bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pharmacokinetic (PK) pharmacodynamic (PD) driven first-in-human study of the oral class I PI3K inhibitor CH5132799, in patients with advanced solid tumors.
Authors: Omlin Aurelius Gabriel , Spicer James F. , Sarker Debashis , Pinato David James , Agarwal Roshan , Cassier Philippe Alexandre , Stavraka Chara , Blanco Monsterrat , Suder Aneta , Allan Suzanne , Heaton Simon , Decordova Shaun , Pope Lorna , Prince Jenny , Noguchi Kohei , Jones Keith , Inatani Michiyasu , Shiokawa Rie , Banerji Udai , Blagden Sarah Patricia 
Published: March 2020

3022 Background: The phosphatidylinositol 3-kinase (PI3K) pathway is a promising target in cancer. CH5132799 is a novel PI3K inhibitor, selectively inhibiting class I PI3Ks (α, β, δ and γ) with no inhibition of class II and III or mTOR, and with potent antitumor activity in preclinical studies (Tanaka et al, Clin Cancer Res; 17; 3272-81, 2011). First-in-human study objectives were determination of maximum tolerated dose (MTD), safety/tolerability, PK/PD and clinical activity (RECIST). Methods: A 3+3 dose escalation design was used. The initial dosing schedule of CH5132799(schedule A) was once a day (QD). Due to a relatively short half-life, a twice a day (BID) schedule (schedule B) was introduced. PK profiles were studied over 72 hours. PD analyses included quantification of various phosphoproteins in platelet rich plasma (PRP). Tumor assessments were performed at baseline and cycle 3 day 1 (C3D1) and FDG-PET scans at baseline, C1D8 and C3D1. Results: 29 patients (pts) with a variety of solid tumors have been treated (A 23 pts, B 6 pts, the most common tumors were breast, oesophageal, colorectal and ovarian). The starting doses were 2 mg (A) and 48 mg (B). The current doses being explored are 96 mg (A) and 72 mg (B). The most frequently reported drug-related AEs were Grade 1/2 diarrhea, nausea, fatigue, anorexia and anemia. 1 DLT (Grade 3 elevated LFT) was observed in a hepatocellular carcinoma pt at 48 mg BID. MTD has not yet been determined. The preliminary mean ±SD Cmax and AUC at 96 mg QD were 202±129 ng/ml and 1407±935 ng·hr/ml respectively, which is consistent with an efficacious exposure based on preclinical models. Some patients achieved the expected exposure at over 32 mg. From single dose of 48mg there was a reduction of phosphorylation of AKT in PRP after treatment, consistent with pathway modulation. A patient with clear cell ovarian cancer and a PIK3CA mutation treated at 48 mg BID showed >50% decrease in SUV on a PET scan at C1D8 and a 75% decrease in CA-125 at C2D1. 5 pts exhibited SD (>8 weeks). Conclusions: CH5132799 is well tolerated either QD ≤96 mg or BID ≤48 mg. Dose-escalation continues and updated safety/efficacy/PK/PD data will be presented.
A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid tumors.
Authors: Isambert Nicolas , Hollebecque Antoine , Berge Yann , van Ingen Hein , Brienza Silvano , Destaillats Alice , Soria Jean-Charles , Fumoleau Pierre , Delord Jean-Pierre 
Published: March 2020

3026 Background: Debio 0932 is an oral second-generation heat shock protein 90 (HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier penetration, and promising anti-tumor activity both as monotherapy and combination against a broad range of tumors in pre-clinical models. Here we report the results of the dose escalation part of a phase I study in patients with advanced solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, non-randomized, 3 + 3 dose-escalation study to determine the maximum tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 days of treatment in patients with advanced solid tumours or lymphoma resistant to standard therapy. The starting dose in both treatment groups was 50mg. Doses were increased according to an algorithm based on observed toxicity and dose limiting toxicities (DLT). Tumor assessments were performed every 8 weeks. Results: Patient characteristics and results are summarized below. DLTs occurred at 1600mg in both dose groups. Adverse events (AE) were mostly CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac toxicity was observed. The main reason for treatment withdrawal was progressive disease. Investigator-reported cases of SD and PR were observed. Conclusions: Debio 0932 mono-therapy was generally well tolerated and showed promising signs of efficacy in patients with advanced solid tumors. The recommended phase II dose, established at 1000mg QD, will be tested in an additional 30 patients in an ongoing expansion study. A phase I-II study of Debio 0932 in combination with standard of care in the first- and second-line treatment of NSCLC is planned. [Table: see text]
Rational molecularly targeted combinations: A parallel-arm phase I trial of the humanized anti-IGF-1R antibody dalotuzumab (D) in combination with the allosteric AKT inhibitor MK-2206 or the gamma secretase inhibitor MK-0752, in patients with advanced solid tumors.
Authors: Brana Irene , Gray Jhanelle Elaine , Haluska Paul , Berger Raanan , Golan Talia , Jones Mary Elizabeth , Gunchenko Alexandra , Cheng Jonathan D. , Siu Lillian L. 
Published: March 2020

3027 Background: Two rational strategies to interrogate the IGF-1R pathway were investigated in this parallel-arm phase I trial: 1) vertical inhibition with D and MK-2206 to potentiate PI3K pathway targeting, 2) horizontal crosstalk inhibition with D and MK-0752 to exert effects against cellular proliferation, angiogenesis and stem cell propagation. Methods: Patients (pts) with advanced solid tumors and no prior exposure to agents of the same targets were eligible. Dose escalation was based on a modified toxicity probability interval method (Ji et al, 2010). Arm A is comprised of fixed D dose of 10 mg/m2 IV weekly plus MK-2206 at escalating doses of 90-200 mg PO weekly. Arm B is comprised of fixed MK-0752 dose of 1800 mg PO weekly plus D at escalating doses of 7.5-10 mg/m2 IV weekly. Each cycle = 4 weeks in both arms. Primary objectives were to determine DLT and RP2D of these combinations. Results: 30 patients were enrolled in the dose escalation phase (18 in Arm A and 12 in Arm B) with: median age = 56 (range 36-74); M:F = 13:17; ECOG 0:1 = 12:18; primary diagnosis = colorectal (CRC) (9), NSCLC (3), others (17); prior metastatic regimens = 3 (range 1-4). In Arm A, 1/6 DLT was observed with MK-2206 at 135 mg (G3 serum sickness-like reaction); 2/3 DLTs with MK-2206 at 200 mg (G4 leukopenia/neutropenia; G3 rash). No other G4 or worse adverse events (AEs) were observed. RP2D of Arm A = D 10mg/m2 IV weekly and MK-2206 150 mg PO weekly. Other common AEs in Arm A included: fatigue, rash and nausea. In Arm B, 2/6 DLTs were observed with D at 10 mg/m2 (G3 rash; G3 nausea/vomiting). RP2D of Arm B = D 10mg/m2 IV weekly and MK-0752 at 1800 mg PO weekly based on Ji et al. Other common AEs in Arm B included: anorexia, nausea and fatigue. No PR was observed and SD > 4 months occurred in 4 pts (all in Arm A). PK analyses are ongoing. Conclusions: Targeted combinations of D with MK-2206 or with MK-0752 were both tolerable. Expansion cohorts based on biomarker selection are underway, specifically ovarian cancer with high IGF1 expression/low RAS score for Arm A; and KRAS wild-type CRC with high IGF1/low IGF2 expression for Arm B.
Response of nonenhancing regions in glioblastoma to VEGF-signaling inhibitor cediranib correlates with tumor infiltration.
Authors: Fakhro Summer A , Jennings Dominique , Pinho Marco C , Lin Nancy U. , Sorensen A. Gregory , Batchelor Tracy , Gerstner Elizabeth Robins 
Published: March 2020

3036 Background: Antiangiogenic therapy has limited direct antitumor effect in glioblastoma (GBM). Mainly its benefits may derive from anti-permeability and anti edema effects. In GBMs treated with cediranib we found that regions on MRI that are suggestive of being vasogenic edema, according to Diffusion Tensor Imaging (DTI) data, experience a greater decrease in volume than non-enhancing regions suggestive of being tumor infiltrated. Methods: Thirty-four newly diagnosed GBM patients were scanned on 3Tesla Siemens at two pre-therapy time points (2 days apart). Patients were treated with cediranib, standard radiation and temozolomide. Due to technical difficulties, 4 patients were left out of the analysis. Diffusion images were acquired with TR=7500ms, TE=84ms and b-values 0 and 700s/mm2 in 42 directions. A board certified radiologist determined the extent of abnormality on FLAIR and T1-weighted post contrast images. Non-enhancing regions (NER) were determined by subtracting the T1 enhancing area and any necrosis from the FLAIR abnormality. Volume of NERs was observed at baseline and day 47 of treatment. Mean Apparent Diffusion Coefficient (ADC) and mean Fractional Anisotropy (FA) of the NER were used to represent extent of tumor burden. Tumor Infiltration Index (TII), a measure based on comparing DTI metrics in metastatic tumors to GBM, was also derived. Twelve patients with metastatic cancer to the brain who underwent the same imaging and analysis pretreatment were used. High FA and low ADC and TII represent areas with more tumor burden. Results: There was a significant correlation between mean FA in the NERs at baseline and the percent volume reduction of the NER at day 47 (rho=0.45, p<0.02). Similarly, ADC and TII were correlated with percent volume reduction in the NER. Conclusions: DTI metrics have been used in GBMs to measure tumor infiltration. We found volume reduction of NERs to be inversely correlated to tumor burden. Thus, glioma patients with greater vasogenic edema may benefit from a different treatment paradigm than patients with lower vasogenic edema. [Table: see text]
Phase I dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.
Authors: Seto Takashi , Esaki Taito , Hirai Fumihiko , Arita Shuji , Nosaki Kaname , Makiyama Akitaka , Kometani Takuro , Fujimoto Chinatsu , Hamatake Motoharu , Takeoka Hiroaki , Agbo Felix , Shi Xiaojin 
Published: March 2020

3045 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label dose-escalation study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients (pts) with advanced solid tumors (NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a 14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000 mg/m2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762 dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at doses of 6 (n=3), 9 (3), 21 (6), and 30 mg (8). The most common primary tumor site was lung (n=14). All pts had received ≥1 prior chemotherapy and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0) elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated AST and ALT (Cycle 1; combination therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs resolved following treatment discontinuation. The most frequently reported adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia (50%), hypertension (25%) and fatigue (15%). Overall, the most common AEs were bradycardia (55%), neutropenia (45%), and hypertension, fatigue, and rash (30% each). AEs grade ≥3 were reported in 11 pts, the most common being neutropenia (45%) and leukopenia (25%). No pt died due to an AE. AZD7762 exposure (Cmax, AUC) increased in an approximately linear manner. Gemcitabine did not appear to affect AZD7762 PK. Arithmetic mean t½ and geometric mean CL of AZD7762 across the dose groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in combination with gemcitabine. There were no objective responses; five pts (all lung cancer) had stable disease. Conclusions: The maximum tolerated dose of AZD7762 in combinationwith gemcitabine 1000 mg/m2 was determined as 21 mg in Japanese pts.
A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.
Authors: Moore Amy Patricia , Truong Thach-Giao , Thurn Kenneth Ted , Thomas Scott , Ryan Charles J. , Jahan Thierry Marie , DuBois Steven G. , Chan John K. , Rugo Hope S. , Collisson Eric Andrew , Raha Paromita , Chen Stephanie , Reinert Anne , Daud Adil , Munster Pamela N. 
Published: March 2020

3058 Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.
Evaluation of toxicities of target therapy phase I and II trials on glioblastoma multiforme patients treated by curative radiotherapy: A meta-analysis.
Authors: Santos Marcos Antonio , Lefeuvre Delphine , Le Teuff Gwenael , Bouda Damien , Bourgier Céline , Domont Julien , Dhermain Frederic , Soria Jean-Charles , Deutsch Eric , Pignon Jean-Pierre 
Published: March 2020

3063 Background: An important limitation of the combination of target therapies (TT) to radiation (RT) is its potentially high level of toxicity. The objective of this study was to describe and quantify the drug related acute adverse events presented by patients taking part in phase I and/or phase II trials on TT combined to curative RT for the treatment of glioblastoma multiforme (GBM). Methods: A meta-analysis of summary data including all phase I, I/II and II trials published between 2000 and 2011 on newly diagnosed GBM patients treated by TT with RT was performed. Pooled incidence rates (IR) of all and specific toxicities were estimated using a generalized linear mixed model with fixed and random study effects. The pooled median of progression-free (PFS) and overall survivals (OS) were also considered. These results were compared to those obtained by patients receiving standard treatment (ST). Results: Twenty-one trials (8 phases I, 3 phases I/II and 10 phases II), testing 9 different drugs, have been selected, including 915 patients. The median follow-up varied from 1.4 to 34.0 months. The estimated pooled IR of all toxicities was 68.6 [53.5-88.0] per 1000 person-months of follow-up, compared to 20.7 [17.6-24.1] on ST (p<0.001). The pooled IRs of thrombocytopenia, neutropenia or leucopenia, fatigue, gastrointestinal events and treatment-related deaths are 11.2 [7.5-16.9], 9.0 [6.1-13.4], 6.4 [4.1-10.0], 5.5 [2.9-10.2] and 3.2 [1.6-6.4], compared to 4.1 [2.8-5.8], 4.9 [3.5-6.6], 4.6 [3.2-6.4], 0.8 [0.3-1.6] and 0.1 [0.0-0.6], respectively, on ST. Median survival times are 7.7 [6.1-9.8] and 13.8 months [11.9-16.1] on TT studies, and 6.9 [5.8-8.2] and 14.6 [13.2-16.8], on ST, for PFS and OS, respectively, without statistically significant difference (p=0.39 and 0.55). The heterogeneity among specific toxicities and survival endpoints may be partially explained by the study design and/or the intake or not of temozolomide. Conclusions: The use of TT combined to RT represented a significative increase in severe adverse events in patients with GBM compared to ST, whereas no significant difference was observed in survival endpoints. Grants from French Cancer League.
Microarray genomic expression (MAGE)-based therapy for heavily pretreated patients with metastatic solid tumors.
Authors: Rebollo Joseba , Gonzalez Manuel Sureda , Fernandez-Morejon Francisco Jose , Bretcha Pere , Rey Severino , Gonzalez Ramon , Farre Jose , Brugarolas A. 
Published: March 2020

3064 Background: Oligonucleotide-MAGE assay to identify tumor targets and potential active drugs based on molecular profiling in chemotherapy resistant/refractory (R/R) patients with metastatic solid tumors. A potential clinical benefit has been observed by Von Hoff et al (JCO 2010;20:4877-83). Methods: Patients (pts) with R/R metastatic solid tumors were included in the study. Pathology confirmed fresh-frozen biopsies were obtained and molecular profiling oligonucleotide-MAGE (Agilent Whole Human Genome 4x44K) results, confirmed whenever possible by IHC, were used to identify potential therapy targets. Results were discussed and offered to pts and the response evaluated using RECIST criteria. OS and PFS were measured from the beginning of therapy. All pts signed informed consent. Results: From August 2010 we performed 70 procedures in 69 pts. No complications derived from the biopsy were observed. Thirty pts did not follow therapeutic recommendations and 9 pts are too early to evaluate. Thirty procedures from 29 pts are clinically evaluable. Ten pts were male and 19 female, with a median (M) age of 57 years (range 41-70). Seven pts had breast cancer, 5 NSCLC, 5 pancreas, 4 CRC, 2 ovary and one each of gastric, parotid gland, biliary tree, head and neck, esophagus and gallbladder cancers, respectively. The M previous treatments were 3 (range 1 to >6). Oligonucleotide-MAGE assay confirmed resistance in 82% of drugs previously used. A M of 3 conventional (range 0-5) and 2 experimental (range 0-4) potentially active drugs were identified. Partial response was observed in 7 (26.9%), stable disease >2 months in 12 (46.1%) and progression in 7 (26.9%) pts. Four pts were not evaluable. MPFS was 4 months (95%CI: 1.815-6.185), MOS was 6 months (95%CI: 3.4-8.6) and 1-year projected OS was 21%. Conclusions: We confirmed that it is possible to identify new potentially active drugs in heavily pretreated solid tumor pts with oligonucleotide-MAGE assay. Therapy based on these drugs showed to be active in one fourth of treated pts. These assays might be also integrated in early tumor stages to aid in the selection of chemotherapy drugs, and for this reason deserve further studies. Updated results will be presented.
OM-RCA-01, an FGFR1 specific humanized antibody for the treatment of renal cell carcinoma (RCC).
Authors: Tsimafeyeu Ilya , Zaveleva Elina , Low Walter 
Published: March 2020

3070 Background: Fibroblast growth factor (FGF) receptor 1 (FGFR1) is a potential therapeutic target for the treatment of metastatic RCC. We investigated the preclinical activity of OM-RCA-01, a novel therapeutic humanized anti-FGFR1 antibody with high affinity (Kd of 1.59 nM), in RCC. Methods: To assess the effect of anti-FGFR1 antibody on FGF-mediated signaling, the human renal carcinoma Caki-1 FGFR1-expressing cells were dosed with OM-RCA-01 at 100, 10, and 1 mcg/ml. Control wells were left untreated. Three hours after dosing, bFGF was added at a concentration of 50 ng/ml. Additional control wells were treated with OM-RCA-01 without FGF-stimulation. Cell growth inhibition was determined using Promega’s Cell Titer-Glo assay. CR female NCr nu/nu mice were set up with 1 mm3 Caki-1 tumor fragments sc in flank. Tumor sizes were measured in a blind fashion twice a week with a vernier caliper. Mice with established tumors were randomly divided into vehicle, non-specific IgG or OM-RCA-01 groups per 10 animals in group. Endpoint was significant differences in tumor growth delay. Results: In vitro study showed that bFGF increased proliferation of the human FGFR1-expressing renal carcinoma cells (p=0.011). OM-RCA-01 antibody significantly inhibits FGF-triggered cell proliferation in comparison with control. In vivo, the tumors in untreated mice or mice treated with non-specific IgG continued their aggressive growth to reach the size of 2000 cm3, at which point the mice were killed. In contrast, treatment with OM-RCA-01 not only significant arrested further growth of the tumors (p=0.006) but also demonstrated differences in tumor volume compared with vehicle already on Day 13. A similar anti-tumor activity of OM-RCA-01 was observed when the antibody was given in low (1 mg/kg) or high (10 mg/kg) doses (p=0.917). Administration of 10 mg/kg antibody for up to 35 days resulted in minimal body weight loss and no observations of gross toxicity were made. Conclusions: Targeting FGFR1 blocks FGF/FGFR1 pathway in RCC. Monoclonal antibody OM-RCA-01 has significant early anti-tumor efficacy in Caki-1 xenograft model. Isolated blocking of FGFR1 by low-dose antibody could be safe and effective.