bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I and pharmacokinetic trial of the antitemolerase agent KML001 (KML) and cisplatin (CDDP) in advanced solid tumors.
Authors: Edelman Martin J. , Feliciano Josephine Louella , Styblo Miroslav , Liu Tao , Lapidus Rena G. , Saunders Jesse , Gobburu Joga 
Published: March 2020

2515 Background: Telomerase is overexpressed in most solid tumors and rarely expressed in adult tissues and is therefore a promising target. We have previously demonstrated that KML001 (sodium metaarsenite) displaces hTERT from the nucleus and is cytotoxic (Clin Cancer Res 14:4593-602, 2008). We have also demonstrated that it is synergistic with cisplatin. Methods: Pts with advanced solid tumors, PS 0-1, normal renal and hepatic function were eligible. Treatment was with CDDP 75 mg/m2 day 1 and KML p.o. daily days 1-14 on a 21 day cycle. It was planned that KML doses would be escalated by 2.5 mg beginning at 15 mg/day. A 3+3 design was employed. Blood specimens for arsenic and platinum pk were obtained at hours 0,1,2,3,4,5,6, 24 and day 15 and 22. Tumor blocks were required to assess for telomerase expression. Results: 18 patients (7M,11F) are evaluable for toxicity. Pts were heavily pretreated (median number of prior regimens =3). 16 had prior platinum therapy. The dose limiting toxicity was QTc interval prolongation seen in three patients in cohort 3 (20 mg) (two during cycle 1, one during cycle 2). A PR was seen in a patient with heavily pretreated SCLC in cohort 1. 1 other pt with SCLC and 2 with NSCLC also experienced reduction in disease burden. 10/18 pts received >3 cycles of therapy. Other common toxicities observed were nausea, vomiting and cytopenias. Significant, but not dose limiting, neutropenia or thrombocytopenia (> grade 3) was observed in cohorts 1 and 2. Myelosuppression was primarily seen in pts with prior radiotherapy. Non-compartmental analysis for inorganic arsenic (iAs) and the mono (MAs) and dimethylarsenic (DMAs) metabolites was performed (Table). Conclusions: 1. The combination of KML-001 and CDDP is feasible and active. 2. We are currently evaluating CDDP 75 mg/m2 and KML 17.5 mg in an expansion cohorts of advanced SCLC and NSCLC. 3. Studies of telomerase expression are in progress. (R21CA130349-01) Clinical trial information: NCT01110226. [Table: see text]
A phase I and biodistribution study of ABT-806i, an 111indium-labeled conjugate of the tumor-specific anti-EGFR antibody ABT-806.
Authors: Gan Hui Kong , Burge Matthew E. , Solomon Benjamin J. , Holen Kyle D. , Zhang Yumin , Ciprotti Marika , Merdan Thomas , Munasinghe Wijith , Pedersen Michelle , Hintzman Patricia F. , Fox Gerard B. , Humerickhouse Rod A. , Scott Andrew Mark 
Published: March 2020

2520 Background: ABT-806 is a humanized antibody targeting a conformationally exposed epitope only available when tumor Epidermal Growth Factor Receptor (EGFR) is overexpressed or (EGFRvIII) mutated. A prior trial treated 8 patients (pts) with a chimeric homologue (single-dose 5-40 mg/kg), with a minor response in one squamous cell carcinoma of skin pt. A prior phase 1A study of ABT-806 treated 26 pts (2-24 mg/kg IV q2w), with prolonged SD in one head and neck (H&N) cancer pt. No pt had a typical EGFR-inhibitor rash. The current study gathers further ABT-806 clinical data, assesses ABT-806i dosimetry in normal and malignant tissues and examines its relationship to clinical and PK/PD data. Methods: Pts with advanced tumors likely to express EGFR, ECOG 0-2, measurable disease and adequate organ function were enrolled. ABT-806i scans comprised ABT-806i 5-7mCi injection followed by whole body and regional SPECT scans over one week. Cohort (C) 1 pts (n=6) had ABT-806i scans alone. C2 pts (n=12) had ABT-806i scans at baseline and at week 6 (after 3 fortnightly doses of ABT-806; 6 pts at 18 mg/kg and 6 at 24 mg/kg). Subjects with PR/SD could receive ABT-806 on an extension study until progression. Results: 18 pts (M:F 11:7; median age 57 yrs) with tumors of H&N (6), colon (3), lung (2), brain (2), bladder (1), cervical (1) and other (3) were treated. An H&N pt had a confirmed PR whilst 5 pts had SD (lasting 37 and 24 wks in an adrenal carcinoma and H&N pt respectively). Two potential toxicities were seen at 24mg/kg on the extension study: equivocal rash (G1; three transient lesions on nose) and allergic reaction (Sweet’s syndrome, G2). Dosimetry in C1 pts confirmed safe radiation exposure levels to normal tissues. Many pts showed high, specific tumor uptake of ABT-806i, including 1 pt with an intracranial tumor. ABT-806i uptake was not significantly affected by concurrent ABT-806 treatment. Ongoing analyses of how ABT-806i uptake correlates with tumor EGFR and clinical response may inform the recommended phase 2 dose of ABT-806. Conclusions: The high therapeutic index and specificity of ABT-806 merits further investigation as monotherapy or an antibody-drug conjugate. ABT-806i may have utility as a bioimaging agent. Clinical trial information: NCT01472003.
A first-in-human trial of RG7116, a glycoengineered monoclonal antibody targeting HER3, in patients with advanced/metastatic tumors of epithelial cell origin expressing HER3 protein.
Authors: Meulendijks Didier , Lolkema Martijn P. J. K. , Voest Emile E. , De Jonge Maja J. , Sleijfer Stefan , Schellens Jan HM , Fleitas Tania , Cervantes-Ruiperez Andres , Martinez-Garcia Maria , Taus Alvaro , Soerensen Morten Mau , Thomas Marlene , Meneses-Lorente Georgina , Adessi Celine , Di Scala Lilla , Keelara Abiraj , Jacob Wolfgang , Weisser Martin , Lassen Ulrik Niels 
Published: March 2020

2522 Background: The Human Epidermal Growth Factor Receptor 3 (HER3) is a key heterodimerization partner for other HER family members thereby acting as a downstream signal amplifier. This is a first in human study evaluating the safety of RG7116, a humanized anti-HER3 monoclonal antibody with potent HER3 signal inhibition. Due to a glycoengineered Fc-part this antibody displays enhanced antibody-dependent cellular cytotoxicity as compared to conventional antibodies. Methods: Patients (pts) with advanced or metastatic carcinomas with centrally confirmed HER3 protein expression were included. A “3+3” dose escalation design was performed starting at 100 mg flat dosing in a q2w regimen. In addition to single agent RG7116 (Part A), RG7116 plus cetuximab (Part B) and RG7116 plus erlotinib (Part C) combinations are evaluated. The results of Part A are presented. Results: Twenty-five pts have been enrolled in 6 cohorts (100 to 2000 mg). No DLTs were observed. Pts had a median (range) of 3 (2 to 6) prior chemotherapy lines. Nine infusion-related reactions (IRRs) Gr 1 to 3 occurred in 7 pts. Three drug-related AEs Gr 3 were reported, 1 IRR, 1 GGT increase, and 1 neutropenia. Only 1 patient was tested positive for human anti human antibodies (HAHA). The PK of RG7116 was non-linear from 100 mg up to 400 mg, possibly as a result of target-mediated drug disposition. Both Cmax and AUC showed a greater than doseEproportional increase over the same dose range, accompanied by a decline in total clearance. Dose proportionality was observed from 800 mg onwards. PD effects were observed from the first dose level onwards with HER3 membranous protein down-regulation in skin and from 200 mg onwards in ontreatment tumor samples. Five pts (1 NSCLC, 2 CRC, 1 SCCHN, 1 BC) had a best response of SD. Confirmed SD (>16 weeks) was observed in 2 pts. One BC patient achieved a PR in 18 FDG-PET and significant shrinkage of non-target tumor lesions on CT scan. Conclusions: RG7116 is the first glycoengineered monoclonal anti-HER3 antibody in clinical development. RG7116 monotherapy was well tolerated, and demonstrated preliminary signs of clinical activity. Clinical trial information: NCT01482377.
Combination of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial.
Authors: Heist Rebecca Suk , Gandhi Leena , Shapiro Geoffrey , Rizvi Naiyer A. , Burris Howard A. , Bendell Johanna C. , Baselga Jose , Yerganian Scott B , Hsu Karl , Ogden Janet , Vincent Loïc , Richter Oliver von , Locatelli Giuseppe , Asatiani Ekatherine , Infante Jeffrey R. 
Published: March 2020

2530 Background: PI3K/mTOR and MAPK signaling pathways are often deregulated in tumors. Simultaneous inhibition of these pathways with the MEK1/2 inhibitor, pimasertib, plus the dual PI3K/mTOR inhibitor, SAR245409, (ClinicalTrials.gov NCT01390818) was investigated. Methods: This was a phase Ib, modified 3+3, dose-escalation trial in patients (pts) with advanced solid tumors. Pts received pimasertib and SAR245409 at the following dose levels (DLs): DL1, 15/30; DL2a, 30/30; DL2b, 15/50; DL3, 30/50; DL4a, 60/50; DL4b, 30/70; DL5, 60/70; DL6a, 90/70; DL6b 60/90 and DL7, 90/90 mg (once-daily, qd). After the qd maximum tolerated dose (MTD) was established, twice-daily (bid) dosing was tested: DL1a, 60/30; DL1b, 45/50 and DL2 60/50 mg bid. A recommended phase II dose (RP2D) was determined. Enrollment continued at the RP2D in four expansion cohorts (18 pts each): dual KRAS/PIK3CA mutated (mt) colorectal cancer (CRC), triple-negative breast cancer, KRAS mt non-small cell lung cancer (NSCLC) and BRAFmt melanoma. Results: 53 pts were treated qd and 7 pts bid. The most common tumors were CRC (n=16), NSCLC (n=8), ovarian and pancreatic (n=7, each). At DL6b 2/3 pts had dose-limiting toxicities (DLTs; both grade [Gr] 3 nausea/vomiting). DL6a was confirmed as the MTD for the qd schedule. At bid DL1a 2/4 pts (both Gr 3 skin rash) and at DL1b 2/3 pts (Gr 3 skin rash and Gr 3 asthenia) had DLTs. DL5 was the RP2D based on tolerability after prolonged exposure. The most common adverse events in qd schedule were: rash (62%, 13% Gr 3), diarrhea (56%, 4% Gr 3), fatigue (51%, 2% Gr 3), nausea (49%, 2% Gr 3), vomiting (45%, 2% Gr 3), peripheral edema and pyrexia (34%, each) and visual impairment with underlying serous retinal detachment (21%). Preliminary pharmacokinetic results suggest no drug-drug interaction. There were 4 partial responses: KRAS mt CRC (n=1) and low-grade ovarian cancer (n=3, 1 KRAS mt/PIK3CA mt and 2 wild-type). Enrollment in expansion cohorts at DL5 is ongoing. Conclusions: Continuousqd dosing of pimasertib and SAR245409 is tolerated and has shown signs of activity. Phase II trials are being planned. Clinical trial information: NCT01390818.
Safety, pharmacokinetics, and preliminary activity of the α-specific PI3K inhibitor BYL719: Results from the first-in-human study.
Authors: Gonzalez-Angulo Ana M. , Juric Dejan , Argilés Guillem , Schellens Jan HM , Burris Howard A. , Berlin Jordan , Middleton Mark R. , Schuler Martin H. , Geel Robin Van , Helgason Thorunn , Bootle Douglas , Boehm Markus , Goggin Timothy K. , Demanse David , Quadt Cornelia , Baselga Jose 
Published: March 2020

2531 Background: BYL719 is an oral small-molecule inhibitor of the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which is encoded by the PIK3CA gene, one of the most commonly mutated genes in human cancers. BYL719 inhibits proliferation of PI3Kα-driven cancer cell lines in vitro and causes regression of PIK3CA-mutant tumor models in vivo. Methods: This Ph I study was performed in patients (pts) with advanced solid tumors carrying a somatic mutation of PIK3CA. Dose escalation used an adaptive Bayesian logistic regression model with overdose control. Following determination of the maximum tolerated dose (MTD), an expansion cohort was opened at the MTD to evaluate safety, pharmacokinetics (PK), and clinical activity in pts with PIK3CA-mutant advanced solid tumors, including estrogen receptor-positive (ER+) metastatic breast cancer (mBC). Results: During dose escalation 36 pts received doses up to 450 mg/d, where 4/9 pts had dose-limiting toxicities (DLTs). The MTD for once-daily dosing was declared as 400 mg/d. As of Nov 20 2012, DLTs were hyperglycemia, nausea, vomiting, and diarrhea. The most common BYL719-related adverse events (all grades, all cohorts, >25%) were hyperglycemia (49%), nausea (45%), diarrhea (40%), decreased appetite (38%), vomiting (30%), and fatigue (27%). 39 pts are enrolled in the MTD dose-expansion cohort. Investigation of a twice-daily regimen is also ongoing. BYL719 has a favorable, approximately dose-proportional PK profile with a Tmax of 2h and a T½ of 11h at the MTD. Partial responses were seen in 7 pts (in ER+ breast [2], cervical, trichilemmal, endometrial, ovarian, and head &neck cancer [1 each]); 17 pts stayed on study for >24 weeks. For 67 pts (76%) treated at doses of ≥270 mg/d, the median progression-free survival (mPFS) was 3.6 months (mo; 95% CI: 3.5–5.5 mo). mPFS in 15 ER+ HER2– mBC pts treated at ≥270 mg/d was 5.5 mo (95% CI: 3–7 mo). Conclusions: BYL719 displays dose-proportional and predictable PK. The safety profile is favorable, with mostly manageable on-target toxicities. At doses of ≥270 mg/d, tumor regression and prolonged disease control were observed in heavily pretreated pts with various tumor types carrying a PIK3CA mutation. Clinical trial information: NCT01219699.
First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors.
Authors: Smith David C. , Rosen Lee S. , Chugh Rashmi , Goldman Jonathan Wade , Xu Lu , Kapoun Ann , Brachmann Ranier K , Dupont Jakob , Stagg Robert J. , Tolcher Anthony W. , Papadopoulos Kyriakos P. 
Published: March 2020

2540 Background: The WNT pathway is a key oncologic pathway in numerous tumor types. Vantictumab is a first-in-class anti-Cancer Stem Cell (CSC) antibody that interacts with the extracellular domain of 5 Frizzled receptors (1, 2, 5, 7, 8) and blocks canonical Wnt signaling (PNAS 109, 11717). In patient-derived xenograft models, vantictumab inhibits growth of many tumor types, reduces CSC frequency, promotes differentiation of tumor cells, and synergizes with many chemotherapeutic agents. Methods: Using a 3+3 design, vantictumab was given intravenously, first every 1 week (q1w) or q2w, and, ultimately, q3w. Objectives were determination of maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: 18 patients have been treated in 5 dose-escalation cohorts (0.5 & 1 mg/kg q1w; 0.5 mg/kg q2w; 1 & 2.5 mg/kg q3w). Most common related adverse events (AEs) included Grade 1 and 2 fatigue, vomiting, abdominal pain, constipation, diarrhea and nausea. Only related Grade ≥3 AEs were dose-limiting toxicities of Grade 3 diarrhea and vomiting in 1 patient at 1 mg/kg q1w. Vantictumab clearance was dose-dependent, consistent with target-mediated drug disposition, with the half-life ranging from 1.5 (0.5 mg/kg) to 3 days (2.5 mg/kg). Exposure at highest dosed cohorts correlates with efficacy in preclinical tumor models. PD biomarkers indicate manipulation of WNT pathway in patient tumors and surrogate tissue. 1 patient at 0.5 mg/kg q1w had a bone fracture on Day 110 with an ~4-fold increase by Day 28 of β-C-terminal telopeptide (β-CTX), a marker for bone degradation. A revised safety plan and less frequent dosing enabled further dose escalation. Upon β-CTX doubling, 2 patients received zoledronic acid, and β-CTX returned to baseline. 3 patients with neuroendocrine tumors (NETs) had stable disease (SD) for 7+, 3.5, and 9+ months; ~2-, 4- and 7-fold longer, respectively, than on prior therapy. Conclusions: Vantictumab is well tolerated up to 2.5 mg/kg q3w. Bone toxicity appears manageable and reversible. Prolonged SD in 3 patients with NETs may represent single-agent activity. Dose escalation continues. Clinical trial information: NCT01345201.
A dose-escalation phase I study of a first-in-class cancer stemness inhibitor in patients with advanced malignancies.
Authors: Langleben Adrian , Supko Jeffrey G. , Hotte Sebastien J. , Batist Gerald , Hirte Hal W. , Rogoff Harry , Li Youzhi , Li Wei , Kerstein David , Leggett David , Hitron Matthew J. , Li Chiang 
Published: March 2020

2542 Background: Cancer Stem Cells (CSC) are considered to be fundamentally responsible for malignant growth, relapse, metastasis, and resistance to conventional therapies. BBI608 is an orally-administered first-in-class cancer stemness inhibitor which blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells by inhibition of the Stat3, Nanog and b-catenin pathways, and has shown potent anti-tumor and anti-metastatic activities pre-clinically. Methods: A phase 1 dose escalation studyin adult patients with advanced cancer who had failed standard therapies was conducted to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary anti-tumor activity of BBI608. A modified Simon accelerated titration scheme was used for dose escalation, with a cycle consisting of twice-daily oral administration of BBI608 for 4 weeks. Cycles were repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or other discontinuation criteria were met. Results: Fourteen cohorts (N=41) were dosed from 20 mg to 2000 mg/day with adverse events being generally mild; the most common being grade 1-2 diarrhea, nausea, anorexia and fatigue. Four grade 3 events included diarrhea (n=3) and fatigue (n=1). MTD was not reached and further dose escalation was limited by pill burden. By the 400 mg/day dose level the plasma concentration of BBI608 was sustained for over 8 hours at a concentration above 1.5 uM (several fold above the IC50). 17/26 patients evaluable for tumor response achieved SD, for a DCR of 65%. Prolonged TTP was observed in 12/26 evaluable patients (46%), including patients with colorectal (CRC), head and neck, gastric, ovarian, melanoma, and breast cancer. In the subset of patients with CRC (N=18), SD was seen in 8/12 evaluable (67%). A median PFS of 14 weeks and median OS of 47 weeks were observed in evaluable CRC patients. Conclusions: Dose escalation of BBI608, a first-in-class cancer stem cell pathway inhibitor, has been achieved without dose limiting toxicity. BBI608 has shown an excellent safety profile, favorable pharmacokinetics, and encouraging signs of clinical activity particularly in CRC Clinical trial information: NCT01775423.
Influence of mild and moderate hepatic impairment on the pharmacokinetics (PK) of the pan-HER inhibitor dacomitinib.
Authors: Giri Nagdeep , Plotka Anna , Liang Yali , Boutros Tanya , Ni Grace , Masters Joanna , DeMicco Michael , Pardo Patricia , Bello Carlo , O'Connell Joseph 
Published: March 2020

2568 Background: Dacomitinib (D) is a highly selective irreversible small molecule inhibitor of the HER family of tyrosine kinases in clinical development for NSCLC.Prior clinical studies of D, which has minimal renal excretion (~3%), enrolled pts with protocol-defined adequate liver function. Liver metastases, leading to abnormal liver function tests, are common in pts with advanced cancer. This study evaluated the effect of hepatic impairment on PK and safety of D following a single oral dose in subjects with mild or moderate hepatic impairment. Methods: In this phase I, open-label, parallel group study, 25 subjects with either normal hepatic function (n=8) or mild (Child-Pugh A; n=8) or moderate (Child-Pugh B; n=9) hepatic impairment were administered a single, oral dose of D (30 mg). PK samples were collected at intervals up to 264 h post-dose and safety was assessed by laboratory abnormalities, physical examination, vital signs, ECGs, and AE monitoring. Analysis of variance was performed on natural log-transformed AUC and Cmaxto estimate adjusted mean differences between groups and 90% CIs, which were exponentiated to produce the adjusted GMR and 90% CI of the ratios. Results: GMR and 90% CI for AUCinf and Cmax (preliminary analyses) are listed.Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Moderate hepatic impairment decreased D exposure by 15% and 20% for AUCinf and Cmax, respectively, vs normal hepatic function, but the 90% CI was relatively wide, and included 1. Plasma protein binding of D was similar in the 3 groups. No clinically significant treatment-related AEs were reported. Conclusions: Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Mean D exposure appeared slightly lower in subjects with moderate impairment. Dose reduction of D in subjects with mild or moderate hepatic impairment may not be necessary. A single 30 mg dose of D was well tolerated in subjects with mild or moderate hepatic impairment. Clinical trial information: NCT01571388. [Table: see text]
A first-in-human phase I study of CZ48, a lactone ring protected oral camptothecin, in patients with advanced solid tumors.
Authors: Mahalingam Devalingam , Shaheen Montaser F. , Sarantopoulos John , Weitman Steven , Giovanella Beppino C. , Cao Zhisong , Coil Douglas , Markides Constantine , Liu Lucy , Verschraegen Claire F. 
Published: March 2020

2578 Background: CZ48, the 20-O-propionate ester of camptothecin (CPT), is a prodrug of CPT first described by Cao et al. in 1998. The side-chain is enzymatically cleaved in tissues. This gives rise to CPT, a potent inhibitor of topoisomerase I. Methods: An open-label, single-arm, dose-escalation Phase I study was performed to determine the maximum tolerated dose (MTD) of CZ48 in patients with advanced solid tumors. Initial dosing started qd po 80mg/m2, advancing to 2560mg/m2 for 21 consecutive days, followed by 7 days rest. Dosing was restarted in cohorts of 3 patients tid po at 18mg/m2 and escalated to 1g/m2on a 5 days on, 2 days off schedule for 28 days. Patients were prescreened by measuring CPT levels in plasma following a single pilot dose of CZ48. Dose was doubled until occurrence of at least Grade 2 adverse event, at which time 3+3 patient cohorts with a dose escalation of 33%-100% were implemented. DLT in 2/6 patients defined the MTD as the preceding DLT dose. PK parameters were measured prior to dosing, days 1-5, and day 28 of Cycle 1. Results: Poor absorption led to initial qd dosing reaching 2560mg/m2 with no signs of DLT. Subsequent tid dosing showed improved plasma levels and arrival at DLT. 34 patients were treated across 8 dose levels from 18 to 1000 mg/m2. The most frequent study-related adverse effects were cystitis, vomiting, diarrhea and fatigue. Grade IV toxicities observed were febrile neutropenia, anemia, and thrombocytopenia. Preliminary PK data in the qd dosing showed poor correlation between dose and Cmax or AUC, while PK in tid patients showed slightly improved correlation between dose and both CZ48 AUC (Pearson's correlation coefficient ϱ=0.476, p<0.01) and CZ48 Cmax(ϱ =0.51, p<0.01). Evidence of clinical activity with stable disease ≥ 6 months was observed in 2 heavily pre-treated colon and one breast cancer patient. Conclusions: The MTD of tid po CZ48 administered 5 days on, 2 days off of 28-day cycle is between 750 mg/m2 and 576 mg/m2. Overall toxicity is relatively mild, with DLT being cystitis and myelosuppression. Even with tid dosing, PK values correlate poorly to dose. A new formulation with 3-5 fold higher preclinical absorption values is being considered for introduction into the trial. Clinical trial information: NCT00947739.