bluuebunny/crossref_metadata_2025 huggingface dataset:
ARRY-649, a member of a novel class of Eg5 kinesin inhibitors
Authors: Miglarese M. R. , Wallace E. , Woessner R. , Allen S. , Hans J. , Lemieux C. , Dewolf W. , Lyssikatos J. , Lee P. , Koch K.
Published: March 2020

13045

Background: Inhibitors of the Eg5 motor kinesin selectively disrupt mitotic spindles in dividing cells. This selective targeting of microtubule dynamics in dividing cells is expected to translate to broad-spectrum anti-tumor activity while avoiding neuropathic side effects caused by taxanes. To date, quinazolinone Eg5 inhibitors, exemplified by ispinesib, represent the only Eg5 inhibitors reported in clinical trials. Methods: We used X-ray crystallography, biochemical and cell-based assays, pharmacokinetic profiling and in vivo efficacy studies to identify and optimize a potent series of Eg5 inhibitors. Results: We have discovered a distinct series of potent Eg5 inhibitors, exemplified by ARRY-649. ARRY-649 inhibited Eg5 with an IC50 of 0.7 nM, blocked phosphorylation of histone H3 in HeLa cells with an IC50 of 0.3 nM and showed sub-nanomolar activity against a broad panel of human tumor cells lines in in vitro viability assays. Further evaluation of mechanism-of-action in tumor cell lines revealed that ARRY-649 induced a monopolar spindle phenotype and subsequent apoptosis characteristic of Eg5 inhibition. In contrast to paclitaxel, ARRY-649 retained potent activity against multi-drug resistant human tumor cells lines selected to overexpress P-glycoprotein. ARRY-649 demonstrated robust efficacy in the HT-29 human colon tumor xenograft model and was well-tolerated at efficacious doses and schedules. Durable complete- and partial-regressions were observed upon intraperitoneal administration on a 5 mg/kg q4dx3 schedule in the HT-29 model. Similar results were obtained using the HL-60 myelomonocytic xenograft model. Conclusions: ARRY-649 represents a distinct class of potent Eg5 inhibitors with robust activity in preclinical models of human cancer. Based on these observations, we have progressed novel Eg5 inhibitors toward clinical development.

[Table: see text]
Phase II study of docetaxel (D) plus bevacizumab (B) in Her/2 negative metastatic breast carcinoma (MBC)
Authors: Chan D. , Allen H. , Hu E. , Reese D. , Patel G. , Gottlieb C. , Wax A. , Sosa J. , Slamon D. , Kabbinavar F.
Published: March 2020

13047

Background: Taxol+Bevacizumab (B) has clinical activity in Her/2 negative chemotherapy naive MBC with a PFS (11.4 mo), RR (29.9%), and OS (28.4 mo). We are conducting a single arm Phase 2 trial to assess the efficacy of Docetaxel (D)+B. Primary endpoint: time to progression. Secondary endpoints: response rate (CR + PR), response duration, overall survival and safety. Methods: Eligibility criteria: MBC with no prior therapy; Her/2 negative by FISH, ECOG PS 0 or 1; measurable disease by RECIST, Hgb ≥ 9 g/dL, ANC ≥ 1.5 × 109/L, Platelet count ≥ 100 × 109/L, Creatinine ≤ 2.0 mg/dL, Total bilirubin ≤ 1.0 × upper limit of normal, no CNS metastasis, no MI or stroke within 6 mo, no GI perforation, no major surgery within 28 d, and no bleeding diathesis or coagulopathy. Pts receive B 15 mg/kg IV and D 75 mg/m2 IV Q 3 wk. Response assessed radiographically Q 3 cycles. Treatment is until disease progression or unacceptable toxicity. Results: Since Apr 2005, 43 of the planned 75 pts have been enrolled. 21 pts have had at least one assessment resulting in approximately 40% response rate. Common Gr3/4 AE’s have been neutropenia, febrile neutropenia, hypertension. Gr3 LVEF decline seen in one pt. No treatment related deaths occurred. Conclusions: D+ B is well tolerated, with no new safety concerns and manageable toxicities. D+B appears active in MBC. Updated efficacy and safety data will be presented. Study supported by Genentech, Inc. San Francisco, CA.

No significant financial relationships to disclose.
Phase I/II trial of capecitabine (C), dacarbazine (D) and imatinib (I) (CDI) for patients (pts) metastatic medullary thyroid carcinomas (MTC)
Authors: Hoff P. M. , Hoff A. O. , Phan A. T. , Sherman S. I. , Yao J. , White N. , Phan L. , Abbruzzese J. L. , Gagel R. F.
Published: March 2020

13048

Background: MTC is a rare tumor that responds poorly to conventional chemotherapy. 5-FU and D are frequently used, with an expected response rate of around 15%. MTC is often associated with multiple endocrine neoplasia type 2, an autosomal dominant syndrome caused by a mutation in the RET proto-oncogene which encodes RET, a tyrosine kinase receptor. I is a tyrosine kinase inhibitor with activity against c-Kit, PDGF and possibly RET, and we postulated that its addition to chemotherapy would increase its efficacy against this disease. Methods: We designed a phase I/II trial combining escalating doses of oral C, IV D and oral I. Pts with any advanced solid tumors were eligible for the phase I part of the trial. Results: 13 pts were entered and 12 were eligible (7 MTC, 2 adrenocortical, 1 islet-cell, 1 insular thyroid and 1 small cell). 4 pts did not complete one cycle (1 pt withdrew after 5 days and 2 pts progressed in less than 10 days and were replaced for toxicity analysis, 1 had a DLT and is included). 3 patients were entered in dose level 1, without DLT. 2 out of 6 pts developed DLT at the second dose level (1 G 3 fatigue and 1 G3 hypokalemia). Three additional pts are being entered on dose level 1. The first one had PD after 7 days and is being replaced. For the 11 pts who were evaluable, best response was 3 SD (range 3 to 9 + months) and 8 PD. Conclusions: The combination of CDI is feasible but has resulted in an unexpected pattern of toxicity in this patient population, with fatigue and hypokalemia as the DLT. No significant diarrhea or hand-foot syndrome was seen. Only G1 and 2 fluid retention and neutropenia have been encountered. Only minor reduction in tumor size has been seen among these heavily pretreated pts. Once the phase I is complete, the trial will continue in a phase II setting for untreated MTC pts.

[Table: see text]

[Table: see text]
Phase I trial of bortezomib and celecoxib in patients with advanced solid tumors
Authors: Dunder S. , Chaudhary U. B. , Green M. , Meyer M. , Brescia F. , Kraft A. , Montero A. , Salzer S.
Published: March 2020

13051

Background: The ubiquitin-proteosome pathway plays an important role in cell cycle regulation, neoplastic growth, and metastasis. Nuclear factor-kB (NF-kB) is a key transcription factor in cancer, primarily regulated by proteosome-mediated degradation of the inhibitor protein I kappa B alpha-associated protein kinase (IkBa). Interruption of this degradative pathway, with the 26S proteosome inhibitor bortezomib, has displayed significant clinical anti-tumor activity, in multiple myeloma and lymphomas. The role of bortezomib in the treatment of advanced solid tumors, however, is unclear at present. Preclinical work in multiple myeloma cell lines has demonstrated synergy in cytotoxicity and growth inhibiton with the combination of bortezomib and the cyclooxygenase (COX)-2 inhibitors. We therefore hypothesized that the combination of the COX-2 inhibitor celecoxib and bortezomib is a potentially active combination in the treatment of advanced solid tumors. Towards this aim, we are conducting a phase I study to determine the maximum tolerated dose (MTD) and toxicity profile of bortezomib and celecoxib. Methods: Patients with advanced solid tumors and an ECOG PS of 0–2 received escalating doses of bortezomib (1.0–1.6 mg/m2), either weekly for 5 of 6 weeks or twice weekly for 2 of 3 weeks, and celecoxib (200–400 mg twice daily). Accrual was planned to a maximum of 6 cohorts, each with a minimum of 3 patients. Only those dose-limiting toxicities (DLTs) occurring during the first cycle were used to define the MTD. DLTs included any grade 4 hematologic toxicity related to therapy, or any grade 3 or 4 non-hematologic toxicity. Results: To date, 10 patients (median age of 63y) have been treated. Represented tumor types include stage IV: colorectal, pancreatic, bladder, leiomyosarcoma, head and neck squamous cell carcinoma, hepatocellular, and renal cell. A median number of 2 cycles were administered. Thus far, no DLTs have been observed. No cumulative toxicities have been noted. No objective tumor response has been observed, however, stable disease was maintained in one heavily pre-treated patient with metastatic papillary renal cell cancer for 5 months. Conclusions: The combination of bortezomib and celecoxib is safe and well tolerated, with no dose-limiting toxicities thus far.

[Table: see text]
Characterization of functional heparan sulfate motifs overexpressed on multiple myeloma cells using single chain antibody variable fragments generated by phage display
Authors: Delcommenne M. , Klingemann H. , Fung H. C. , Gregory S. A.
Published: March 2020

13060

Background: Multiple myeloma (MM) is the most prevalent plasma cell neoplasm and is characterized by the infiltration of the bone marrow by terminally differentiated B lymphocytes. Although novel drugs have recently been introduced, the disease remains incurable. No therapeutic antibody is as yet available for treatment of MM. One of the key molecules involved in multiple myeloma (MM) tumor progression is syndecan-1, a cell surface heparan sulfate (HS) proteoglycan expressed on both MM cells and normal plasma cells. Syndecan-1 regulates cell interactions with soluble molecules and the extracellular matrix through its heparan sulfate chains. These chains allow it to bind multiple growth factors such as Fibroblast Growth Factor type 2 (FGF-2), WNT, Hepatocyte Growth Factor (HGF), midkine, all of which promote survival and metastasis of MM cells. In addition, syndecan-1 on MM cells binds and internalizes osteoprotegerin, the RANKL antagonist, through its HS chains and depletes it from the bone marrow milieu, which triggers osteoclastogenesis. Methods: Using the phage display technique, we have generated a panel of MM-specific human antibody variable fragments (scFvs) against the MM cell line RPMI-8226. These scFvs were tested against a variety of cell lines and primary normal bone marrow or myeloma cells. The biochemical identity of the targeted antigens was determined. Results: Two of the selected scFvs, D4A4 and D6B10, reacted against heparan sulfate motifs that were highly expressed in MM cell lines and patient MM cells but absent (scFv D6B10) or poorly expressed (scFv D4A4) in normal plasma cells. Binding of scFv D6B10 to MM heparan sulfate chains required NS sulfation, 6-O-sulfation and, to a lesser extent, 2-O-sulfation. Additional experiments indicated that FGF-2, midkine and osteoprotegerin competed with scFv D6B10 for binding to HS. Conclusions: This study indicates that the structure of syndecan-1-associated HS is altered in MM cells and may influence its capacity to bind to growth factors and promote tumor progression. Human therapeutic antibodies derived from scFvs D4A4 and D6B10 may be useful for immune targeting of MM cells and interfering with pro-survival signaling pathways.

No significant financial relationships to disclose.
Cullin-3 is a potential novel target for breast cancer chemoprevention and treatment
Authors: Miao W. , Loignon M. , Hu L. , Basik M. , Batist G.
Published: March 2020

13070

Background: Nrf2 is a master transcription factor regulating multiple phase II carcinogen-detoxifying enzymes. Modulating Nrf2 is a current chemoprevention strategy under investigation. Nrf2 levels are regulated by the Keap1, which functions as a substrate adaptor protein targeting Nrf2 to the Cullin-3 (Cul3)-dependent ubiquitin E3 ligase complex. Methods: We used RT-PCR and Western blot to measure the mRNA and protein levels of Nrf2, Keap1 and Cul3 in human breast cancer cell lines. SiRNA and retrovectors were used to construct stable Cul3 silenced breast cancer cell lines. Agilent DNA microarray analysis was used to study the Cul3-slienced cells. Results: We discovered that Nrf2 protein levels in both nucleus and cytoplasm are significantly decreased in all breast cancer cell lines examined compared to normal human mammary epithelial cells (HMEC). This was confirmed with IHC analysis in 8 out of 10 breast cancer specimens containing normal mammary tissues for comparison. Since RT-PCR showed no change in Nrf2 mRNA levels in the breast cancer cell lines, we examined the degradation pathway of Nrf2, and we found that Cul3 is significantly overexpressed in all three breast cancer cell lines studied compared to HMEC. Silencing Cul3 using siRNA results in restoration of Nrf2 protein level, along with multiple carcinogen-detoxifying enzymes, such as GCS. The Cul3 silenced cells showed remarkable growth retardation compared to the wild type MCF-7 cell line both in vitro and in vivo in a mouse mammary fat pad cancer xenograft model. Microarray analyses of Cul3 siRNA-slinced cells demonstrated upregulation of several detoxifying genes, altered cell cycle markers and several upregulated tumor suppressor genes. Conclusions: Nrf2 is significantly downregulated in breast cancer cells, which is related to the overexpression of Cul3, and may represent sensitivity of these cells to carcinogenic transformation. Knocking down Cul3 constitutively upregulates the Nrf2 as well as multiple carcinogen-detoxifying genes. Moreover, it significantly suppressess the proliferation of cancer cells in vitro and growth of xenograft tumors in vivo. These data suggest that Cul-3 is a potential new target for breast cancer chemoprevention and treatment.

No significant financial relationships to disclose.
Uridine glucuronosyltransferase 2B7 polymorphisms and epirubicin pharmacokinetics
Authors: Sawyer M. B. , Scarfe A. , Tonkin K. , Joy A. A. , Damaraju S. , Damaraju V. , Pituskin E. N. , Hanson J. , Clemons M. , Mackey J. R.
Published: March 2020

13071

Background: Epirubicin (epi) is a widely used anthracycline for the treatment of breast cancer. In contrast to its optical isomer doxorubicin, epi is predominantly glucuronidated by uridine glucuronosyltransferase 2B7 (UGT2B7). UGT2B7 has a T to C polymorphism at position -161 in the enhancer region which correlated with efficacy of morphine glucuronidation (Sawyer et al. Clin Pharmcol Ther 2003). Methods: We performed a prospective pharmacogenetic study of FEC100 (5-fluorouracil 500 mg/m2, Epi 100 mg/m2 and cyclophosphamide 500 mg/m2) given every 3 wks in early stage breast cancer pts. Drug levels were drawn at 1 and 24 hrs. We have determined levels of epi, epi-glucuronide (epiG), epirubicinol (epiol), and epiol-glucuronide (epiolG) in 78 of the 120 pts. The levels of epi and its metabolites were measured using an HPLC with fluorescence detection using the method of Fogli et al with modifications. Patient characteristics-median (range): age 50 (28 - 67), sex 77 F/ 1 M, baseline AST 22 U/L (13–66), ALT 20 U/L (5–90), bilirubin 7 umol/L (2–24), creatinine 73 umol/L (51–126). Results: 14 pts were TT homozygotes, 45 were CT heterozygotes, and 19 were CC homozygotes. Concentrations (ng/ml, median (range)) of epi, epiG, epiol, and epiolG at 1 hr respectively were 91 (39–481), 280 (0–981) 76 (14–212) 76 (0–276). There was no relationship between epiG concentration and genotype: 315 (median) TT, 263 CT, 288 CC. Patients with a TT genotype had a lower epiol concentrations (median, ng/ml) at 24 hr: 12 TT, 23 CT, 25 CC; p = 0.04. Conclusions: This analysis shows a relationship between UGT2B7 genotype and epi pharmacokinetics. We are completing analysis of all 120 samples and plan to perform a formal NONMEM analysis.

No significant financial relationships to disclose.
Non-linear relationship between HER-2 expression and response to trastuzumab in breast cancer cells
Authors: Valabrega G. , Montemurro F. , Giordano S. , Aglietta M.
Published: March 2020

13083

Background: Currently, eligibility for treatment with the mAb trastuzumab (T) in breast cancer patients is assessed by semiquantitative immunohistochemical (IHC) analysis of HER-2 expression, where 3+ score represents overexpression, and/or by Fluorescence In Situ Hybridization (FISH), which detects HER-2 gene amplification. However, both methods do not measure small but potentially significant differences in protein expression. Methods: We modulated HER-2 expression by RNA interference (siRNA) in the human HER-2-overexpressing breast cancer cell line SKBR3. Protein expression was measured by Western Blot analysis. Cells expressing different levels of HER-2 protein were then treated with T, to assess the mAb effect on cell proliferation and apoptosis. Results: Compared with the parental cell line, SKBR3 cells transfected with 10, 20, and 30 nM HER2 specific siRNAs, showed a reduction of HER-2 protein levels of 40%, 55% and 70%, respectively. Despite up to a 70% decrease in HER-2 expression, transfected cells still scored 3+ at IHC (Dako HercepTest®). Interestingly, this reduction rendered cancer cells more sensitive to T treatment. In fact, we found that sensitivity to T follows a bell shaped curve, depending on different amounts of HER-2. When T was administered at the standard dose of 10 μg/mL, cells showing a 40% reduction of the HER-2 resulted more sensitive to the growth inhibitory effect of T, compared with parental SKBR3 cells and with cells showing lower levels of receptor. Furthermore, these cells were sensitive to T concentrations lower than standard (6 vs 10 μg/mL), which were markedly less effective in cells expressing higher or lower levels of HER-2 receptor. Conclusions: The observation that cells expressing significantly different amounts of HER-2 protein are all scored as “overexpressors” by conventional IHC suggests that quantitative analysis of HER-2 receptor in breast cancer might be more appropriate for the selection of candidates to T treatment. Moreover, we showed that the inhibitory effect of T depends in a non-linear manner on the quantity of HER-2 protein and that the level of HER-2 expression can influence the sensitivity to T, which requires an optimal drug/receptor ratio.

No significant financial relationships to disclose.
hCNT1 in Waldenström’s macroglobulinemia (WM) and small lymphocytic lymphoma (SLL) patients (pts): A possible predictive biomarker of 2-chloro-2`-deoxyadenosine (2-CDA) clinical activity
Authors: Rabascio C. , Saronni L. , Antoniotti P. , Raia V. , Bertolini F. , Laszlo D. , Cassatella M. , Marziliano N. , Arbustini E. , Martinelli G.
Published: March 2020

13087

Background: The resistance mechanism to 2-CDA is not completely known. In this study we used pharmacogenomic to identify genetic factors that influence drug response and to better investigate 2-CDA complex intracellular metabolism. Methods: Using Real-time PCR method (ABI-PRISM 7000 machine) we amplified seven genes, encoding for equilibrative and concentrative nucleoside transporter (hENT1, hCNT1), deoxycytidine and deoxyguanosine kinase (dCK, dGK), 5`-nucleotidase (5`NT), ribonucleotide reductase catalytic and regulatory (RR1, RR2) subunits, in bone marrow (BM) at baseline of 17 pts with WM or SLL in order to verify the correlation between gene expression and clinical outcome. All pts were treated with a combination therapy (2-CDA 0.1 mg/kg sc injection and Rituximab at standard schedule). Quantitation was performed using the Delta CT calculation: the value of gene expression was normalised to the calibrator (healthy tissue cells). Results: hCNT1 and 5’NT gene expression analysis has shown lower values in pts than in controls. The other markers didn’t show any significance. Two pts achieving partial remission (PR) presented 100 times lower hCNT1 levels (median 6.8*10−4, range 6.8–6.9*10−4) than pts (n = 10) in complete remission (median 7.9*10−2, range 0.1–4.6*10−1; p = 0.03). Conclusions: hCNT1 seems to be the most important gene involved in 2-CDA clinical activity and its expression may correlate with prognosis. Compared to controls, the low plasmatic RNA level of hCNT1 exhibited by our pts doesn’t seem to be predictive of lack of clinical activity of 2-CDA. However the lower level of hCNT1 plasmatic expression detected in the two pts who achieved only PR could suggest a possible relationship between reduced hCNT1 plasmatic expression and a diminished clinical activity of 2-CDA. Thus it might be important to explore the possibility of standardizing a quantitative method in order to identify a threshold value which could be predictive of drug resistance.

No significant financial relationships to disclose.
Immunoglobulin G fragment C receptor polymorphisms and response to trastuzumab-based treatment in patients with HER-2/neu-positive metastatic breast cancer
Authors: Musolino A. , Naldi N. , Bortesi B. , Capelletti M. , Pezzuolo D. , Missale G. , Laccabue D. , Camisa R. , Franciosi V. , Ardizzoni A.
Published: March 2020

13090

Background: A potential mechanism of action of the humanized anti-HER-2/neu monoclonal antibody Trastuzumab involves antibody-dependent cellular cytotoxicity (ADCC) with the activation of immune effector cells via their immunoglobulin G fragment C receptors (FcγRs). Trastuzumab has been shown to engage both activation (FcγRIIIa; FcγRIIa) and inhibitory (FcγRIIb) antibody receptors on myeloid cells and several FcγR polymorphisms have been identified that may affect the antibody-dependent cytotoxicity of natural killer cells and macrophages. Methods: Forty consecutive HER-2/neu-positive (FISH+) metastatic breast cancer patients receiving a trastuzumab-based treatment (combined with paclitaxel for the majority) were examined for the FcγRIIIa 158 valine (V)/phenylalanine (F), FcγRIIa 131 histidine (H)/arginine (R), and FcγRIIb 232 isoleucine (I)/threonine (T) polymorphisms. A PCR-RFLP based assay using genomic DNA was performed for FcγRIIIa and FcγRIIa genotyping, while PCR-SSCP methods using complementary DNA were utilized for FcγRIIb. Patients’ peripheral blood mononuclear cells were drawn before treatment initiation and their trastuzumab-mediated killing function was measured by 51Cr release using a HER-2/neu-expressing human breast cancer cell line as a target. The results were then correlated with clinical outcome of these patients. Results: Median age was 60 years (range 26–83 years). Thirty-six (90%) patients received a trastuzumab-based treatment as first-line therapy. The overall clinical benefit rate (CR+PR+SD) was 65% (95% Confidence Interval: 62–71%), including 8 (20%) complete and 11 (27.5%) partial responses. Median survival was 22.3 mo with a median PFS of 7 mo. Trastuzumab-based treatment was well tolerated and no changes in cardiac function were observed. Conclusions: This study evaluates for the first time the potential role of FcγR polymorphisms in predicting response to trastuzumab-based treatment. Results according to this study purpose will be presented at the meeting.

No significant financial relationships to disclose.
The mechanism of low molecular weight heparin (LMWH) inhibition of tumor growth
Authors: Smiley S. L. , Henry D. O. , Wong M. K.
Published: March 2020

13093

Background: Clinical studies show that LMWHs improve survival in cancer patients. There is compelling and mounting evidence that non-anticoagulation factors are at play, and that these may be contributing in a major way to improved patient outcome. Methods and Results: Dalteparin, enoxaparin, and tinzaparin were tested for their in vivo ability to inhibit tumor lines engineered for aggressive angiogenesis-driven growth. Therapeutic daily doses of drug administered the day following tumor inoculation resulted in significant angiogenesis and tumor inhibition. We previously showed that LMWHs inhibit fibroblast growth factor (FGF) -induced mitogenesis of Tumor Derived Endothelial Cells (TDECs) in a time and concentration dependent manner in vitro. We now show that this endothelial inhibition occurs through LMWHs-mediated reduction of phosphorylation and down stream signaling through ERK. The potency of LMWH was significantly reduced when TDECs were pretreated with heparinase- suggesting that the molecular target for LMWH may be the cell surface, low affinity FGF receptor system. Both our in vivo and in vitro studies demonstrate that angiogenesis and tumor inhibition are greatest for dalteparin > tinzaparin > enoxaparin. Clues to the heparin-TDECs interaction comes from tracking the real-time movement of FGF using a highly fluorescent nanocrystal bead decorated on its surface with FGF. High resolution video-microscopy shows FGF binding onto TDEC surfaces, but once heparin enters the environment, FGF detaches from the TDECs and migrates to the heparin. This ultimately results in significant TDEC growth inhibition as compared to controls. Conclusion: LMWH treatment at pharmacologic doses significantly blunts tumor growth and angiogenesis. This inhibition resides in part via heparin’s ability to sequester FGF from the low affinity receptor system on tumor endothelial cells.

No significant financial relationships to disclose.
Extended phase I study of AS1411 in renal and non-small cell lung cancers
Authors: Laber D. A. , Taft B. S. , Kloecker G. H. , Bates P. J. , Trent J. O. , Miller D. M.
Published: March 2020

13098

Background: AS1411 is an oligonucleotide aptamer that binds to nucleolin, a protein expressed on the surface of tumor cells. A dose-escalating phase I trial in patients with various advanced cancers revealed no serious toxicities and consequently did not reach an MTD. There was evidence of activity, especially in renal cell carcinoma (RCC). This study has been reopened for further dose escalation to reach an optimal biological dose (OBD; unless an MTD is reached) in patients with RCC and non-small cell lung cancer (NSCLC). Methods: Patients had advanced RCC or NSCLC refractory to standard treatment. AS1411 was administered as a single continuous 7-day iv infusion, with the option of a second cycle. Patients were enrolled in cohorts of 3. If no serious toxicity was observed within 28 days, the dose was escalated to the next level. Toxicity was graded using the NCI CTCAE v3.0. The study plan was to enroll additional patients at the OBD such that a total of 12 RCC and 12 NSCLC patients received a 7-day infusion. Blood and urine samples were taken for pharmacokinetic analysis. Tumor responses were assessed every 28 days using the RECIST guidelines. Results: No serious adverse events have been observed up to a dose of 22mg/kg/day, which was associated with a mean peak plasma concentration of 1.5 μM. Response findings to date are as follows: of 5 RCC patients, 1 maintains a near-complete response 18 months after treatment, 3 have ongoing stable disease (SD; 1 at 3 months, 2 at 2 months) and a fourth had progressive disease (PD) at 2 months post-treatment; of 3 NSCLC patients, 1 has an ongoing SD and 2 had PDs at 1 month post-treatment. Recruitment and follow up continues. Conclusions: A 7-day infusion of AS1411 at 22mg/kg/day was not associated with any serious adverse events and achieved peak plasma concentrations in the range at which killing of various cancer cell lines is observed in vitro. A single further escalation is planned to reach a dose of 40mg/kg/day. Observation of additional cases of stable disease in RCC supports the previous observations of anti-cancer effects in this disease.

[Table: see text]
Metronomic chemotherapy (MC) with irinotecan (CPT-11) in patients with diagnosis of metastatic colorectal cancer (MCRC): clinical and pharmacodynamic evaluation
Authors: Loupakis F. , Bocci G. , Allegrini G. , Cerri E. , Barletta M. T. , Masi G. , Fioravanti A. , Orlandi P. , Del Tacca M. , Falcone A.
Published: March 2020

13111

Background: Preclinical studies have demonstrated that the frequent administration of low doses of cytotoxic drugs over prolonged periods of time (MC) reduces tumour cell growth through inhibition of angiogenesis. The antitumor effect of a MC with cyclophosphamide is due to an increase of thrombospondin-1 (TSP-1) plasma level, an endogenous inhibitor of angiogenesis. Methods: An exploratory study was conducted to assess the feasibility, the activity and the optimal metronomic dose of CPT-11 when administered as protracted continuous infusion (c.i.) in pretreated MCRC. A pharmacodynamic evaluation of anti- and pro-angiogenic factors, such as TSP-1 and vascular endothelial growth factor (VEGF), was performed. Weekly blood samples were taken. Three different CPT-11 dose levels have been evaluated: 1.4, 2.8 and 4.2 mg/sqm/day; 25%, 50% and 75% of the maximum CPT-11 tolerated dose in c.i. (5.6 mg/sqm/day), respectively. Results: Between Apr 04 and May 05 20 patients have been enrolled. Patients characteristics were: M/F = 11/9, median age = 71 years (range 51–79); PS 0/1/2 = 8/11/1; sites of metastasis: single/multiple = 7/13; median of previous lines of chemotherapy: 3 (range 1–5). No toxicities of grade >1 NCI scale have been observed. No objective responses were observed, but 4 patients (20%) had a stable disease with a median duration of 14 weeks (range 11–20). TSP-1 plasma levels significantly increased after one week and remained higher than the baseline for more than 8 weeks (120.1±10.3% vs. 100% of day 0). VEGF levels did not significantly change during the CPT-11 infusion. No statistical differences have been found for TSP-1 and VEGF concentrations among the three dose levels. Conclusions: CPT-11 metronomic chemotherapy is feasible. Plasma TSP-1 markedly increased during metronomic CPT-11 administration, suggesting a modulation of the angiogenic process in cancer patients. Supported by A.I.R.C.

[Table: see text]
A phase I trial combining motexafin gadolinium (MGd) with docetaxel in the treatment of advanced solid tumors
Authors: Pandya K. J. , Phan S.
Published: March 2020

13115

Background: MGd is a novel therapeutic agent that concentrates in tumors and generates reactive oxygen species. Pre-clinical models show that MGd enhances in tumors the cytotoxic activity of selected chemotherapies, including taxanes. This phase I trial studied the combination of MGd and docetaxel. Methods: Patients (pts) with advanced solid tumors, adequate bone marrow, hepatic and renal function were eligible. Cohorts of 3 pts were treated with MGd starting at 2.5 mg/kg followed 30 minutes later by docetaxel 75 mg/m2. Treatments were repeated q3wks. The primary objective was to determine the maximum tolerated dose (MTD) of MGd in combination with docetaxel on this schedule and to determine the dose limiting toxicities (DLT). The secondary objective was to evaluate the response rate. MGd dose was escalated in successive cohorts while docetaxel dose remained fixed. Results: Sixteen pts were entered (9 males, 7 females) at MGd dose of 2.5 to 10 mg/kg. The median age was 60.5 yrs (range 35 -75). ECOG PS0 (4), 1 (14). Diagnoses included prostate (1); ovarian (2); breast (2) and non-small cell lung (NSCLC) (11). Median number of prior chemotherapy regimens: 2 (range 1–14), 7 pts had previously received a taxane: paclitaxel 5, docetaxel 2. Reported toxicities (all grades) include urine discoloration from excretion of MGd (68%), fatigue (87%), diarrhea (81%) and nausea (56%), Grade 3 neutropenia (37.5%) febrile neutropenia (6%), neuropathy (foot drop) was seen in 1 patient, therefore additional pts were entered (4 registered, but 1 never treated) at 10 mg/kg dose. Recurrence of prior radiation esophagitis was seen in 1 pt therefore it was felt that DLT was reached and study was closed. Responses are as follows: PR by CT in 1 breast and 4 NSCLC, and by PSA in 1 prostate; SD by CT in 1 breast and 2 NSCLC. Conclusion: MGd 10 mg/kg in combination with docetaxel 75 mg/m2 is feasible and did not increase docetaxel toxicity while showing promising responses. Phase II study of this combination is underway in NSCLC.

[Table: see text]
Targeting tumour markers: What makes therapy discriminating?
Authors: Johnson K. , Ward R.
Published: March 2020

13129

Background: Therapy in inoperable non-small cell lung cancer has limited effectiveness. New therapy directed at tumour markers is attractive but limited by marker prevalence and intrinsic effectiveness. Prior work (Abstract 9639, 2005 PASCO) on 191 trials of first line therapy shows a “typical drug” needs at least a 35% difference in response rate, treatment versus control, to predict a survival gain. The current work describes the characteristics of targeted drugs likely to predict this gain at smaller differences, i.e., more discriminating drugs. We determine how much greater effects on response rate and survival, compared to the typical drug, need to be to predict this survival gain. Methods: By using 1.0, 1.1, 1.2, 2.0-fold increments in response rates over traditional therapy and the same increments for median survival up to that used for response, we defined 55 differently constructed targeted drugs. The drugs were all analysed at each of four marker prevalence rates, 5%, 20%, 50% and 100%, each analysis determining the response rate difference needed to predict a survival gain. For each analysis individual trial response rates were modified in one arm before applying linear regression. The response rate difference to predict a survival gain is the portion of the prediction band fully exceeding zero. Results: Improvements in discrimination were rare and highly sensitive to marker prevalence. Little improvement occurred for any drug with 5% or 20% prevalence, and if no survival improvement occurred, discrimination worsened (up to 90%). If both tumour response and survival were doubled, discrimination improved to 33%, 27%, 17%, and 7% for marker prevalence of 5%, 20%, 50%, or 100%, respectively. Modest changes (×1.4, ×1.6) in response and survival only improved discrimination with 100% prevalence. Clearly improved discrimination (to 20% or less) only occurred with at least ×1.8 increase in response and survival and 50% or more prevalence. Conclusions: The results show that targeting a marker only substantially improves discrimination if it doubles both tumour response rate and median overall survival and if marker prevalence is at least 50%. This approach may help rationalize aspects of drug development in oncology.

No significant financial relationships to disclose.
A phase II trial of epigenetic therapy with hydralazine and magnesium valproate associated to doxorubicin and cyclophosphamide for locally advanced breast cancer
Authors: Arce-Salinas C. , Segura-Pacheco B. , Vela-Chavez T. , Bargallo-Rocha E. , Pérez-Cárdenas E. , Taja-Chayeb L. , Trejo-Becerril C. , Revilla-Vazquez A. , Dueñas-González A.
Published: March 2020

13147

Background: DNA methylation and histone deacetylation are the most studied epigenetic alterations in cancer. Hydralazine and magnesium valproate are proven DNA methylation and histone deacetylase inhibitors respectively that in combination exert antitumor effects by their own and potentate the effect of chemotherapy. Methods: Open label two-stage design phase II trial to evaluate safety and efficacy of hydralazine and magnesium valproate plus chemotherapy in terms of pathologic complete response as neoadjuvant treatment. A total of 42 patients will be accrued. Untreated patients with histological confirmation of breast cancer in clinical stage IIb-IIIa, and hematological, renal and hepatic normal function are elegible. Patients with any collagen disease and any cardiovascular condition were excluded. Treatment consisted on four 21-day courses of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 plus epigenetic therapy starting 7 days before the first cycle of chemotherapy and continued until the end of chemotherapy. Oral hydralazine dosed according to acetylator phenotype and magnesium valproate at 30mg/Kg. After chemotherapy patients were evaluated with mammography and then submitted to surgical resection. Results: 17 patients in the first-stage have been accrued. Their characteristics are as follows: Median age 45-y (39–67), 67% were stage IIIa, median size of tumor was 5 cm (3–10 cm). All patients had clinically positive axillary nodes, with median size of 2 cm (1–5 cm), 80% were ductal carcinomas and 80% had either intermediate or high grade; 77% were ER-positive and 30% over-expressed HER2. Hematological toxicity was the most common side effect, neutropenia grade 3/4 was found in 35% of cases, anemia grade 3/4 was present in 15% of cases and most presented transient grade 2 depressed level of consciousness. Seven patients have completed planned treatment, clinical responses were CR 2, PR 4 and SD 1; in 1 of 7 a pathological complete response was seen. Conclusions: Epigenetic therapy with hydralazine and magnesium valproate associated to conventional chemotherapy is well tolerated. Its antitumor efficacy is pending to evaluate.

No significant financial relationships to disclose.
Interim analysis of phase I trial of 17-DMAG
Authors: Cartwright E. P. , Kummar S. , Muir C. A. , Ivy P. , Conley B. A. , Scripture C. D. , Figg W. D. , Murgo A. J. , Doroshow J. H. , Gutierrez M. E.
Published: March 2020

13148

Background: 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin (17-DMAG) binds specifically to heat-shock protein 90, leading to degradation of oncogene client proteins, inhibiting tumor growth. Based on in vitro/in vivo data, 17-DMAG has potent antitumor activity. Methods: 17-DMAG was administered by 1–2 hour infusion twice weekly for 4 weeks/cycle. Eligibility criteria included: solid tumor or lymphoma, ECOG ≤ 2 and adequate organ function. Exclusion criteria: brain metastases, pregnancy, prolonged QTc, or uncontrolled illness. Accelerated titration escalation design, one patient/cohort enters until a single patient experiences dose-limiting toxicity (DLT) or two patients exhibit grade ≥ 2 (G2) toxicity (except nausea / vomiting) during the first cycle. The maximum tolerable dose (MTD) is the dose level at which no more than 1/6 patients experience DLT and the dose below that at which at least 2/6 patients have DLT. Primary objectives: to determine the toxicity profile, and MTD of twice weekly 17-DMAG. Secondary endpoints: pharmacokinetics (PK) and pharmacodynamics of 17-DMAG. PK were determined by LC-MS on blood samples collected before and serially up to 48 hours after 17-DMAG infusion. Results: 6 patients (one patient per dose level) with the following diagnoses were accrued and treated: renal cell, pancreatic, medullary thyroid, NSCLC, and two colorectal cancers. The DLT and MTD have not yet been achieved. 17-DMAG toxicities have been acceptable, nausea/vomiting being the most common toxicity observed. Three patients developed G1 nausea, one patient had G3 nausea. Two patients had G2 vomiting. Other G1 toxicities included: diarrhea, weight loss, fatigue, elevated transaminases, hair loss, and leukocytopenia. PK results showed significant intra-patient variability as the dose was increased from 1–12 mg/m2 over 6 dose levels; the mean AUC increased from 370–970 ng*hr/mL, and the mean Cmax increased from 36–79 ng/mL. There was a 5-fold range in clearance (range: 6.5–33.1 L/h), but there was no association between dose and clearance. Following a single dose, the terminal phase half-life ranged from 16.4 - 24.3 hours. Conclusions: Since the DLT and MTD have not been reached, accrual will continue.

No significant financial relationships to disclose.
Early prediction of response in patients with advanced/metastatic non-small cell lung cancer during chemotherapy with FDG-PET-CT
Authors: Lee D. , Kim S. , Kim H. , Choo J. , Song J. , Han J. , Kim H. , Lee J.
Published: March 2020

13154

Background: To evaluate the use of 18-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) for prediction of response and survival early during the course of treatment in patients with advanced/metastatic NSCLC. Methods: Between May 2004 and November 2005, 31 patients (gender, 23M, 8F; stage, 2IIIB/29IV, histology, 6 squamous cell ca, 22 adenoca, 3 NOS; age median 57 (30–73 y)) with histopathologically proven NSCLC stage IIIB/IV were enrolled into this study. PET-CT was performed prior to and after one cycle of treatment. Early changes of primary tumor FDG-uptake measured by standardized uptake values (SUV) were correlated with best response to therapy as assessed by CT scan according to WHO response criteria. Results: Patients underwent standard treatment with gemcitabine/vinorelbine (15), gemcitabine/cisplatin (1) gemcitabine/vinorelbine/cisplatin (1), irinotecan/cisplatin (9) or gefitinib (5). In the 25 patients evaluable for response, other 6 patients ongoing, 9 patients achieved a partial response (36%), 5 showed stable diseases and 11 were progressive. Using a cut-off value of 20% reduction of FDG-uptake as a criterion for a response in PET-CT, subsequent best response was predicted with a sensitivity of 88.9% and a specificity of 87.5%. The positive predictive value of a metabolic response was 80.0% and the negative predictive value 93.3%, respectively. There was a significant correlation between the decrease of tumor metabolic activity and subsequent best response (p< 0.001). The median time to progression for PET-CT responder was 10.1 months when compared with that of non-responders with 2.6 months (log-rank p=0.009). Conclusions: Using FDG-PET best response to standard treatment and patient outcome can be predicted very early and therefore, the use of PET-CT may allow to reduce side effects and costs of ineffective therapy in non-responding patients

No significant financial relationships to disclose.
Predictive markers for the treatment of colorectal cancer with cetuximab
Authors: Razis E. , Briasoulis E. , Kostopoulos I. , Bobos M. , Christodoulou C. , Papamichael D. , Rigatos S. K. , Papakostas P. , Kosmidis P. , Fountzilas G.
Published: March 2020

13500

Background: Cetuximab is an anti-EGFR monoclonal antibody with activity in colorectal cancer. Patients most likely to benefit should be identified using molecular markers. Methods: A retrospective analysis was performed on patients treated with cetuximab who had paraffin embedded tissue available for testing. Tumor specimens were tested for EGFR (31G7, Zymed), PTEN (28H6, Novocastra) and pAkt 1/2/3 (Thr 308, Santa Cruz) expression by IHC. The EGFR gene status was investigated by FISH (Vysis). Results: Seventy-two patients were identified. EGFR expression was detected in 32/68 patients tested. PTEN was positive in all cases tested (64/64) and pAkt in 52 of 64 patients, in >70% of cells in 21/64 cases. Most patients were treated with cetuximab in various combinations, three patients received it as a single agent and 7 patients in more than one line of therapy. Median follow-up from diagnosis was 30.7 months and from Cetuximab initiation 6.9 months. Median survival from diagnosis has not been reached yet but from initiation of Cetuximab it is 13.6 months. 19 patients achieved a PR and 1 a CR. Most patients with PR were treated in first or second line however, 6 patients achieved a PR in 3rd line and 3 in subsequent lines. The patient with complete response, was treated in first line with CPT 11 and Cetuximab. TTP was 7.4 months for patients treated with Cetuximab in 1st line, 7.5 in 2nd line and 5.3 in 3rd line. Survival did not correlate significantly with any of the immunohistochemically assessed parameters. TTP correlated significantly with pAkt overexpression for patients treated in 3rd line (p=0.0065). The CR was seen in the only patient with EGFR amplification.The presence of skin toxicity did not correlate with response to therapy. Conclusions: Overexpression of pAkt may correlate with response to Cetuximab in colorectal cancer.

No significant financial relationships to disclose.
TGFalfa, EGFR and p70S6K expression in aggressive colorectal cancer (CRC)
Authors: Tampellini M. , Longo M. , Cappia S. , Bacillo E. , Brizzi M. , Bitossi R. , Sculli C. M. , Alabiso I. , Dogliotti L. , Papotti M.
Published: March 2020

13505

Background: Autocrine TGFa in CRC cells regulates cell adhesion via p70S6K phosphorylation in in vitro studies. The aim was to evaluate whether TGFa expression might be correlated with a higher metastatic behavior in vivo. Methods: 101 primitive CRC tumor samples with paraffin blocks available were retrospectively collected. All the specimens were immunohistochemically evaluated for EGFR clone 2–18C9 (Dako), and TGFa clone 213–4 (Calciochem) expression. A score of 0 to 3 was assigned according to staining intensity and extension. EGFR was also evaluated in randomly selected specimens with clone 111.6 (Neomarks) in 81 cases and clone 31G7 (Zymed) in 28 cases. Selected samples were stained for downstream signalling molecules STAT, p-akt, p-MAP kinase, mTor, p-mTor and p70S6K. Patients were divided into 2 groups according to tumor stage at diagnosis: group A stage II-III (51 pts); group B stage IV (50 pts). Results: EGFR clone 2–18C9 reacted in 68/101 (67.3%) cases. Positivity rates and correlation coefficients were: clone 111.6 42/81 (51.9%), r=0.54 (p<0.01); clone 31G7 20/28 (71.4%), r=0.76 (p<0.0001). TGFa was expressed in 79/101 (78.2%) cases. EGFR and TGFa diffuse staining (score 2, 3) was recorded in 14/51 (27.5%) and 18/51 (35.3%) patients in group A, and 26/50 (52.0%) and 27/50 (54.0%) in group B (p=0.01 and p=0.06). EGFR and TGFa coexpression was evident in 23/51 (45.1%) in group A and in 34/50 (68.0%) in group B (p=0.02). No difference in downstream signaling molecule expression was evident between the 2 groups. A positive correlation trend was recorded for p70S6K which was expressed in 8/20 (40%) and in 8/12 (66.7%) samples of group A and B (p=0.15). Conclusions: EGFR, TGFa and p70S6K expression was more common in patients with advanced stage at diagnosis confirming in vitro data. EGFR scores obtained with commercial antibodies from Zymed and Dako had a significant correlation.

No significant financial relationships to disclose.
Prognostic value of pathological nodal status and tumor regression grade in patients with rectal cancer (RC) treated with pre-operative chemoradiotherapy
Authors: Bertolini F. , Iachetta F. , Giacobazzi P. , Depenni R. , Zironi S. , Bertoni F. , Frassoldati A. , Luppi G. , Conte P.
Published: March 2020

13524

Background: The main objective of this study is to clarify the correlation between pathological nodal status and Dworak tumor regression grade (TRG) (Dworak et al. Int Colorectal Dis 1997, 12:19–23) after pre-operative chemoradiotherapy. Methods: From May 1998 to February 2005, 112 patients with locally advanced rectal cancer were diagnosed at Centro Oncologico Modenese and treated with pre-operative concomitant pelvic irradiation (50 Gy in 25 fractions) and chemotherapy with 5-FU in continuous infusion (225 mg/msq/daily). We considered for our analysis only pathological stage III cases. Results: Clinical positive nodal status (by CT scan or ultrasonography) was present in 71 patients on 106 (66.9%) at diagnosis. Among all radically resected patients (106), pathologic assessment of lymph nodes in surgical specimens was performed; average number of nodes examined was 11 (range: 2–22). Thirty patients (28.3%) had a positive nodal status at pathological examination: 19 (63.3%) were pN1 (≤3 lymph nodes) and 11 (36.7%) were pN2 (>3). The nodal status changed from 66.9% (clinical evaluation) to 28.3% (pathologic evaluation). Among stage III patients 5 (16.7%) had a TRG 3, 12 (40%) TRG 2, 11 (36.7%) TRG 1 and 2 (6.6%) TRG 0. At a median follow-up of 32,3 months, 20/106 patients relapsed (18.8%); of these 20, 10 (50%) had a positive pathologic nodal status. In this subset recurrence occurred in 5/10 (50%) pN1 patients (1 local and 4 with distant metastases) and 5/10 (50%) pN2 patients (2 local and 3 with distant metastases). The 3-y DFS was 63% (68% pN1 and 54% pN2) (p=0.32). The 3-y OS was 84% (94% pN1 and 68% pN2, p=0.72). The 3-y DFS in post-operative stage III patients according to tumor regression grade was 81% for TRG 2–3 and 38% TRG 0–1 (p<0.026). Conclusions: In stage III patients, TRG is confirmed as a relevant prognostic factor in locally advanced rectal cancer treated with neo-adjuvant chemo-radiotherapy. In the same subset of patients the number of positive nodes seems to impact on the prognosis, even not reaching a significant relevance.

No significant financial relationships to disclose.