bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimizing targeted agents development in pancreatic cancer: A fine-needle aspirate biopsy (FNAB) based ex vivo and in vivo assay
Authors: Rubio-Viqueira B. , Mezzadra H. , Iacobuzio-Donahue C. , Jimeno A. , Zhang X. , Maitra A. , Altiok S. , Hidalgo M. 
Published: March 2020

3002 Background: While targeted therapeutics effectively inhibit tumor growth with less toxicity than conventional chemotherapy, in general cancer patients show highly variable responses to them. This study aimed to develop and validate methods that permit the prediction and assessment of the efficacy of targeted therapeutics by using tumor fine needle aspiration biopsy (FNAB) samples Methods: A series of human primary pancreatic cancer were xenografted in nude mice by implanting tumor materials from surgically resected pancreatic cancer patients. Animals were treated with an epidermal growth factor receptor (EGFR) inhibitor, erlotinib, and the mTOR inhibitor temsirolimus or vehicle. Tumors were sampled by FNAB prior to (baseline) and after therapy. Tumor cells obtained by FNAB at baseline were exposed to erlotinib or temsirolimus for six hours ex vivo to prospectively predict tumor response. The degree of inhibition in phosphorylation of ERK1/2 and S6-Ribosomal Protein (S6-RP) downstream to EGFR and mTOR, respectively, were assessed by Western blot to determine the efficacy of the targeted drugs ex vivo and in vivo. The results were correlated with drug-mediated changes in tumor volumes. The effect of drugs on protein phosphorylation ex vivo was also analyzed in patient FNAB samples to show the clinical feasibility of the approach. Results: The degree of inhibition of target pathway activity in tumor cells treated with erlotinib or temsirolimus ex vivo closely correlates with tumor sensitivity in vivo. Xenograft animals sensitive to therapy showed the highest average inhibition of target protein phosphorylation in ex vivo assays, whereas tumors resistant to drugs gave the lowest one. Patient tumor samples yielded adequately cellular material to analyze the effect of erlotinib and temsirolimus in ex vivo assays. Conclusions: FNAB can be used to test ex vivo tumor response to targeted agents. These effects predicted pharmacodynamic as well as antitumor effects in a serie of pancreatic cancer xenografts. Implementation of these novel methods in clinical trials may be useful to identify patients that are likely to benefit from targeted therapeutics before being exposed to drugs and their potential side effects. No significant financial relationships to disclose.
Enzymatically-targeted 131I therapy for herpesvirus-associated malignancies
Authors: Fu D. , Lemas V. , Foss C. , Fox J. , Pomper M. , Ambinder R. F. 
Published: March 2020

3010 Background: Epstein-Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV) are associated with tumors including AIDS-related lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma and Kaposi’s sarcoma. Both viruses encode kinases that selectively phosphorylate nucleoside analogs such as ganciclovir and FIAU. We hypothesized that it might be possible to use the viral enzymes to specifically concentrate 131I-FIAU in tumor cells harboring virus and thus deliver therapeutic radiation. Bortezomib is a potent stimulator of viral kinase expression in gammaherpesvirus tumor cell lines. Methods: We evaluated the effect of 131I-FIAU on human cancer xenografts in SCID mice. These included a tumor line engineered to constitutively express the EBV thymidine kinase (EBVTK), and a control engineered with a sham vector (SHAM), as well 2 EBV(+) Burkitt’s lymphoma (BL) lines, and 1 KSHV(+) primary effusion lymphoma (PEL) cell line. Mice were treated with buffer, bortezomib 2 ug/gm, or I-FIAU, or I-FIAU and bortezomib in combination. For imaging, mice, 125I -FIAU and SPECT were used. For therapy, 131I-FIAU was used and tumor dimensions were monitored with calipers. Results: Treatment with buffer had no effect on on 3 EBVTK tumors and 3 SHAM tumors all of which increased in volume. Treatment with 1.4 mCi 131I-FIAU alone led to tumor responses (>90% volume reduction at 10 days) in 3/3 mice with EBVTK tumors and 0/3 mice with SHAM tumors. Treatment with 131I-FIAU alone had no effect on BL (0/3) or PEL (0/9) xenografts and all tumors increased in volume. Treatment with bortezomib induced modest responses in all tumors but had no greater effect on EBVTK tumors than SHAM tumors. However, treatment with bortezomib and 131I-FIAU led to marked tumor regression (>95%) in each of the virus-associated tumors (3/3 BL, 9/9 PEL). SPECT imaging with 125I-FIAU showed selective concentration of radiolabel in tumor tissue in the EBVTK tumor (2/2) and in viral tumors (6/6) when bortezomib was administered. There was no selective concentration in the absence of bortezomib treatment in the viral tumors (0/8). Conclusions: Treatment with bortezomib leads to selective concentration of labeled FIAU in the herpesvirus-associated tumor xenografts evaluated and to regression of tumor when the isotope is 131I. No significant financial relationships to disclose.
A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with advanced solid tumours
Authors: Shaw H. , Plummer R. , Vidal L. , Perrett R. , Pilkington M. , Temple G. , Fong P. , Amelsberg A. , Calvert H. , De Bono J. 
Published: March 2020

3027 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: Patients (pts) with advanced solid malignancies were enrolled. BIBW 2992 was given orally as a continuous once daily dose from 10 mg, doubled in successive cohorts until drug-related toxicity > grade 2, when escalation of no more than 50% was allowed. All pts had pharmacokinetic sampling and pre- and post-treatment skin biopsies. DNA sequencing of tumour cell EGFR and HER2 was performed on pts achieving objective response. Results: Twenty-six pts were treated (14 M/11 F). Median age: 53 (range: 30–68). ECOG PS 0/1: 7/19. 19 pts completing ≥ 28 days were evaluable for adverse events (AEs). Three dose-limiting toxicities (DLT) were seen. One pt with HER2+ breast cancer who had previously received trastuzumab and lapatinib treated at 30 mg of BIBW 2992 developed dyspnoea with radiological interstitial changes, which fully recovered on drug discontinuation. The 2 other DLTs were grade 3 acneiform skin rash, at doses of 40 mg and 50 mg daily. AEs resolved on drug discontinuation and the pts were dose reduced to 30 mg and 40 mg, respectively. The 50 mg dose level is being expanded. One pt treated at 50mg developed grade 3 diarrhoea in cycle 2 and was dose reduced to 40mg with resolution of the AE. Other AEs were mild (CTCAE v3 grade 1 or 2); nausea, diarrhoea, mucositis and fatigue. Two female pts with lung adenocarcinoma treated with 10 mg and 40 mg daily had confirmed partial responses (PR) and remain on study after 14 and 5 months, respectively. The pt with PR at 10mg has a complex heterozygous EGFR mutation in tumour cells, including a deletion and missense mutations of 4-amino acids (WT: KELREATSPKANKEILD; Patient: KEP—-SPRANKEILD) in the kinase domain, but a wildtype HER2 domain. One pt with cervical and one pt with colorectal cancer had stabilization of disease and tumour markers for 6 and 4 months, respectively. Conclusions: BIBW 2992 shows promising activity with skin rash as the main AE. Maintained PR seen in lung adenocarcinoma indicates effective mutated EGFR kinase modulation at the lowest evaluated dose level. Exploration of BIBW 2992 in Phase II is warranted. [Table: see text]
Topical vitamin K3 (Vit K3, Menadione) prevents erlotinib and cetuximab-induced EGFR inhibition in the skin
Authors: Perez-Soler R. , Zou Y. , Li T. , Tornos C. , Ling Y. 
Published: March 2020

3036 Background: The EGFR inhibitors erlotinib and cetuximab cause skin toxicity in about 75% of patients. The occurrence of skin toxicity correlates with clinical benefit. About half the patients with skin toxicity report significant discomfort. There are currently no scientifically based or proven methods for preventing or treating effectively the skin toxicity secondary to EGFR inhibitors. Methods: We screened a number of EGFR activators and phosphatase inhibitors for their ability to abrogate EGFR inhibition secondary to erlotinib and cetuximab in A431 cells. P-EGFR expression was assessed by western blot analysis. Vit K3 was selected for further in vivo studies. The skin toxicity secondary to the topical application of Vit K3 was evaluated in nude mice. The highest non-toxic concentration was used to determine the ability of topical Vit K3 to prevent EGFR inhibition in the skin of nude mice treated with EGFR inhibitors. Results: Vit K3 was the most potent EGFR activator identified, the maximum effect being observed at concentrations of 0.1–0.5 mM. In the presence of erlotinib or cetuximab, 0.1- 0.5 mM Vit K3 completely prevented EGFR inhibition. The maximum non-toxic concentration of Vit K3 applied topically BID × 10 days to nude mice was 15 mM. At this concentration, topical Vit K3 caused P-EGFR upregulation in the skin. In animals treated with erlotinib (100 mg/kg daily × 5 days), there was no detectable P-EGFR expression in the skin not treated with topical Vit K3 whereas P-EGFR expression was completely restored in the skin treated BID x 5 days with topical Vit K3. Conclusions: Vit K3 is one of the first reported agents to prevent/reverse EGFR inhibition secondary to anti-EGFR agents. The results strongly justify the development of a topical formulation of Vit K3 to treat and prevent the cutaneous toxicity secondary to EGFR inhibitors. [Table: see text]
Toxicity results and early outcome data on a randomized phase II study of docetaxel ± bevacizumab for locally advanced, unresectable breast cancer
Authors: Lyons J. A. , Silverman P. , Remick S. , Chen H. , Leeming R. , Shenk R. , Fu P. , Dumadag L. , Escuro K. , Overmoyer B. 
Published: March 2020

3049 Background: Preclinical models of combination angiogenesis inhibitor bevacizumab (rhuMAbVEGF) and docetaxel demonstrate synergistic suppression of capillary vessel formation. Based upon these data, we developed a randomized phase II trial in order to evaluate the vascular effects on tumor regression with combination bevacizumab/docetaxel vs. docetaxel in the treatment of locally advanced breast cancer. Methods: 49 patients (pts) were randomized to receive neoadjuvant therapy with bevacizumab (10 mg/kg qowk) and docetaxel (two 8-week cycles of 35 mg/m2 weekly x 6 with a 2 wk break) (BD=24) or docetaxel (D=25) alone. Eligible pts had locally unresectable breast cancer with (n=6) or without distant metastasis (n=43); 16 patients presented with inflammatory breast cancer. Pts whose disease responded, sequentially underwent definitive surgery (4 weeks after BD or D), radiation, 4 cycles of conventional Adriamycin/cyclophosphamide, and tamoxifen or anastrazole (if ER/PR+). Results: Among the 49 pts: 7 clinical CRs, 32 PRs, 5 NR, and 5 PD. Of the 37 pts who underwent surgery: the median number of pathologically positive lymph nodes (LN) was 1 (BD=6, D=1; p=0.228); range 0–20; 43% were LN negative. Neoadjuvant treatment toxicity for both arms was acceptable with no significant differences between the two arms. Grade 4 toxicity included BD - new papillary thyroid cancer (1), neutropenia (1), hyperuricemia (1) and colon perforation (1); and D: - hyperglycemia (1) and hyperuricemia (1). 21 patients in each arm experienced a grade 3 toxicity. There were no episodes of uncontrolled hypertension, proteinuria, or thrombosis. Delayed wound healing (unable to start radiation w/in 6 weeks of surgery) occurred in 8 pts: BD=5; D=3 (p=0.691). Only 1 pt (D) experienced a change in LVEF by > 15% or below the institution’s lower limit of normal. Conclusions: Neoadjuvant therapy for locally advanced breast cancer using docetaxel with bevacizumab is well tolerated. Further studies are required to determine the added efficacy from bevacizumab. Correlative studies on impact of treatment on angiogenesis will be reported separately. (Sponsored by grants: K23CA 87725–01, M01 RR 00080, UO1 CA 62502, 5P30 CA43703-NCI/AVON, Aventis) No significant financial relationships to disclose.
A phase I study of reolysin given intravenously to patients with advanced malignancies
Authors: Vidal L. , Pandha H. , Spicer J. , Harrington K. J. , Allen S. , Leader D. , Coffey M. , Thompson B. , Kaye S. , De-Bono J. 
Published: March 2020

3064 Background: Reovirus is a double-stranded RNA virus with minimal pathogenicity in humans that selectively replicates in cells with activated Ras. Activated Ras inhibits the anti-viral effects of double stranded RNA-activated protein kinase (PKR). Reovirus serotype 3 Dearing has selective antitumor activity, in vitro and in tumour xenograft models. Methods: Reolysin was administered as a 1-hr IV infusion every 4-weeks initially for one day; then 3 days then 5-days every 4 weeks. The starting dose was 1×108 tissue culture infectious dose (TCID50) increasing in successive cohorts until observation of drug-related toxicity ≥ grade 2. Endpoints were safety, viral replication, viral shedding, evaluation of immune response and antitumor activity. Results: 24 patients (pts) (median age 60; ECOG 1, 16 males) have been entered into the first 7 cohorts at the following dose levels: 1×108 for 1-day, 1×108 for 3-days and 1×108, 3×108, 1×109, 3×109 and 1×1010 TCID50 for 5-days. A maximum tolerated dose (MTD) has not been reached and no dose-limiting toxicities have been observed. Toxicities have been mild (grade 1 or 2) and have included chills, fever, headache, runny nose, fatigue and myelosuppression. Reverse transcription polymerase chain reaction (RT-PCR) studies of blood, urine, stool and sputum post reovirus administration were negative for viral shedding for all treated pts. All but one pt had neutralising anti-reovirus antibodies detectable pre-treatment. Titres increased after 1-week of treatment and remained high during subsequent courses of treatment. Two pts with metastatic colorectal cancer treated at 3×108 and 3×109 TCID50 had CEA tumour marker reduction by 60% and 27% receiving 6 and 3 courses of treatment respectively. One pt with metastatic pancreatic cancer received 4 courses of treatment with stable disease. One pt with metastatic prostate cancer had a 50% decrease in PSA after treatment at 3×109 TCID50, with evidence of tumor necrosis on CT scanning. Intratumoral reovirus replication has been detected by electron microscopy in tumur biopsies. Conclusions: Reolysin is well tolerated with minimal toxicity. No viral shedding has been detected. Virus-induced tumor necrosis associated with intratumor viral replication after systemic delivery has been observed. [Table: see text]
Phase I study of intravenous CCI-779 in combination with bryostatin-1 in solid tumors
Authors: Haas N. B. , Lewis N. , Cohen R. B. , Malizzia L. , Einarson M. B. , Walker M. A. , Kim T. , Von Mehren M. , Hudes G. R. 
Published: March 2020

3067 Background: mTOR regulates translation of messenger RNA critical for angiogenesis and cell growth. CCI-779 inhibits mTOR signaling through p70S6 kinase (S6K), which phosphorylates the ribosomal S6 protein (S6). CCI-779 is active in renal carcinoma (RCC) and other solid tumors. Based on our finding that bryostatin-1 (bryo) inhibits S6K, and that CCI-779 + Bryo additively inhibit S6K and RCC growth in vitro, we initiated a phase I trial to determine the maximum tolerable (MTD) doses and dose-limiting toxicities of this novel combination in patients with solid tumors. Methods: Bryo (20 μg/m2) was administered over 60 minutes IV followed by CCI-779 (10 and 15 mg, planned escalation to 75 mg) IV over 30 minutes, both weekly for 3 of 4 weeks. Serum and peripheral blood mononuclear cell (PBMC) samples were collected for analysis of pharmacokinetics and markers of mTOR inhibition (phospho-S6 and p21waf1). Results: Nine patients (median age 57, 6 RCC, 2 sarcoma and 1 neuroendocrine) are evaluable for toxicity (total cycles=27 cycles, median 4, range 1–7) at the initial 2 dose levels (Bryo 20 μg/m2, CCI-779 10 mg and 15 mg). Cycle 1 toxicity includes grade 3 hypophosphatemia and myelosuppression in one patient each and grade 2 fatigue, stomatitis, and anemia. One patient developed reversible grade 3 pneumonitis after 7 cycles. Of 7 patients with therapy-resistant disease, 5 (4 RCC and 1 sarcoma) had stable disease lasting up to 7 months. A therapy-naive patient with RCC has 23% tumor reduction after 2 cycles at dose level 2 (CCI-779=15 mg). PBMC proteins from 5 patients show consistent decreases in phospho-S6 at 2–6 hours-post treatment compared with pre-treatment baseline measurement, with recovery by 24–72 hours after dosing. In parallel with inhibition of phosphorylation of S6, PBMC levels of p21waf1 were completely inhibited in all 5 patients. Conclusions: The combination of bryo and CCI-779 is feasible, with antitumor activity in RCC and mTOR pathway inhibition observed at submaximal doses. Dose escalation is continuing. No significant financial relationships to disclose.
Phase I study of BAY 57–9352, a VEGFR-2 inhibitor, in cycles of 14 days on/7 days off in patients with advanced solid tumors
Authors: Strumberg D. , Mross K. , Scheulen M. , Frost A. , Hedbom S. , Rajagopalan P. , Voliotis D. , Wensing G. , Christensen O. 
Published: March 2020

3089 Background: BAY 57–9352 (BAY) inhibits the VEGFR-2 and VEGFR-3 tyrosine kinases, in addition to PDGFR-β and c-kit. BAY showed anti-tumor activity in colon, breast, pancreatic, and NSCLC preclinical models. Methods: This study investigated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of oral BAY in 14 days on/7 days off treatment cycles until discontinuation due to toxicity or progression. PK was assessed on days 1 and 14 of cycle 1. Dynamic contrast-enhanced MRI (DCE-MRI) was performed at baseline and in cycles 1–3. Plasma biomarkers (VEGF, sVEGFR-2) were assessed at each cycle. Results: 77 patients (pts) were enrolled at doses from 20 mg once daily to 1500 mg twice daily (bid). Common tumor types were CRC (31%) and RCC (16%). Frequent drug-related adverse events (≥5% pts) were hypertension (all grades, 11 pts [14%]; grade 3, 10 [13%]), hoarseness (10 [13%], only grade 1/2), anorexia (7 [9%], only grade 1/2), myalgia (6 [8%], only grade 1/2), fatigue (5 [6%], only grade 1/2), and diarrhea (all grades, 4 [5%]; grade 3, 1 [1%]). Hypertension in cycle 1 caused a dose reduction/interruption in 3 pts. One pt had diarrhea in cycle 7 requiring a dose reduction. One pt discontinued due to fatigue in cycle 8. BAY AUC increased dose-proportionally up to 900 mg bid. As measured by DCE-MRI, pts with CRC showed the greatest decrease in iAUC60 of Gd-DTPA, a parameter related to tumor blood flow and permeability. One pt with RCC achieved a partial response (PR); another had significant tumor shrinkage not reaching formal criteria (RECIST) for PR. PD responses (VEGF and sVEGFR-2 levels) increased in a dose-dependent manner up to 900 mg bid. Conclusions: The MTD was not reached for BAY up to 1500 mg bid in a 14 days on/7 days off schedule. BAY had a favorable safety profile. Tumor efficacy was shown in individual patients. The PD effect of BAY was demonstrated by DCE-MRI and plasma biomarkers. The recommended dose for Phase II evaluations is 900 mg bid. [Table: see text]
Evaluation of gefitinib biological effects in patients with solid tumors amenable to sequential biopsies—Final results
Authors: Kulesza P. , Brahmer J. R. , Jimeno A. , Baker S. D. , Spitz A. , Li J. , Rudek M. A. , Messersmith W. A. , Hidalgo M. 
Published: March 2020

3090 Background: Biological effects of gefitinib are not well understood. The goals of this study are to assess the effects of gefitinib on EGFR signaling pathways in tumor and normal tissue, as well as the relationship between pharmacologic and pharmacodynamic (PD) endpoints. Methods: Patients (pts) with a diagnosis of a solid tumor and amenable to serial biopsies received gefitinib in two sequential cohorts of 12 pts each at doses of 250 or 500 mg orally once a day. Biopsies of tumor and skin as well as plasma and oral buccal swabs were collected at baseline and 28 days after treatment for correlative studies. Plasma samples for pharmacokinetic studies were obtained on d1 (from 0–8h), and pre-treatment trough samples were obtained on d2, d3, d8, d15, d22, and d28 of cycle 1. Treatment was continued unless severe drug related toxicity developed or until disease progression. Results: 27 pts (15 M/12F; median age of 61, range 29–77) were treated (13 on 250 mg and 14 on 500 mg). Three pts withdrew prior to d28 biopsy. One pt with metastatic squamous cell skin cancer had a partial response (PR). Of the 4 pts with stable disease (SD) (2-carcinoid, 1-lung, 1-renal), the median time on study was 6 mo (range 3–7 mo). Grade 1–3 toxicities included rash, diarrhea, nausea, anorexia, and fatigue. Plasma exposure to gefitinib was highly variable. At 250 mg, gefitinib average pre-treatment trough concentrations (Css,min) during 28 days of treatment varied 19-fold (mean, 406 ng/ml; range, 104 to 1846 ng/ml); at 500 mg, Css,min varied 11-fold (mean, 502 ng/ml; range, 145 to 1590 ng/ml). Quantitative immunohistochemical staining revealed a correlation between a lower baseline level of tumor Ki-67 and benefit from treatment (PR + SD) (p=0.048). While the change in tumor pMAPK staining (change from baseline) was not different between the two dose levels, Ki-67 change trended greater in the pts on the 500 mg dose (p=0.06). Change from baseline in pMAPK correlated with the development of diarrhea (p=0.03). EGFR (CA) repeat polymorphism length was not related to treatment benefit, toxicity, or changes in pMAPK or Ki-67. Conclusions: The preliminary PD findings are provocative. Further testing of tumor and normal tissues is ongoing. [Table: see text]
OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study
Authors: Maindrault-Goebel F. , Lledo G. , Chibaudel B. , Mineur L. , Andre T. , Bennamoun M. , Mabro M. , Artru P. , Louvet C. , De Gramont A. 
Published: March 2020

3504 Background: The OPTIMOX1 study (JCO 2006) has shown that the strategy of 6 cycles of FOLFOX7 followed by maintenance therapy and FOLFOX reintroduction was as active and better tolerated than FOLFOX4 until progression. The aim of the OPTIMOX2 study was to evaluate a complete stop of chemotherapy after 6 bimonthly cycles of FOLFOX. Methods: Initially planned as a phase III study, OPTIMOX2 was downgraded to a large phase II study since the availability of bevacizumab. Patients (pts) were randomized between an OPTIMOX1 arm: 6 cycles of FOLFOX7 followed by LV5FU until progression and reintroduction of FOLFOX7, and the OPTIMOX2 arm: 6 cycles of FOLFOX7, complete stop of chemotherapy and reintroduction of FOLFOX7 before the tumor progression reached the baseline measures. Results: 187/200 planned pts were included between Feb 2004 and Nov 2005. Response rates were (OPTIMOX1 arm/OPTIMOX2 arm): CR 2%/2%, PR 54%/51%, stable 24%/33%, progression 11%/7%, non assessable 9%/7%. Median PFS were (OPTIMOX1 arm/OPTIMOX2 arm) 36/28 weeks (p=.01), PFS in responders 41/30 weeks (p=.001), PFS in stable patients 34/26 weeks (p=.23). Median duration of disease control (DDC), addition of PFS of first FOLFOX7 administration plus PFS of FOLFOX reintroduction if no progression at first evaluation, was 41 weeks in the OPTIMOX1 arm and 36 in the OPTIMOX2 arm, p=.17. Median duration of chemotherapy-free interval in the OPTIMOX2 arm was 25 weeks (5.7 months). Conclusions: Maintenance LV5FU therapy prolongs PFS. The quality of life of almost 6 months CFI can balance a small advantage in DDC for maintenance therapy. Our next goal is to evaluate maintenance therapy with targeted agents alone. [Table: see text]