bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective analysis of temozolomide (TMZ) plus BCNU wafers and TMZ alone in the primary treatment of glioblastoma multiforme
Authors: Bota D. A. , Taylor S. A.
Published: March 2020

11519

Background: GBM is the most common and aggressive primary brain tumor with a median survival around 1 year. Two agents have shown promise and received recent approval by the Food and Drug Administration. A combination of these agents is frequently used with little data about the efficacy or toxicity. Methods: A retrospective review of patients (pts) treated between 1/2000 and 6/2004 was done to look at pts treated in such a manner. This review was approved by the IRB of the University of Kansas. Twenty-three pts were identified who had received TMZ or TMZ after surgery plus BCNU wafers (TMZ/B) at initial histologic diagnosis of their GBM. Median age was 53 years (26–71). Median KPS was 80 (50–100). 65% had subtotal resection and 35% gross total resection. The decision to place the wafers was at the discretion of the surgeon at the time of surgery. 10 pts received the wafers. All pts received standard radiation therapy. All pts received concurrent TMZ at 75mg/m2 during radiation therapy (XRT) and 150–200mg/m2 days 1–5 every 28 days depending upon myelosuppression seen during XRT. Results: Ten patients received TMZ/B and 13 received the TMZ alone. There were no differences between the groups in age or performance status (p>0.3). At this time, 2/10 in the TMZ/B group and 1/13 in the TMZ are alive. Overall survival was the same in both groups. Median overall survival was 534 days for TMZ/B (95% confidence interval 369–700) and 596 days TMZ (95% CI 373–819). Toxicity was the same. Conclusions: This is a retrospective non randomized exploratory study which suggests there is no difference in survival or toxicity between the two treatments. Randomized studies will be needed to confirm this in larger pt numbers. At the present time, pts are frequently ineligible for experimental trials due to the frequent use of the BCNU wafers in the neurosurgical community. The results of TMZ may preclude the need for the wafers.

[Table: see text]
Concomitant accelerated hyper-fractionated radiotherapy and temozolomide in the treatment of high grade astrocytoma: Updated results
Authors: Hashem T. , Metwaly H. , Abouelfetouh M.
Published: March 2020

11523

Background: The safety and efficacy of accelerated hyper-fractionated radiotherapy (RT) combined with temozolomide (TMZ) in patients with high grade astrocytoma have already been reported.Updated results on survival will be presented. Methods: Twenty-four patients with newly diagnosed and histologically proven high grade astrocytoma were enrolled onto this study. Treatment protocol included RT delivered in fractions of 150 cGy 3 times daily with at least 4-hour intervals between fractions to a total dose 4050 cGy. The target volume was the tumor plus the edema with a 2-cm margin. A boost of 1800 cGy was given to the tumor plus a 2-cm margin to a total dose of 5850 cGy delivered in 39 sessions over 2.5 weeks. TMZ dose was (150 g/m2/day 7 d/wk) given 2 hours prior to RT, throughout the course of RT. Results: Of the 24 patients included 5 (21%) developed G2 & G3 neutropenia, and 4 patients (17%) developed G2 & G3 thrombocytopenia. Non-hematologic toxicities were: G2 & G3 vomiting in 8 (33%) patients, G2 & G3 fatigue in 13 (54%) patients, G2 skin rash in 4 (17%), and G2 acute radiation reaction in 2 (8%) patients. The12 months and 18 months survival rates were 67% and 51.5% respectively. Patients aged <45 years and those who underwent debulking surgery had better survival rates (69% & 70%) in comparison to those aged ≥45 years and those who underwent biopsy only (27% & 36%). Conclusions: The results achieved particularly with respect to survival are promising and should be confirmed.

No significant financial relationships to disclose.
Pharmacokinetic and pharmacodynamic correlations of flavopiridol in the treatment of chronic lymphocytic leukemia
Authors: Phelps M. A. , Wu D. , Byrd J. C. , Lin T. S. , Blum K. A. , Schaaf L. , Johnson A. J. , Colevas A. D. , Grever M. R. , Dalton J. T.
Published: March 2020

12000

Background: Previous clinical trials with 72-hr and 24-hr infusions of flavopiridol were unsuccessful in producing responses in significant numbers of patients (pts). We utilized pharmacokinetic (PK) modeling to develop a 4.5 hr IV infusion strategy with a 30 mg/m2 loading dose delivered in the first 0.5 hr. and an equal or increased dose delivered over the following 4 hrs to achieve target concentrations of 1.5 to 2.0 μM. This strategy was employed in a phase I study for single agent treatment of CLL. Methods: Plasma samples obtained from pts up to 48 hrs after the start of infusion were extracted and analyzed via LC/MS/MS for parent drug concentration. Non-compartmental analysis was employed in WinNonlin® to analyze flavopiridol plasma concentration vs. time data in 42 patients receiving one or two dosing levels. Patient biographical and response or pharmacodynamic (PD) data, including age, gender, previous treatment, hepatic and renal function, phosphate, albumin and lactate dehydrogenase (LDH) levels, lymph node status, and splenomegaly were collected. In addition, genomic analysis for single nucleotide polymorphisms (SNPs) in flavopiridol metabolizing and transporting enzymes along with correlation of PK, PD and genomic data is underway. Results: Complete PK data has been generated on 41 of the 42 patients treated in cohorts 1 through 3 and is summarized below. 14 of the 42 patients received an escalated dose in cycle 2. As anticipated, the escalated dose achieved concentrations within the targeted window 1.5 to 2.0 μM. This dosing strategy has resulted in response in 45% (19 of 42) of pts treated. Conclusions: PK modeling enabled accurate dose determination for achieving targeted clinical flavopiridol plasma concentrations. Ongoing analysis for correlation of modeled PK parameters with PD and pharmacogenomic data will further enhance our understanding of flavopiridol action in CLL and other malignancies.

[Table: see text]

No significant financial relationships to disclose.
A pharmacokinetic study of gemcitabine at fixed dose rate infusion in patients with impaired hepatic function
Authors: Felici A. , Di Segni S. , Colantonio S. , Milella M. , Ciccarese M. , Cecere F. , Nuvoli B. , Ferretti G. , Citro G. , Cognetti F.
Published: March 2020

12009

Background: The aim of this study was to evaluate if hepatic dysfunction leads to increased toxicity of gemcitabine (gem) at fixed dose rate, and to characterize the pharmacokinetic (PK) of gem and its major metabolite (2`,2`-difluorodeoxyuridine- 2dFdU) in patients (pts) with normal and altered liver function. Methods: Eight pts with metastatic pancreatic or biliary tract cancer were treated with the followed schedule: gem 1000 mg/m2 at 10/mg/m2/min fixed rate days 1,8, and 15 every 28 days for a maximum of six cycles. Three pts had normal serum bilirubin level and AST level less than two times the upper limit of normal (ULN) (Cohort I); four pts had bilirubin level from 1.6 to 7.0 mg/dL and normal AST level, one pt had serum bilirubin level less than 1.6 mg/dL and AST level greater than two times the ULN (Cohort II). The PK parameters measured were: plasmatic peak concentration (Cmax), area under the plasma concentration-time curve (AUCexp), total plasma clearance (Cl p) and half life (t1/2). Results: Patient characteristics were: median age 62 yrs (range 28–75), male/female 4/4, median cycles cohort I: 6 cycles (3–6), median cycles cohort II: 3 cycles (1–5), median follow-up: 30 weeks (range 3–79) and median weeks of treatment: 14 (1–25). The rate of dose reduction was the same in the two cohorts, as the rate of omitted administrations. Patients with liver dysfunction tolerated gemcitabine without increased toxicity and neither AST nor bilirubin elevation was observed after drug administration. PK parameters were calculated at the first cycle and the results are presented below (see table ). Conclusions: The pharmacokinetics of gemcitabine at fixed dose rate in patients with impaired liver function seems similar to control; no difference between the two cohorts was observed in terms of toxicity and dose reduction.

[Table: see text]

No significant financial relationships to disclose.
A phase I study of triapine in combination with irinotecan in refractory tumors
Authors: Schelman W. R. , Holen K. , Mulkerin D. , Kolesar J. , Thomas J. , Kruse M. , Oliver K. , Marnocha R. , Eickhoff J. , Wilding G.
Published: March 2020

12011

Background: Triapine is a small molecule inhibitor of ribonucleotide reductase and has anti-tumor activity alone and in combination with other agents in advanced solid tumors. Based on its ability to limit DNA repair, Triapine has been postulated to act synergistically with irinotecan. This study was conducted to determine the toxicities and efficacy of Triapine with irinotecan. Correlative studies included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy. Methods: This study used standard eligibility criteria with the following exceptions: patients must have had no prior irinotecan and no G6PD deficiency. The treatment plan consisted of irinotecan on day 1 with Triapine on days 1- 3 of a 21-day cycle. Starting dose (level 1) was irinotecan (150 mg/m2) and Triapine (85 mg/m2/day). RECIST was used to measure response. Results: 10 patients have been enrolled; 5 men, 5 women. Tumor types: 4 pancreatic, 2 cholangio, 1 esophageal, 1 sarcoma, 1 lung, 1 ovarian. Grade 3–4 toxicities at least possibly related to Triapine at any dose level were as follows: neutropenia (3), leukopenia (2), fatigue, hypoxia, nausea, vomiting, thrombocytopenia, abdominal cramping, hypocalcemia, and thrombosis. The first patient enrolled at level 1 developed a DLT (Grade 3 hypoxia). Consequently, irinotecan and Triapine doses were reduced to 100 mg/m2 and 60 mg/m2/day, respectively (level -1). One of 6 patients experienced a DLT at this dose level. Further patients were then enrolled at level 1. There were 2 DLTs of 4 patients at level 1. One partial response (NSCLC) was seen. Conclusions: Unacceptable toxicities were seen at dose level 1; however, dose level -1 was well tolerated. The trial has therefore been amended in order to evaluate a higher dose of irinotecan (150 mg/m2) with the level -1 dose of Triapine (60 mg/m2/day). Accrual continues at this dose level. Antitumor activity in NSCLC was noted at level 1.

[Table: see text]
Pharmacokinetic (PK) and tolerance profiles of oral tegafur/uracil (UFT) given as three versus two daily intakes
Authors: Etienne-Grimaldi M. C. , François E. , Renée N. , Cardot J. M. , Douillard J. Y. , Gamelin E. , Chateau Y. , Clouet J. , Dupuis S. , Milano G.
Published: March 2020

12013

Background: This phase II randomized bioequivalence cross-over study compared the tolerance and PK profiles of oral UFT (tegafur-uracil) given as 3 daily intakes (tid, usual schedule) to that obtained with 2 daily intakes (bid). Methods: Twenty-one metastatic colorectal cancer patients were enrolled (16 men, 5 women ; mean age 64, extremes 42–79 ; ECOG PS ≤ 1). Tegafur-uracil (300 mg/m2/d) and leucovorin (90 mg/d) were given for 2 consecutive four-week cycles separated by one rest week. Patients were randomized for receiving 1st cycle either tid (arm A, 12 patients) or bid (arm B, 9 patients). For each schedule, PK was evaluated at steady state, over 24 h. Plasma concentrations of tegafur, uracil and fluorouracil (FU) were analyzed by HPLC. Results: Analysis of tolerance (digestive toxicity mainly, OMS grade) showed a tendency (p = 0.08) for a greater toxicity with the bid schedule (29% grade 2, 14% grade 3) relative to tid (24% grade 2 only). Although daily doses were similar, FU and uracil AUC0–24h were respectively 1.8 and 2.0-fold higher for bid as compared to tid (95% CI were 1.5–2.1 and 1.6–2.6, respectively, p < 0.0001). For tegafur, the 1.2-fold difference was of borderline significance (p = 0.057). The greater the FU AUC0–24h, the higher the toxicity intensity (p = 0.044). Analysis of systemic exposure with respect to daily time revealed that FU (p < 0.01) and uracil (p < 0.03) AUC corresponding to the morning intake were significantly higher than those corresponding to the afternoon or evening intakes, with AUC ratio as high as 1.6 for FU and 2.9 for uracil. Such a circadian influence was not observed for tegafur. Conclusions: To reach bioequivalence, bid tegafur-uracil administration will require lower doses than those given tid. The circadian variability observed for FU and uracil PK concords with that previously reported for dihydropyrimidine deshydrogenase activity.

No significant financial relationships to disclose.
Safety, efficacy and pharmacokinetics of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, as monotherapy in patients with locally advanced or metastatic pancreatic cancer (PC)
Authors: Strumberg D. , Scheulen M. E. , Hilger R. A. , Krauss J. , Marschner N. , Lordick F. , Bach F. , Reuter D. , Edler L. , Mross K.
Published: March 2020

12504

Background: Nimotuzumab (OSAG101, Theraloc) is a humanized monoclonal antibody (mAb) that binds to the EGFR. In preclinical studies the antibody has shown potent antitumor activity. Based on phase I data, the recommended dose has been established at 200 mg weekly. A previous phase II study in children with high grade brain tumors showed activity of nimotuzumab as a monotherapeutic agent, even in prognostically very unfavorable pontine glioma. No drug related side effects were reported. The present ongoing phase II study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic PC. Methods: Pts who failed standard chemotherapy with gemcitabine or another first line regimen for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given iv as induction therapy at 200 mg once weekly for 6 weeks. Follow up by CT was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), time to disease progression, and safety. Blood samples were collected prior to first dose, at end of infusion, and 3h, 6h, 48h, as well as every time before subsequent nimotuzumab doses were administered. Nimotuzumab concentrations in serum were measured by cellular ELISA. Results: Enrollment is complete, with treatment ongoing. In total, 55 pts were treated (28 women/ 27 men; ECOG status of 1 [n= 41] or 0 [n=14], median age 63.6 yrs [range 46–83 yrs]). Pts evaluable for response: n= 36; CR:0; PR:0; SD:6 pts (median TTP 19.2 weeks; 14.1–26.1). The only reported treatment-related adverse event was rash grade 1 in 1 pt. After 200 mg single dose, the mean value of Cmax was calculated to 141 ± 33 μg/ml. The t1/2 was calculated to 45 h, volume of distribution to 1.46 ± 0.3 l, respectively. The total clearance was determined to 23 ± 6 ml/h. The trough values after 168 h were 6.2 ± 6.3 μg/ml. Conclusions: These data confirm that nimotuzumab is safe and well tolerated. To improve efficacy, a combination trial with gemcitabine is planned.

[Table: see text]
Trastuzumab mimotope vaccination of HER-2/neu transgenic mice results in prolonged tumor-free survival and reduced tumor load
Authors: Riemer A. B. , Brämswig K. H. , Pehamberger H. , Scheiner O. , Zielinski C. C. , Jensen-Jarolim E.
Published: March 2020

12510

Background: Passive immunotherapy with the humanized monoclonal antibody trastuzumab (Herceptin) to date is the most effective treatment for patients with HER-2/neu overexpressing breast cancer. In previous studies we could show that active immunization with peptide mimotopes, i.e. structural mimics of the epitope recognized by trastuzumab, leads to formation of antibodies again recognizing HER-2/neu in mice. Functional in vitro analyses of the induced antibodies demonstrated “trastuzumab-like” properties, such as receptor internalization, inhibition of signaling, and antibody-mediated cytotoxicity against HER-2/neu overexpressing breast cancer cells. The aim of the present study was to test the effects of trastuzumab mimotope vaccination in vivo, namely in a HER-2/neu transgenic mouse model. Methods: We used BALB-neuT mice, which carry the activated neu oncogene on the BALB/c background. These mice constitute the most aggressive animal model for HER-2/neu driven carcinogenesis, as all females uniformly develop mammary carcinomas at the age of 12 weeks. One group of mice was immunized with the previously described trastuzumab mimotope - KLH conjugate, a control group with the carrier protein KLH alone, and a further control group was left naïve. Mice were palpated weekly to monitor tumor development and size, and blood samples were taken at regular intervals to follow up the induced immune responses. Results: Trastuzumab mimotope immunizations lead to delayed tumor development and thus to an increase in tumor-free survival. When tumors occurred, they were smaller and grew more slowly than in the control mice. In contrast, control KLH immunizations did not affect tumor growth kinetics as compared to the naïve mice. Serum analysis demonstrated that all immunized animals had mounted an anti-KLH immune response, so we accredit the observed tumor-inhibitory effects in the mimotope group to the biologic properties of induced anti-HER-2/neu antibodies. Conclusion: These results indicate that epitope-specific vaccination with mimotopes elicits trastuzumab-like antibodies that are effective in vivo against HER-2/neu overexpressing tumor cells also in HER-2/neu expressing organisms.

[Table: see text]
Establishment of a predictive classifier of node-positive breast cancer patients treated by FEC100 chemotherapy using gene expression profiling
Authors: Campone M. , Charbonnel C. , Magrangeas F. , Minvielle S. , Genève J. , Martin A. , Deporte R. , Bataille R. , Campion L. , Jézéquel P.
Published: March 2020

13004

Background: In breast cancer treatment, biomarkers providing information about chemotherapy sensitivity are needed. FEC100 combination, frequently prescribed in Europe, is still applied empirically to patients. Our study’s goal was to establish a classifier of sensitivity to this regimen using gene expression data and classical clinicopathologic parameters. Methods: The study retrospectively included 151 patients belonging to the FEC100 arms of two multicentric phase III clinical trials: PACS01 (n = 128) and PEGASE01 (n = 23) (FNCLCC). Patients had unilateral breast cancer, showed no evidence of distant metastasis, were node-positive, aged less than 65-year-old. Median follow-up was 5 years. The number of relapses were respectively 23 and 10. We used cDNA nylon microarrays containing 7,000 genes to analyze gene expression profiles of tumor. Patients were split into a training set and a test set. A 3-step analysis based on Cox regression was applied: 1) elimination of non discriminant genes, 2) robust (resampling) univariate selection of discriminant genes and 3) development of multivariate models combining the discriminant genes, the Nottingham Prognostic Index (NPI) (developed in 2 binary variables) and the hormonal receptors. As a final step, after dichotomization of the retained genes, a risk score was built and applied first on the test set, and then on the whole cohort. Kaplan-Meier curves and logrank tests were performed to assess the new risk score. Results: The new risk score (one gene [G6224] and NPI) permitted to separate patients from the test set in 3 significantly different groups; it was also an improvement on NPI (test set: NPI, p = 0.0005; risk score p = 0.0001 - whole cohort: NPI, p = 2.10−5; risk score, p = 1.10−10). Conclusions: We identified G6224 whose expression combined with NPI showed a good capacity for classifying breast cancer patients who received FEC100 chemotherapy. Our results strengthen the interest of G6224 since it was previously described in various solid tumors as a prognostic biomarker with a tumor-suppressor activity.

No significant financial relationships to disclose.
The value of pharmacogenomic analysis of microsatellite instability (MSI) and XPD, XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma
Authors: Artac M. , Pehlivan S. , Akcan S. , Pehlivan M. , Gelen T. , Itirli G. , Aksoy N. H. , Ozdogan M. , Savas B. , Bozcuk H. S.
Published: March 2020

13011

Background: Previous work suggests that DNA repair enzyme polymorphism and microsatellite instability (MSI) may bear prognostic value in metastatic colorectal carcinoma (MCRC), but this is either retrospective or do not involve irinotecan-based regimens. Methods: We prospectively treated 43 MCRC patients with irinotecan-based regimens (XELIRI or IFL). MSI was measured by PCR at 5 different chromosomal loci: BAT-25, BAT-26, D5S346, D2S123, and D17S250. XPD (Lys751Gln) and XRCC1 (Arg399Gln) polymorphisms were also analysed by PCR-RFLP method. Clinical outcome variables; overall survival (OAS), progression free survival (PFS) and the occurrence of grade 3 or 4 hematological and gastrointestinal (GIS) toxicities were evaluated. Results: MSI subtypes MSS, MSI-L and MSI-H were seen in 23.3%, 43.3% and 33.3% of cases. In the univariate analysis for OAS (n=43) only XPD and XRCC1 polymorphisms were significant (P=0.05 and P=0.04, respectively). After adjustment for performance status (ECOG=0, 1 vs. 2) and disease extent (single vs. multiple metastatic site), XRCC1 genotype and performance status retained significance (P=0.04, HR=2.85, and P=0.02, HR=3.19, respectively). Arg/Gln versus Arg/Arg and Gln/Gln versus Arg/Gln genotypes indicated approximately 3 times increased risk of death for each comparison. Type of presentation (metastatic versus local disease at first presentation) was the only significant predictor of PFS in the univariate analysis (n=40, P=0.003). After adjustment for performance status and disease extent, type of presentation retained its significance (P=0.003, HR=4.35). MSI was not associated with survival. Although absence of “liver only” disease was associated with the occurrence of grade 3–4 GIS toxicity, it lost significance in the multivariate analysis. None of the factors tested correlated with the likelihood of grade 3–4 hematological toxicity. Conclusions: XRCC1 genotype independently predicted overall survival in metastatic colorectal carcinoma patients treated with irinotecan-based chemotherapy. However, MSI status did not emerge as a prognostic factor in our cohort.

No significant financial relationships to disclose.
Escalating weekly doses of cetuximab: A phase I trial in advanced solid tumors
Authors: Ho C. , Eisen D. , Beckett L. A. , Luciw P. , Gumerlock P. H. , Gandara D. R. , Davies A. M.
Published: March 2020

13012

Background: Cetuximab, an IgG1 monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is FDA-approved at a 400 mg/m2 loading dose, followed by 250 mg/m2 weekly maintenance. Clinical activity of cetuximab has been reported to correlate with grade of skin toxicity, and skin toxicity is reported to increase with increasing dose. We therefore examined the safety and feasibility of escalating weekly cetuximab doses. We hypothesized that increased dose would correlate with rash severity as a surrogate for tumor response. Methods: Four dose levels were tested: cetuximab loading 400 mg/m2 and 250,300,350,400 mg/m2 weekly maintenance. Dose limiting toxicity (DLT) was defined as: grade 4 platelets, grade 3 platelets with bleeding, febrile neutropenia, grade 4 cutaneous toxicity, grade 3 cutaneous toxicity necessitating holding cetuximab for > 4 weeks or any other grade ≥ 3 non-hematologic toxicity. Rash was evaluated using two additional validated dermatology methods: acne lesion counting and global acne grading scale (Int J Derml.1997;36:416–18, J Am Acad Derm.1996;35:559–65, Arch Derm.1982;118:23–25). Results: Twelve patients with advanced solid tumors were treated, including 3 H&N, 2 pancreas, 2 breast, 2 lung, 2 colorectal and 1 bladder. Patient characteristics: age range 44–84, median 62; gender: 10 M; KPS ≥80/<80=7/5; prior chemo ≤1:>1=5:7; median cycles 2 (1–8). Treatment was generally well tolerated. There were no DLTs. The most common grade 3/4 toxicities were acneiform rash (1) and lymphopenia (2). The majority of patients (6) had a Grade 2 rash. In 10 evaluable patients, there were no responses; 3 patients had stable disease. Correlative science studies are ongoing evaluating EGFR expression and polymorphisms, pEGFR, pMAPK, pAKT, Ki67, p27 levels and K-ras mutations. Conclusions: 1) Cetuximab 400 mg/m2 loading dose and 400 mg/m2 weekly maintenance is feasible and well tolerated. Doses up to 400 mg/m2 did not portend increased toxicity and a MTD was not reached on this schedule. 2) Grade of rash did not increase with increasing doses of weekly cetuximab in this limited population. 3) To date, cetuximab has not demonstrated RECIST response in this cohort of pretreated patients with solid tumors. 20 additional patients are being evaluated at the highest dose level.

No significant financial relationships to disclose.
Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab
Authors: Scherle P. , Liu X. , Li J. , Fridman J. , Li Y. , Yao W. , Williams W. , Levy R. , Vaddi K. , Newton R. , Friedman S.
Published: March 2020

13021

Background: HER-2, a member of ErbB family of receptor tyrosine kinases, is an important regulator of cell proliferation and survival, and is a clinically validated target of therapeutic intervention in HER-2 positive metastatic breast cancer patients. In HER-2 overexpressing cells, the extracellular domain (ECD) is frequently cleaved, rendering the remaining transmembrane portion of HER-2 (p95) constitutively active. The presence of both serum ECD and cellular p95 protein have been linked to poor clinical outcome as well as reduced effectiveness of some therapeutic treatments, suggesting that signaling via p95 is clinically relevant and may represent an attractive target for therapeutic intervention. Methods: Through medicinal chemistry efforts, we have identified a series of potent, selective small molecule inhibitors of ADAM metalloproteases, exemplified here by INCB7839. These compounds were tested both in vitro and in vivo for inhibition of HER-2 ECD cleavage and anti-tumor activity in the HER-2 overexpressing BT-474 cell line. Inhibition of circulating HER-2 ECD levels was monitored in a phase I multiple dose escalation study in healthy volunteers. Results: We demonstrate that these inhibitors effectively blocked HER-2 cleavage in HER-2 overexpressing human breast cancer cell lines. When used in combination, INCB7839 dramatically enhanced the antiproliferative activity of suboptimal doses of the anti-HER-2 antibody, trastuzumab, in HER-2 overexpressing/shedding breast cancer cell lines, accompanied by reduced ERK and AKT phosphorylation. Consistent with these in vitro data, INCB7839 reduced serum ECD levels in tumor-bearing mice and enhanced the antitumor effect of trastuzumab in a xenograft tumor model derived from the HER-2 overexpressing BT-474 breast cancer cell line. In a phase I clinical trial, INCB7839 demonstrated a dose-dependent decrease in the circulating levels of HER-2 ECD present in healthy volunteers. Conclusions: Collectively, these findings suggest that blocking HER-2 cleavage with selective ADAM inhibitors, especially in combination with anti-HER-2 antibody therapy, may represent a novel approach for treating HER-2 overexpressing breast cancer patients.

[Table: see text]
TYMS polymorphism analysis prediction of bolus 5-fluorouracil toxicity
Authors: Gusella M. , Bolzonella C. , Bertolaso L. , Bononi A. , Crepaldi G. , Padrini R. , Ferrazzi E.
Published: March 2020

13022

Background: Currently there is no protocol for selecting colorectal cancer patients at risk for drug toxicity prior to 5-fluorouracil(5FU)-based chemotherapy. Thymidylate synthase (TYMS) is 5FU main molecular target and its expression is linked to cellular sensitivity or resistance to the drug. Three genetic polymorphisms have been shown to influence TYMS expression: a polymorphic tandem repeat sequence (2 or 3 repeats; 2R and 3R) and a single nucleotide polymorphism, G > C, within the promoter enhancer region and a 6 bp deletion in the 3’UTR of the gene. Methods: This prospective study endpoint was to test weather TYMS polymorphisms might predict high grade toxic events in Caucasian patients with colo- rectal carcinoma treated with adjuvant bolus 5-FU-based chemotherapy. 142 patients, 98 males, mean age 66,7±9,1 were studied at the first cycle of treatment. TYMS genotypes were determined from the peripheral blood mononuclear cells by polymerase chain reaction and restriction fragment length polymorphism. Toxic event occurrence was collected through self-administered questionnaire and physical examination and scored through WHO scales. Results: 40% of patients had no or minimal adverse events while 35% suffered grade 3–4 toxicity. At univariate analysis, there was a trend of association between 3R/3R genotype and a reduced risk of adverse events (chi test for trend, p=0.057) and again a significant association between 6bp/6bp genotype and high grade toxicity (chi test for trend, p=0.03). Analysing all the three polymorphism together, 77% of patients bearing 6bp/6bp combined with at least one 3RG allele suffered grade 3–4 toxicity, while patients bearing homozigote 6bp deletion had no or minimal side effects in 90% of cases. The other genotype combinations had an intermediate toxic risk. The differences were statistically significant (chi test p=0.02). Conclusions: TYMS combined 5’UTR and 3’UTR polymorphism analysis may help in predicting high grade toxic events in Caucasian patients treated with repeated boluses of 5-FU. Funded by AIRC-Veneto.

No significant financial relationships to disclose.
Phase I trial of docetaxel, carboplatin and lenalidomide in patients with advanced solid tumors
Authors: Kalmadi S. R. , Davis M. , Dowlati A. , O’Keefe S. , Cline-Burkhardt M. , Pelley R. J. , Borden E. C. , Dreicer R. , Bukowski R. M. , Mekhail T.
Published: March 2020

13027

Lenalidomide (LEN) is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and different toxicity. It may interfere with the expression of angiogenic factors (TNF-alpha & IL-6), vascular endothelial growth factor (VEGF) and induce apoptosis in resistant cell lines. In preclinical trials it has shown synergy with chemotherapy. Primary objective of this study was to determine the maximum tolerated doses (MTD) of docetaxel (D) and carboplatin (Cb), combined with oral LEN. Secondary objectives were toxicity and activity. Eligibility included pathologically proven solid tumors, ≤ 2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function. Patients (Pts) with active brain metastases, or prior treatment with D, Cb, or LEN, were excluded. Treatment was continued for a maximum of 6 cycles, followed by optional continuation of LEN until disease progression or toxicity. MTD was defined as the dose level (dl) immediately lower than that producing dose limiting toxicity (DLT) during cycle 1 in ≥ 2 of 3–6 pts. DLT were ≥ grade (G) 3 non-hematological, or G 4 hematological toxicity. No growth factors were used during cycle 1. Four pts were treated at dl I, D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 10 mg orally daily for 14 of a 21d cycle. Dose de-escalation was done following the first cohort due to DLT. 10 pts were treated at lower dl -1, D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 5 mg orally daily for 14 of a 21d cycle. 3 of 14 pts had prior chemotherapy. Tumors included non small cell lung cancer (NSCLC) (9), and one each with thymic, rectal, apocrine carcinoma, angiosarcoma and unknown primary. The median number of cycles was 4 (range 1–6). DLTs occurred in 3 of 4 pts at dl I (G 3 electrolyte (E) (2), G 4 neutropenia (N) (1) and 1 of 10 pts at dl-1 (G 4 N). Overall G 3/4 toxicities were: N (7), thrombocytopenia (2), and E (2). There were no treatment-related deaths or irreversible toxicities. Of the evaluable pts, 5 had a partial response (5/9 NSCLC), & 5 had stable disease. D 60 mg/m2, and Cb AUC 6 on Day 1, and LEN 5 mg orally daily for 14 days of a 21 d cycle is the MTD without use of prophylactic growth factors. This combination is active and further evaluation in a phase II trial is warranted.

[Table: see text]
A novel telomerase-specific oncolytic virotherapy for human cancer: preclinical evaluation of safety, biodistribution, and efficacy
Authors: Fujiwara T. , Kagawa S. , Kawamura H. , Nagai K. , Nohara R. , Tanaka N. , Urata Y.
Published: March 2020

13057

Background: Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed an adenovirus 5 vector (Telomelysin [OBP-301]), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an IRES. Methods: We examined the antitumor effect of Telomelysin as a single agent or in combination with systemic administration of chemotherapeutic drugs such as docetaxel in tumor xenograft models. IND-supporting preclinical toxicology and pharmacodynamic studies were also performed to characterize the safety, pharmacokinetics and biological activity of Telomelysin. Results: Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines derived from various organs, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. In nu/nu mice carrying subcutaneous human tumor xenografts, intratumoral injection of Telomelysin resulted in a significant inhibition of tumor growth, which was significantly enhanced in combination with systemic administration of docetaxel. Moreover, Telomelysin replication in the distant, un-injected tumors was demonstrated. Viral DNA was identified in tissues outside of the injection site; however, toxicology studies including pathological examinations in mice and cotton rats demonstrated that local injection of Telomelysin could be well-tolerated with an acceptable safety profile. Conclusions: The hTERT promoter confers competence for selective replication of Telomelysin in human cancer cells, an outcome that has important implications for the treatment of human cancers. Telomelysin has been already manufactured under GMP conditions for initial clinical trials. Upon FDA approval, a phase I dose-escalation study of intratumoral injection of Telomelysin for various solid tumors will be started.

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Thymidylate synthase gene expression in solid tumors predicts for response to pemetrexed in vitro
Authors: Eismann U. , Oberschmidt O. , Ehnert M. , Fleeth J. , Lüdtke F. , Struck S. , Schulz L. , Blatter J. , Ma D. , Hanauske A.
Published: March 2020

13058

Background: Pemetrexed (P) is a novel antifolate which targets thymidilate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). The aim of the present study was to identify gene expression thresholds for these enzymes in human tumor specimens in order to separate P-sensitive from P-resistant patients. Methods: Soft-agar cloning assays were performed on freshly biopsied tumor cells exposed one hour to clinically achievable concentrations of P. In parallel, RNA was isolated, transcribed to cDNA and subsequently used for multiplex real-time PCR. Gene expression data were normalized against beta-actin transcripts followed by correlation against cloning assay results. Iterative calculations (fourfold analysis) were done for each enzyme separately to find the best cutoff for prediction of sensitivity to P. Results: Sensitive and resistant tumor samples were statistically significant different in gene expression of TS, DHFR, and GARFT (p < 0.003). 81% of all tumors with a TS copy number < 144 (related to 104 copies β-actin) were sensitive to P in vitro. (specificity = 0.69; chi2 = 14.14). Statistical tests demonstrated that gene expression of TS, DHFR, and GARFT are dependent variables and that TS transcription is the leading variable. The combination of TS, DHFR, and GARFT expression data was not superior to TS alone. Conclusions: TS expression is the most meaningful predictor for sensitivity (≤ 144 copies) or resistance (> 144 copies) to Pemetrexed in fresh tumor tissue. This observation forms a rationale for clinical trials using TS expression as predictor for clinical response.

No significant financial relationships to disclose.
A pharmacogenetic study of irinotecan: Genetic polymorphisms in the coding region of UGT1A1 gene and SN-38 glucuronidation in the body
Authors: Araki K. , Fujita K. , Ando Y. , Nagashima F. , Yamamoto W. , Endou H. , Miya T. , Kodama K. , Narabayashi M. , Sasaki Y.
Published: March 2020

13078

Background: Pharmacogenetic testing of UGT1A1*28, a promoter variant of UGT1A1 gene, for estimating a risk of irinotecan toxicity has been introduced into clinical practice. Purpose: To elucidate clinical significance of UGT1A1*6 and UGT1A1*27, the variants in exon 1 that are found mostly in Asians. Methods: Pharmacogenetic relationships were explored between the genotyping results and ratio of area under the concentration-time curve (AUC) of SN-38 and its glucuronide (SN-38G) as a surrogate for a UGT1A1 activity (AUCSN-38/AUCSN-38G) in 36 Japanese patients who received various regimens of irinotecan chemotherapy at doses from 50 to 180 mg/m2. Results: No patients were homozygous for UGT1A1*28 and none had UGT1A1*27. One was heterozygous for UGT1A1*28. Two were homozygous and ten heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 that existed on the different chromosomes. The remaining 21 patients did not have any variants studied. The 2 patients who was simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the 2 patients who were homozygous for UGT1A1*6 had significantly higher AUCSN-38/AUCSN-38G than the others (P = 0.004). Conclusions: Concurrence of the two UGT1A1 variants, UGT1A1*28 and UGT1A1*6 even in their heterozygous statuses, remarkably altered drug disposition of irinotecan and could enhance susceptibility to the drug. Patients who are homozygous for UGT1A1*6 should also be monitored cautiously. Genotyping of UGT1A1 polymorphisms in the coding region together with UGT1A1*28 is necessary for predicting irinotecan toxicity at least for Asian patient population.

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A phase I trial of bexarotene and docetaxel in patients with advanced solid tumors
Authors: Pishvaian M. J. , Firozvi K. , Hwang J. J. , Marshall J. L. , Ramzi P. , Malik S.
Published: March 2020

13085

Background: Retinoids have been used to treat a wide variety of malignancies. Bexarotene is a synthetic retinoid that binds preferentially to the RXR subclass of retinoid receptors. In the initial phase I trial of bexarotene, a subset of patients with non-small cell lung cancer (NSCLC) had prolonged stabilization of disease and survival. In vitro evidence suggests that the effects of retinoids may be enhanced when used in conjunction with taxanes. This is a phase I trial designed to determine the maximum tolerated dose of docetaxel in combination with a fixed dose of bexarotene. Methods: Patients with pathologically confirmed solid tumors for whom no standard therapies exist, who have an ECOG performance status ≤2, adequate organ function and normal serum triglycerides were eligible. Each cycle was 4 weeks long. Oral bexarotene was given at 400 mg/m2 daily. Docetaxel was given weekly for 3 out of 4 weeks at two dose levels, 25 or 30 mg/m2, for up to 6 cycles. For patients exhibiting disease stabilization or response, treatment with bexarotene was continued until disease progression. Restaging studies were performed after every 2 cycles. Results: To date 10 patients have been enrolled, half of whom had NSCLC - 7 male, mean age = 61 (range 37–73), 100% PS = 0 or 1. 29 cycles were completed (range 1 to 8). 7 patients have been treated at 25 mg/m2 and 3 at 30 mg/m2 of docetaxel. Hypothyroidism, hypertriglyceridemia, and fatigue were common but generally mild. Two patients experienced grade III fatigue, and 1 each experienced grade III hypertriglyceridemia, neutropenia, and cough. There were no grade IV toxicities. Two patients were taken off study because of non-fatal radiation recall pneumonitis that was controlled with steroids. In this heavily pretreated population, of 8 patients assessable for response, 5 had stable disease for at least 2 cycles. One patient with NSCLC had a partial response that persisted for 6 cycles. Conclusions: Bexarotene and docetaxel (at a minimum of 25 mg/m2) can be safely coadministered. Care should be taken in patients who have been previously irradiated. Enrolment and dose escalation for the phase I trial is still ongoing. A phase II trial of the combination as second line therapy in NSCLC is planned.

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Preclinical evaluation of the dual specific Src/Abl kinase inhibitor AZD0530 in lung cancer
Authors: Gautschi O. , Purnell P. , Evans C. P. , Yang J. C. , Holland W. S. , Bold R. J. , Virudachalam S. , Lara P. N. , Gandara D. R. , Gumerlock P. H.
Published: March 2020

13108

Background: AZD0530 is a highly selective, orally available, dual specific Src/Abl kinase inhibitor in clinical development. We tested this agent in multiple lung cancer cell lines in vitro. We hypothesized that activity of AZD0530 may depend on the level of activated (pY416-)Src, and that Src inhibition may decrease Bcl-xL protein levels and lower the barrier to apoptosis. Methods: NSCLC (A549, Calu-1, Calu-6) and SCLC (H69, H526) cells were incubated with 0.001–100 μM AZD0530 for 1–72hrs. Proliferation (MTT), DNA-content (flow cytometry), and protein levels of Src, pY416-Src, PARP, and Bcl-xL (Western blotting) were assessed. Results: Basal pY416-Src was detectable in most cell lines except H526. AZD0530 decreased pY416-Src levels at submicromolar concentrations in pY416-Src positive cells. In A549, Calu-1 and Calu-6, AZD0530 blocked cell growth in a time- and dose-dependent way (IC50 = 7–25 μM) by arrest in G1, retaining a cytostatic effect at submicromolar concentrations in A549 and Calu-1. AZD0530 induced apoptosis in 10–22% of these cells at micromolar concentrations, accompanied by a decrease of Bcl-xL protein in A549 and Calu-1. In H69 and H526, growth inhibition by AZD0530 was limited (IC50 >100 μM). Conclusions: 1) AZD0530 induced apoptosis at micromolar concentrations, and inhibited cell growth at micromolar to submicromolar concentrations in some cell lines. 2) pY416-Src is a potential marker for drug responsiveness, but other factors should also be tested. 3) Decrease of Bcl-xL by AZD0530 may render cancer cells more sensitive to chemotherapy. These data suggest that Src kinase inhibitors merit further testing in lung cancer, both alone and in combination with other agents. (Support: Swiss National Science Foundation, Swiss Cancer League, AstraZeneca).

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The activity of CKD601, telomerase inhibitor, against gastric cancer cell lines and resistance mechanism, which is associated with hTERT expression and ALT
Authors: Jung J. , Park Y. , Jong H. , Im S. , Song Y. , Kim W. , Bang Y.
Published: March 2020

13126

Background: CKD601, a newly developed telomerase inhibitor, shows an anti-cancer effect through its inhibitory effect on telomerase, by intercalation of the drug into the structures of the G-quadruplex. No study has been conducted to assess the anti-cancer effects of CKD601 in regards to gastric cancer. We attempted to confirm the anti-cancer effect of CKD601 in the gastric cancer cell line, and to investigate the mechanisms of the anti-cancer effect and resistance in some cell lines. Methods: After long-term drug exposure, we performed Southern analysis, TRAP, and β-Gal staining about the extracted DNA, RNA, and protein from the gastric cancer cell lines and the U2OS cell line to confirm the anti-cancer effect of CKD601. We attempted to investigate the change in the hTERT expression of cancer cells as a result of exposure to CKD601 by RT-PCR and real-time PCR, and to confirm the presence of the ALT (alternate lengthening of telomere) mechanism by metaphase telomere FISH and IF. Results: The anticancer effect of CKD601, including the shortening of telomere, inhibition of telomerase activity, cellular aging, and decreased growth rates, was observed in some gastric cancer cell lines (SNU-1 and SNU-601). SNU-484 and SNU-668 cell lines showed no anti-cancer effect of CKD601. The resistance mechanism of SNU-484 was the significant overexpression of hTERT following exposure to CKD601. ALT, another mechanism that functions in the maintenance of telomere length, was detected in SNU-668 following exposure to CKD601, and it is the resistance mechanism against CKD601. Conclusions: CKD601 is active in gastric cancer by the inhibition of telomerase activity. The resistance mechanisms of gastric cancer cell lines against CKD601 are the induction of the overexpression of hTERT and the ALT mechanism.

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No significant financial relationships to disclose.
iMTD (individualized maximal tolerated dose) protocol: A clinical strategy to address interindividual heterogeneity to antiangiogenic therapy
Authors: Li V. W. , Li W. W.
Published: March 2020

13130

Background: The determination of optimal biological dose is critical to the successful development of antiangiogenic agents. Recent studies suggest that genetic heterogeneity of angiogenesis and interindividual variations in efficacy response to angiogenic inhibitors and their side effects exist. Imiquimod, approved to treat skin cancer, is a topical immune response modifier with antiangiogenic effects mediated by interferons and interleukins. Although efficacy is associated with increased dosing frequency, adverse events are dose limiting. In clinical studies, imiquimod had a 75% efficacy rate in treating basal cell carcinoma (BCC) when dosed 5×/week × 12 weeks, but moderate to severe local inflammation was seen in up to 50%. Methods: The dose frequency that results in gross clinical skin inflammation is one marker of individual heterogeneity. To optimize efficacy while minimizing side effects, we devised a treatment algorithm termed Individualized Maximal Tolerated Dose (iMTD) to determine the optimal treatment frequency per patient. Imiquimod was applied in an incremental titrating fashion to BCC neoplasms (N=52): 2×/wk × 2 wks escalating to 3×/wk × 2 wks, then M-F × 2 wks, then daily × 2 wks. Dose frequency was increased until the threshold of inflammation, then lowered to the last best-tolerated dose. Tumor response and the maximal required/tolerated dose frequency (MTD) for each patient was recorded. Results: The iMTD protocol resulted in 52/52 complete responses with 0/52 cases of undesired inflammation. In order to achieve these results, a significant interindividual variation in dose tolerance was observed: 62% (32/52) required/tolerated 3×/week dosing for complete clearance, 29% (15/52) daily treatment, and 8% (4/52) 5×/week treatment. Conclusions: Because interindividual heterogeneity to response is not addressed in most clinical trial protocols, a single dose frequency among study cohorts generates outcomes that includes both responders and non-responders. When therapy is titratable by dose scheduling, the iMTD strategy may optimize clinical results while minimizing toxicities, a goal of antiangiogenic therapy.

No significant financial relationships to disclose.