bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of vorinostat plus docetaxel in patients with solid tumor malignancies
Authors: Schneider B. J. , Bradley D. , Smith D. C. , Egorin M. , Kalemkerian G. , Dunn R. , Daignault S. , Hussain M. 
Published: August 2020

2528 Background: Vorinostat is an inhibitor of histone deacetylase 6, which results in the acetylation of tubulin and the stabilization of microtubules. Since taxanes bind to stabilized microtubules, the administration of vorinostat followed by docetaxel, we hypothesized, should result in synergistic cytotoxicity. A phase I trial was conducted to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in ≤ 30% of patients (pts). Methods: Eligible pts had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after ≥1 prior chemotherapy regimen not containing docetaxel, a performance status of 0–2 and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle. Docetaxel was given intravenously over 1 hour on day 4. The time-to-event continuous reassessment method guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m2, respectively. Blood was collected on days 1 and 4 of cycle 1 to measure drug levels by HPLC. Results: 12 pts were enrolled: median age 65 yrs (49–74); gender 9M:3F; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles was 2. 2 pts were treated at DL -1, 4 pts at DL 0, 5 pts at DL 1 and 1 pt at DL 2. 5 DLTs occurred in 5 pts: grade 4 neutropenic fever/sepsis (n = 2), anaphylactic reaction (n = 1), myocardial infarction (n = 1) and GI bleed (n = 1). Other toxicities included grade 4 neutropenia (n = 2), pulmonary embolus (n = 1) and GI bleed (n = 1). The estimated probability of DLT for DL -1 was .32 (90% posterior probability interval [PI], .11 to .53) for DL 0, .38 (90% PI, .16 to .58) and for DL 1, .43 (90% PI, .23 to .64). The trial was stopped due to excessive toxicity. No responses were noted. Conclusions: Combination vorinostat plus docetaxel was poorly tolerated with excessive DLTs requiring study termination. PK analysis will be presented. Supported in part by a grant from Merck & Co., Inc. [Table: see text]
Design of a phase 0 microdosing trial for correlation of platinum-induced DNA damage to chemotherapy outcomes
Authors: Pan C. , Li T. , He M. , de Vere White R. , Gandara D. , Mack P. , Lara P. N. , Turteltaub K. , Henderson P. 
Published: August 2020

2543 Background: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS), an ultrasensitive method for measuring radiocarbon, can detect [14C]carboplatin bound to the DNA of cancer cells from cell culture, mice bearing tumor xenografts and patients receiving subtoxic microdoses of compound. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [14C]carboplatin. Relevant parameters such as drug influx/efflux, intracellular drug inactivation, DNA damage and repair, were measured and correlated with response to chemotherapy. A Phase 0 microdosing trial has been designed to study patients with non-small cell lung or bladder transitional cell cancers who are planning to receive Pt-based chemotherapy. One microdose of [14C]carboplatin is administered to these patients 4 hours before biopsy. Pt-induced DNA damage and repair in tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Results: Preclinical studies showed that AMS can detect Pt-DNA damage when cancer cells and mice with tumor xenografts are exposed to one microdose of [14C]carboplatin. The levels of microdose-induced DNA damage are directly proportional to the damage caused by a therapeutic drug dose (p<0.001); and these levels of DNA damage correlate with chemoresistance as measured by MTT assay. Measuring drug uptake/efflux and intracellular inactivation allows insights into resistance mechanisms. These data support the conclusion that the levels of DNA damage induced by microdosing can potentially predict chemoresistance in patients. Consequently, a Phase 0 microdosing trial is in progress. Conclusions: These results support a phase 0 microdosing trial employing AMS to identify chemoresistance and determine the underlying chemoresistant mechanisms for personalized therapy before patients receive cytotoxic chemotherapy. [Table: see text]
Metabolism and transport pathways of the blood stable camptothecin AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin)
Authors: Milewska M. , Horn J. , Monks N. , Moscow J. A. , Arnold S. M. , Leggas M. 
Published: August 2020

2553 Background: AR-67 is a 3rd generation camptothecin analog with superior stability of its active lactone form (>85%). This stability has been credited in part to the -R10 hydroxyl group (-OH); a group also present on the two clinically approved analogs, topotecan and irinotecan. As with SN-38, the active metabolite of irinotecan, the -OH of AR-67 may be a site for glucuronidation by a UDP glucuronosyltransferase. Moreover, many camptothecins are substrates for the efflux transporter BCRP (ABCG2) and the anionic carboxylate may be a substrate for the liver uptake transporter OATP1B1 (SLCO1B1). Pharmacogenetic studies have established that significant portions of the population have polymorphisms in these genes, which lead to altered pharmacokinetics and toxicity profiles of their substrates. This report describes in-vitro metabolism and transport studies with AR-67 as well as identification of metabolites in plasma and urine from patients enrolled in a phase I study. Methods: AR-67 and its metabolites were detected using chromatography methods with fluorescence or MS/MS detection. In vitro metabolism studies were done with UGT and CYP450 enzyme isoforms expressed in Sf9 cells. In vivo AR-67 metabolic products were identified in clinical plasma and urine specimens. Collection of clinical specimens has been described (control #09-AB-30336-ASCOAM). AR-67 uptake and efflux studies were performed in cells transfected with ABCG2 or SLCO1B1. Results: AR-67 glucuronidation was demonstrated to occur in vitro, primarily by UGT1A8. AR-67 was also found to be a substrate of CYP3A4 and CYP3A5. Only limited glucuronide and oxidation metabolite peaks were observed in patient samples at the highest concentrations. Diminished accumulation of AR-67 lactone was observed in BCRP expressing Saos-2 cells and significant uptake of AR-67 carboxylate was observed in OATP1B1 expressing cells. Conclusions: Unlike SN-38, AR-67 was not found to be a major substrate of UGT1A1, but was rapidly processed by UGT1A8, an isoform that is highly expressed in the GI tract. These data may explain the absence of diarrhea during this phase I study. The pharmacologic significance of ABCG2 and SLCO1B1 polymorphisms should be explored further in the context of population studies. [Table: see text]
Phase I, pharmacokinetic, and pharmacodynamic study of carboplatin and topotecan administered in two different schedules
Authors: Boss D. S. , Siegel-Lakhai W. S. , Schoemaker-van Egmond N. E. , Pluim D. , Rosing H. , Ten Bokkel-Huinink W. W. , Beijnen J. H. , Schellens J. H. 
Published: August 2020

2561 Background: Preclinical studies showed sequence dependent synergy of the combination of topoisomerase I inhibitors and platinum agents. This trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) of carboplatin (carbo) and topotecan (topo) in patients (pts) with solid malignancies in two different schedules. Methods: In part 1, pts received carbo as a 60 min IV infusion on day 1 and topo as a 30 min IV infusion on days 1, 2 and 3 (C→T). The sequence of drug administration was reversed in part 2 of the study (T→C): topo on days 1, 2, and 3, followed by carbo on day 3. In both schedules, the PK was determined of each agent in plasma and the TopI catalytic activity and Pt-DNA adducts in white blood cells (WBC) and tumor tissue. Results: 41 pts were included in this trial. Dose-limiting toxicities (DLTs) during C→T included grade (G) 4 thrombocytopenia and febrile neutropenia. The MTD was reached at carbo target AUC 4 min.mg/mL and topo 0.5 mg/m2/day. DLTs during T→C included G4 neutropenia, thrombocytopenia and neutropenic fever, G3 nausea and G4 vomiting. Carbo target AUC 6 min.mg/mL and topo 0.9 mg/m2/day was the MTD in this schedule. No schedule dependent differences in PK were found (clearance (Cl) of unbound carbo: 0.6 vs 0.7 mL/min, p=0.14; Cl of total topo: 24.1 vs 29.6 L/h, p=0.08; Cl of topo lactone: 84.5 vs 83.7 L/h, p=0.96). WBC and tumor samples were collected from 30 and 27 pts, respectively. Pt-DNA levels were not schedule dependent in WBC (range C→T = 0.44–4.13, and T→C = 0.22–6.07 fmol*h/μg DNA) and in tumor tissue (range C→T = 0.20–0.96, and T→C = 0.62–1.8 fmol/μg DNA). Also, no schedule dependent effects were seen in TopI catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C→T schedule. One pt with ovarian cancer had a complete response (T→C schedule), 2 pts with ovarian cancer (C→T schedule) and 3 pts treated in the T→C schedule (ovarian, SCLC and gastric cancer) had a partial response. Conclusions: T→C was better tolerated as both hematological and non-hematological toxicities were milder. Other than the investigated PD factors must explain the schedule dependent differences in toxicities. No significant financial relationships to disclose.
Phase I study of TP300 in patients (pts) with advanced solid tumors
Authors: Anthoney D. A. , MacPherson I. , Twelves C. , Crawford D. , Siller C. , Nemat S. , Abe M. , Miwa M. , Evans J. 
Published: August 2020

2563 Background: TP300 (CH4556300) is a synthetic camptothecin analogue and potent topoisomerase I inhibitor designed to have superior efficacy, tolerability and pharmacokinetic (PK) characteristics compared to current inhibitors. Intravenous (i/v) TP300 undergoes rapid chemical conversion to the active compound CH0793076, then enzymatic conversion to an active metabolite, CH0793011. The objectives of this study were to determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and PK profiles of TP300; antitumor activity and pharmacodynamics (PD) were also evaluated. Methods: Eligible pts with refractory, advanced solid tumors who had adequate PS, hematologic, renal, and hepatic function were recruited into this open-label, modified- Fibonacci dose escalation (“3 + 3” pts/dose level, with expansion at the MTD) study. TP300 was given as a 1-hour i/v infusion 3-weekly; the starting dose was 1 mg/m2. The MTD was defined as the dose level below that where > 2 of 3–6 pts experienced DLT. PK profiles of TP300, CH0793076 and CH0793011 were analysed; DNA strand breaks in peripheral blood mononuclear cells (PBMCs) were measured with the comet assay as a PD marker. Results: 32 pts (m=20; f=12), median age 58 (range 31–72), received TP300 at doses of 1, 2, 4, 8, 12, then 10mg/m2. The MTD was 10mg/m2; DLTs seen at 12mg/m2 (2/4 pts) and 10mg/m2 (3/12 pts) included anaemia, thrombocytopenia and febrile neutropenia. Other grade 3/4 toxicities included lethargy, chills and lower back pain. Diarrhoea was uncommon. Seven pts, all previously treated with irinotecan, had disease stabilisation for 1.5–5 months. CH0793076 PK (AUC and Cmax) were linear from 1 to 10mg/m2. There was a strong PD relationship between CH0793076 AUC and fall in neutrophils, the threshold AUC for DLT neutropenia being 5 hr.umol/L. DNA strand breaks were detected consistently in PBMCs on completion of TP300 infusion . Conclusions: The Phase II starting dose will be 8mg/m2 because hematologic toxicity was seen in cycle 1 at the MTD. As the AUC of CH0793076 at MTD is substantially greater than that of SN38 in pts treated with irinotecan, and CH0793076 is almost equipotent to SN38 pre-clinically, a PK advantage for TP300 is confirmed. Further investigation is warranted. [Table: see text]
Phase I clinical trial with VEGFR2-epitope peptide and gemcitabine for patients with advanced pancreatic cancer
Authors: Yamaue H. , Miyazawa M. , Ohsawa R. , Tani M. , Kawai M. , Hirono S. , Ina S. , Tsunoda T. , Nakamura Y. 
Published: August 2020

2567 Background: The prognosis of pancreatic cancer patients is one of the most dismal of all cancers. Gemcitabine is a potent anticancer drug for pancreatic cancer, however, one should consider that the clinical benefit of anticancer drugs is limited and other potent therapeutic tool is eagerly awaited. Vascular endothelial growth factor (VEGF) is a glycoprotein which is predominantly related to the neoplastic angiogenesis. VEGF-receptor 2 (VEGFR2; Flk-1 and KDR) is an essential target for tumor angiogenesis. We first identify the epitope peptides of vascular endothelial growth factor receptor 2 (VEGFR2) and confirmed that stimulation using these peptides induces CTLs with potent cytotoxicity in HLA class I-restricted fashion. Methods: We proceeded to Phase I clinical trial using gemcitabine and one of these peptides. Patients were sequentially allocated to cohorts of 6 patients per group receiving 0.5, 1.0, 2.0mg of peptides/body. No intra-patient dose escalation was permitted. The eligibility criteria are: being aged between 20- and 80- year old, expecting the survival more than 3 months after the initiation of this treatment, adequate organ function including bone marrow function, and having HLA-A*2402 (A24) genotype. The enrolled patients received 4 cycles of VEGFR2 peptide sc. and 3 cycles of 1,000 mg/m2 gemcitabine weekly. Results: No patients had grade 3 and 4 toxicity, and dose escalation was succeeded without any DLT. CTL response was observed in 50%, 67%, and 67% of 0.5mg, 1.0mg, and 2.0mg cohort, respectively. The delayed type hypersensitivity of the peptide-injection site was recognized in 83%, 67%, and 100% of 0.5mg, 1.0mg, and 2.0mg cohort, respectively. Therefore, we concluded that MTD should be 2.0mg of peptide. Disease control rate (>SD) was 67% (12/18 patients), and one patient had PR. The median survival time was 8.72 months. Conclusions: These results are promising to proceed the pivotal clinical trial, and the randomized phase II/III trial will start in 2009. No significant financial relationships to disclose.
Biomodulation of capecitabine by weekly paclitaxel and carboplatin in patients with advanced solid tumor malignancies: A dose-escalating phase I study
Authors: Lustberg M. B. , Nuovo J. , Thomas J. P. , Monk P. J. , Kim S. , Villalona-Calero M. , Bekaii-Saab T. 
Published: August 2020

2569 Background: A principal determinant of the therapeutic index with capecitabine-based treatment is the grade of thymidine phosphorylase (TP) activity in malignant tissue. The beneficial interactions of paclitaxel and carboplatin in upregulation of TP promise to make capecitabine more tumor specific and to provide the expected synergy. On the basis of the time-dependency and transiency for this upregulation we performed a phase I study of capecitabine in combination with weekly paclitaxel and carboplatin (CTX). Methods: Patients with advanced solid tumors received carboplatin on day 1, paclitaxel on days 1, 8, 15 and capecitabine orally twice a day on days 8–21, every 4 weeks. There were 5 planned dose levels (DL 1–5). Paclitaxel was escalated from 60 mg/m2 to 80 mg/m2 (DL 4) then 100 mg/m2 (DL 5). Capecitabine from 500 mg/m2 bid to 750 mg/2 bid (DL 2) then 1000 mg/m2 bid (DL 3–5). Carboplatin dose was fixed at AUC 6. Paraffin-embedded tissue was evaluated for expression of TP, thymidylate synthase and dihydropyrimidine dehydrogenase by immunohistochemistry. Results: 32 patients from Ohio State University (OSU) were enrolled. 84% had prior therapy. The most common grade 3/4 toxicities were neutropenia (59%), leukopenia (56%), and fatigue (16%). DLTs included neutropenic fever (1), prolonged neutropenia or thrombocytopenia (2) and diarrhea (1). The MTD was at DL 2. There were 10 confirmed responses [4 CR (esophagus, stomach, unknown primary and ampullary); 6 PRs (Pancreas (3), unknown primary, anal and esophagus] and stabilization of disease > 3 months in 12 patients. In normal tissue, there was no difference in expression levels of both TS and TP. On the other hand, in cancer tissue, TP levels seem to correlate with response whereas TS did not. Conclusions: CTX demonstrates acceptable tolerability. The recommended doses for phase II studies are capecitabine 750 mg/m2 bid, paclitaxel 60 mg/m2/week and carboplatin AUC=6. The acceptable toxicity profile in this dose schedule, and the promising antitumor activity observed warrant further evaluation of this regimen. Two phase II trials are already underway at OSU using this regimen for patients with pancreatic cancer and adenocarcinomas of unknown primary, the latter already actively enrolling patients. Pretreatment tumoral TP levels may help predict patients that are more likely to respond to CTX. Correlation of IHC data with responses will be presented at the meeting. [Table: see text]
Phase I study of oral gemcitabine prodrug (LY2334737) alone and in combination with erlotinib in patients (pts) with advanced solid tumors
Authors: Koolen S. , Witteveen P. O. , Garcia-Ribas I. , Callies S. , Andre V. , Kronemeijer R. H. , Nol A. , Beijnen J. H. , Voest E. E. , Schellens J. H. 
Published: August 2020

2576 Background: LY2334737 (LY) is an orally available valproic acid prodrug of gemcitabine that was developed to overcome the extensive first-pass metabolism of gemcitabine to 2',2'-difluorodeoxyuridine (dFdU). The objectives of this study were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of LY as monotherapy and in combination with erlotinib. Methods: Eligible pts had ECOG PS < 2 and adequate hematologic, renal and hepatic function. In Arm A, LY was given daily for 14 days in a 3-week cycle. Pts assigned to Arm B also received erlotinib daily 100 mg continuously. Dose escalation was based on observed toxicity and the modified continual reassessment method (mCRM). The dose was maximally increased by 100% depending on the toxicity observed in the previous cohort. PK of LY, gemcitabine, dFdU and intracellular metabolites were determined. Results: 33 pts (21 m, 12 f, median age 60 yrs (range 24–81)) were treated at 5 different dose-levels (range 5–50 mg/day). Pts received a median of 3 cycles (range 2–17). Three out of 7 pt treated with 50 mg experienced 5 dose limiting toxicities (DLT). DLTs observed at 40 and 50 mg include fatigue (4 pt), thrombocytopenia (1 pt), GGT elevation (1 pt), AST/ALT elevation (1 pt), fever (1 pt), and pulmonary embolism (1 pt). One death was possibly related to LY intake. This pt, treated with 40 mg LY, developed on day 15 dyspnea, hypovolemic shock, and suddenly died. No grade 3 or 4 toxicities were reported at dose-levels < 40 mg. The most common adverse events were fatigue, vomiting, nausea, pyrexia, anorexia, and diarrhea. Two pts with mesothelioma were stable for > 9 months. One pt with refractory prostate cancer presented a PSA CR as assessed by investigator. The PK show dose-proportional increase in exposure of both LY and gemcitabine. Both LY and gemcitabine are rapidly cleared, thus no accumulation occurs. The metabolite dFdU accumulates due to its long half life. Conclusions: LY displays linear PK. The dose level of 50-mg is non-tolerable and 40-mg is being confirmed as the MTD as single agent and in combination with 100 mg erlotinib. Antitumor activity warrants further development. Pt accrual is ongoing. [Table: see text]
A phase I study of capecitabine, oxaliplatin (CapOx), and lapatinib (L) in metastatic or advanced solid tumors
Authors: Dennie T. , Alberti D. , Oliver K. , LoConte N. , Mulkerin D. , Wilding G. , Holen K. , Fleming R. , Bowen C. , O'Neill V. 
Published: August 2020

2579 Background: CapOx is a standard treatment for patients (pts) with metastatic colorectal cancer (mCRC) and has been shown to be equivalent to FOLFOX in a phase III study. L is a tyrosine kinase inhibitor with targeting of the EGF and Her-2 receptors. Preclinical data suggest there may be synergy between L and Cap as well as L and Ox. This phase I study was designed to determine the maximum tolerated dose (MTD) of CapOx and L. Methods: Pts eligible for treatment included those with advanced or metastatic cancers, ECOG PS 2 or less, adequate renal and liver function, and ≤ 3 prior chemotherapy regimens. Treatment over a 21-day cycle was as follows: Ox, single IV infusion on Day 1; Cap, twice-daily oral administration on Days 1 through 14; L, continuous once-daily oral administration. Pts were treated with escalating doses of L (starting at 1000 mg daily) and Cap (starting at 1500 mg/m2/day), while Ox was kept at 130 mg/m2. The primary endpoint was determination of MTD. Results: Ten pts (9/10 female, median age 62 yrs.) were enrolled. One pt had breast cancer and the remainder had non- colorectal GI malignancies (esophagus, hepatobiliary, and pancreas). One pt at dose level 0 experienced dose-limiting toxicity (DLT) (dehydration, elevated bilirubin, hypokalemia). Two pts at dose level 1 (L 1000, Ox 130, Cap 2000) had DLTs of hypokalemia and diarrhea. At an intermediate dose level of L 1000, Cap 1700, Ox 130, two pts experienced DLTs (grade 2 fatigue/anorexia, grade 3 fatigue and dizziness). The MTD was determined to be L 1000 mg daily, Cap 1500 mg/m2/day, Ox 130 mg/m2. There were no treatment-related grade 4 toxicities. The most common grade 3 toxicity was diarrhea (4 pts). There were no grade 3 neuropathies, hematologic toxicities, or rash, and only one case of grade 3 fatigue. One pt with pancreatic cancer had a confirmed partial response (PR) to treatment, and 3 others had stable disease for > 90 days. Conclusions: The regimen of CapOx and L has efficacy in the treatment of solid tumors with established responsiveness to fluoropyrimidines or Ox. The MTD was L 1000 mg daily, Ox 130 mg/m2, and Cap 1500 mg/m2/day. This regimen will be investigated further in a Phase II study involving pts with mCRC. [Table: see text]