bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors.
Authors: Mehra Ranee , Camidge D. Ross , Sharma Sunil , Felip Enriqueta , Tan Daniel Shao-Weng , Vansteenkiste Johan F. , De Pas Tommaso Martino , Kim Dong-Wan , Santoro Armando , Liu Geoffrey , Goldwasser Meredith , Dai David , Radona Marietta , Boral Anthony , Shaw Alice Tsang 
Published: March 2020

3007 Background: LDK378 is a novel, potent and selective small molecule anaplastic lymphoma kinase (ALK) inhibitor (IC50 0.00015 μM), that does not inhibit c-MET (IC50 3.2 μM). Tumor regression has been observed in ALK-driven NSCLC xenografts. A first-in-human, Phase I study is being conducted to determine the MTD and safety profile in patients (pts) with tumors with ALK rearrangement, amplification or mutation. Other objectives were safety, PK and antitumor activity in pts with ALK-driven NSCLC, both naïve to ALK inhibitors and relapsed following previous ALK inhibitor treatment, and other ALK-positive cancers. Methods: Adult pts with advanced malignancies harboring a genetic alteration in ALK who progressed on standard therapy or for whom there was no effective therapy, were given once daily oral LDK378 on a continuous 21-day schedule. Dose escalation, starting at 50 mg/day, was guided by a Bayesian logistic regression model (BLRM) to determine the MTD. Results: At a January 5th 2012 cutoff,31 pts (primary site: lung 26 pts; breast 3 pts; other 2 pts; median age 52 years; 87% ECOG PS 0/1) were enrolled and received LDK378 at doses of 50–750 mg/day. Two dose limiting toxicities, Grade (Gr) 3 alanine aminotransferase elevation (1 pt), and Gr 3 hypophosphatemia (1 pt) occurred in 8 pts at a 400 mg dose level. BLRM allowed dose escalation, and there were no DLTs in 4 pts at 500 mg. Median duration of treatment with LDK378 was 7 weeks (range <1–22+). At the cutoff date, 13 (42%) pts discontinued treatment: 1 (3%) due to adverse events (AEs), and 12 (39%) due to disease progression; 18 (58%) pts were still on treatment. The most frequent AEs (all Gr) were nausea (45%), vomiting (36%), and diarrhea (29%). The most frequent Gr 3/4 AEs were diarrhea and dyspnea (2 pts [7%] each). At doses ≥400 mg steady state exposures exceeded efficacious exposures in xenograft models. Of 16 pts with available response data (RECIST, per investigator) there were 4/6 responses in crizotinib (CRZ)-treated pts, and 2/10 responses in CRZ-naïve pts, of whom 7 were treated below 400 mg. All responses were in NSCLC. Conclusions: Daily oral LDK378 is well tolerated up to 500 mg/day, and escalation continues at 750 mg/day. Preliminary responses have been seen in both CRZ-naïve and CRZ-relapsed pts.
A phase I study of selective cyclin dependent kinase inhibitor P1446A-05 administered on an intermittent schedule in patients with advanced refractory tumors.
Authors: Gupta Sudeep , Jain Minish Mahendra , Maru Anish , Nag Shona Milon , Somani Naresh , Mehta Ajay O. , Kulkarni Sujay , Acharya Shivani Anil , Dhobe Poornima , Jadhav Nitin 
Published: March 2020

3011 Background: Cyclin-dependent kinases (Cdks) have emerged as important targets in anticancer drug development. P1446A-05 is a potent and specific inhibitor of Cdk4-D1 (IC50-0.09µM), Cdk1-B (IC50-0.025µM), and Cdk9-T (IC50-0.022µM). This study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT), safety profile, pharmacokinetics, and antitumor activity of orally administered P1446A-05 in patients with advanced refractory tumors. Methods: This study was conducted at 5 centers in India. P1446A-05 was administered in escalating doses across 5 cohorts of eligible pts starting with a dose of 75 mg once a day (OD) for 14 days in a 21 day cycle utilizing a modified Fibonacci scheme for dose escalation. 10 pts positive for cyclin D1 expression in the tumor were enrolled at MTD. Treatment was continued until unacceptable toxicity or disease progression. For pharmacokinetic analysis, blood samples were collected on days 1 and 13/14 of cycle 1 at multiple time points. In consenting pts, skin and tumor tissue biopsies were collected on days 1 (pre-dose), 8 and 15 of cycle 1. Results: A total of 29 patients were dosed. Two DLTs (abdominal pain and acute renal failure) were reported at 850 mg/d. The MTD was 600 mg/d and diarrhea was reported as 1 DLT at this dose level. Six SAEs including one death related to study drug were reported. Pharmacokinetic analysis demonstrated a median half-life of 16 to 26 h and linear increase in exposure at steady state across tested doses. Plasma concentration at 300 mg/d dose level crossed efficacy exposure of 100mg/kg of five day dosing in SCID mice. The recommended phase II dose is 600 mg OD on this schedule. Stable disease for 4 to 6 cycles was reported in 5 pts. Of them, one patient each with breast cancer, spindle cell sarcoma in neck, and nasopharyngeal carcinoma had cyclin D1 over expression. No objective responses were observed in this group of heavily pretreated patients. Conclusions: The safety profile of P1446A-05 is considered acceptable. On this dosing schedule, the MTD is determined as 600 mg/day. Further testing of P1446A-05 in phase II studies is planned.
A first-in-human phase I study to evaluate the fully human monoclonal antibody OMP-59R5 (anti-Notch2/3) administered intravenously to patients with advanced solid tumors.
Authors: Tolcher Anthony W. , Chugh Rashmi , Chambers Glenda , Thorpe Villette , Dupont Jakob , Hill Dawn , Xu Lu , Kapoun Ann , Smith David C. 
Published: March 2020

3025 Background: The Notch pathway plays a central role in embryonic development, the regulation of stem and progenitor cells, and is implicated centrally in many human cancers. OMP-59R5 is a fully human IgG2 originally identified by binding to Notch2. It inhibits the signaling of both Notch2 and Notch3 receptors. Mouse xenograft studies using minimally-passaged, patient-derived xenografts show that OMP-59R5 impedes tumor growth and eliminates cancer stem cells (CSCs) in many tumor types. OMP-59R5 modulates the expression of stromal genes and genes associated with the function of tumor vascular pericytes. As such, OMP-59R5 is a novel anti-cancer agent that inhibits tumor growth through direct actions on tumor cells, including CSCs, and effects the stroma and vasculature. Methods: A phase I dose escalation study (3+3 design) was initiated in solid tumor patients. OMP-59R5 was administered to study safety, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy, and to determine the maximum tolerated dose (MTD). Results: Twenty-four patients have been enrolled in 5 dose-escalation cohorts at doses of 0.5, 1, 2.5, and 5mg/kg administered weekly (QW) and 5mg/kg administered every other week (QOW). The most frequently reported drug-related adverse events were: mild to moderate diarrhea, fatigue, nausea, vomiting, decreased appetite, and constipation. Diarrhea was dose related and occurred at doses ≥2.5mg/kg weekly and appears less pronounced with every other week dosing. Two dose-limiting toxicities (grade 3 diarrhea and grade 3 hypokalemia) occurred at 5mg/kg QW and 2.5mg/kg was established as an MTD for QW dosing. A QOW dosing schedule is currently under investigation. The PK of OMP-59R5 was characterized by fast and dose-dependent clearance. Two patients (Kaposi’s sarcoma at 5mg/kg and adenoid cystic carcinoma at 2.5mg/kg) had prolonged stable disease for ≥110 days. PD analyses for Notch pathway modulation are ongoing. Conclusions: OMP-59R5 is generally well tolerated. An MTD of 2.5mg/kg QW has been established and a QOW schedule is currently under study. Updated results will be presented.
Phase Ib safety trial of CVX-060, an intravenous humanized monoclonal CovX body inhibiting angiopoietin 2 (Ang-2), with sunitinib.
Authors: Rosen Lee S. , Mendelson David S. , Gordon Michael S. , Goldman Jonathan Wade , Allen Jeffrey Warren , Curti Brendan D. , Chen Charles , Perea Rachelle , Gollerkeri Ashwin 
Published: March 2020

3032 Background: CVX-060 (CVX) is a humanized monoclonal antibody fused to two Ang2 binding peptides. The recommended phase 2 dose (RP2D) is15 mg/kg/wk by intravenous (IV) infusion. Sunitinib (Sun), a kinase with many targets including VEGFR1-3, is dosed 50 mg/day orally x 4/6 wks. Methods: Patients (pts) with solid tumors were to receive CVX at doses of 6, 12, or 15 mg/kg/wk with Sun 50 mg/day x 4/6 wks in successive cohorts. Standard definitions of dose limiting toxicities (DLTs) were used. Serum PK was assessed by ELISA. Results: Thirty-four pts were treated at 5 dose levels (DL) –see table. The median age was 62 years (29-76), ECOG performance status 0-1. The safety of CVX plus lower Sun dose was established in DL 1.1 due to DLTs at the initial cohort. The safety of full dose Sun was further established in 1.2 before further escalating the CVX dose. Overall, DLTs related to CVX and Sun included hemorrhage (DL 1.0), asymptomatic proteinuria (DL 1.2), ischemic colitis/lower GI bleed/recurrent lower GI bleed (DL 3.0) and abdominal pain/microperforation on CT (DL 3.0). The most common adverse events (AEs) related to either agent were fatigue (68%), diarrhea (50%), nausea (47%), hypertension (35%), and dysgeusia (32%). The majority of AEs were Gr 1 to 2. There were no PK interactions between CVX and Sun. Total serum Ang2 (bound plus free) increased with CVX treatment. Of the 34 patients, 24 (71%) remained on study ≥ 8 weeks and 2 patients continue on treatment ≥ 9 months. Anti-drug antibodies were seen in 16 patients at low titers without effects on PK or safety. Conclusions: In pts with advanced disease, CVX is able to be combined at the RP2D with Sun at its labeled dose without exacerbation of Sun-associated toxicities. Combination trials of CVX and other VEGF inhibitors are planned. [Table: see text]
A phase Ib dose-escalation study of TRC105 in combination with bevacizumab for advanced solid tumors.
Authors: Mendelson David S. , Rosen Lee S. , Robert Francisco , Chiorean E. Gabriela , Goldman Jonathan Wade , Seon Ben K. , Alvarez Delia , Adams Bonne J. , Theuer Charles P. , Leigh Bryan R. , Gordon Michael S. 
Published: March 2020

3034 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is a human/mouse chimeric anti-CD105 monoclonal antibody that completed phase I testing and is being studied in multiple phase II trials. Methods: Pts with advanced solid tumors (non-CNS), ECOG PS 0-1, and normal organ function were treated with escalating doses of intravenously administered TRC105 plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk and assessed for safety, PK, and response. Results: Twelve pts were treated (3 with TRC105 at 3 mg/kg q1wk + BEV at 15 mg/kg q3wk, 5 with TRC105 at 6 mg/kg q1wk + BEV at 15 mg/kg q3wk, and 4 with TRC105 at 6 mg/kg q1wk + BEV at 10 mg/kg q2wk), and 10 have completed the DLT evaluation period. TRC105 at 6 mg/kg q1wk + BEV at 15 mg/kg q3wk resulted in grade 1-3 headaches with sinus congestion following the cycle 1 day 1 (C1D1) dose in 5 of 5 pts that improved with continued dosing. Treatment with BEV 10 mg/kg q2wk and sequential dosing with Bev starting on C1D1 and TRC105 on C1D8 resulted in decreased frequency and severity of headaches, allowing dose escalation to continue. TRC105 serum concentrations that saturate CD105 binding sites (>200 ng/mL) were achieved continuously at 6 mg/kg q1wk. At 3 mg/kg q1wk TRC105 + 15 mg/kg q3wk BEV, one pt with BEV-resistant ovarian cancer had stable disease for 6 cycles and one pt with refractory hepatocellular cancer who failed sorafenib and sunitinib had an AFP decrease from 1578 at baseline to 179 at the end of cycle 3. Two of three evaluable pts at 6 mg/kg q1wk TRC105 + 15 mg/kg q3wk BEV with VEGF-refractory tumors (HCC and CRC) are ongoing in C4 with stable disease. Dose escalation continues and TRC105 dose levels of 8 and 10 mg/kg are planned. Conclusions: The combination of TRC105 and BEV was tolerated with early evidence of activity in VEGF-refractory pts by sequential administration during initial dosing in C1.
Phase I study of safety and pharmacokinetics of fruquintinib, a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases in patients with advanced solid tumors.
Authors: Li Jin , Cao Junning , Zhang Jian , Fan Songhua , Sai Yang , MU Hua 
Published: March 2020

3038 Background: Fruquintinib is a novel oral small molecule compound discovered and developed by Hutchison MediPharma that selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has demonstrated potent inhibitory effects on multiple human tumor xenografts. This first-in-human study is conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of fruquintinib. Methods: This phase I study used the 3+3 design for dose-escalation of fruquintinib given once daily (QD) in 28-day cycles in patients with solid tumors who had failed standard therapies. Endpoints included safety, PK, and preliminary efficacy measurements. Results: To date 16 patients were enrolled in 5 dose cohorts of 1-6 mg QD, with age 42-69 yr, 44% male, ECOG 0-1 and all heavily pretreated. Tumor types included 9 colorectal, 3 lung, 3 breast, and 2 gastric (one patient with bi-primary carcinoma of breast and colon). The most common adverse events included hypertension (50%), proteinuria (43.8%), hand-foot syndrome (HFS 43.8%), diarrhea (31.2%), and hoarseness (25%). Grade 3/4 AEs were diarrhea (25%), HFS (12.5%), thrombocytopenia (6.2%), and hyperbilirubinemia (6.2%). Three DLTs were observed: 2 grade 3 HFS both at 6mg and 1 grade 3 hyperbilirubinemia at 4mg. PK analysis showed good and rapid absorption followed by slow terminal elimination with a half-life of approximately 37 hours which was consistent across all dose groups. Both Cmax and AUC exhibited good dose proportionality over the studied dose range with low inter-patient variability following single and multiple doses. Among 8 evaluable patients, 2 (1 colorectal and 1 gastric) had confirmed partial response for more than 4 months; 5 had stable disease, including 3 SDs of 3-8 months. Conclusions: Fruquintinib was well tolerated at doses up to 4 mg QD to date and demonstrated excellent pharmacokinetic properties. Encouraging clinical activity was observed. Further clinical studies are warranted and under planning.
Improved sorafenib activity on hepatocellular carcinoma in Notch3 silenced in vivo and in vitro models.
Authors: Baglioni Michele , Giovannini Catia , Gramantieri Laura , Baron Toaldo Marco , Ventrucci Cristiano , D'Adamo Stefania , Cipone Mario , Chieco Pasquale , Bolondi Luigi 
Published: March 2020

3061 Background: Sorafenib is the only approved drug for the treatment of the advanced stage of HCC. Although its efficacy has been proven with randomized clinical trials, the clinical benefit seen in overall survival for advanced HCC patients treated with sorafenib could be improved. New molecules or combination of novel targeted agents to improve sorafenib efficacy for advanced stage HCC patients are needed. Notch genes are a family of receptors involved in many cell fate regulations, their expression has been found altered in many tumors, including HCC. The aim of this study was to study the combination of sorafenib and Notch3 signaling inhibition to improve sorafenib’s therapeutic effect. Methods: HepG2 and Huh7 cellular models were used for Notch3 stable silencing by retroviral introduction of specific interfering RNAs Xenograft models in both Notch3 stable shRNA cell lines have been developed using NOD/SCID mice. Animals bearing tumors were treated with 60 mg/kg of sorafenib for 21 consecutive days. Notch3, p21 and pGSK3βSer9 protein expression were also analyzed in 20 human HCCs. Results: Notch3 silencing (shN3) in HuH7 and HepG2 cell lines treated with sorafenib showed an increase in cell death (3.8 to 5 fold increase) when shN3 cell lines were compared with their relative controls (GL2). A difference in tumor growth was observed between GL2 negative control vs shN3 xenografts in both HepG2 and Huh7 after 21 days of sorafenib treatment. Two tailed student’s t test (shN3 vs GL2) P=0,04 and P=0,01 for Huh7 and HepG2 respectively. Molecular investigations have shown the involvement of p21 and GSK3β in the enhanced response to sorafenib in Notch 3 silenced models. A significant inverse correlation between Notch3 and pGSK3βSer9 proteins accumulation (Spearman ρ= -0.666) (p < 0.01) and a direct correlation between Notch3 and p21 proteins expression (Spearman ρ= 0.681) (p < 0.01) was found in HCC samples obtained from patients. Conclusion: Our preclincal findings outline the effect of combined Notch3 inhibition and sorafenib. The molecular mechanisms responsible for sorafenib induced cell death associated with Notch3 silencing relays on inhibition of p21/CDKN1A and GSK3βSer9. This study is supported by a grant from Bayer Healthcare, Italy.
Integrated next-generation sequencing and patient-derived xenografts to personalized cancer treatment.
Authors: Garralda Elena , Calles Antonio , López-Ríos Fernando , Jones Siân , Kann Lisa M. , Angiuoli Samuel V. , Diaz Luis A. , Velculescu Victor E. , López-Casas Pedro P. , Sarno Francesca , Martinez Raquel , Gomez-Martin Carlos , Conde Esther , Belda-Iniesta Cristobal , Valencia Alfonso , Hidalgo Manuel 
Published: March 2020

3068 Background: The knowledge of actionable somatic genomic alterations present in each tumor is making possible the era of personalized cancer treatment. Methods: Using massively parallel sequencing we performed whole exome sequencing analysis of tumor and matched normal blood samples of 8 patients (2 pancreatic adenocarcinoma, 1 neuroendocrine tumor, 1 glioblastoma, 1 uveal melanoma, 1 colon cancer) to identify putatively actionable tumor specific genomic alterations. We used 2 in silico methods (Polyphen and SIFT) to estimate the functional significance of a given confirmed mutation. Primary xenografts (PDX), generated by direct engraftment of tumor samples from the patients into immunocompromised mice, were used as an in vivo platform that provided the opportunity to test proposed personalized medicine strategies. Results: At this time exome sequencing analyses have been performed for 5 patients (1 patient died prematurely, 1 tumor sample was insufficient, 1 result is pending). More than 30 million bases of target DNA were analyzed in the tumor and normal samples in every case, with at least 70 distinct reads at each base. Tumor specific mutations (Muts) and copy number variations (CNVs) were identified: 5 Muts in the neuroendocrine tumor; 62Muts/6CNVs and 38Muts/10CNVs in the pancreatic tumors; 63Muts/23CNVs in the glioblastoma; 5 Muts in the melanoma. All samples profiled contained actionable alterations with the most relevant mutations affecting NF1, PTPN11, EPHA3, CDKN2A, FAS (glioblastoma); PI3KCA, ARID1A, ARID1B, DDR2, SMAD4, TP53, KRAS, PTCHD3 (pancreatic); CREB3L3, ITPR2 (neuroendocrine); GNA11, TAOK3 (melanoma). PDX from the pancreatic cancer patient was treated with a PI3K inhibitor and dasatinib, reported to be effective in discodin domain receptor 2 (DDR2) mutant cancer with no effect. Accordingly treatment of that patient with dasatinib was not effective and the level of this mutation in the tumor was observed to be low. Conclusions: Detection of actionable tumor-specific genomic alterations in the clinical setting is feasible. In silico methods and primary xenografts can help in the challenge of linking confirmed mutations to protein function and ultimately to clinical utility.
A phase I study of HM781-36B, a novel pan-HER inhibitor, in patients (pts) with advanced solid tumors.
Authors: Kim Tae Min , Lee Keun-Wook , Oh Do-Youn , Lee Jong-Seok , Im Seock-Ah , Kim Dong-Wan , Han Sae-Won , Kim Yu Jung , Kim Tae-You , Kim Jee Hyun , Park Kyung-Mi , Son Jeewoong , Bang Yung-Jue 
Published: March 2020

3076 Background: HM781-36B is a pan-HER tyrosine kinase inhibitor, which showed a potent activity against the gefitinib- or erlotinib-resistant, EGFR L858R/T790M double mutant cells. A phase I study was conducted to determine the MTD, pharmacokinetics, and antitumor activity. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation part, and additional 12 pts were enrolled in the expansion cohort of molecular enrichment. Results: In dose-escalation part, 43 pts (median age: 55 yrs (range 25-82), M:F=25:18, ECOG PS 0/1/2/3: 23/17/2/1, median prior chemotherapy: 4) were treated. DLTs were G3 diarrheas in 5 pts, one at 12 mg, 16 mg, 24 mg, and two at 32 mg. The MTD was determined as 24mg. The most common drug-related adverse events were diarrhea, stomatitis, rash, pruritus, and anorexia. Among 41 evaluable pts, 4 pts achieved PR (1 unconfirmed, duration of response: 11.9 mo, 7.07 mo+, 4.5 mo+), and 19 pts had SD. Two of 4 PR pts were Her2-positive breast cancer pts. The median duration of treatment in pts with PR or SD was 3.87 (2.47- 15.17) months. In the dose range of 0.5 to 24 mg, it showed linear pharmacokinetics proportional to dose-escalation, relatively short half-life, and little accumulation. Additional 12 pts in the expansion cohort are under treatment at 24 mg (6 pts: EGFR-mutant NSCLC, 3 pts: Her2-positive gastric cancer, 2 pts: Her2-positive breast cancer, 1 pt: rectal cancer). Conclusions: HM781-36B was safe and well tolerable in advanced solid tumors. Preliminary evidence of anticancer activity has been observed. Updated data will be presented at the meeting.