bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of circulating tumor cell (CTC) patterns among disease-free breast cancer patients vaccinated with a preventive HER2/neu E75-peptide vaccine
Authors: Amin A. , Stojadinovic A. , Holmes J. P. , Storrer C. E. , Smith A. M. , Jama Y. H. , Craig D. , Ponniah S. , Peoples G. E. 
Published: March 2020

3059 Background: The quantity of CTC and post-treatment reduction predict outcome in medically treated metastatic breast cancer patients (BCa); however, the impact on survival of CTC in patients at risk for recurrence rendered free of disease after multimodality treatment is unknown. We conducted a pilot study to assess CTC in clinically disease-free node-positive (NP) BCa patients, and to determine the effect on CTC of vaccination with the immunogenic HER2/neu peptide E75. Methods: The CellSearch System (Veridex, LLC Warren, NJ) was used to enumerate total CTC and HER2/neu+ CTC in 20 ml of blood from selected samples obtained from patients (n=16) throughout and after the E75 vaccination series. Standard prognostic factors were collected on these patients as were measures of their immunologic response to the vaccine. Results: 14/16 patients (88%) had at least 1 CTC and 10/16 (63%) had 2 or more CTC identified. Standard clinical prognostic factors (tumor size, grade, lymph nodes and HER2/neu overexpression) did not correlate with number of CTC. Thus far, 9 patients have had multiple samples collected prior to, during and/or after the vaccine series. Early levels of CTC were significantly higher (mean±SE=5.2±0.5) vs. post-vaccination levels (0.3±0.1, p=0.005). Levels of HER2/neu+ CTC were also significantly different (early 3.4±0.3 vs. post 0.4±0.1, p=0.01). All patients showed a decline in CTC from early to post levels while demonstrating HER2/neu immunity as measured by DTH to the E75 peptide post- vaccination (22.9±1.8 mm vs. control 4±0.9 mm, p=0.006). Conclusions: CTCs are readily demonstrated in clinically disease-free NP BCa patients. Prognostic indicators do not seem to correlate with the number of CTCs. CTCs decline during the course of vaccination. These data suggest a potential role for the CTC assay in assessing response to preventive vaccine-based immunotherapy. The views expressed in this abstract are those of the authors and do not necessarily reflect the official policy or position of the Departments of Army or Navy, Department of Defense or the U.S. Government. No significant financial relationships to disclose.
Cytotoxicity of bevacizumab is enhanced by β-glucan in tumors expressing membrane-bound VEGF
Authors: Salvador C. , Li B. , Hansen R. , Cramer D. , Yan J. 
Published: March 2020

3060 Background: Bevacizumab (B-Mab) is a murine-derived monoclonal antibody with human IgG1 framework against vascular endothelial growth factor (VEGF). Soluble PGG β -glucan functions with complement activation product iC3b to activate complement receptor 3 (CR3) and recruit neutrophils and macrophages leading to CR3 (iC3b-receptor)-dependent cytotoxicity of tumors coated with iC3b. In mouse xenograft models, PGG β-glucan has a synergistic effect with human anti-tumor antibodies. Consequently, we hypothesized that the IgG1 antibody B-Mab is capable of binding surface VEGF (sVEGF) on tumor cells thereby activating complement, and synergizing with PGG β-glucan to elicit CR3-dependent cytotoxicity. Methods: SCID mouse xenografts with SKOV-3 human ovarian carcinoma cells were established in groups treated intravenously as follows: PBS treated as control (C), PGG β-glucan alone (B), B-Mab alone (A) and combination PGG β-glucan + B-Mab (B+A), twice weekly for 4 weeks. After implantation, tumors were allowed to grow until they were 300 mm3 before treatment. Results: SKOV-3 tumors in SCID mice showed sVEGF expression and had a complement deposition after B-Mab treatment. In vitro CR3-dependent cytotoxicity assay of B-Mab alone and B-Mab plus active moiety of β-glucan resulted in 0.2% and 19% cytotoxicity respectively. Tumor-bearing SCID mice treated with combination (A+B) showed significant difference in tumor growth inhibition and long-term survival as compared to the other treated groups. Moreover, neutrophil infiltration was markedly increased in the combination (A+B) group compared to the other groups. Conclusions: We have shown that combination treatment with bevacizumab and β -glucan imparts synergistic tumor cytotoxicity that achieves growth inhibition of VEGF-expressing tumor in vivo. Combination therapy should be considered as a potential therapeutic approach in patients with sVEGF positive tumors. (Supported by NIH grant RO1 CA86412 and gift research fund from Biothera, Inc.) No significant financial relationships to disclose.
Phase I study of oral LBH589, a novel deacetylase (DAC) inhibitor in advanced solid tumors and non-hodgkin’s lymphoma
Authors: Prince H. M. , George D. , Patnaik A. , Mita M. , Dugan M. , Butterfoss D. , Masson E. , Culver K. W. , Burris H. A. , Beck J. 
Published: March 2020

3500 Background: LBH589 is a novel deacetylase inhibitor (DACi) which induces apoptosis of tumor cells at nanomolar levels. In this phase 1 study, we evaluated the safety and tolerability of LBH589 in pts with advanced solid tumors or non-hodgkins lymphoma. Methods: LBH589 was administered orally on Monday, Wednesday, and Friday (MWF) weekly. Western blots on peripheral blood lymphocytes were used to study histone acetylation (HA). Plasma PK profiles were analyzed on Days 1 and 15. Results: Thirty two pts have been treated (Median age 63 years; 18 M, 14 F). Pts received 15 mg (3), 30 mg (10), the dose-limiting toxicity level (DLT), or 20 mg (19), the maximum tolerated dose (MTD). Tumor types included: CTCL (10), renal cell (6), melanoma (6), prostate (4), hepatic (1), rhabodomyosarcoma (1), mesothelioma (1), colon (1), bladder (1), and parotid gland (1). Three DLTs were reported; G3 diarrhea and transient G4 thrombocytopenia at 30 mg and G3 fatigue at 20 mg. The most common adverse events were anorexia, nausea, fatigue, diarrhea and transient thrombocytopenia. Of the 1,057 ECGs, 1 pt (20 mg) had a QTcF of 503 msec, an isolated event after the first dose with no recurrence on continued therapy. The mean change in QTcF from baseline was < 10 msec during the first cycle in all cohorts. No increase in HA was seen at 15 mg, but did increase in 50% of pts at 72 hrs post dose in both the 20 mg and 30 mg cohorts. LBH589 was rapidly absorbed in plasma (Tmax 1.5 hr), then declined with a mean terminal half-life of 16 hrs. Cmax and AUC increased linearly with doses between 15–30 mg. Two cutaneous T- cell lymphoma (CTCL) pts achieved a complete response (5 and 7 months) and 4 CTCL pts attained a partial response (6.5, 8, 9 and 18+ months). Stable disease was achieved in 7 pts: CTCL-2 pts (2 and 3 months); RCC-2 pts (3.5 and 7 months); melanoma-1 pt (4 months), mesothelioma-1 pt (2.5 months) and parotid gland-1 pt (5 months). Fifteen pts progressed on treatment and 4 pts were not evaluable for response. Conclusions: At 20 mg MWF every week, LBH589 oral produced a sustained pharmacodynamic effect on HA for ≥72 hours post dose in 50% of pts. Cardiac data indicates no clinically-significant effect on QTcF. Preliminary evidence of tumor response was observed at this dose and schedule in CTCL pts. No significant financial relationships to disclose.
A phase 1b study of oral rapamycin (sirolimus) in patients with advanced malignancies
Authors: Ratain M. J. , Napoli K. L. , Moshier K.Knightley , Jiang X. , Fleming G. F. , Gajewski T. F. , Jacobsen E. , Cohen E. E. 
Published: March 2020

3510 Background: Rapamycin (R) analogues are being studied as cancer therapies since mTOR is recognized as a relevant target in several cancer types. However, R is readily available, has been well-studied in organ transplant patients, was the first recognized mTOR inhibitor, and demonstrates efficacy in preclinical cancer models. The aims of this study were to define R’s maximum tolerated dose (MTD), observed toxicities, dose-limiting toxicities (DLT), pharmacokinetics and effect on inhibition of phosphorylation of p70 S6 kinase (S6K) in peripheral T-cells (PTL). Methods: R was administered orally once weekly to successive cohorts of patients using an adaptive escalation design based on whole blood concentrations ([R]), using a validated HPLC procedure. S6K was assessed by stimulating CD3+ cells ex-vivo with PMA and ionomycin for 1 hour, followed by Western blot analysis using antibodies directed against phospho-Thr389 of S6K versus total S6K as a loading control. Results: 24 subjects have been enrolled in dose cohorts of 10 mg, 20 mg, 30 mg, and 60 mg. The mean [R] observed on day 2 of week 1 (24 hr after 1st dose) was 5.5±2.7, 11.6±6.0 and 22.6±10.7 ng/mL, for dose levels 10 mg, 20 mg and 30 mg, respectively. [R] decreased by ∼50% by day 4 of week 1 (2.7±1.0, 6.9±4.0 and 11.0±7.7 ng/mL, respectively). By day 1 of week 2 (prior to the next dose of R), [R] had decreased below the limit of quantitation (2 ng/mL) for all subjects at 10 mg, 3 of 7 at 20 mg, and 4 of 6 at 30 mg. Preliminary analysis suggests that sustained phospho-S6K inhibition was achieved in some patients at 30 mg. The most common toxicities observed included nausea (50%), diarrhea (42%), asthenia (38%), hyperglycemia (58%), anemia (46%), and lymphopenia (33%). DLTs observed include 1 patient with grade 3 pneumonia at 20 mg, 1 patient with grade 3 dehydration at 30 mg, and 1 patient with grade 3 asthenia at 60 mg. Stable disease has been observed in 46% of evaluable patients. Conclusions: R can be feasibly administered orally on a once weekly schedule with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors. Preliminary evidence suggests that prolonged suppression of phospho-S6K in PTL is possible at well-tolerated doses. No significant financial relationships to disclose.
A randomized phase II study of two different schedules of RAD001C in patients with recurrent/metastatic breast cancer
Authors: Ellard S. , Gelmon K. A. , Chia S. , Clemons M. , Kennecke H. , Norris B. , McIntosh L. , Seymour L. 
Published: March 2020

3513 Background: RAD001C exerts antiproliferative and antiangiogenic effects by mTOR (mammalian target of rapamycin) inhibition. mTOR is critical in the transduction of proliferative signals mediated via the PI3K/Akt pathway. This signal transduction pathway is relevant to HER2 and ER signaling, and in PTEN mutated tumors, thus mTOR may be a central and relevant factor in breast cancer. Methods: Multi-center randomized phase II study assessing two oral schedules of RAD001C: Arm A (A)_10 mg daily, or Arm B (B)_70 mg weekly, assessed clinically each 4 weeks, imaged each 8 weeks. Eligibility: Patients (pts) with measurable metastatic breast cancer (MBC) who may have received adjuvant chemotherapy (CT), with up to one prior CT for advanced/recurrent disease. Stratification factors: 0 or 1 prior CT for MBC; presence/absence of visceral metastases. Primary endpoint: clinical/radiologic response and early progression (<8 wks). Two-stage accrual design with 15 evaluable pts in each arm in first phase. If =1 response and <10 early PD, add 15 pts. Arm B was discontinued after stage 1 as no responses were seen. A higher than expected occurrence of pneumonitis (Pn) occurred in both arms, higher in arm A. Results: Median age was 60yrs, 32 pts had prior CT, 20 pts had liver metastases. The most common drug related toxicities were fatigue, rash, anorexia, diarrhea, stomatitis, cough and pneumonitis; pulmonary effects appeared schedule related. (See results table below) Conclusions: Daily oral RAD001C has activity in MBC. The final results of this randomized Phase II trial will provide data to plan future breast cancer trials of RAD001C. [Table: see text] [Table: see text]
Phase I trial of SU014813 in patients (pts) with advanced solid malignancies
Authors: Fiedler W. M. , Giaccone G. , Lasch P. , Van der Horst I. , Brega N. M. , Raber S. , Shalinsky D. , Ljubmir V. , Bokemeyer C. , Boven E. 
Published: March 2020

3521 Background: SU014813 is an oral multi-targeted small molecule RTK inhibitor of VEGFRs, PDGFRs, sKIT & FLT-3 at nM concentrations. This study was designed to determine the safety, PK, PD, & preliminary efficacy of SU014813. Methods: Cohorts of pts with (w/) relapsed or refractory solid tumors received oral SU014813 at 25, 50, 100, 150, 200, or 250 mg on a 4 wks on/1 wk off (4/1), or 100 or 150 mg on a continuous dose (CD) schedule. The MTD was defined as the highest dose at which 0 of 3 or 1 of 6 pts encountered DLT during Cycle 1. Primary study endpoints included safety & PK. Plasma VEGF receptor & ligand concentrations were measured by ELISA & antitumor activity was assessed by CT scan. Results: 77 pts (57 M, 20 F; mean age 54.3 yrs) w/ chemorefractory solid tumors (22 CRC, 12 NSCLC, 12 sarcoma, 6 RCC,25 other) were enrolled. The rate of grade 3/4 AEs increased at doses above 100 mg w/hypertension & fatigue occurring in 18 % & 12 % of pts, diarrhea (9%) & thrombocytopenia (5%). The MTD was determined to be 100 mg CD, which was well-tolerated w/ manageable G3 diarrhea (n=2/6). PK was generally dose-proportional; at 100 mg CD, Cmax = 255 ng/mL, Tmax = 3 h, C24h = 63 ng/mL. SU014813 decreased plasma VEGFR2 & R3 concentrations in a dose- dependent manner (50–200 mg doses) but rebounded off treatment (4/1 schedule). Plasma VEGF generally increased after treatment but effects were variable. Twelve pts had an objective response at =50 mg daily dose levels; 1 pt w/ RCC had CR (183 days [d]);11 pts had PR (2 RCC, 2 thymoma, 2 NSCLC, 1 CRC, 4 other)(median 235 d; range 35- 470); 14 pts had stable disease (SD; median 178 d, range 58–554). Seven other pts who did not meet RECIST response criteria had long disease stabilization (median 200 d; range 180 - 440). Conclusions: SU014813 has a manageable safety & tolerability profiles at the doses studied. The MTD & recommended Ph II dose were determined to be 100 mg CD, as SU014813 had linear PK, modulated plasma VEGF receptors consistent with RTK inhibition, & demonstrated encouraging preliminary activity w/ durable responses across several tumor types. [Table: see text]
Phase I and DCE-MRI evaluation of CDP791, a di-Fab PEG conjugate that inhibits VEGFR2
Authors: Jayson G. C. , Ton C. , Parker G. J. , Jackson A. , Mullamitha S. , Zinkewich-Peotti K. , Felix R. , Soranson J. , Rolfe L. 
Published: March 2020

3523 Background: VEGF inhibitors are of proven clinical value. However, very few drugs specifically inhibit VEGFR2. CDP791 is a di-Fab PEG conjugate that binds VEGFR2 with a Kd of 49pM. Methods: We performed a single site, open label, dose-escalation study of CDP791. Cohorts of patients received between 0.3 and 30 mg/kg every 3 weeks until disease progression. DCE-MRI was performed at each dose level. Results: Thirty-one patients with colorectal, ovarian or renal cancer or other tumors were treated. There was no observed dose limiting toxicity or maximum tolerated dose. At doses of 10mg/kg or above, 7/16 patients developed cutaneous hemangiomata that regressed upon drug withdrawal. Biopsy of these confirmed that CDP791 was co-located with unphosphorylated VEGFR2. DCE-MRI revealed a dose- dependent inhibition of tumor growth over 20 days post-treatment, although there was no measurable change in Ktrans, an indicator of blood flow and capillary permeability. Fourteen patients received extended treatment and 5 (with renal (x2), colorectal, endometrial cancer and melanoma) had stable disease after 6 cycles. Plasma concentrations of CDP791 >10mcg/mL were sustained across the 21-day cycle for doses 10mg/kg and above. Conclusions: CDP791 is a pure VEGFR2 antagonist that is well tolerated up to doses of 30mg/kg. The drug is mechanistically active, associated with hemangiomata and dose-level dependent inhibition of tumor growth but not with reduction in vascular permeability or blood flow on DCE-MRI. These data imply that the drug is active in patients but challenge our understanding of the regulation of tumor vascular permeability. In addition, they suggest that serial 3-dimensional measurements of short-term tumor growth patterns are a sensitive method to detect biological therapy-related tumor growth inhibition. [Table: see text]
Phase 1 study of a focal adhesion kinase (FAK) inhibitor PF-00562271 in patients (pts) with advanced solid tumors
Authors: Siu L. L. , Burris H. A. , Mileshkin L. , Camidge D. R. , Rischin D. , Chen E. X. , Jones S. , Yin D. , Fingert H. 
Published: March 2020

3527 Background: PF-00562271 is a potent ATP-competitive inhibitor of FAK and, to a lesser extent, Pyk2. FAK transduces signaling from integrins and growth factors to modulate multiple properties important in neoplasia, including tumor cell invasion, proliferation and survival. Structure-activity relationships and preclinical antitumor activity are reported (W.G. Roberts et al, Proc AACR, 2007). Methods: Phase 1 dose-escalation study of PF-00562271 given as twice daily oral doses in 21 day cycles. Endpoints included safety, tolerability, PK, PD (serial tumor biopsies) and antitumor activity. PD was also evaluated by tumor glucose metabolism using FDG-PET. Dose escalation was performed in sequential cohorts of 3–6 pts. Results: 32 pts received 5 mg up to 105 mg BID with demographics M:F = 10:22; median age 60 (range 38–80). Primary tumor sites: colorectal (10), breast (4), neuroendocrine (2), lung (2), gastric (2), SCC (2), ovary (2), others (8). A total of 136 cycles have been administered, median = 3.2, range = 1–10+. Adverse events (AEs) possibly related to PF-00562271 in over 10% of pts included nausea, vomiting, fatigue, anorexia, abdominal pain, diarrhea, headache, sensory neuropathy, rash, constipation, dizziness. AEs were generally CTC grades 1–2 and reversible. Cmax and AUC increased dose-dependently, and AUC accumulated over 6-fold by day 14. Doses over 15 mg BID produced steady-state plasma concentrations, exceeding target efficacious levels predicted from preclinical models. On day 14, PET scans in one pt demonstrated significant (46%) decline in SUV of metastatic ovarian carcinoma, associated with improved tumor-related symptoms. Nine pts tolerated over 3 cycles and another 4 pts continued treatment over 6 cycles with stable disease. At 105 mg BID, dose- limiting toxicities included nausea, vomiting, diarrhea. Conclusions: At the doses evaluated, PF-00562271 is tolerable with extended BID oral administration and exhibits favorable PK and PD. Additional dose and schedule evaluations continue, and updated clinical and biomarker results will be presented. No significant financial relationships to disclose.
Application of pharmacodynamic assays in a phase Ia trial of Apo2L/TRAIL in patients with advanced tumors
Authors: Pan Y. , Xu R. , Peach M. , Huang C. , Branstetter D. , Durbin B. , Herbst R. , Eckhardt G. , Mendelson D. , Holland P. 
Published: March 2020

3535 Background: Recombinant human (rh) Apo2L/TRAIL is a dual pro-poptotic receptor agonist (PARA) that induces apoptosis by binding to pro-apoptotic receptors DR4 and DR5, which recruit a death inducing signaling complex upon ligand binding. This results in activation of the effector caspase 3/7, that subsequently cleaves intracellular substrates to execute cellular apoptosis. A Phase1a trial is underway to evaluate the safety and tolerability of rhApo2L/TRAIL in patients with advanced tumors. The aim of this study was to develop and validate high-throughput pharmacodynamic assays to monitor rhApo2L/TRAIL activity in easily accessible patient samples such as serum. Methods: To monitor rhApo2L/TRAIL activity in patients, we optimized assays to measure the release of the apoptotic markers caspase 3/7, cytokeratin 18 (CK18), and genomic DNA (gDNA) in serum. Serum caspase 3/7 levels were monitored using the Caspase Glo kit, which generates a luminescent signal upon cleavage of a caspase 3/7 substrate; cleavage of the caspase substrate CK18 was measured using an optimized form of the M30 ELISA assay; gDNA was measured using a β-actin-specific TaqMan real-time PCR assay. Mice bearing Colo205 xenografts were treated with rhApo2L/TRAIL and sera were collected and assayed for apoptotic markers. Upon validating these assays, we monitored the levels of apoptotic markers in cancer patients who received rhApo2L/TRAIL. Results: We detected transient increases in apoptotic markers in mouse sera 8–24 hr after treatment with rhApo2L/TRAIL. This increase was dose-dependent and correlated with active caspase 3 detected by IHC in Colo205 tumors. In the phase Ia study, increases in serum caspase 3/7 and gDNA levels were observed in >50% of colorectal, lung and sarcoma patients evaluated. Preliminary analyses show the percentage of increase correlates using both analytes and is dose-dependent. Conclusions: These findings support the use of serum-based pharmacodynamic assays as a means to monitor rhApo2L/TRAIL activity in patients with advanced tumors. A complete analysis of all patient serum samples from the ongoing phase Ia trial will be reported. No significant financial relationships to disclose.
Dual targeting of vascular endothelial growth factor (VEGF) with sorafenib and bevacizumab: Clinical and translational results
Authors: Azad N. S. , Annunziata C. , Barrett T. , Chen C. , Steinberg S. , Kwitkowski V. E. , McNally D. , Kotz H. , Minasian L. , Kohn E. C. 
Published: March 2020

3542 Background: VEGF is a major mediator of angiogenesis in malignancy. We targeted the VEGF pathway in series by combining the VEGFR2/Raf kinase inhibitor sorafenib (S) with bevacizumab (B), a selective anti-VEGF antibody. We hypothesized that this combination would suppress angiogenesis and tumor growth, with corresponding changes in correlative dynamic imaging. Methods: Eligible pts had non-curable solid tumors, ECOG performance status 0–1, good end organ function, and no prior exposure to S or B. We enrolled pts at S 200 mg po BID and B 5 mg/kg IV q2weeks (dose level [DL] 1) and escalated each drug sequentially. The MTD was DL1; 24 additional pts were enrolled at this dose and randomized to single agent S (Arm 1) or B (Arm 2) for one month, then S+B thereafter. Serum samples for cytokine analysis, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18FDG- PET scans were performed at 0, 2, and 6 weeks. DCE-MRI and PET scans measured vascular permeability (Ktrans) and metabolic activity (standardized uptake values [SUV]), respectively. The Wilcoxon signed rank test was used to evaluate the differences between the paired imaging values at the test time points in an exploratory fashion. Results: 7/38 pts (6/14 ovarian ca pts and 1/3 renal cell ca pts) had partial responses (8+-20 mo; median 15). Grade 3–4 toxicities included hypertension (10), proteinuria (2, DLT), and thrombocytopenia (1, DLT). Common grade 2 toxicities were hand-foot syndrome (18), fatigue (13), infection (13), and hypertension (12). DCE-MRI Ktrans decreased with S+B compared to baseline (p<0.03, both arms); no significant change occurred with either S or B treatment alone or between arms. No significant changes in PET SUV measurements occurred with treatment. Correlation of dynamic imaging parameters with response was not possible due to the limited patient numbers. Serial cytokine analysis is presently being performed and will be included at the time of presentation. Conclusions: S+B is active in solid tumors with manageable toxicity. DCE-MRI shows a decrease in vascular permeability with S+B treatment. A larger trial is necessary to evaluate if DCE-MRI changes can be predictive of response and is ongoing now in ovarian cancer. No significant financial relationships to disclose.