Dephosphorylated PTEN, a tumor suppressor gene product is able to inhibit Akt phosphorylation. Our objective was to investigate the molecular mechanism of the observed inhibition of proliferation, by evaluating the correlation between caffeine stimulation and cAMP/PTEN/Akt-inhibition signaling pathway in the sarcoma cell lines. Methods: MG63 human osteosarcoma cells and HT1080 human fibrosarcoma cells were cultured for 72 hours with 0-10mM caffeine. Then the viabilities were evaluated by WST assay. Phosphorylation of PTEN and Akt were assessed by western blotting after stimulation with caffeine for 30 min. Effects of caffeine on PTEN+ cells and PTEN− cells were evaluated by siRNA procedure. Results: Proliferations in both of the cell lines were inhibited by caffeine, and the inhibitory effects were dose-dependent (0.5-10mM). The phosphorylations of PTEN and Akt were suppressed by caffeine stimulation. The Akt phosphorylation was decreased by caffeine in PTEN+ cells, but the effect was only a little in PTEN- cells. Conclusions: We revealed that caffeine inhibits cell proliferation through cAMP/PTEN/Akt inhibition signaling pathway in the sarcoma cells. We elucidated a novel molecular mechanism by which caffeine induces apoptosis in sarcoma cells. No significant financial relationships to disclose.
ChemoID assay for anaplastic spinal ependymoma.
Authors: Jagan Valluri, Pier Paolo Claudio, Sarah E Mathis, Anthony Alberico, Gerrit A. Kimmey, Mark Jeffrey Mogul, Rajesh Sehgal, Aneel A. Chowdhary, Maria R. B. Tria Tirona, Thomas Dougherty
Journal: Journal of Clinical Oncology (2013)

e13040 Background: Cancer stem-like cells (CSLCs) can resist certain chemotherapies, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for individualized anticancer treatments. Methods: We have developed ChemoID, an in vitro chemotherapy assay, designed to predict the sensitivity and resistance of a given patient’s CSLCs and bulk of tumor cells to a variety of chemotherapy agents. Results: A 5-month female (Patient A), and a 21-year old male (Patient B), both affected by anaplastic WHO grade 3 ependymoma were screened using the ChemoID assay. A range of concentrations flanking the clinical doses for vincristine, carboplatin, cyclophosphamide, etoposide, cisplatin, methotrexate, cytosine arabinoside, oxaliplatin, irinotecan, avastin, procarbazine, lomustine, and busulfan were tested. The CSLCs and bulk of tumor ependymoma cells of Patient A were found moderately sensitive (30% cell kill) to only cisplatin and procarbazine, both as single agents and in combination. Following 6 cycles of vincristine, carboplatin, cyclophosphamide, etoposide, and cisplatin in various combinations, Patient A rapidly progressed and proton beam therapy was recommended. The CSLCs and bulk of tumor ependymoma cells of Patient B were found highly sensitive (80% cell kill) to the combination of irinotecan and avastin, which resulted in 18 months free of disease progression. After recurrence, chemotherapies were tested in combination with benzyl-isothiocyanate (BITC), a bioactive natural food component contained in extracts from cruciferous vegetables. BITC greatly increased the chemosensitivity in Patient B to the combination of irinotecan and avastin, resulting in average 90% CSLCs and bulk of tumor ependymoma cell eradication. MRI scan of Patient B showed over 50% tumor regression after two months of treatment with a combination of irinotecan, avastin, and supplements containing BITC. Conclusions: Our findings suggest that no patients are alike in their chemotherapy response. ChemoID assay that measures cell death of CSLCs and bulk of tumor cells from patient biopsies to standard chemotherapy agents in vitro is a feasible approach to personalized anticancer treatments.
Is age a predictor of outcome in epithelial ovarian cancer?
Authors: E. Chalas, J. Villella, A. Buhl, K. Vandenheuvel, E. Komaroff, M. L. Pearl
Journal: Journal of Clinical Oncology (2004)

5120 Background: To determine the impact of age on outcome of primary therapy in epithelial ovarian carcinoma (EOC) Methods: Retrospective chart review of 215 patients with EOC who underwent cytoreductive surgery and primary chemotherapy with intent to control disease by a team of gynecologic oncologists at two tertiary care institutions from 1997 to 2003. Established clinical indicators of outcome were subjected to univariate and multivariate analyses with SAS version 8.02. Results: In a univariate analysis, variables associated with age were: medical comorbidities (p<0.001), postoperative complications (p<0.026), stage (p=0.005) and worsening performance status throughout treatment (p<0.0012 to p<0.0001). Age was not associated with preoperative CA 125 value, rate of optimal cytoreduction, estimated blood loss,enrollment in a clinical research protocol or CA125 level prior to fourth course of therapy CA125. Stage, age, optimal cytoreduction and CA125 were significant predictors of all cause mortality, but in multivariate analysis of 143 patients with Stage III/IV EOC, only CA125 remained an independent predictor of outcome (p<0.0001). Patients with elevated CA125 are six times more likely to die. Conclusions: Older patients can receive therapeutic treament for EOC. When controlled for stage, patients with elevated CA125 have a six fold increase in the risk of death. No significant financial relationships to disclose.
Ten- and 15-year prostate cancer-specific survival in patients with nonmetastatic high-risk prostate cancer randomized to lifelong hormone treatment alone or combined with radiotherapy (SPCG VII).
Authors: Sophie D. Fossa, Anders Widmark, Olbjorn Harald Klepp, Fredrik Wiklund, Anders Angelsen, Jan-Erik Damber
Journal: Journal of Clinical Oncology (2014)

4 Background: After a median observation time of 7.6 years, Scandinavian Prostate Cancer Group VII randomized trial showed a significant 12% reduction of prostate cancer-specific mortality in patients with locally advanced or histologically aggressive prostate cancer who received three months of total androgen blockade followed by radiotherapy and continuous antiandrogen therapy compared to patients with hormonal treatment only (Widmark et al :Lancet [2009]; 373,1174). Here we provide the 10 (15)-year survival results after a median observation time of 10.7 years. Methods: Between February 1996 and December 2002, 875 patients with locally advanced prostate cancer were randomized (Randomization ratio 1:1). Primary endpoint was prostate cancer-specific survival analyzed by intention to treat. This updated analysis is based on death registry data of the Norwegian patients (2/3 of the population), and on data recorded in CRF database available for the Swedish patients. A Swedish death registry analysis is underway, and will be included in the final analysis at the meeting. Results: Prostate cancer death occurred in 118 out of 439 of the antiandrogen treatment group and in 45 out of 436 men in the combination treatment group (p&lt; 0.0001), with death due to any cause in 210 out of 439 and 161 out of 436 men (p=0.0006), respectively. The 10 (15) year cumulative prostate cancer-specific mortality was more than halved after combined treatment: 18.9% (30.7%) and 8.3% (12.4%) (HR=0.35;[p&lt;4.1E-10 for 15 year results]), and overall mortality was 35.3% (56.7%) and 26.4% (43.4%) (HR=0.70; P=0.0006 for 15 year results), respectively. Conclusions: Addition of local radiotherapy to hormonal treatment in patients with non-metastatic locally advanced or high-risk prostate cancer more than halved the 10 and 15 year prostate cancer-specific mortality and substantially decreased overall mortality.
CALGB 30206: Phase II study of induction cisplatin (P) and irinotecan (I) followed by combination carboplatin (C), etoposide (E), and thoracic radiotherapy for limited stage small cell lung cancer
Authors: M. J. Kelley, J. A. Bogart, L. D. Hodgson, R. H. Ansari, J. N. Atkins, X. F. Wang, M. R. Green, E. E. Vokes
Journal: Journal of Clinical Oncology (2007)

7565 Background: We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens for patients with untreated LS-SCLC. Methods: Eligibility: measurable disease, performance status (PS) 0–2, no prior therapy, and adequate organ function. Treatment: Induction with P 30 mg/m 2 and I 65 mg/m 2 both IV day 1 and 8 q21 days ×2 cycles. Beginning day 43 daily chest irradiation (200 cGy/fraction) to 70 Gy concurrent with C AUC=5 IV day 1 and E 100 mg/m 2 days 1–3 q 21 days x3 cycles (5 chemotherapy cycles total). Endpoints: Primary - to differentiate a 45% and 60% 2-year survival rate (&gt;39 pts alive/75 pts; a=0.091, β=0.098); secondary-response rates to induction and overall therapy, overall and progression-free survival, and toxicity. Results: Characteristics: Between 11/03 and 9/05, 78 patients were enrolled (2 ineligible): male/female, 43/33; white/black, 74/2; median age 61 (range, 41–79); PS 0/1, 50/26; wt loss &gt;5% in 10 (2 missing data). Two full induction cycles were delivered to 73 (96%) patients; all planned treatment was delivered to 50 pts (66%). Efficacy: To date, 41 (54%) pts have died before 2 yrs. P+I induction chemotherapy resulted in 4 (5 %) CR, 45 (59 %) PR; Overall RR 64% (95% CI 53–74%). Best response to therapy among 76 evaluable pts was 23 (30%) CR and 40 (53%) PR. The 95% CI for ORR is 73–90%. With median follow-up of 18 m, median PFS and OS are 12.6 m (95% CI 10.1–14.7) and 16.1 m (14.1–23.9). Toxicity: Frequent (&gt;20%) grade 3/4 toxicities over all therapy in 77 patients were: neutropenia 25%/58%, hemoglobin 35%/1%, platelets 26%/26%. Maximum hematological toxicity was grade 3/4 in 16%/70% of patients. Maximum non-hematological toxicity was grade 3/4 in 47%/12% including: esophagitis in 27%/3% and dehydration in 21%/1%. No fatal toxicities. Conclusions: This treatment regimen, employing irinotecan doublet induction therapy followed by 70 Gy concurrent radiation and “standard” etoposide carboplatin has tolerable toxicity but did not produce a 2 year survival rate of &gt;50%. New strategies for augmenting median and overall survival among patients with LS-SCLC are needed. [Table: see text]
Candidate drug BIBR1532 induces telomere shortening and growth inhibition in lymphoid cell lines
Authors: M. Ladetto, I. Ricca, M. Compagno, D. Ferrero, A. Rocci, P. Omedè, F. De Marco, M. Dell Aquila, M. Boccadoro, C. Tarella
Journal: Journal of Clinical Oncology (2004)

6605 Background: Telomerase inhibition is a new strategy that might be useful in inducing senescence and growth inhibition (GI) in cancer cells. Antisense oligonucleotides and more recently pharmacological inhibitors have been used in this setting. Candidate drug BIBR1532 is a non-nucleoside inhibitor of h-TERT. In solid tumor cell lines, it induced telomere erosion and GI (Damm K et al, The Embo J, 2001). BIBR1532 has never been tested in hematological cancers. B-cell tumors were chosen due to their marked difference in TL according to germinal center (GC) origin (i.e. GC-derived vs. extra GC-derived) (Ladetto et al ASH meeting 2003 #796). Methods: The extra-GC derived myeloma cell line KMS11 and GC-derived lymphoma cell lines CA46 and DHL16 were cultured in standard conditions ± BIBR1532 (provided by Klaus Damm MD, Boehringer Ingelheim Pharma, Germany). BIBR1532 10 microM was given thrice a week. KMS11, CA46 and DHL16 have been cultured for 7, 5 and 2 months respectively resulting in 80 mitotic divisions for KMS11 and CA46 and 25 for DHL16 without treatment. Cell growth was assessed thrice a week. Cell aliquots were taken every 20 days to assess TL. Propidium iodide assay was used to verify whether GI was due to apoptosis or prolipherative arrest. Results: As expected based on GC-status, cell lines had different baseline TL: CA46 and DHL16 had a 6000bp TL, while KMS11 had only 2900bp TL. Without BIBR1532 no telomere erosion occurred. Treated cells lost 45bp at each mitotic division. As TL approached 2500bp progressive GI was observed. This occurred after 10 mitotic divisions for KMS11 and 55 for CA46. A plateau effect was noticed for KMS11 cells after 42 mitoses. No GI was so far observed in DHL16 cells as expected based on baseline TL. Propidium iodide showed that GI was due to G1 arrest. Conclusions: This is the first study on the use of BIBR1532 on B-lymphoid cell lines. It proves that: a) BIBR1532 induces telomere shortening and GI in lymphoid cell lines; b) baseline TL of cell lines predicts timing of GI onset; c) GI seems to be due to G1-arrest. Telomerase inhibitors are worthwhile of further investigation for the treatment of B-cell tumors. No significant financial relationships to disclose.