tbuckley/cabot-search huggingface dataset:
Ophthalmic acid in plasma: A possible predictor for elevated risk of erlotinib-induced hepatotoxicity.
Authors: Akinobu Hamada, Yuki Kai, Jiichiro Sasaki, Sho Saeki, Hiroto Kishi, Shinji Fujii, Hiroshi Semba, Takeshi Isobe, Yutaka Hashimoto, Hirotsugu Kohrogi, Hideyuki Saito
Journal: Journal of Clinical Oncology (2012)

e13072 Background: Erlotinib is metabolized by cytochrome P450 enzymes to form a para-hydroxyaniline metabolite that is further metabolized to quinone-imine. Erlotinib is detoxified when it conjugates with sulfate or glucuronide. We recently demonstrated that patients who experienced severe erlotinib-induced hepatotoxicity had higher metabolic ratios of glucuronides than those who developed moderate toxicity; this finding indicates that glucuronidation could be saturated and high levels of reactive metabolites might be trigger of glutathione (GSH) depletion. Ophthalmic acid (OA), which is an analog of GSH, may be a useful biomarker for hepatotoxicity because it is a sensitive indicator of GSH depletion in animal model. GSH acts as an enzyme-catalyzed antioxidant when cells and organisms experience electrophilic stress that arises from metabolic processes. Here, we examined the association between plasma concentration of OA and hepatotoxicity in patients who were treated with erlotinib in Japanese patients. Methods: We assessed data from 26 patients with NSCLC who each received a 150 mg dose of erlotinib. Plasma concentrations of OA and erlotinib were measured at before treatment using the liquid chromatography-quadrupole mass spectrometer system. Results: All 26 patients experienced one or more erlotinib-induced adverse events. The most frequent erlotinib-induced adverse events were mild to moderate skin rashes and diarrhea. There seemed to be a relationship between the plasma concentration of erlotinib and the grades of skin rashes and diarrhea. Interestingly, OA was detected only in one patient who developed grade 4 hepatotoxicity, indicating that this patient, who had a higher level of OA (36.9 ng/mL) in plasma. In contrast, the other 25 patients, who did not develop hepatotoxicity, had no detectable OA in plasma. Thus, the plasma concentration of OA was not related to the plasma concentration of erlotinib nor to the grade of skin rash. Conclusions: OA might be useful as a predictive biomarker of hepatotoxicity if measured before starting erlotinib treatment. Larger studies are needed to investigate the association between OA levels and the development of severe hepatotoxicity.
Diastolic blood pressure (dBP) and pharmacokinetics (PK) as predictors of axitinib efficacy in metastatic renal cell cancer (mRCC)
Authors: O. Rixe, J. Dutcher, R. Motzer, G. Wilding, W. M. Stadler, M. Garrett, Y. Pithavala, S. Kim, J. Tarazi, B. I. Rini
Journal: Journal of Clinical Oncology (2009)

5045 Background: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of VEGF receptors 1, 2, 3. An association between dBP elevation and clinical outcome has been previously reported (Rini, ASCO. 2008). The objective of this pooled analysis of two phase II mRCC studies was to explore the relationship between PK, dBP, and clinical efficacy. Methods: PK data from two phase II studies in cytokine-refractory mRCC patients (pts) and 8 single-dose healthy volunteer (HV) studies were included (n = 109 mRCC pts and 240 HV) in the population PK analysis; the efficacy analysis included mRCC pts only. PK data was analyzed using nonlinear mixed-effects modeling to estimate population PK parameters (mean and inter-individual variability). Mean steady-state area under the plasma concentration-time curve (AUC) at the end of cycle 1 and the dBP during axitinib therapy were utilized as predictors of clinical efficacy in the mRCC pts using logistic regression and Kaplan-Meier analyses. Results: The median overall survival (mOS) for mRCC pts with at least 1 dBP measurement ≥90 mmHg (n = 59) during axitinib therapy was 130 weeks vs. 42 weeks (p &lt; 0.01) for pts without any dBP ≥90 mmHg (n = 50). The mOS of pts with an AUC below the median (605 ng.hr/ml; n = 54) was 69 weeks vs. 88 weeks (p &gt; 0.05) for pts with an AUC above the median (n = 55). Among pts with dBP ≥90 mmHg, mOS was 120 weeks and 131 weeks (p &gt; 0.05) for pts with AUC below and above the median (n = 23 and 36), respectively. Among pts without dBP ≥90 mmHg, mOS was 42 weeks and 43 weeks (p &gt; 0.05) for pts with AUC below and above the median (n = 31 and 19), respectively. An 82% increase in probability of a partial response was predicted for a 10 mmHg higher dBP during therapy. There was no apparent correlation between the AUC and maximum dBP during axitinib therapy. Conclusions: dBP ≥90 mmHg during axitinib therapy is a strong predictor of clinical efficacy in patients with mRCC, and is not merely a reflection of higher axitinib drug levels. These data support an ongoing pivotal phase III trial in previously treated mRCC that incorporates a dose-titration scheme based on patient tolerance and BP. [Table: see text]
Phase I/II dose escalation study of OncoVex<sup>GM-CSF</sup> and chemoradiotherapy (CRT) in untreated stage III/IV squamous cell cancer of the head and neck (SCCHN)
Authors: K. Harrington, M. Hingorani, M. Tanay, J. Matthews, K. Newbold, L. Renouf, R. S. Coffin, I. McNeish, C. Nutting
Journal: Journal of Clinical Oncology (2009)

6018 Background: OncoVEX GM-CSF is a gene deleted (ICP34.5-/ICP47) oncolytic HSV-1 that encodes human GM-CSF. OncoVEX GM-CSF causes direct oncolytic tumour cell destruction and immune activation by releasing tumour antigens and GM-CSF, effects that may co-operate with CRT to increase loco-regional control in SCCHN. Methods: Patients (pts): Stage III/IVA SCCHN, N1-N3, ECOG 0–1, normal haematologic, biochemical, immune function. Pts received CRT (70 Gy/35 fractions with concomitant cisplatin 100 mg/m 2 (d 1, 22, 43) and dose-escalating (10 6 , 10 6 , 10 6 , 10 6 pfu/mL [cohort 1]; 10 6 , 10 7 , 10 7 , 10 7 [cohort 2]; 10 6 , 10 8 , 10 8 , 10 8 [cohort 3]) OncoVEX GM-CSF by intratumoral injection (d 1, 22, 43, 64). Pts underwent neck dissection 6–10 weeks after CRT. Primary endpoints were safety and recommended dose/schedule for future study. Secondary endpoints were anti-tumor activity, viral replication and HSV antibody levels. Results: 17 pts were treated, 9 at the top dose (15 males, median 58 years). DLT and MTD were not reached. There were no delays to CRT delivery. 13 pts had PR or CR by CT, 5 pts achieving rapid CR following only 2 or 3 viral doses. Pathological CR was observed in 94% of pts at neck dissection. Transient low level injection site viral shedding was seen in 3 pts. HSV was detected in injected and adjacent uninjected tumors by qPCR and immunohistochemistry, including at levels higher than the input dose, indicating replication. All seronegative pts seroconverted. 11 of 17 (65%) pts remain in remission at median follow-up of 23 months. No pts had local relapse, 1 pt had a new primary tumor, 3 pts distant metastatic disease, 1 pt intercurrent disease, 1 pt lost to follow up. Conclusions: OncoVEX GM-CSF combined with cisplatin-based CRT is well tolerated in pts with SCCHN. Viral replication was confirmed. Long-term locoregional control was achieved in 100% of pts, 65% of pts remaining in complete remission. Further study is warranted. [Table: see text]
Phase I trial of patupilone plus carboplatin in patients with advanced cancer
Authors: M. Gore, S. Kaye, A. Oza, C. Keyzor, L. Pyle, R. Pereno, I. Sklenar, S. Zaknoen, A. Johri
Journal: Journal of Clinical Oncology (2005)

5087 Background: Patupilone, a natural epothilone, is a microtubule-targeting cytotoxic that has demonstrated clinical activity in taxane-sensitive and -resistant tumors and produces synergistic inhibition of cancer cell growth when combined with carboplatin. We investigated the safety and tolerability of patupilone in combination with carboplatin in a phase I study of patients (pts) with advanced solid tumors. Methods: Pts received patupilone once every 3 weeks starting at 3.6 mg/m2 and escalating by 1.2-mg/m2 increments to 6.0 mg/m2 via 5–10 min IV infusion, immediately followed by carboplatin AUC 5 or 6 via 60-min IV infusion. Results: A total of 37 pts were enrolled in 4 cohorts. The majority (70%) of pts had platinum-sensitive relapsed ovarian cancer. No DLTs were reported until cohort 2, in which 1 of 6 pts treated with patupilone 4.8 mg/m2 + carboplatin AUC 5 had grade 3 elevated liver enzymes. Pts in cohort 3 received patupilone 4.8 mg/m2 + carboplatin AUC 6, and 1 of 6 pts reported a DLT (grade 3 nausea and vomiting). In cohort 4, 3 of 6 pts who received patupilone 6.0 mg/m2 + carboplatin AUC 6 had a DLT including grade 4 fatigue, grade 3 nausea and abdominal pain, and grade 3 abdominal pain. Thus, the MTD of patupilone in combination with carboplatin AUC 6 was 4.8 mg/m2. In an expansion cohort, 16 additional pts have been enrolled at the MTD with 2 pts discontinuing because of grade 3 fatigue. Among all pts enrolled, the most common adverse events included diarrhea (84%), fatigue (68%), nausea (60%), and vomiting (43%). Overall, 10 pts experienced peripheral neuropathies at least once: 8 pts had grade 1, 1 pt had grade 2, and 1 pt had grade 3. There were no cases of grade 4 peripheral neuropathy and only 3 grade 3 hematologic toxicities. Of the 29 pts with ovarian or peritoneal cancer who were evaluable by CA-125 assessment, 22 had a response of at least 50%. Of the 21 pts with ovarian or peritoneal cancer who were evaluable by RECIST, 8 had a complete or partial response, 3 had stable disease, and 5 had progressive disease; response is currently unknown for 5 pts. Conclusions: This study suggests that the combination of patupilone 4.8 mg/m2 + carboplatin AUC 6 is well tolerated and demonstrates antitumor activity in a pt population previously treated with platinum therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharma AG, Novartis Novartis Pharma AG, Novartis Novartis Pharma AG, Novartis Novartis Pharma AG, Novartis Novartis Pharma AG, Novartis
A single-arm, multicenter, open-label phase II trial of cabazitaxel as second-line treatment for patients with locally advanced or metastatic transitional cell carcinoma (TCC).
Authors: Avivit Peer, Avivit Neumann, Daniel Keizman, Stephen Jay Frank, Raanan Berger, Larisa Leitzin, Ester Pinto, Victoria Neiman, Eli Rosenbaum
Journal: Journal of Clinical Oncology (2015)

372 Background: For patients with advanced TCC who have progressed on a platinum-based regimen, no widely accepted standard second line therapy currently exists. A 2-stage phase II study was conducted to assess the activity and toxicity profile of the microtubule inhibitor cabazitaxel (Jevtana; FDA-approved in hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen) in patients with metastatic TCC after failure of prior platinum-based chemotherapy. ClinicalTrials.gov NCT01600339. Methods: Patients with one prior platinum based systemic therapy for metastatic TCC received cabazitaxel at a dose of 25 mg\m 2 every 21 days with prophylactic GCSF support, until disease progression or unacceptable toxicity. The primary endpoint was objective tumor response rate (ORR). Secondary endpoints included safety, time to progression (TTP), and overall survival (OS). Results: Twenty-three patients were enrolled to the study, 19 of whom received treatment. Male\female ratio was 15\4 and the median age was 67 (range, 56-81) years. Partial response (PR) was observed in 1 patient (5.3%), 10 patients (52.6%) achieved stable disease (SD), including 8 (42.1%) that had prolonged SD (≥16 weeks).Furthermore, the disease control rate (PR or prolonged SD) was 47.4%. The median TTP and OS were 4.2 (95% CI, 2.0-6.0) months and 9.9 (95% CI 5.6-13.2) months, respectively. The median number of treatment cycles was 5 (range 1-10). One patient experienced Grade 5 toxicity. Neutropenic fever occurred in 10.6% of patients. Most common toxicities were anemia and diarrhea. Conclusions: Cabazitaxel had modest efficacy in the treatment of advanced TCC, and there was no evidence of a significant response. Toxicity profile was considerable. The role of Cabazitaxel in urothelial carcinoma may need further evaluation in rational combination strategies, but not as a single agent. Clinical trial information: NCT01600339.
Comparison of enzastaurin pharmacokinetics and safety in the once daily (QD) and twice daily (BID) dose regimens: A phase I study
Authors: A. Hanauske, L. Musib, K. Weigang-Köhler, E. Yilmaz, T. Graefe, B. Kuenen, D. Thornton, M. Lahn, C. Darstein, G. Giaccone
Journal: Journal of Clinical Oncology (2007)

14021 Background: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathway to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. Objectives of this phase 1b study included the comparison of safety and PK data for enzastaurin and its active metabolites in the QD (once daily) and BID (twice daily) regimens. Methods: Patients (pts) with advanced or metastatic cancer were enrolled. In cycle 1, pts received 500 mg enzastaurin QD from days 1–15 and 250 mg BID from days 16–30. In subsequent 21-day cycles, 500 mg/m 2 pemetrexed was administered as a 10-minute intravenous infusion on day 1, with 250 mg enzastaurin BID. Folic acid and vitamin B 12 supplementation was given to pts prior to and during pemetrexed administration. For comparison of enzastaurin QD versus BID, PK sampling was performed on days 15 and 29 of cycle 1. Results: Interim data for cycle 1 are presented for 26 patients who received 1 dose of enzastaurin. Twenty patients (9 F, 17 M; median age 60 years [range: 43–80]; ECOG =2) completed cycle 1. Hematological toxicities (grade [Gr] =3) were reported on a total of 9 pts. Lymphopenia occurred in 8 pts in BID regimen (1 Gr 3) and 2 pts in QD. Leukopenia (n=1), neutropenia (n=1), hypokalemia (n=1) and SGPT increase (n=1) were reported only in BID regimen. Chromaturia (n=15) was observed in both regimens. Hypoalbuminemia (n=2) and fatigue (n=2) were equally common in both regimens. Pharmacokinetic data for the two regimens is shown in the table . Exposures increased by approximately 50% and 40% for enzastaurin and total analyte (enzastaurin + metabolites), respectively. Conclusions: In comparison to QD dosing, enzastaurin exposures are increased modestly after BID dosing. This increase in exposure did not cause any clinically significant worsening of toxicities in most patients. [Table: see text] [Table: see text]
T20/DP178, an Ectodomain Peptide of Human Immunodeficiency Virus Type 1 gp41, Is an Activator of Human Phagocyte N-Formyl Peptide Receptor
Authors: Shao Bo Su, Wang-hua Gong, Ji-Liang Gao, Wei-Ping Shen, Michael C. Grimm, Xiyun Deng, Philip M. Murphy, Joost J. Oppenheim, Ji Ming Wang
Journal: Blood (1999)
Survival predictors in second-line chemotherapy for metastatic gastric cancer
Authors: P. O. Bohanes, D. Courvoisier, T. Perneger, P. Morel, O. Huber, A. D. Roth
Journal: Journal of Clinical Oncology (2009)

e15575 Background: Many patients (pts) with metastatic gastric cancer (MGC) are in good condition after first line chemotherapy (chemo) and are offered further treatment. However there is no established predictor to select pts who will most likely benefit from second line chemotherapy (SLC). Methods: We conducted a retrospective review of all patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma who were treated until death at our institution and died between 01.1994 and 06.2008. Prognostic values of the tumour characteristics, pts characteristics at SLC, previous curative surgery (PCS) and sensitivity to previous chemo were analysed by Cox univariate and multivariate regression for overall survival (OS). Results: 65 pts with MGC were treated at our institution up to their death. Of these, 43 pts (65%) received SLC. 24 pts (55.8%) received CPT-11 based SLC. 4 pts (9.3%) docetaxel-platin, anthracyclines and fluoropyrimidine based SLC. 3 pts (7%) oxaliplatin and 3 pts (9.3 %) other chemo. Median OS from the start of SLC was 30.1 weeks. 25 pts (58.1%) had disease control (response and stable disease) lasting at least 12 weeks under SLC. Potential prognostic variables with their frequencies and prognostic values are listed in the Table . Multivariate analysis showed that PCS was significant predictor for OS (HR=0.46, p&lt;.05). PFS1 of more than 26 weeks was a strong significant OS predictor (HR=0.41, p&lt;.05). Interaction test between PFS1 and PCS was not significant (p=0.48). Conclusions: Benefit from a SLC in MGC is highly related to former sensitivity to first line chemo. This is of major importance in the design of trials in MGC in a second line setting. [Table: see text] No significant financial relationships to disclose.
Bone marrow biopsy for staging Hodgkin's lymphoma: the value of bilateral or unilateral trephine biopsy.
Authors: M Luoni, S Fava, P Declich
Journal: Journal of Clinical Oncology (1996)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1996.14.2.682 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 8636790 Bone marrow biopsy for staging Hodgkin's lymphoma: the value of bilateral or unilateral trephine biopsy. M LuonixM LuoniSearch for articles by this author , S FavaxS FavaSearch for articles by this author , P DeclichxP DeclichSearch for articles by this author https://doi.org/10.1200/JCO.1996.14.2.682 PDF "Bone marrow biopsy for staging Hodgkin's lymphoma: the value of bilateral or unilateral trephine biopsy.." Journal of Clinical Oncology, 14(2), pp. 682–683© 1996 by American Society of Clinical Oncology
Facilitators and barriers to advance care planning in oncology.
Authors: Joanna Paladino, Rachelle Bernacki, Mathilde Hutchings, J. Andrew Billings, Susan Block
Journal: Journal of Clinical Oncology (2014)

84 Background: For seriously ill patients to plan for the end of life, they need to discuss with their clinicians their prognosis, values, and goals, yet such conversations often begin very late in the course of illness. To promote early advance care planning (ACP) in oncology, facilitators and barriers to these conversations need to be identified. Objectives: 1. To determine the effectiveness of “triggers” that remind oncologists to complete ACP discussions with outpatients whom they expect might die within a year. 2. To prospectively evaluate clinician-identified barriers to these conversations. Methods: A cluster-randomized controlled trial. The intervention includes: clinician identification of patients at high risk of death within a year; 2½ hour training program on the use of the Serious Illness Conversation Guide; an email trigger/reminder, immediately before an outpatient visit, for the oncologist to conduct an ACP discussion using the Conversation Guide; clinician reports of why they deferred such conversations. Results: Eighty-eight enrolled oncology clinicians (MDs, NPs, PAs) screened 15,576 patients and identified 1,743 for whom they would not be surprised about death within a year. To date, 332 patients have consented to enrollment; 104 patients and 40 clinicians entered the intervention arm; 124 subsequent visits were triggered, resulting in 62 completed conversations. 79% of the conversations occurred after 1 trigger; 92% by the second trigger. Of the 62 triggered visits that did not result in an immediate conversation, clinicians identified the following reasons: 26% not enough time; 20% clinician attitudes about the impact and timing of such conversations (i.e., they take away hope, patient not sick enough); 46% immediate patient issues making conversation inappropriate (i.e., patient acutely ill, anxious, depressed, or not ready); and 8% “other.” Conclusions: An email trigger in the outpatient oncology clinic is highly effective in promoting ACP conversations for trained clinicians. The majority of clinician-identified barriers to such discussions reflect beliefs about the impact and timing of the discussion and concerns about the patient’s immediate condition; time constraints only account for about a quarter of delays. Clinical trial information: NCT01786811.
Phase I clinical and pharmacological trial of trabectedin (T) in 3 hour infusion every 3 weeks (3h/q3w) in patients with advanced cancer and hepatic function disorder
Authors: R. Salazar, B. Pardo, M. Majem, M. García, A. Montes, C. Cuadra, E. Ciruelos, H. Cortés-Funes, C. Lebedinsky, L. Paz-Ares
Journal: Journal of Clinical Oncology (2006)

2080 Background: Trabectedin (ET-743) is a marine-derived DNA and transcription interacting agent with activity in pretreated soft tissue sarcoma, breast, prostate and ovarian cancer. T is associated with 2 types of liver function alterations: a frequent acute and reversible elevation of ALT and AST and a less frequent cholestasis, usually reflected by low grade increases in alkaline phosphatase (AP) and bilirubin (B). The main predictors of dose limiting toxicity (DLT) or T-related serious adverse events appear to include elevated baseline or intercycle peaks of AP, B and ALT &gt; 5 × ULN (Gomez J, ASCO 2000). The objectives of this trial are to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of T 3h/q3w in patients (pts) with advanced cancer and baseline liver dysfunction. Methods: All pts are stratified according to basal liver function as follows: STRATUM (S) I: ULN &lt; AP ≤ 1.5 × ULN S II: 1.5 × ULN &lt; AP ≤ 2.5 × ULN S III: AP &gt; 2.5 × ULN All pts had to have AST and ALT ≤ 2.5 × ULN, albumin &gt; 2.5 g/dl and B &lt; 2.5 mg/dl. T concentrations in plasma are determined using a validated LC-MS/MS method. PK parameters were calculated by non-compartmental methods. Results: 32 pts were recruited.Median age: 54 years (26–76); PS≤1:28 pts; prior chemotherapy (CT): 31 pts (97%); median number of prior CT: 2 (1–6); B &gt; ULN: 0 pts. In S I, T was administered at 1.1 mg/m 2 (3 pts) and 1.3 mg/m 2 (13 pts). Two DLTs were reported at 1.3 mg/m 2 : neutropenia G4 &gt; 5 days with febrile neutropenia and G3 ALT not recovered by day +28. In S II no DLT occurred in 4 pts at T 0.9 mg/m 2 nor 3 pts at T 1.1 mg/m 2 , 1 out of 4 pts at 1.3 mg/m 2 suffered DLT: G3 AST not recovered by day +24. In S III one out of 2 pts at 0.9 mg/m 2 had DLT: AP increase. Initial PK evaluation from S I and II (8 from each) showed a long half life (geometric mean (GM) S I: 124.6 h, S II: 118.8 h) and wide distribution (GM Vss S I: 2366 l/m 2 , S II: 3830 l/m 2 ). GM clearance: 18.3 l/(hr*m 2 ) in S I; 26.3 l/(hr*m 2 ) in S II. Clearance is somewhat lower than in normal liver function population (GM under equal dexamethasone treatment 33.8 l/hr*m 2 ) in study ET-B-010. Conclusions: The recommended dose (RD) of T for pts with mild AP elevations (&lt; 1.5 ULN) and B levels &lt; ULN is 1.3 mg/m 2 3h/q3w. The study is ongoing to define the RD for S II and III [Table: see text]