bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of ON 01910.Na, a novel modulator of polo-like kinase 1 (Plk1) pathway, and development of a cyclin-B1-based predictive assay in pancreatic cancer
Authors: Jimeno A. , Chan A. , Zhang X. , Wheelhouse J. , Solomon A. , Cosenza S. C. , Reddy M. , Rudek M. , Kulesza P. , Reddy E. , Hidalgo M. 
Published: March 2020

3569 Background: Plk1 is a key mitotic regulator of the transition through the G2/M checkpoint in the cell cycle. This work aimed to evaluate the activity of ON 01910.Na, a Plk1 pathway modulator, in in vitro and in vivo models of pancreatic cancer (PaCa) and to discover biomarkers predictive of efficacy. Methods: ON 01910.Na was tested in 12 PaCa cell lines. Studies assessing Plk1 related markers were conducted to identify biomarkers. For validation a live collection of PaCa xenografts from fresh tumor samples obtained at the time of surgical resection was used (PancXenoBank). The ex vivo assay was based on fine-needle aspirate (FNA) biopsies. Results: ON 01910.Na showed equal activity to gemcitabine against PaCa cell lines. The activity of ON 01910.Na correlated with suppression of two downstream mediators of PLK1, CDC25C and cyclin B1 (by mRNA and protein). ON 01910.Na was tested in xenografts from representative pancreatic cell lines. The selected markers were evaluated in an ex vivo assay, using intra-tumor pharmacokinetics to select the dose of the assay. Cyclin B1 mRNA evaluation yielded the most optimal combination of accuracy and reproducibility. Knockdown of cyclin B1 by siRNA had no effect per se or in the response of the resistant MiaPaca2 to either of the drugs. We next used the ex vivo assay to profile ten patient-derived cases from the PancXenoBank. Two cases were catalogued as potential responders. From each of these ten cases, a group of mice bearing at least 20 tumors received vehicle or ON 01910.Na for 28 days. There was a correlation between the ex vivo cyclin B1 assay and the sensitivity to the tested agent, as the 2 cases prospectively identified as sensitive met pre-specified criteria for response. Of the 8 tumors predicted to be resistant, only one was sensitive. In IHC testing cases showing ex vivo cyclin B1 down-regulation had also decreases in cyclin B1 protein, and there was a correlation between activity and IHC changes in cyclin B1. Conclusions: ON 01910.Na demonstrated significant activity in a preclinical model of PaCa. A rationally designed ex vivo cyclin B1-based assay not only identified cases sensitive to ON 01910.Na, but also replicated the pharmacodynamic events occurring after in vivo exposure. No significant financial relationships to disclose.
Phase I study of ZEN-008 (AN-152), a targeted cytotoxic LHRH analog, in female patients with cancers expressing LHRH receptors
Authors: Emons G. , Kaufmann M. , Günthert A. , Gründker C. , Loibl S. , Tzekova V. I. , Velikova M. T. , Tomov S. , Sindermann H. , Engel J. , Schally A. V. 
Published: March 2020

3571 Background: Human ovarian, endometrial, and breast cancers commonly express receptors for luteinizing hormone releasing hormone (LHRH-R). LHRH-R can be used for targeted chemotherapy with ZEN-008 (AN-152), in which doxorubicin (DOX) is linked to [D-Lys(6)]- LHRH. Preclinical studies showed a significantly reduced cardiotoxic potential of ZEN-008 compared with DOX, as well as activity in multi-drug resistant tumor models. This study assessed dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of ZEN- 008 given once every 3 weeks in female patients. Methods: Patients (pts) with tumors proven immunohistochemically to be LHRH- R positive and had progressive disease following chemotherapy were eligible if prior therapy did not exceed 70% of the recommended maximum lifetime dose for DOX. Starting at 10 mg/m2, doses were doubled between pts until side effects of CTCAE grade 2 or higher, then escalation following a modified Fibonacci scheme, with 3–6 pts/group. Safety monitoring included pituitary and cardiac function. Response evaluation followed the RECIST criteria. HPLC with fluorescence detection was used for plasma PK of ZEN-008 and free DOX. Results: Seventeen pts (13 with ovarian, 2 with breast cancer) received ZEN-008 by intravenous infusion over 2 hours at dosages of 10, 20, 40, 80 mg/m2 (1 pt and 2 cycles each). At 160 mg/m2 6 pts had 24 cycles, 1 pt ongoing at 3+ cycles), and at 267 mg/m2 7 pts had a total of 30 cycles, 1 pt ongoing at 4+ cycles). Short-lasting leukopenia/neutropenia of CTCAE Grade 4 was dose limiting in 2 pts at 267 mg/m2. One pt at this dose level had an allergic skin reaction during infusion, subsequent cycles with anti-allergic pre-medication were tolerated. At 160 mg/m2 1 pt with ovarian cancer had CR (lymph node metastasis), at 267 mg/m2 1 pat with ovarian cancer had a transient PR, and 3 pts had stable disease for 5+ cycles. PK analyses showed dose- dependent plasma levels of ZEN-008 and only minor (10–30%) release of DOX. Conclusions: Leukocytopenia was identified as a rapidly reversible DLT in heavily pretreated pts at a ZEN-008 dose of 267 mg/m2, given three-weekly, which is therefore also considered recommended Phase II dosage. Evidence of therapeutic activity was found at 160 and 267 mg/m2. [Table: see text]
A phase I study of vorinostat (VOR) in combination with capecitabine (CAP) in patients (pts) with advanced solid tumors
Authors: Tang P. , Oza A. , Townsley C. , Siu L. , Pond G. , Sarveswaran P. , Webster S. , Zwiebel J. , Chen E. 
Published: March 2020

3576 Background: VOR (suberoylanilide hydroxamic acid; SAHA) is a small molecule inhibitor of histone deacetylase (HDAC) that binds directly to the enzyme’s active site in the presence of a zinc ion. Aberrant HDAC activity has been implicated in a variety of cancers. The combination of 5-fluorouracil and VOR is synergistic in preclinical tumor models. Methods: This phase I study evaluated safety, tolerability, and the recommended phase II dose (RPTD) of VOR and CAP in pts with advanced solid tumors. VOR was administered orally daily while CAP was administered orally bid on days 1–14 of a 21 d cycle. Results: Three dose levels have been evaluated (VOR (mg/d)/CAP (mg/bid)): 300/750, 300/1,000 and 400/1,000. Twenty-three pts have been treated: 6M/17F, median age 59 (range 41–73), ECOG 0:1:2 = 9:13:1, prior therapy 1:2:3 or more = 3:7:13. Pts had colorectal cancer (n=6), nasopharyngeal (n=3) and various other tumors. A total of 104 cycles have been administered, with median = 2 (range 1–15). One dose limiting toxicity (DLT) (grade 3 diarrhea) occurred in 6 patients at dose level 1. No DLT were observed at dose level 2, and 2 DLTs (grade 3 fatigue and grade 3 nausea/vomiting) occurred at dose level 3. RPTD was determined to be VOR 300 mg/d and CAP 1,000 mg/bid. Most common toxicities of any grade and at least possibly attributable (n=22) are: thrombocytopenia (59% of pts), fatigue (55%), nausea (55%), vomiting (50%), hypoalbuminemia (45%), anemia (41%), diarrhea (41%), anorexia (41%), elevated creatinine (36%), lymphopenia (36%), hyponatremia (36%), and hyperglycemia (36%). Common grade 3 toxicities included: hand-foot syndrome (23% of pts), diarrhea (14%), fatigue (14%), and lymphopenia (14%). One pt died on study from ventricular fibrillation due to sotalol and hypocalcemia from pre-existing hypoparathyroidism. Five patients with various tumor types had PR (2 confirmed, 3 unconfirmed) (2 nasopharyngeal, 1 each of ovarian, endometrial and squamous cell carcinoma of head and neck). In addition, disease stabilization was seen in 12 patients. Conclusions: VOR and CAP are well tolerated, and this combination is active in several tumor types. Further evaluations of VOR and CAP are warranted. No significant financial relationships to disclose.
Final results from an open-label, randomised, phase II study of adecatumumab (MT201), a fully human anti-EpCAM antibody, in patients with metastatic breast cancer
Authors: Awada A. H. , Schmidt M. , Scheulen M. E. , Obrist P. , Marschner N. , Dirix L. , Dittrich C. , Reinhardt C. , Schuler M. 
Published: March 2020

3588 Background: High-level expression of the epithelial cell adhesion molecule (EpCAM) has been associated with unfavourable prognosis in various cancers. Adecatumumab was developed as a low-affinity IgG1 antibody targeting EpCAM-positive cancer cells. Methods: EpCAM-positive metastatic breast cancer patients without CNS metastases, with no indication for trastuzumab were eligible; an initial restriction to a maximum of one previous chemotherapy for metastatic disease was subsequently removed. 109 EpCAM- positive patients were enrolled. Patients were stratified into high- and low-level EpCAM expression (n = 74 and 35, respectively) according to immuno-histochemistry testing, and subsequently randomised to receive either high-dose (6 mg/kg/q2w) or low-dose (2 mg/kg/q2w) adecatumumab (n = 54 and 55, respectively). Primary endpoint was clinical benefit rate (CBR = objective response + stable disease) at week 24 with secondary parameters exploring time to progression (TTP) and safety. Results: The primary endpoint (CBR at week 24: >25%) was not met in any of the 4 groups according to central radiological review. Exploratory analyses of the Kaplan-Meier curves, however, showed a lower probability for tumor progression in patients receiving high dose adecatumumab (HR: 0.67 [0.47–0.94]; p=0.047). A similar trend was also observed in patients with high-level EpCAM expression (HR: 0.71 [0.49–1.03]; p=0.116). Further (retrospective) analysis using more stringent criteria for the definition of high-level EpCAM expression indicated an inverse correlation of staining intensity and frequency with probability of progression. An increased incidence of CTC grade 1 and 2 AE was found in the high-dose group with main side effects being gastrointestinal and constitutional symptoms. Conclusions: The observation of dose- and target-dependent activity of adecatumumab warrants further investigation. Definition of the optimum dose and regimen as well as exploration of the predictive value of EpCAM testing will be key in future development. No significant financial relationships to disclose.
A phase I dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors
Authors: Sweeney C. , Verschraegen C. , Chiorean G. , Lee F. , Jones S. , Tye L. , Bello A. , Chao R. , Burris H. 
Published: March 2020

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.
A phase I study of lapatinib and topotecan in patients with solid tumors
Authors: Molina J. R. , Erlichman C. , Kaufmann S. , Adjei A. , Rubin S. , Friedman R. , Reid J. , Qin R. , Felten S. 
Published: March 2020

3598 Background: Drug resistance to topotecan can be the result of BCRP/ABCG2 expression. BCRP is a member of the ABC transporter family that pumps anticancer drugs out of the cell. Lapatinib is a potent and selective dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 (Her2/Neu). 4-aminoquinazoline tyrosine kinase inhibitors have been shown to enhance the cytotoxicity of topotecan through inhibition of BCRP-mediated drug efflux in cancer cells. Methods: Thirty-seven patients with advanced stage cancers were enrolled at escalating dose levels of lapatinib and topotecan in cohorts IA, IB and IIB (MTD). Treatment schedule included lapatinib (750 - 1500 mg/d) daily for 21 (cohort IA) or 28 days (cohort IB) and topotecan (2.4 - 4.0 mg/ m2), days 1, 8 and 15; cycles were repeated every 28 days. Three patients were treated at each dose level, 18 on cohort IA, 9 on cohort IB and 10 at MTD (cohort IIB). Assessments of toxicity were performed with each cycle and clinical response was determined per RECIST criteria every other cycle. Results: The MTD for cohorts IA and IB was reached at a dose of 1250 mg of lapatinib and 3.2 mg/m2 of IV topotecan on days 1, 8 and 15. No DLT were seen during the dose escalation stage of cohorts IA and IB. Ten patients were enrolled at the MTD. There were no grade 4+ events. Thirteen grade 3+ events, considered to be related to treatment, were seen in 6 patients. The most common grade 3+ toxicities included dehydration (2) diarrhea (2), nausea (3), vomiting (2), neutropenia (1), thrombocytopenia (1), and fatigue (1). No abnormalities in left ventricular ejection fraction were noted. Stable disease was seen in 46% of the 37 patients. Conclusions: The combination of lapatinib and topotecan is a well-tolerated regimen. The MTD for the combination is lapatinib 1,250 mg orally once daily for 21 or 28 days and topotecan 3.2 mg/m2 on days 1, 8 and 15. Pharmacokinetic analysis for drug interaction will be available for presentation at the meeting. Supported in part by GSK and Mayo Clinic No significant financial relationships to disclose.
The dual specific Src/Abl kinase inhibitor AZD0530 inhibits the formation and activity of human osteoclasts
Authors: Klein-Nulend J. , van Duin M. A. , Green T. P. , Everts V. , de Vries T. J. 
Published: March 2020

3602 Background: Gene knockout studies have demonstrated the critical importance of the non-receptor TK Src to osteoclast bone resorptive function. Deregulated Src TK activity is also reported as a hallmark of the invasive cancer cell. Bone metastatic cancer cells interact with and activate osteoclasts in a destructive cycle of bone degradation and stimulation of tumor cell growth. Therefore targeting Src activity would appear to be a rational therapeutic approach in treating metastatic bone disease. We have reported previously (AACR 2005) on the activity of the dual Src/Abl kinase inhibitor AZD0530 in inhibiting the bone resorptive activity of mature rabbit osteoclasts in a bone slice model. Here we tested the effect of AZD0530 in a human co-culture system, examining its activity on i) osteoclast formation by peripheral blood mononuclear cells (PBMCs) co-cultured with osteoblasts, and ii) osteoclastic bone resorption. Methods and Results: PBMC adhesion to osteoblasts and osteoblast morphology was not affected by AZD0530 (0.1–10 μM). However, AZD0530 inhibited the formation of multinucleated osteoclast-like cells dose dependently. PBMC-osteoblast co-cultures were then exposed to 1 μM AZD0530 for different time intervals. AZD0530 was most effective in inhibiting the formation of osteoclast-like cells when added at the onset of osteoclastogenesis, suggesting that Src activity is important during the initial induction of osteoclast formation. Formation of actin rings, to which c-Src co-localizes, is a prerequisite for osteoclastic bone resorption. The effect of AZD0530 on formation of actin rings was analyzed using the co-culture system on cortical bone slices. AZD0530 prevented migration of osteoclast precursors to the bone surface, and the subsequent formation of actin rings. On withdrawal of the drug, this process was reversible. Conclusions: Our data suggest that Src activity is pivotal for the formation, migration and activity of osteoclasts. Data reported elsewhere suggest AZD0530 will also impact on tumor cells directly. AZD0530 is a promising new anti-cancer drug with potential to additionally treat metastatic bone disease through its inhibition of both osteoclast activity and tumor cell invasion into and within the bone micro-environment. No significant financial relationships to disclose.
A randomized trial of prophylactic cranial irradiation (PCI) versus no PCI in extensive disease small cell lung cancer after a response to chemotherapy (EORTC 08993–22993)
Authors: Slotman B. , Faivre-Finn C. , Kramer G. , Rankin E. , Snee M. , Hatton M. , de Schaetzen G. , Collette L. , Senan S. 
Published: March 2020

4 Background: Prophylactic cranial irradiation (PCI) significantly reduces the risk of brain metastases (BM) and improves survival in patients with limited disease small cell lung cancer. Development of BM is often accompanied by deterioration of physical and psychological functioning and response to therapy is poor. Patients with extensive disease (ED SCLC) are at high risk for BM. This randomized study assesses PCI in patients with ED SCLC. Methods: Patients (18–75 years; WHO=2) with confirmed ED SCLC and any response to 4–6 cycles of chemotherapy, were randomized to receive PCI (doses ranging from 20 Gy/5 fr to 30 Gy/12 fr) or no PCI. The primary endpoint was the cumulative incidence of symptomatic BM. CT or MRI of the brain was performed whenever any of the pre-defined “key-symptoms” was present at baseline or during follow-up. The study was sized to detect a hazard ratio of 0.44 with 80% power and 2-sided 5% significance (52 events, 287 patients). Results: Between Feb ’01 and Mar ’06, 286 patients entered the trial, 76% with residual disease in the thorax and 71% at distant sites. Baseline characteristics were well balanced. Only 6% of patients in the PCI arm were not treated and 3% interrupted treatment. Acute toxicity was mild: nausea/vomiting was reported by about 30% of PCI-treated cases and about 30% reported late reactions (mostly mild headache). PCI significantly reduced the risk of symptomatic brain metastases (Gray P<0.0001, HR=0.27, CI: 0.16–0.44). The 1-year cumulative incidence of symptomatic BM was 14.6% on PCI (CI 8.3–20.9) versus 40.4% in controls (CI 32.1–48.6). PCI had no impact on extra-cranial progression rates (Gray P>0.1), but it significantly prolonged progression-free survival time (P=0.0218, HR=0.76, CI: 0.59–0.96) and overall survival (P=0.0033, HR=0.68, CI: 0.52–0.88). The 1-year survival rate was 27.1% for the PCI and 13.3% for the control arm. Conclusions: PCI significantly reduces the risk of symptomatic brain metastases, and significantly improves both disease-free and overall survival in patients with ED SCLC. PCI should be offered to all ED patients showing a response to initial chemotherapy. No significant financial relationships to disclose.
Impact on quality of life of adding cetuximab to irinotecan in patients who have failed prior oxaliplatin-based therapy: The EPIC trial
Authors: Eng C. , Maurel J. , Scheithauer W. , Wong L. , Lutz M. , Middleton G. , Stoller R. , Zubel A. , Lu H. , Sobrero A. F. 
Published: March 2020

4003 Background: EPIC, a multinational phase III clinical trial examined the impact of cetuximab on survival in pretreated EGFR- expressing metastatic colorectal (MCRC) patients (pts). Pts were randomized to either cetuximab 400 mg/m2 followed by 250 mg/m2 weekly and irinotecan 350 mg/m2 q 3 weeks or irinotecan alone. The primary endpoint was overall survival (OS) with quality of life being one of the secondary endpoints. Methods: Health Related Quality of life (HRQoL) of pts in this trial was assessed through the EORTC QLQ-C30 questionnaire, version 3.0. Pts completed the questionnaire pretreatment, every second cycle, and at first follow-up visit. HRQoL was compared between treatment arms using a Wei-Lachin test. Results: Baseline demographics were balanced between the arms. Cetuximab plus irinotecan (n=648) was superior to irinotecan alone (n=650) in progression-free survival (HR 0.69, p<.0001) and response rate (16.4 vs 4.2%, p<.0001). OS was comparable between the arms, but may have been influenced by subsequent therapy: 46% of subjects in the irinotecan alone arm received cetuximab, 89% of them in combination with irinotecan. Baseline HRQoL scores did not significantly differ between treatment arms for 11 of the 15 scales. For 4 scales (Social Functioning, Fatigue, Dyspnea, and Appetite Loss), there were statistically significant differences in baseline scores, in favor of the cetuximab plus irinotecan arm. Non- compliance rates (missing questionnaires) were similar between the arms. A statistically significant difference was noted for pts in the cetuximab plus irinotecan arm in HRQoL on 10 of the 15 scales as compared to patients in the irinotecan arm, with the scores of the cetuximab plus irinotecan arm consistently higher, as noted by the scales of Global Health Status (p=.047), pain (p< .0001), and nausea (p<.0001). Conclusions: In addition to statistically significant improvements in PFS and RR in patients receiving cetuximab plus irinotecan compared with irinotecan alone, HRQoL was better preserved on the combination arm with less deterioration in symptom scores (pain, nausea, insomnia), as well as global health status scores. No significant financial relationships to disclose.