bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recombinant erythropoietin (Epo)/darbepoetin (Darb) associated venous thromboembolism (VTE) in the oncology setting: Findings from the Research on Adverse Drug Events And Reports (RADAR) project
Authors: Gleason K. , Tigue C. , Yarnold P. , McKoy J. , Angelotta C. , Courtney D. , Edwards B. , Bohlius J. , Bennett C. 
Published: March 2020

2552 Background: Cancer patients are at increased risk for VTE as compared to the general population, making VTE as a sADR difficult to detect in the oncology setting. In 2004, two phase III trials identified higher mortality rates among epo-treated cancer patients who were receiving chemotherapy in “off-label” settings- with these studies identifying higher VTE rates in the treatment arms. We reviewed data on epo/darb-associated VTE in the oncology setting. Methods: Data sources were meta-analyses and the FDA’s MedWatch database. Results: Since 1996, only 259 VTE reports (darb: n=30, epo: n=229) of VTE in the setting of chemotherapy and epo/darb were reported to MedWatch. Meta-analyses findings are tabulated below: Conclusions: In 2004, package inserts for Epo/Darb were revised, identifying increased risks of VTE with these agents in the oncology setting. Identification of this adverse drug reaction thirteen years after Epo received FDA approval for this indication (and had been prescribed to > 500,000 cancer patients) illustrates difficulties inherent with current pharmacovigilance efforts. [Table: see text] No significant financial relationships to disclose.
A phase I study evaluating a novel schedule of oral eniluracil (EU) combined with escalating doses of oral 5-fluorouracil (5- FU)
Authors: Infante J. R. , Jones S. F. , Lawton M. , Wing P. , Malik R. K. , Peters W. P. , Burris H. A. 
Published: March 2020

2560 Background: 5-FU, a commonly utilized cytotoxic, is rapidly catabolized by dihydropyrimidine dehydrogenase (DPD), and requires anabolic conversion for anti-tumor activity. It has poor oral bioavailability due to DPD in the GI tract and liver, and toxicities such as hand-foot skin reaction. In addition, high levels of DPD are associated with 5-FU resistance. EU is a mechanism-based irreversible inactivator of DPD. Early studies in combination with oral 5-FU demonstrated activity; however, 3 Phase 3 studies were negative, due to an unrecognized inhibition of 5-FU anabolic activation by EU (Fourie et al; 2006 ASCO Proceedings; a 2058). Lower doses of eniluracil given 12–20 hrs prior to 5- FU preserves the desired DPD inhibition, without inhibiting these anabolic enzymes. Methods: The objectives are to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and DPD activity in peripheral blood mononuclear cells (PBMCs) following administration of a fixed dose of EU in combination with escalating doses of 5-FU. The combination of oral 5.0 mg EU 12 to 20 hours prior to oral 5-FU, is given qW for 3 weeks in 28 day cycles. Results: Twenty subjects have been enrolled, at 5-FU doses of 30, 40, 50, 60, and 70 mg. A total of 39 cycles have been administered, with 4 patients currently on study. The oral combination of EU and 5-FU has been well tolerated. All toxicities have been grade 1 or 2 with the exception of two grade 3 toxicities reported at the 50mg dose (anemia and neutropenia). The grade 3 neutropenia is the only observed DLT and resulted in a 1 week delay in initiation of cycle 2. No CR or PR noted, but 4 patients (2 previously treated with 5-FU) with 4 cycles of SD. 95–100% of DPD inhibition achieved at the time of 5-FU dosing and PK results demonstrate a dose proportional increase in 5-FU Cmax and AUC, and a half life of ∼3.5 hours. Conclusions: The oral combination of 5mg of EU given 12–20 hrs prior to 5-FU has been well tolerated and achieves full functional inhibition of DPD in all patients. The MTD is not yet defined and the next cohort is enrolling at the 80mg dose. EU in combination with 5-FU may provide a promising therapeutic option for patients with tumors known to be resistant to 5-FU due to high levels of DPD. No significant financial relationships to disclose.
Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors
Authors: Manda S. , Mauser C. , Bokar J. , Cooney M. , Brell J. , Krishnamurthi S. , Savvides P. , Ivy P. , Remick S. , Dowlati A. 
Published: March 2020

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.
Absorption, metabolism, and excretion of 14C gimatecan (LBQ707) after oral administration in patients with advanced cancer
Authors: Woo M. M. , Rodriguez L. , Gu H. , Crenshaw-Williams K. , Rocha F. , Freestone S. , Dickson J. , Jodrell D. , Mangold J. B. 
Published: March 2020

2564 Background: Gimatecan (Gim), a new potent oral topoisomerase I inhibitor is a lipophilic 7-oxyiminomethyl derivative of camptothecin. Its in vitro cytoxicity is more sustained than CPT-11 and topotecan, it has excellent anti-tumor activity in mouse xenografts, and shown good tolerability with Ph I activity. The study aim was to profile its disposition in cancer patients. Methods: 4 patients with advanced cancer received a single oral 1.5 mg dose of [14C] Gim (60 μCi) followed by standard Gim treatment on Day 15. Whole blood, plasma, urine, and feces were collected over 7 days with spot fecal collections up to Day 19. Total radioactivity was measured by liquid scintillation counting. Gim and metabolite concentrations in plasma and excreta were measured by LC- MS/MS and HPLC with radiometric detection. Results: Gim showed a rapid first-order absorption and a long elimination phase and was well tolerated. The median (range) Tmax for Gim was 1 h (0.5 to 3 h) and mean t1/2 and oral clearance values were 91 h and 0.6 L/h, respectively. Gim was the major moiety and its active metabolite LCF775 (t-butyl-mono-hydroxy Gim) was the main metabolite (albeit minor, 2–9%) in plasma. Trace glucuronide and sulfate metabolites were also detected in plasma. Mean recovery of radioactivity in urine (0-Day 7) and feces (0-Day 11) was 70.5 % (56.2–80.0%) of the dose. Incomplete recovery is attributed to opiates use in 2 patients and incomplete (sporadic) fecal sampling at later timepoints. Fecal excretion (0-Day 11) was prolonged and major in 3/4 patients (46- 73% of the dose, of which 14–23% is the unchanged Gim suggesting the drug is well absorbed). An additional 1.3–3.5% was recovered in spot collections (Days 14, 15 and 19). Urine excretion (0-Day 7) was 7.2–10.3% of the dose in 3 patients, one patient (cachectic, on opiates) excreted only 21% in feces and 46% in urine. Gim and several Gim metabolites (and glucuronide conjugates thereof) were the major components in excreta. Conclusions: Gim and its minor metabolite, LCF775 were the principal pharmacologically active components in plasma. Fecal excretion is the main elimination pathway in most patients. A long half-life (90hr) of Gim, uncomplicated metabolism, and good oral absorption make Gim an attractive candidate for Ph II development. [Table: see text]
Phase I and pharmacological study of orally administered indibulin in advanced solid tumors
Authors: Oostendorp R. L. , Witteveen P. O. , Schwartz B. , Beijnen J. H. , Voest E. E. , Schellens J. H. 
Published: March 2020

2565 Background: Indibulin (ZIO-301/D-24851) (N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid) a novel, oral, synthetic, anti-mitotic drug is widely active against human tumor cell lines and xenografts, including multidrug resistant and taxane refractory tumors. Indibulin destabilizes microtubule polymerization; its tubulin binding site is distinct from taxanes and vinca alkaloids. In preclinical studies indibulin lacks neurotoxicity typically associated with other tubulin binding drugs. Methods: Phase I study to evaluate safety, pharmacokinetics (PK), maximum tolerated dose (MTD) and dose limiting toxicity (DLT) in patients with advanced solid tumors. Initial dosing was in lactic acid drinking solution, which later was converted to a capsule formulation. Administration was po daily for 14 consecutive days at 21 day intervals at pre-determined dose increases between cohorts. Results: 31 patients (20 M, 11F) with advanced refractory cancers were treated; 14 received 20–80 mg/dose po in lactic acid solution and 17 po capsules 100–600 mg/dose. Median age was 60 y (29–72 y); median number of prior therapies was 4 (1–8); ECOG PS = 2. Median number of cycles was 2 (1–14). Patients continued on study until disease progression or significant toxicity. DLT for solution was nausea and emesis, ascribed to lactic acid. To date, no MTD or DLT observed with oral capsules at 600 mg daily; dose escalation continues using a twice daily schedule. No neurotoxicity has been observed. There was a disproportionate increase of the AUC with dose, with declining AUC corrected for dose starting at the 250 mg dose-level. The terminal half-life at the 600 mg dose was 25.2 ± 2.4 h. Prolonged disease stabilization was seen in 2 adenoid cystic carcinoma patients for 3 and 14 months and in one prostate cancer patient for 5 months. The latter patient went off study after 5 months due to liver function disorder (ALT CTC grade 2 and AST grade 3). Conclusions: Indibulin was well tolerated at doses showing preliminary clinical activity. Target plasma concentrations above the IC50 have been achieved. Dose escalation twice daily continues. Prolonged disease stabilization was noted in adenoid cystic carcinoma and prostate cancer. [Table: see text]
Time finding study of chronomodulated irinotecan (I), fluorouracil (F), leucovorin (L) and oxaliplatin (O) (chronoIFLO) against metastatic colorectal cancer: Results from randomized EORTC 05011 trial
Authors: Garufi C. , Focan C. , Tumolo S. , Coudert B. , Iacobelli S. , Tubiana N. , Marreaud S. , Lentz M. , Gorlia T. , Lévi F. 
Published: March 2020

2566 Background: We previously showed that a) irinotecan (I) could be combined with chronoFLO in MMC patients; b) least toxic times (LTT) for combined I and oxaliplatin respectively correspond to the middle of the rest-phase and the middle of acivity-phase in tumor-bearing mice; c) chrono I showed adequate activity in a randomized phase II trial; and d) MMC resistance can be partly overcome with chronoIFL. Methods: The objective was to identify the LTT for I characterized by a minimal dose reduction/delay among the first 3 courses (c). Assuming that the toxic effect of I had a 24-h periodicity patients were randomized in 6 groups with I peak delivery (180 mg/m2, 6-h sinusoidal infusion on day 1) at 1:00, 5:00, 9:00 am, 1:00, 5:00, or 9:00 pm. . All the groups received also chronoFLO on days 2–5, q 3 weeks (F 700 mg/m2/d & L 150 mg/m2/d; from 22:15 to 9:45 with peak delivery at 4:00 , O 20 mg/m2/d from 10:15 to 21:45, with peak delivery at 16:00). Based on a logistic regression model, a 15% reduction in toxic events in the first 3 c, 186 patients were considered necessary to estimate the LTT with a 95% CI (calculated by bootsrap) of less than 6 h. Results: 197 of 199 randomized MMC patients were considered for tolerability and safety with median age 61 years (30–81), sex (M 68% - F 32%) and PS (0/1/2 73/23/4%); therapy was 1st line in 77 patients and 2nd line in 23%. Thithy-one percent of severe protocol violations occurred, 16% of pump malfunctions (>10% dose delivery deviation). Median number of c was 6 (1–18). There were 3 toxic deaths. The observed LTT for I tolerability was 3:15 am (95 CI: 3:40–1:50 pm, NS). Grade 3–4 diarrhea ranged from 34 to 51.6% with LTT at 1:53 pm (4:29 -2:53 am, not significant, NS); neutropenia from 9 to 25% with LTT at 3:26 pm (10:50 - 4:55 am, NS). Age was a negative prognostic factor for diarrhea (p =0.01). Conclusion: This trial failed to show a statistically significant LTT for this combination in MCC patients. The safety profile of I combined with ChronoIFLO was acceptable, with diarrhea and neutropenia within previously reported range. No significant financial relationships to disclose.
Prognostic factors for cancer patients with good performance status considered for inclusion in phase I clinical trials
Authors: Bonneterre M. , Penel N. , Vanseymortier M. , Dansin E. , Clisant S. , Vendel Y. , Degardin M. , Adenis A. , Beuscart R. , Bonneterre J. 
Published: March 2020

2568 Background: For investigators, the selection of patients to be considered for phase I clinical trials is difficult, because of the lack of objective criteria for a rational decision-making process. From October 1997 to October 2002, we retrospectively assessed prognostic factors for cancer patients considered for Phase 1 trials. Methods: 148 consecutive patients who had been screened for inclusion in 6 different phase I trials were included in the present study. 70 out of them actually received the phase I treatment. Univariate (Log-Rank test) and multivariate analysis (Cox proportional hazard ratio model) were performed to determine the prognostic factors related to overall survival (OS) after screening. Results: The study comprised 63 men and 85 women, with a median age of 54 (range 23–79). The most frequent primary cancer sites were: breast (38 cases), head and neck (28 cases), lung (18 cases) and colorectal (17 cases). 91 out of them had a performance status PS = 0. The median OS of the 148 patients was 5.7 months (173 days, range 1–2,421). Univariate analysis identified PS = 1, Body Mass Index < 20, liver and visceral metastasis, serum albumin < 38 g/L, lymphocytes count < 0.7 x 109/L and granulocytes count > 7.5 x 109/L as poor prognostic factors. The Cox model identified serum albumin < 38 g/L (HR 2.51 [1.51–4.18], p=0.0001) and lymphocyte count < 0.7 x 109/L (HR 2.27 [1.13–4.62], p=0.024) as independent prognostic variables for OS. All patients presenting with both prognostic factors died within 90 days. Conclusion: We propose a simple model, easily obtained at the patient bedside, which can discriminate patients who have a life expectancy of over 3 months and thus could be enrolled in phase-I anti-cancer trials. No significant financial relationships to disclose.
A phase I dose escalation study of selenomethionine (SLM) in combination with fixed dose irinotecan (Iri) in patients with solid tumors
Authors: Rustum Y. , Pendyala L. , Creaven P. , Ross M. , Brady W. , Badmaev V. , Prey J. , Fakih M. G. 
Published: March 2020

2574 Background: SLM reduces Iri toxicity in xenograft models at associated selenium (Se) concentrations (Con) = 15μM. We conducted a phase I clinical trial of a fixed dose Iri with escalating doses of SLM in order to identify the highest safe dose of SLM that achieves and maintains Se Conc > 15μM. Methods: A standard 3–3 escalation was conducted. Iri was given at 125mg/m2/week x 4 weeks every 6 weeks. SLM was started 1 week prior to 1st dose of Iri. A loading BID dose of SLM was given for 1 week, followed by a daily maintenance dose. Selenium trough levels were obtained on days 8 and 29 of the study (days 1 and 22 irinotecan) and once every 6 week-cycle. Seven dose-levels of SLM were investigated (loading/maintenance, in mcg): 3,200/2,800, 3,200/3,200, 4,000/3,200, 4,000/4,000, 4,800/4,800, 5,600/5,600, and 7,200/7,200. Results: 31 patients enrolled on this study: age (median 57, range 21–80), Male/Female 21/10, ECOG 0/1 (15/16), 31 with prior chemotherapy, 12 with prior radiation, 22 colorectal and 9 mixed solids. Dose escalation was successful up to dose level 7 (7,200mcg SLM PO BID × 1 week followed by 7,200mcg SLM PO QD), which was declared the recommended dose. 2 Dose limiting toxicities occurred on study: one DLT of Grade (G) 3 febrile neutropenia, G3 sepsis, G3 dehydration occurred on dose-level 1; one DLT of G3 febrile neutropenia, dehydration occurred on dose-level 7. Both DLT occurred in a setting of partial small bowel obstruction related to peritoneal carcinomatosis. Non-DLT = G3 treatment-related toxicities included: 3 G3 neutropenia (< 1 week) at DL2, 3 & 7; 2 G3 diarrhea lasting < 48 hours on DL5 & 7. A lower incidence of G2+ toxicities was noted in patients with higher Se Conc (86% for Se < 15; 67% for Se 15–20; 57% for Se> 20 μM). Toxicities related to SLM were limited to garlic-like smell to breath, sweat, and urine in few patients. Responses included 7 confirmed stable diseases and 2 confirmed partial responses. A Se Con > 15 μM was achieved at all SLM dose levels of 4,800 mcg and above. Conclusions: Doses of SLM up to 7,200 mcg BID × 7 days followed by 7,200 mcg QD can be administered safely with standard doses of Iri. Formal phase II and III studies are needed to determine if SLM reduces Iri toxicity. No significant financial relationships to disclose.
A phase I study of TPI287: A third generation taxane administered weekly in patients with advanced cancer
Authors: Hwang J. J. , Marshall J. L. , Ahmed T. , Chun H. , Basche M. , Cohn A. , Kurman M. , Tapolsky G. , Tapolsky G. , Allen E. 
Published: March 2020

2575 Background: TPI 287 is an investigational taxane designed to not be a substrate for mdr-1 and to bind to mutant tubulin. In preclinical studies, TPI 287 demonstrated activity against multiple human tumor xenografts in nude mice, including xenografts that expressed mdr-1 and that were resistant to other taxanes. The safety and tolerability of TPI 287 when administered weekly for 3 weeks followed by a 1 week rest (4 week cycle) was examined in this Phase 1 dose escalation study in patients (pts) with advanced neoplasms. Materials and Methods: TPI 287 was administered over 1 hour weekly for 3 weeks followed by 1 week of no treatment. Treatment cohorts consisted of 3 pts and were expanded to 6 pts in the face of dose-limiting toxicity (DLT); pts could remain on study until the development of progressive disease or an intolerable adverse event. DLT was defined as Gr 4 heme toxicity lasting 7 days; febrile neutropenia, Gr 3 thrombocytopenia with bleeding, Gr 3 elevation of transaminases lasting 7 days or any other Gr 3/4 toxicity other than nausea or vomiting. Results: 25 pts (M:F 16:9, median age 60, range 24 - 86) were enrolled in 7 dose levels ranging from 7–185 mg/m2. Pts’ cancers included colorectal (6 pts); NSCLC (2); prostate (2); squamous cell carcinoma (2) and 1 pt each with cervical, breast, ovarian, gastric, pancreatic, bladder endometrial, NSCLC, SCLC, glioblastoma, melanoma, renal cell and hepatocellular carcinoma. All pts but 1 had received prior chemotherapy (median no. prior treatments: 3 (range, 1–7). Drug related adverse events included nausea, vomiting, diarrhea, fatigue, anorexia, rash, anemia and peripheral neuropathy. 1 pt., who was inadvertently treated with inadequate marrow reserve, experienced Gr 4 neutropenia and died of sepsis. DLT of Grade 3 peripheral neuropathy has been observed. PK data to date reveal that AUC is generally dose linear. At a dose of 127.5 mg/m2, clearance was 30.2 + 11.9 L/hr/m2 and t1/2 8.6 + 1.3 hrs. Results are similar with non-compartmental methods and 2-compartment modeling. Conclusions: TPI 287 can be safely administered in doses of up to 127.5 mg/m2 weekly x 3. No significant financial relationships to disclose.
A phase I study of EC145 administered weeks 1 and 3 of a 4-week cycle in patients with refractory solid tumors
Authors: Sausville E. , LoRusso P. , Quinn M. , Forman K. , Leamon C. , Morganstern D. , Bever S. , Messmann R. 
Published: March 2020

2577 Background: Folic acid is internalized via two main pathways; a reduced folate carrier (RFC) or a folate-specific receptor (FR). While FR is minimally distributed in normal tissues, it is over-expressed in many human tumors, including cancers of the ovary, lung and kidney. Experimental data indicate that EC145, a conjugate of folic acid and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), is a high-affinity ligand for the folate receptor (FR) but not for RFC. EC145 is also highly active against FR-positive KB tumors in vivo. This phase I trial assessed the safety and pharmacokinetics (PK) of escalating bolus doses of EC145. Methods: The phase I study treated eligible patients with EC145 as an intravenous bolus according to a ‘flat dose‘ escalation plan on days 1, 3, 5 (week 1) and 15, 17, 19 (week 3) of a 4-week cycle. Endpoints included determination of a safe and tolerable EC145 dose, development of a PK model, and identification of antitumor activity. Results: As of Dec 2006, 16 patients had received bolus EC145 (1.2, 2.5 or 4 mg; n = 3, 11 and 2, respectively). EC145 was generally well tolerated at bolus doses < 2.5 mg with one patient continuing on study for 6 cycles. Overall, the most common side effects were fatigue (n = 9), constipation (n = 7) and neuropathy (n = 6). DLT at 4 mg included reversible ileus and neuropathy. Formal PK analysis will be available at the time of presentation. One patient has had a minor response and another has exhibited disease stabilization > 5 months (both ovarian cancer patients). Upon declaration of the bolus MTD, the trial was amended to explore the utility of a 1-hour EC145 infusion to take full advantage of potential high affinity interaction between EC145 and the FR to effect drug targeting. As of Jan 2, 2007, three patients had been accrued to a dose level of 2.5 mg over 1 hr, and all tolerated the therapy without significant toxicity. Conclusions: EC145 may be administered safely as a 2.5 mg intravenous bolus dose on days 1, 3, 5 (week 1) and 15, 17, 19 (week 3) of a 28-day schedule. No significant financial relationships to disclose.