bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemopredictive assay for patients with primary brain tumors.
Authors: Claudio Pier Paolo , Valluri Jagan , Mathis Sarah E , Alberico Anthony , Alberico Thomas , Denvir James , Kimmey Gerrit A. , Mogul Mark Jeffrey , Sehgal Rajesh , Chowdhary Aneel A. , Mozayen Mohammad , Tirona Maria R. B. Tria , Matt Laurie Beth , Oakley Gerald , Denning Krista L , Dougherty Thomas 
Published: March 2020

2089 Background: Cancer stem-like cells (CSLCs) in primary brain tumors can resist certain chemotherapies, thereby causing relapse of the disease. Thus, development of a test that identifies the most effective chemotherapy management offers great promise for personalized anticancer treatments. Methods: We have developed an ex vivo ChemoID assay designed to predict the sensitivity and resistance of CSLCs and bulk of tumor cells of a given patient's solid tumor to a variety of chemotherapy agents by measuring the percentage of cell death. In a retrospective study of five patients with malignancies of the central nervous system, we assessed the correlation between the results of the ChemoID assay and clinical response. Two anaplastic WHO grade-III ependymomas, two IDH-1 negative WHO grade 4 glioblastomas, and one medulloblastoma were tested. Tumors were classified as responsive (50-100% cell kill), intermediately responsive (30-50% cell kill), and nonresponsive (0-30% cell kill) to chemotherapy. Treatment selection was blinded to assay results. MRI and CT scan determined response to therapy. Results: The ChemoID assay performed on the tumor bulk produced a correct prediction in 4 out of 5 cases (p = 0.4, Fisher's Exact Test; PPV = 75%, NPV = 100%) when compared to the drugs received. The same assay performed on the CSLCs produced a correct prediction in all 5 cases (p = 0.1, Fisher's Exact Test; PPV=NPV=100%). Conclusions: An assay such as ChemoID that measures cell death of CSLCs and bulk of tumor cells appears to be beneficial in selecting specific standard chemotherapy agents ex vivo for patients with malignancies of the central nervous system.
Analysis of high-dose methotrexate with rituximab versus other treatment regimens for primary central nervous system (CNS) lymphoma.
Authors: Lindhorst Scott Michael , McSherry Frances , Desjardins Annick , Friedman Henry S. , Peters Katherine B. 
Published: March 2020

2090 Background: The most effective and least toxic treatment regimen for primary CNS lymphoma is a matter of debate. Most current regimens utilize various doses of high-dose methotrexate combined with other agents. The utility of deferred radiation is also under study. Methods: We evaluated 28 patients with primary CNS lymphoma treated with methotrexate 3.5 g/m2 and rituximab, as well as alternative regimens. Median, 12-month, and 24-month survival were compared for the various treatment regimens, as well as for patients who received radiation and those who did not. Results: Survival rates were significantly better in the methotrexate-rituximab treatment cohort than the other regimens examined (Log-Rank p-value 0.0437). 12-month survival for the methotrexate-rituximab cohort was 72.7% (95% CI, 37.1% to 90.3%) versus the alternative treatment cohort 12-month survival of 49.4% (95% CI, 23.7% to 70.8%). 24-month survival for the methotrexate-rituximab cohort was 72.7% (95% CI, 37.1% to 90.3%) versus the alternative treatment cohort 24-month survival of 39.5% (95% CI, 14.9% to 63.6%). Median survival for the alternative treatment cohort was 11 months (95% CI, 2.2 to 28.6), while the median survival for the methotrexate-rituximab regimen was not reached. Stratified by radiation, survival rates were significantly better in the radiation cohort than the cohort without radiation (Log-Rank p-value 0.0040). 12-month survival for the radiation cohort was 90% (95% CI, 47.3% to 98.5%) versus the cohort without radiation 12-month survival of 40.5% (95% CI, 17.7% to 62.3%). 24-month survival for the radiation cohort was 90% (95% CI, 47.3% to 98.5%) versus the cohort without radiation 24-month survival of 33.7% (95% CI, 12.9% to 56.1%). Median follow-up for all patients was 21.5 months (95% CI, 16 to 42.1). Conclusions: The combination of methotrexate at 3.5 g/m2 with rituximab is a valid treatment regimen for primary CNS lymphoma. Patients may be spared toxicity by using a methotrexate dose of 3.5 g/m2 rather than 8 g/m2. The addition of radiation provided a significant survival advantage in this observational study, however, radiation deferred until progression may be a viable alternative.
Phase I study of anti-PlGF monoclonal antibody (mAb) RO5323441 (RO) and anti-VEGF mab bevacizumab (BV) in patients with recurrent glioblastoma (GBM).
Authors: Lassen Ulrik Niels , Chinot Oliver L. , McBain Catherine , Sorensen Morten , Larsen Vibeke Andree , Barrie Maryline , Roth Patrick , Krieter Oliver , Wang Karen , Habben Kai , Tessier Jean , Lahr Angelika , Whiley Matt , Weller Michael 
Published: March 2020

2092 Background: BV inhibits VEGF and is approved for progressive GBM following prior therapy. The placental growth factor (PlGF) is a member of the VEGF family and PlGF expression has been shown to correlate with tumor stage and survival in several human malignancies. In cancer patients (pts) PlGF is up-regulated upon treatment with VEGF inhibitors. RO is a humanized IgG1 mAb directed against PlGF that has demonstrated antitumor activity in an orthotopic GBM model. Single agent RO was previously tested in advanced solid tumors. Methods: Eligibility criteria included histologically confirmed GBM with documented radiographic progression upon front line therapy, ≥18 years of age, KPS ≥70, adequate bone marrow reserve and organ function. Prior treatment with VEGF/PLGF targeted therapies was not permitted. Three to six pts were enrolled per dose level (DL), the MTD defined as the dose with DLTs ≤ 1/6 pts during 28-days of cycle 1, using CTCAE v4. Results: A total of 22 pts (16m/6f) have been enrolled in 3 DLs: RO 625mg (4 pts), 1250mg (6), and 2500mg (12) IV every 2 weeks (q2w), each in combination with BV 10mg/kg IV q2w. Median age: 58 years (range 37-72). RO serum concentrations increased proportionally, while serum exposures of BV were similar between all DLs. Two pts experienced a DLT: Meningitis G3 (1250 mg) and cerebral infarction G3 (2500 mg). Most commonly reported adverse events included hypertension (14 pts), headache (11), dysphonia (10), fatigue (6), nasopharyngitis (5), epistaxis (4), constipation (4), nausea (3), and arthralgia (3). Across all DLs tested, the overall response rate by RANO criteria was 22.7%. Conclusions: The tolerability of RO in combination with BV is acceptable; a MTD was not determined. Anti-PlGF treatment does not appear to add on clinical activity observed for single agent BV in recurrent GBM. Clinical trial information: NCT01308684.
Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma.
Authors: Desjardins Annick , Sampson John Howard , Peters Katherine B. , Ranjan Tulika , Vlahovic Gordana , Threatt Stevie , Herndon James Emmett , Friedman Allan H. , Friedman Henry S. , Bigner Darell D. , Gromeier Matthias 
Published: March 2020

2094 Background: Current therapies for glioblastoma are limited by ineffective delivery beyond the blood-brain barrier, limited diffusion of macromolecules, and lack of tumor specificity. Sustained direct intracerebral infusion at slow flow rates [convection-enhanced delivery (CED)] can overcome delivery barriers. PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. PVSRIPO recognizes nectin-like molecule-5, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report the results of an ongoing phase I study evaluating PVSRIPO when delivered by CED. Methods: Eligible on study are adult patients with: 1-5 cm of measurable supratentorial recurrent glioblastoma ≥1cm away from the ventricles; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS ≥70%; and positive anti-poliovirus titer. PVSRIPO is delivered intratumorally by CED over 6.5 hours. PVSRIPO dose escalation is accomplished by increasing agent concentration, allowing flow-rate and infusion volume to remain constant. Two-step continual reassessment method is used for dose escalation, with one patient each treated on dose levels 1-4, and a possibility of up to 13 patients on dose level 5. Results: Thus far, a total of five patients have been treated on study. No related or unrelated grade 3 or higher adverse events have been observed. Grade 1 adverse events possibly related to the study drug or procedure include one each of fever, cough, nasal congestion, vomiting, headache, hemiparesis, and lethargy. Grade 2 adverse events include one each of diarrhea and seizure. Patient #1 had failed bevacizumab prior to enrollment and remains disease free more than 9 months post PVSRIPO. Two more patients are disease free 8+ and 2+ months post treatment, respectively. One patient had pathology confirmed disease recurrence two months post treatment and one patient came off study due to clinical decline four months post treatment. Conclusions: Infusion of PVSRIPO via CED is safe thus far and encouraging efficacy results are observed. Updated results will be presented. Clinical trial information: NCT 01491893.
Molecular screening for cancer treatment optimization (MOSCATO 01): A prospective molecular triage trial—Interim results.
Authors: Hollebecque Antoine , Massard Christophe , De Baere Thierry , Auger Nathalie , Lacroix Ludovic , Koubi-Pick Valerie , Vielh Philippe , Lazar Vladimir , Bahleda Rastislav , Ngo-camus Maud , Angevin Eric , Varga Andrea , Deschamps Frederic , Gazzah Anas , Mazoyer Clement , Richon Catherine , Vassal Gilles , Eggermont Alexander M. , Andre Fabrice , Soria Jean-Charles 
Published: March 2020

2512 Background: Characterization of the genomic alterations (GA) that could drive tumor growth of an individual patient (pt) is now critical to better select targeted therapies in phase I trials. Methods: Pts with advanced solid tumors, who failed at least one line of standard therapy, were offered an on-purpose tumor biopsy for molecular characterization. Biopsies were mainly obtained using 18G needles under CT or ultra-sound control, from metastatic or primary tumor sites. DNA extracted from fresh tumor biopsies was analyzed by CGH (Agilent platform) (if ≥ 50% tumor cells in the sample) and by sequencing for 30 target genes (if ≥ 30% tumor cells in the sample). An expert panel of scientists and clinicians reviewed results to determine the biological signification of the GA and match such pts to the most relevant targeted therapy available (mainly in early clinical trials). PFS using therapy based on GA was compared to the PFS for the most recent therapy on which the pt had just experienced progression (PFS ratio). Results: From December 2011 to august 2012, 129 heavily pretreated pts (median of 3 previous lines) were consented. Among them, 111 (86%) had a dedicated tumor biopsy. An actionable target was identified in 52 patients (40%). Among them, 25 pts (23% of biopsied pts) have been treated with a targeted therapy. The median time between biopsy and molecular results was 21 days [17 – 28]. GA of interest encompassed FGF ligand or receptor amplification (n=9), cyclin amplification or deletion (n=4), KRAS/BRAF/NRAS mutation (n=3), PI3K amplification or PTEN deletion (n=3), EGFR amplification or mutation (n=3) (outside lung cancer), HER2 amplification (n=2) (outside breast cancer), EML4/ALK translocation (n=1). Among the 25 pts treated according to their GA, we observed 5 PR (20%), 14 SD (56%) and 3 PD (12%). Three pts (12%) were not evaluable because of early discontinuation of the therapy. PFS ratio was >1.3 among 9 out of 19 evaluable pt (47%). Conclusions: High throughput molecular analysis is feasible in daily practice. It allows enrichment of phase I trials with specific GA, and leads to promising anti-tumor activity (20% PR as compared to the classical 7-10% PR obtained in all comers phase I trials). Clinical trial information: NCT01566019.
A phase I first-in-human study of REGN910 (SAR307746), a fully human and selective angiopoietin-2 (Ang2) monoclonal antibody (MAb), in patients with advanced solid tumor malignancies.
Authors: Papadopoulos Kyriakos P. , Sahebjam Solmaz , Kelley Robin Katie , Tolcher Anthony W. , Razak Albiruni R.A. , Patnaik Amita , Bedard Philippe L. , Arcos Rebecca , Adriaens Lieve , Brownstein Carrie M. , Lowy Israel , Gao Bo , DiCioccio A Thomas , Trail Pamela , Siu Lillian L. 
Published: March 2020

2517 Background: REGN910 is a selective, fully human Ang2 MAb that potently blocks signaling through the Tie2 receptor regulating tumor angiogenesis and growth. In multiple mouse xenograft models of human solid tumors, REGN910 inhibits tumor growth. Methods: This first-in-human phase I study (3+3 design) explored the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of REGN910 as a single agent. REGN910 was given IV at escalating doses. At RP2D, expansion cohorts were initiated to confirm safety and assess anti-tumor activity in about 20 patients (pts). Results: 37 pts [17M/20F; median age 57 (range 22-82); ECOG PS 0(9)/1(28)] were enrolled. Twenty-three (23) pts were enrolled in the dose escalation cohorts. No DLTs were reported, and a MTD was not reached. Most common G1/2 treatment-related adverse events (TRAEs) were fatigue 7(19%), peripheral edema 6(17%), diarrhea 5(14%), abdominal distension 4(11%), and decreased appetite 4(11%). There were no ≥ Grade 3 TRAEs. A confirmed sustained PR (16 wks) was observed in 1 pt with adrenocortical cancer treated at 1 mg/kg. SD (range 6.9-46.8 wks) was reported for 17 of 32 (53%) pts evaluable for efficacy. Fourteen pts received treatment >16 wks. One pt with thyroid cancer had SD for 46 wks, and 1 pt with hepatocellular cancer had SD for 16 wks with ≥50% decline in alpha-fetoprotein. Across all dose levels, REGN910 pharmacokinetics appeared linear and dose-proportional. The PK profile was characterized by an initial distribution and a single mono-exponential elimination phase. Total circulating serum Ang2 levels appeared saturated following treatment in all cohorts, indicating systemic target engagement at all doses tested. Conclusions: Administration of REGN910 in patients with advanced cancer is well tolerated, with generally mild and moderate TRAEs. Dose escalation is completed, and enrollment to the expansion cohorts continues. The safety profile supports combination with chemotherapy and/or other anti-angiogenic agents. Clinical trial information: NCT01271972.
Phase I, first-in-human, open-label, dose-escalation study of U3-1565, a fully human anti-HB-EGF monoclonal antibody, in patients with advanced solid tumors.
Authors: Moore Kathleen N. , Bendell Johanna C. , Olszanski Anthony J. , Desai Madhuri , Jansen Mendel , Scheyer Richard David , Senaldi Giorgio , LoRusso Patricia 
Published: March 2020

2519 Background: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member and a ligand for EGFR and Her4. U3-1565 is a fully human anti-HB-EGF monoclonal antibody with preclinical anti-tumor and anti-angiogenesis activity. In this study, we evaluated safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of U3-1565 in patients with advanced solid tumors refractory to standard treatment. Methods: The 3+3 method of enrollment and dose-escalation was used to test U3-1565 at 2, 8, 16, and 24 mg/kg once every two weeks (with the second dose given three weeks after the first), and at 24 mg/kg weekly. Results: 15 patients (11 females, 4 males; median age 62 (range 47-77) years; 5 CRC, 5 NSCLC, 3 ovarian and 2 other cancer) were enrolled, 3 in each dose level cohort. No dose-limiting toxicity was observed and a maximum tolerated dose was not reached. The highest administered dose of 24 mg/kg weekly generated Cmin above the predetermined target concentration corresponding to Cave resulting in 90% preclinical tumor growth inhibition. U3-1565 was safe and well tolerated with related AE consisting of infrequent and non-dose-related G2 (fatigue, anemia, and appetite loss, seen in 20, 13, and 7% of cases, respectively) and G1 toxicities. No anti-U3-1565 antibody was detected. U3-1565 showed bi-exponential disposition with Cmax and AUC increasing proportional to the dose across all dosing regimens. 13 patients discontinued the study, 12 due to progressive disease and 1 due to non-drug-related AE. After 6 months on study, 2 patients entered study extension phase: A 77 year-old female with NSCLC given 24 mg/kg every two weeks, showed SD (best SLD change -3%) for 26 weeks before progression; and a 76 year-old female with CRC given 24 mg/kg weekly, showed PR (best SLD change -35%) and remains on treatment after 71 weeks. Conclusions: U3-1565 is safe and well tolerated up to 24 mg/kg weekly. Anti-tumor activity was observed and is being further explored in an open-label, dose-expansion study. Clinical trial information: NCT0129041.
A phase I, dose-escalation trial of continuous and pulsed-dose afatinib (A) combined with pemetrexed (P) in patients (pts) with advanced solid tumors: Final analysis.
Authors: Chu Quincy S. , Sangha Randeep S. , Hotte Sebastien J , Sergenson Gwen , Chand Vikram K. , Sufan Roxana , Gu Yu , Schnell David , Hirte Hal W. 
Published: March 2020

2523 Background: A is an irreversible ErbB Family Blocker that has shown additive effects when combined with P in EGFR-mutant NSCLC cell lines. This Ph I trial assessed the MTD, safety and PK of continuous and pulsed-dose A + P in pts with advanced solid tumors. Methods: In a3+3 dose-escalation design, IV P (500 mg/m2) was administered on day (d) 1 of each 21-d cycle combined with either continuous oral A qd (Schedule A; SA) on d1–21 (d2–21 in Cycle 1) or pulsed-dose oral A qd (Schedule B; SB) on d1–6 of each 21-d cycle. In SA, A starting dose was 30 mg, escalated to maximum of 50 mg. Once the MTD was reached in SA, A was administered at a starting dose of 50 mg in SB. Pts received up to 6 cycles of P with the option for A monotherapy thereafter. P and steady state A PK were analyzed by intra-individual comparison in SA only for possible drug–drug interaction. Results: 53 pts were treated (SA: n=23, median age 58 yrs; ECOG 0/1/2 [30%/65%/4%]; SB: n=30, median age 62 yrs, ECOG 0/1/2 [27%/70%/3%]). MTD of A in SA was 30 mg; 8 pts had dose-limiting toxicities (DLTs) in Cycle 1 (40 mg: 2/3 pts; 30 mg; 6/19 pts). 30-mg cohort included 19 evaluable pts; 1 pt was replaced during expansion (incomplete PK collection) and had a DLT. MTD of A in SB was 50 mg; 11 pts had DLTs in Cycle 1 (70 mg: 4/5 pts; 60 mg: 6/17 pts; 50 mg: 1/6 pts). Most frequent drug-related AEs in SA were diarrhea (91%), stomatitis (65%) and rash (61%) and in SB were diarrhea (83%), rash (83%) and fatigue (80%); most were Grade 1/2. 6 pts in SA and 8 pts in SB completed 6 treatment cycles; 1 pt in each schedule remain on treatment. Best response in SA was 1 confirmed partial response (CPR; NSCLC, prior sequential chemotherapies and erlotinib) and 6 pts with stable disease (SD). In SB, best response was 1 CPR (bladder cancer, prior sequential chemotherapies) and 10 pts with SD. No clinically relevant PK interactions between A and P were observed. Conclusions: Continuous or pulsed-dose A combined with P exhibited a manageable safety profile. No clinically relevant PK interactions were seen in SA. Continuous dose A 30 mg/d with P 500 mg/m2 (d1 of each 21d cycle) is the recommended dose for further Ph II studies. No apparent safety or dose advantage was observed in SB. Clinical trial information: NCT01169675.
Phase Ib safety trial of CVX-060, an intravenous humanized monoclonal CovX body inhibiting angiopoietin 2 (Ang-2), with axitinib in patients with previously treated metastatic renal cell cancer (RCC).
Authors: Gollerkeri Ashwin , Gordon Michael S. , Burke John M. , Hauke Ralph , Tomasek Jiri , Richards Donald A. , DiSimone Christopher , Tykodi Scott S. , Mehta Amit R. , Chen Charles , Perea Rachelle , Vogelzang Nicholas J. 
Published: March 2020

2533 Background: PF-04856884 is a recombinant humanized monoclonal antibody fused to two Ang-2 binding peptides. Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factors (VEGFs) that is approved for patients (pts) with advanced renal cell cancer who failed 1 prior therapy. Metastatic RCC (mRCC) is an angiogenic tumor sensitive to VEGF tyrosine kinase inhibitors. Resistance to VEGF targeted therapy may be mediated by Ang-2. Methods: In Part I (safety lead in) of the study, the primary endpoint was treatment related dose limiting toxicities (DLT) in pts with mRCC who had received 1-3 prior treatments. Pts received PF-04856884 (15 mg/kg/week) plus axitinib (5 mg BID) for 4 week cycles (the recommended Phase II dose of each) and were assessed for DLT, PK, and potential predictive biomarkers (Ang-2 and VEGF-A). For Part II (Phase II portion), pts with mRCC who had received 1 prior anti-VEGF agent were to be randomized to PF-04856884 + axitinib or axitinib alone to assess median progression free survival. Results: Part I enrolled 18 pts with median age of 62.5 years (39-82), and ECOG performance status of 0-1. One pt had a DLT of Grade 4 pulmonary embolism (PE). Most common related AEs: anorexia in 10 pts (56%), diarrhea 8 (44%), fatigue 8 (44%), nausea 7 (39%), hypertension 6 (33%) and vomiting 6 (33%). Treatment-related thromboembolic events (TEEs) were observed: PE in 2 pts (11%), and cerebrovascular accident (CVA), presumed bowel ischemia, and possible cardiac chest pain in 1 pt (6%) each. One pt had Grade 2 venous thrombosis unrelated to either treatment. Due to the reported TEE, PF-04856884 was reduced to 10 mg/kg in pts remaining on study and enrollment to Part II was not initiated. No significant PK interaction was observed. Two pts had partial response (PR) and 1 pt had unconfirmed PR. Twelve pts (66%) remained on study ≥91 days with a median duration of 120 days (8-279). Anti-PF-04856884 antibody results are not available. Conclusions: Due to the higher than expected TEEs, alternate doses of PF-04856884 and/or disease settings are being considered. Clinical trial information: NCT01441414.