bluuebunny/crossref_metadata_2025_split huggingface dataset:
SNS-595 demonstrates clinical activity and dose-proportional pharmacokinetics (PK) in two phase I clinical studies
Authors: Hurwitz H. , Gordon M. , Advani R. , Ebbinghaus S. , Mendelson D. , Wakelee H. , Hoch U. , Silverman J. , Havrilla N. , Adelman D. 
Published: March 2020

3062 Background: SNS-595 is a novel naphthyridine analog with broad and potent activity in preclinical models. Methods: SNS-595 was administered to patients (pts) with advanced solid cancers as an IV infusion over 10 minutes on 2 schedules: (A) qwk x3/1 week off, and (B) q3wks. Pt eligibility included refractory solid tumors and adequate organ function. Results: In study A, 20 patients (pts) were treated in 6 cohorts (dose range 3–24 mg/m2/wk). In study B, 41 pts were treated in 9 cohorts (dose range 3–75 mg/m2/wk). After the MTD in heavily pretreated (HP) pts was found, dose escalation in minimally pretreated (MP) pts was evaluated. The median ages were 60.5 yrs (A) and 59.5 yrs (B), sex 12F/8M (A), 16F/25M (B). All pts had a ECOG PS 0–2. Neutropenia was the dose limiting toxicity (DLT) for both studies. The MTD for A was 15 mg/m2 for HP and MP pts; the MTD for B was 48 mg/m2 for HP and 60 mg/m2 for MP pts. For both studies 2 pts had grade 4 thrombocytopenia; non-hematological toxicities were all grade 1/2. In A, pharmacokinetics (PK) were assessed on Days 1 and 15 (after the 1st and 3rd doses); exposure increased linearly over an 8-fold dose range (1.6–15 mcghr/mL), CL, Vss and T1/2 averaged 2 L/hr/m2, 49 L/m2, 18 hr, respectively, and did not change from Day 1 to 15. In B, PK were assessed on Day 1 after the 1st dose; exposure increased linearly over the 24-fold dose range (1.1–46 mcghr/mL), CL, Vss, and T1/2 averaged 2 L/hr/m2, 53 L/m2, and 21 hrs, respectively. For A, best responses were 4 SD (range 13–22 wks); for B, best responses were 1 PR and 12 SD (range 14–56 wks). Conclusion: SNS-595 was well tolerated and showed clinical activity with both qwk and q3wk dosing. The DLT was non-cumulative neutropenia. SNS-595 demonstrated remarkably predictable PK, with low inter-and intra-patient variability. Based on these data, phase 2 studies of SNS-595 as monotherapy are ongoing, and are planned in combination therapy. [Table: see text]
Frequency of potential therapeutic targets identified by immunohistochemistry (IHC) and DNA microarray (DMA) in tumors from patients who have progressed on multiple therapeutic agents
Authors: Von Hoff D. D. , Penny R. , Shack S. , Campbell E. , Taverna D. , Borad M. , Love D. , Trent J. , Bittner M. 
Published: March 2020

3071 An important question that arises when caring for patients referred for phase I clinical trials is, if one studied the patients’ tumors carefully enough, would there be targets in those patients’ tumors for which a therapeutic agent might already be available. Perhaps treating the patient with that therapeutic agent would be better than trying the phase I agent. To address that issue we have performed IHC assays for up to 13 targets (e.g. Her2/neu, ER, c-kit, etc.) as well as a two color Agilent oligonucleotide microarray with 17, 085 unique probes, on tumors from patients with advanced cancer who have exhausted conventional therapy and who were undergoing a procedure for a cancer related matter (e.g. obstruction, ascites, etc.). Ninety-one patients had excess tissue submitted from the procedure, immediately frozen and subjected to microarray analysis and had IHC performed on sections obtained from the paraffin blocks prepared as part of their standard surgical workup. IHC was considered positive if ≥ 30% of tumor cells were scored as +1 or greater staining. For microarray studies the gene expressions were called significantly increased or decreased if the fold change in expression relative to the nominal tissue of origin reference was significant at p≤0.001. For the 91 patients where frozen tumor was submitted 89 (98%) of them had RNA that was of excellent quality. The findings were a surprise in that IHC identified an average of 1.2 targets (for which a conventional therapeutic agent is available) per patient (range 0 - 4 targets). The DMA identified an average of 3.3 targets per patient (range 0 - 8 targets). Overall, a target was found for 89 (98%) of the patients. This data indicates that using IHC and DMA one can consistently find a potential target for which we have a therapeutic agent in patients’ tumors even thought they have progressed on prior therapies. This has implications for patients’ planning on participating in phase I clinical trials. It is important to conduct a prospective clinical trial to determine whether the targets discovered using IHC and DMA can be used to select therapy which will further benefit the patient who would otherwise be participating in a phase I clinical trial. [Table: see text]
UGT1A1 promoter genotype correlates with pharmacokinetics but not toxicity in patients receiving protracted irinotecan (IRN)
Authors: Stewart C. F. , Panetta J. C. , O’Shaughnessy M. , Throm S. , Liu T. , Billups C. , Gajjar A. , Furman W. L. , McGregor L. M. 
Published: March 2020

3078 Background: Recent USFDA recommendations include a dosage adjustment for patients who are homozygous for the UGT1A1*28 allele (i.e., 7 TA repeats in the promoter) due to an increase in neutropenia when those patients receive IRN. However, this recommendation was based upon data from adults treated with high IRN dosage (e.g., 350 mg/m2). This study evaluates the relationship between UGT1A1 promoter genotype and phenotype (i.e., SN-38 glucuronidation and IRN toxicity) in patients treated with low-dose, protracted IRN. Methods: 31 children treated on 2 institutional protocols received low dosage (20 to 60 mg/m2) i.v. IRN daily for 5 days of 2 consecutive weeks. PK sampling and UGT1A1 genotyping were performed during cycle 1. Patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. All patients were evaluable for gastrointestinal and hematological toxicity, primarily grades 3 and 4 neutropenia and diarrhea. Results: The frequencies of 6/6, 6/7, and 7/7 genotypes were 9/31 (29%), 15/31 (48%), and 7/31 (23%), respectively. Patients with 7/7 genotype had a statistically greater baseline bilirubin than patients with 6/6 or 6/7 genotype (p<0.03), but the difference was not considered clinically significant. In females, the SN-38:IRN AUC ratio was greater in patients with 7/7 vs. 6/6 or 6/7 genotype (0.15 vs. 0.05 vs. 0.09;p<0.005). Similarly the SN-38G:SN-38 ratio was less in females with 7/7 vs. 6/6 or 6/7 genotype (1.5 vs. 4.1 vs. 3.5;p<0.03). Patients with 7/7 genotype did not have a greater incidence of diarrhea (0/7) or neutropenia (0/7) than patients with 6/6 (3/9 with diarrhea, 2/9 with neutropenia) or 6/7 (3/15 with diarrhea, 1/15 with neutropenia) genotype. Conclusions: Although female patients with a 7/7 genotype did have altered SN-38 disposition, toxicity was not increased in patients with the 7/7 genotype treated with a low dose protracted schedule of irinotecan. Therefore, no dosage adjustment for genotype is indicated with this IRN dosing schedule. No significant financial relationships to disclose.
Selection of a phase 3 dose regimen for denosumab based on pharmacokinetic (PK), pharmacodynamic (PD), and safety data from multiple subcutaneous (SC) dosing regimens in breast cancer patients (pts) with bone metastases (BM)
Authors: Peterson M. C. , Jang G. , Kim W. , Gurrola E. , Kinsey A. , Dansey R. 
Published: March 2020

3086 Background: Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation, function, and survival. PK and PD of denosumab (AMG 162), a fully human monoclonal IgG2 antibody to RANKL, from a randomized, double-blind, active-controlled, multidose study in breast cancer pts with BM were evaluated and modeled to assist in dose selection for the pivotal phase 3 study. Methods: Five dosing cohorts (∼40/cohort) received 30-, 120-, or 180-mg denosumab SC Q4W; 60- or 180-mg denosumab SC Q12W. Data through 12 weeks were used for PK/PD modeling and dose decisions. Validated methods were used to quantify all serum and urine analytes. The bone resorption marker uNTx (reported as uNTx/Cr ratio) was used as the PD endpoint, and population PK/PD model parameters were estimated using nonlinear mixed effects modeling methods (NONMEM). A combination of PK/PD trial simulation (TS), clinical chemistries, and safety profiles was utilized for phase 3 dose selection. Results: Exposure to denosumab increased approximately dose-proportionally for both the Q4W and Q12W schedules, and accumulation (3rd vs 1st Q4W dose) ranged from 2.37- to 2.56-fold. The population typical half-maximal inhibitory concentration (IC50) for denosumab to affect uNTx and the typical maximum suppression were estimated to be 12.2 ng/mL and 77.8%, respectively. While denosumab in all cohorts caused rapid and sustained suppression of uNTx from baseline (>60%), TS showed that for a dose of 120 mg Q4W, 97% of subjects would be expected to attain denosumab serum concentrations above their individual IC90 at steady state. TS did not suggest that higher doses (180 mg Q4W) would result in further uNTx suppression, and more asymptomatic decreases in calcium were noted in pts dosed above 120 mg Q4W. Conclusions: The PK and PD of denosumab in pts with BM are consistent with those in other pt populations and demonstrate rapid and substantial suppression of uNTx. Population PK/PD analysis and TS suggests a dose of 120mg Q4W is appropriate for use in a phase 3 program in this study population. [Table: see text]
A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of MN-029, a novel vascular disrupting agent (VDA), in patients (pts) with advanced solid tumors
Authors: Ricart A. D. , Cooney M. , Sarantopoulos J. , Brell J. , Locke K. W. , Gammans R. E. , Medina G. , Zambito A. , Tolcher A. W. , Remick S. C. 
Published: March 2020

3096 Background: MN-029 is a novel VDA that binds reversibly to the colchicine-binding site on tubulin and inhibits microtubule assembly, resulting in disruption of the cytoskeleton of tumor endothelial cells (EC). Disruption of the tumor EC cytoskeleton ultimately leads to a temporary reduction in tumor blood flow. Methods: MN-029 is administered IV as a 10–20 min infusion, at 3-wk intervals in pts with advanced cancer. The study has followed an accelerated titration design, with intrapatient dose escalation. PD effects on tumor blood flow are evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: 28 pts were enrolled (13M/15F), median age 56 (range 35 - 76) and tumor types: colorectal (5), renal (5), hepatocellular (3), ovarian (2), melanoma (2), soft tissue sarcoma (2), carcinoid (2) and others (7). A total of 110 cycles of MN-029 were given, median 3/pt (range 1–20), over 9 dose levels (4, 8, 16, 24, 36, 54, 80, 120 and 180 mg/m2). Escalation proceeded until an initial dose-limiting toxicity (DLT) was observed in 1 pt in the 180 mg/m2 cohort, consisting of a reversible episode (3 hours post dose) of acute coronary ischemia (without sequelae and with preservation of myocardial function) probably due to coronary vasospasm. Therefore, this cohort was expanded to 6 pts, with no further DLTs observed. Common mild to moderate toxicities included nausea, vomiting (which appears dose-related), hypotension, fatigue and diarrhea. There was no significant myelotoxicity, stomatitis or alopecia. Seven pts had stable disease after 3 cycles, including 2 pts with carcinoid tumor (+21 cycles and +17 cycles). PK data generally indicated dose-related increases in Cmax and AUC values, although substantial inter-patient variability was observed. Tumor blood flow reduction assessed by DCE-MRI was recorded at 120 and 180 mg/m2, but not at 80 mg/m2. Conclusions: MN-029 produced reductions in tumor blood flow at doses that were well tolerated. Accrual continues at 225 mg/m2. [Supported in part by grants from MediciNova, Inc. and M01 RR-000080] [Table: see text]
Sphincter preserving surgery after preoperative treatment for ultra-low rectal carcinoma. A French multicenter prospective trial: GRECCAR 1
Authors: Rouanet P. , Rivoire M. , Lelong B. , Rullier E. , Dravet F. , Mineur L. , Vanseymortier L. , Pocard M. , Faucheron J. , Gourgou S. , Saint Aubert B. 
Published: March 2020

3527 Background: GRECCAR 1 is a phase III randomised multicenter trial which compared two preoperative treatments for low rectal carcinoma which should be classicaly treated by abdominoperineal resection (Eligibility: distance between the tumor [T] and the levator ani [LA] less than 2 cm). Methods: Between 2001 and 2005, 207 patients with rectal adenocarcinomas were included in 13 French centers. The average distance between the tumor and the levator ani was 0.8 cm. 72% of the tumors were classified T3 with 60% of N1 on pre treatment endorectal ultrasonography. The mean lenght of the tumors was 5 cm on colonoscopy. Preoperative treatment randomisation was made between high dose radiation (HDR: 45 + 18 Gy: 106 patients) and radio-chemotherapy (RTCT: 45 Gy + 5FU continuous infusion: 101 patients). All surgeons performed homogeous technique for intersphincteric resection. Results: Conservative rate was 83% (HDR) and 86% (RTCT) (p: 0.64) with 84% (140/168) of intersphincteric resection. Conservative rate did not differ according to the distance T-LA: 0 cm: 84% / 1–2 cm: 84% and 3 cm: 91%. No post operative mortality was noticed with a 15% post operative morbidity rate, same in the two arms. Sterilized specimen rate was respectively 7% and 12.5% (p: 0.29), the mean inferior safety margin and radial margin was 1 cm and 4 mm, same in the two groups as the 90% R0 resection rate. On specimen, nodal involvement rate was 5.6% for pT0–1, 29% for pT2 and 56% for pT3–4. No difference was seen for down-staging between the two groups (p: 0.59). With a 22 months follow up, we noticed 92% rate of stoma closure in the conservative group. Seven patients had a local recurrence and 25 metastases with 12 patient’s death. Conclusions: GRECCAR 1 is the first prospective randomized trial which shows an 85% rate of sphincter conservative surgery due to down staging induced by preoperative tretament. No significant difference was seen between HDR and RTCT with a trend for more morbidity in the first group. Intersphincteric resection is a safe technical procedure in order to preserv the striated sphincter with sufficient lateral and inferior margins. No significant financial relationships to disclose.
Cetuximab + capecitabine + irinotecan (CCI) versus cetuximab + capecitabine + oxaliplatin (CCO) as first line therapy for patients with metastatic colorectal cancer (CRC): Preliminary results of a randomized phase II trial of the AIO CRC Study Group
Authors: Heinemann V. , Fischer Von Weikersthal L. , Moosmann N. , Vehling-Kaiser U. , Stauch M. , Oruzio D. , Schulze M. , Walther J. , Weiss J. , Dietzfelbinger H. 
Published: March 2020

3550 Background: Combinations of infusional 5-FU/FA with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) have become standards of care in the treatment of metastatic colorectal cancer. In this trial, 5-FU/FA was replaced by capecitabine, an oral fluoropyrimidine. In addition, cetuximab, an antibody directed against the EGF-receptor was added to further improve treatment efficacy. Methods: Patients (pts) with metastatic CRC (age 18 to 75 years) and measurable disease were randomized to 3-week cycles of therapy. In the CCI-arm, pts received cetuximab (400 mg/m2 iv on day 1 of cycle 1 and 250 mg/m2 iv subsequently), capecitabine (2 × 800 mg/m2 po on days 1 to 14), and irinotecan (200 mg/m2 iv on day 1). In patients >65 years doses of irinotecan and capecitabine were reduced by 20%. In the CCO arm, cetuximab (as described above) was combined with capecitabine (2 × 1000 mg/m2 po on days 1 to 14) and oxaliplatin (130 mg/m2 iv on day 1). Both treatment arms were planned separately according to the optimal design described by Simon (p0 = 0.3, p1 = 0.5, α = 0.1, β = 0.1) with objective response rate (ORR) according to RECIST) as the primary endpoint. Results: The recruitment goal of 92 patients has been achieved. Among evaluable patients, median age in the CCI arm was 63 yrs (range 38–72) and 58 yrs (range 38–74) in the CCO arm. Median Karnofsky performance status was 90% (range 70–100) and 100% (range 70–100), the EGFR-status was positive in 64% and 69% of pts, respectively. The ORR in the CCI arm was 41% (11/27) (95%-CI: 22% to 61%), while in the CCO arm an ORR of 71% (15/21) (95%-CI: 48% to 89%) was documented. Toxicity data were available for 25 pts in each arm. The most common grade 3–4 CTC- toxicities observed in the CCI and the CCO-arm respectively were skin toxicity (4 vs 5 pts), allergic reactions (0 vs 5 pts), diarrhea (5 vs 3pts), neurotoxicity (1 vs 3 pts), and leucopenia (4 vs 5 pts). Conclusion: The preliminary evaluation of this randomized phase II trial suggests the feasibility of both treatment arms. Updated results regarding response rate and progression-free survival will be presented at the meeting. [Table: see text]
The impact of cetuximab on the capecitabine plus oxaliplatin (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC): A randomized phase II trial of the Swiss Group for Clinical Cancer Research (SAKK)
Authors: Borner M. , Mingrone W. , Koeberle D. , Von Moos R. , Rauch D. , Saletti P. , Herrmann R. , Dietrich D. , Lanz D. , Roth A. 
Published: March 2020

3551 Background: XELOX is a valuable alternative to continuous infusion FOLFOX type regimens in the treatment of MCC (Borner et al, JCO 2002, 1759). Cetuximab is an EGFR antibody, which has been shown to improve the efficacy of chemotherapy. A phase II study in first-line treatment of MCC has demonstrated a high response rate combining cetuximab with FOLFOX (Tabernero et al, Proc ASCO 2004, 3512). Methods: Multicenter, randomized two-arm phase II trial: OXA 130 mg/m2 day 1 and oral CAP 1000 mg/m2 bid days 1–14 every 21 days alone or in combination with cetuximab 250 mg/m2 weekly after a loading dose of 400 mg/m2. Treatment was limited to a maximum of 6 cycles. With 37 patients in each arm, the power was 90% to select the truly better arm if the true between-arm difference in response rate (RECIST) is at least 15%. The study was open for accrual until October 2005. Results: We present here the results of 74 patients included in the study. In 67 patients the first response data are available (investigators’ assessment after 3 cycles). The two arms are well balanced for relevant patient, disease and treatment characteristics. The study treatment was well tolerated with grade 3/4 toxicities in < 10% of the cycles in each arm. The frequency of side effects was balanced, but with more frequent skin toxicity in the cetuximab arm (6% versus 0% grade 3/4). Conclusions: Cetuximab seems to positively interact with XELOX in terms of efficacy but not toxicity. The cetuximab/XELOX combination appears to be a valuable option in first-line treatment of MCC especially if high response rates are a primary objective. This trial was supported in part by Merck KGaA and Sanofi-Aventis Switzerland. [Table: see text] No significant financial relationships to disclose.
Cetuximab + FOLFOX6 as first line therapy for metastatic colorectal cancer (An International Oncology Network study, I-03–002)
Authors: Dakhil S. , Cosgriff T. , Headley D. , Boccia R. V. , Badarinath S. 
Published: March 2020

3557 Background: Cetuximab, an IgG1 monoclonal antibody targeting the EGFR, is currently approved for second line treatment of metastatic colorectal cancer (CRC). This phase II trial was designed to evaluate the safety and efficacy of cetuximab combined with FOLFOX6 as first line therapy in this patient population. Promising results have been reported at ESMO in a similar small pilot study. Methods: Eligibility: Age ≥ 18, locally advanced or metastatic CRC, no prior therapy for advanced disease, EGFR expression positive or undetectable. Regimen: Cetuximab 400 mg/M2 (2 hour infusion) day 1; 250 mg/M2 day 8 (and 250 mg/M2 for all subsequent doses); and modified FOLFOX 6 (2 hour infusion); and 5FU bolus 400 mg/M2 day 1 followed by 5FU-CI 2400 mg/M2 over 46 hours (days 1 and 2). Cycles were repeated every 14 days. Results: 82 patients were enrolled in the study. The median number of treatment cycles administered was 8. (range 1–28) At the time of this report, 23 patients are still on study. Reasons for discontinuation of therapy included: Toxicity (14 patients), disease progression (20), investigator /patient decision (11), planned therapy completed (3). Five patients (6%) died on study. Causes of death included: PD (2 patients), acute MI (1), respiratory failure secondary to pneumonia (1), sudden death of unknown cause (1). The most frequently observed toxicity was neutropenia. Grade 3/4 toxicities are listed in the table below. At this early analysis time point, 32 of 60 patients evaluable for response have documented CR/PR (3 CR, 29 PR, overall response rate of 53%). A pre-meeting update is planned for presentation purposes. Conclusion: These findings suggest that the combination of cetuximab with FOLFOX6 is safe and active in first line treatment of patients with metastatic CRC. Updated efficacy and safety data will be presented. [Table: see text] No significant financial relationships to disclose.
Molecular determinants of capecitabine efficacy in colorectal cancer
Authors: Vallbohmer D. , Kuramochi H. , Shimizu D. , Danenberg K. D. , Nielsen J. N. , Lindebjerg J. , Jakobsen A. , Danenberg P. V. 
Published: March 2020

3606 Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text]