bluuebunny/crossref_metadata_2025_split huggingface dataset:
A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors.
Authors: Becerra Carlos , Infante Jeffrey R. , Garbo Lawrence E. , Gordon Michael S. , Smith David A. , Braiteh Fadi S. , Gandara David R. , Jotte Robert M. , Reckamp Karen L. , Janku Filip , Burris Howard A. , Bellew Kevin M. , Gardner Olivia S. , Liu Li , Cox Donna S , Peddareddigari Vijay Gopal Reddy , Blumenschein George R. 
Published: March 2020

3023 Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherapy was given at full recommended doses. Erl was escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts have been enrolled across all arms except trametinib+nab-pac. Preliminary exposure results of trametinib+doc, erl, or pem suggest no PK drug-drug interaction. The predominant DLT for trametinib+doc without growth factors (MTD = 0.5 mg+60 mg/m2) was neutropenia. When administered with growth factors, trametinib+doc has been given up to 1.5 mg+75 mg/m2 with no DLTs. The predominant DLTs for trametinib+erl (MTD = 1 mg+100 mg) were diarrhea and mucositis and for trametinib+pem (MTD = 1.5 mg+500 mg/m2) were mucositis and febrile neutropenia. The MTD for trametinib+pem+carbo has not yet been determined. To date there are 5 PRs in the trametinib+doc group and 2 PRs in the trametinib+pem group. An NSCLC expansion cohort for trametinib+pem is enrolling. Conclusions: Trametinib+doc and trametinib+pem have shown acceptable tolerability and initial evidence of clinical activity.
First-in-human phase I study: Results of a second-generation non-ansamycin heat shock protein 90 (HSP90) inhibitor AT13387 in refractory solid tumors.
Authors: Mahadevan Daruka , Rensvold Diane M , Kurtin Sandra E , Cleary James M. , Gandhi Leena , Lyons John F. , Lock Victoria , Lewis Samantha , Shapiro Geoffrey 
Published: March 2020

3028 Background: AT13387 is a second-generation potent, novel non-ansamycin HSP90 inhibitor (IC50 0.71 nM). AT13387 has good tissue distribution, long tumor t1/2 resulting in extended knockdown of client proteins in cells and animal models of gastric, prostate and melanoma. Methods: AT13387 was administered as a 1-hr IV infusion twice weekly on Days 1, 4, 8, 11, 15 and 18 (Part A) and then subsequently, weekly on Days 1, 8 and 15 (Part B) of a 28-day cycle in a standard 3+3 dose-escalation design. The primary endpoint was to determine the MTD; secondary endpoints included PK, PD, safety and tolerability. Results: As of 1 Dec 2011, 53 patients received 1–12 cycles of AT13387 (median 2). In Part A, AT13387 was evaluated at 5 doses (10, 20, 40, 80, 120 mg/m2). In Part B, 4 additional doses (150, 220, 260 and 310 mg/m2) were explored. Common treatment related toxicities (≥ 10%) included transient and reversible GI disturbance (vomiting, nausea, dry mouth, diarrhea, abdominal pain), fatigue, local infusion site irritation and systemic infusion-related symptoms including chills, rash, itch, cardiovascular (tachycardia, bradycardia, hypertension, hypotension), and visual changes (diplopia, transient flashes, delayed light/dark accommodation, blurred vision). Severity of infusion-related symptoms, GI toxicities, and fatigue at 310 mg/m2 prevented further dose escalation. A dose of 260 mg/m2 has been identified as the once weekly MTD and the study is currently accruing at this dose. Biological evidence of HSP90 inhibition, demonstrated by an increase in HSP70 in PBMCs, was detected at all doses and exhibited evidence of dose dependence. PK demonstrated dose proportionality, without significant accumulation. One durable RECIST PR (8 months) in an imatinib relapsed metastatic GIST patient with c-kit mutations in exons 11 and 17 was observed. Three SD ≥ 6 months (follicular cell thyroid carcinoma, metastatic uveal melanoma, GIST) were also observed. Conclusions: The MTD of AT13387, administered as a once weekly IV, is 260 mg/m2. All drug-related toxicities were generally reversible. Single-agent activity was observed. Dose expansion at MTD and phase II studies are ongoing.
The effect of bevacizumab on targeting of anti-epidermal growth factor receptor and anti-insulin-like growth factor 1 receptor antibodies.
Authors: Heskamp Sandra , Boerman Otto C. , Molkenboer-Kuenen Janneke D.M. , Oyen Wim J.G. , Van Der Graaf Winette T.A. , Van Laarhoven Hanneke W.M. 
Published: March 2020

3035 Background: Bevacizumab and cetuximab are approved antibodies for treatment of patients with metastasized colorectal cancer. However, the combination of bevacizumab and cetuximab does not improve progression free survival (Tol et al. NEJM 2009). This may be explained by the disruption of tumor vascularity by bevacizumab, thereby reducing targeting of other antibodies to the tumor. The aim of this study was to determine the effect of bevacizumab on the targeting of anti-EGFR and IGF-1R antibodies in tumors with SPECT/CT imaging. Methods: Mice with subcutaneous EGFR and IGF-1R-expressing SUM149 xenografts were injected intraperitoneally with a single dose of bevacizumab (10 mg/kg). After four days, mice received an intravenous injection of 17 MBq 111In-labeled cetuximab, an anti-EGFR antibody, or R1507, an anti-IGF-1R antibody. A control group was injected with labeled hLL2 anti-CD22, an irrelevant IgG . Three days after injection, SPECT/CT images were acquired and mice were dissected for ex vivo biodistribution. Tumors were analyzed immunohistochemically to determine vascular density (CD34), EGFR and IGF-1R expression. Results: SPECT imaging revealed that bevacizumab treatment reduced targeting of anti-EGFR and anti-IGF-1R antibodies by 42% and 35%, respectively. Ex vivo biodistribution showed that uptake of 111In-cetuximab in untreated tumors was 35.2 ± 1.6 %ID/g, compared with 19.7 ± 5.3 %ID/g for bevacizumab treated tumors (p = 0.009). A similar effect was observed for 111In-R1507 (control: 26.7 ± 2.8 %ID/g, bevacizumab:18.9 ± 2.8 %ID/g, p =0.009). No significant differences in tumor uptake were observed in mice that received the irrelevant IgG. Immunohistochemical analysis showed that vascular density decreased with 40%, while EGFR and IGF-1R expression was unaltered. Conclusions: Bevacizumab treatment can significantly reduce targeting of other antibodies to tumors. This underlines the importance of timing and sequencing of bevacizumab therapy in combination with other antibodies.
Phase I, first-in-human trial of an oral VEGFR tyrosine kinase inhibitor (TKI) x-82 in patients (pts) with advanced solid tumors.
Authors: Moore Kathleen N. , Jones Suzanne Fields , Kurkjian Carla , Arkenau Hendrik-Tobias , Infante Jeffrey R. , Pant Shubham , Burris Howard A. , McMeekin D. Scott , Gibbons Jay , Harrow Kimberly , Liang Chris , Ramsey Sara , Bendell Johanna C. 
Published: March 2020

3041 Background: VEGFR TKIs have shown benefit in the treatment of various tumor types. Side effects of the TKIs have affected the duration of therapy pts can tolerate, as well as the combinability with chemotherapy. X-82 is a highly potent VEGFR/PDGFR TKI with a smaller volume of distribution and limited tissue accumulation designed to minimize side effects while maintaining target effect. Methods: Pts with advanced solid tumors were enrolled using an accelerated titration scheme followed by 3+3 dose escalation design. X-82 was administered orally once daily (QD) or twice daily (BID) every 28 days. Safety, pharmacokinetic, clinical endpoints and blood-based biomarkers were evaluated. Results: 16 pts were treated across 8 dose levels: 20 (n=1), 40 (n=1), 80 (n=1), 160 (n=1), 300 (n=2), 400 mg QD (n=3), 140 mg BID (n=3) and 200 mg BID (n=4). The most common related adverse events (AEs) by pt were fatigue (4 G1, 1 G2), nausea (3 G1, 1 G2), diarrhea (3 G1), anorexia (1 G1, 1 G2), and vomiting (2 G1). G2 hypertension, resolved with treatment, was experienced by 1 patient. No > G3 related AEs have been reported. Dose proportional exposure was observed with doses up to 160 mg QD, and BID dosing cohorts were added. At 160 mg QD X-82 has plasma concentrations >100 ng/mL for at least 12 hours, the desired exposure predicted preclinically. Preliminary blood biomarker data (n=8) shows >25% decrease in VEGFR1 in 62% of pts and in VEGFR2 in 25% of pts, including pts at 40 and 80 mg cohorts. Efficacy has also been noted, including 1 confirmed complete response lasting 24+ weeks (pancreatic adenocarcinoma), and 6 pts with stable disease lasting 8+ weeks (range 12.1+, 38.3+ weeks), including the pt at 20 mg with SCLC (25.1 weeks). Conclusions: X-82 is a well-tolerated VEGFR/PDFGR TKI designed to minimize side effects while inhibiting target receptors. No MTD has yet been defined, though preliminary biomarker data are encouraging and clinical efficacy has been noted.
Dose-specific clearance of TRC105 (anti-CD105 antibody) in advanced solid tumor patients.
Authors: Spencer Shawn D , Figg William Douglas , Rosen Lee S. , Gordon Michael S. , Hurwitz Herbert , Wong Michael K.K. , Goldman Jonathan Wade , Mendelson David S. , Adams Bonne J. , Alvarez Delia , Seon Ben K. , Theuer Charles P. , Leigh Bryan R. 
Published: March 2020

3042^ Background: CD105 is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels. TRC105 is an anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with advanced solid tumors and normal organ function were treated with escalating doses of intravenously administered TRC105 and assessed for safety and pharmacokinetics (PK). PK parameters for determining dose-linearity were estimated following single doses on in 16 patients at 3, 10 and 15 mg/kg and correlated with safety. Results: TRC105 was tolerated at 10 mg/kg weekly and 15 mg/kg every 2 weeks, but hyproliferative anemia was dose-limiting at 15 mg/kg weekly and was associated with TRC105 accumulation in serum from target saturation. Preliminary evidence of activity was observed with 21 of 45 evaluable patients progression-free at 2 months, including two ongoing responders. The AUC-single dose relationship of TRC105 revealed supra-proportionality in serum exposure at 15 mg/kg compared to 3 and 10 mg/kg. Dose proportionality using a power model revealed a nonlinear pharmacokinetic process (log[AUC] = 0.125*Dose+2.67, r2 = 0.92, ANOVA p<0.0035). The steady state volume of distribution was low (≈ 5.40 L/70kg) indicating TRC105 was confined to the vasculature with a low capacity target (i.e., low relative abundance) making it susceptible to saturation. The post-infusion Cmax however was linearly related to dose (r = 0.85) which suggested the nonlinearity in clearance was attributed to target-mediated disposition. The nonlinear disposition in the presence of low distribution indicated TRC105 bound avidly to endothelial cells. Concentrations expected to saturate CD105 binding were achieved continuously at 15 mg/kg dosed every 2 weeks and 10 mg/kg/wk. TRC105 accumulated at 15 mg/kg/wk as the accumulation factor at 56 days was 1.77-fold over single doses on C1D1. Conclusions: TRC105 clearance decreased above the MTD resulting in drug accumulation and hypoproliferative anemia with weekly dosing. The nonlinearity in clearance was attributed to saturating target-mediated disposition, consistent with binding to proliferating endothelial cells.
A phase I study of TRC105 (Anti-CD105 [endoglin] antibody) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Karzai Fatima H , Apolo Andrea Borghese , Adelberg David , Madan Ravi A. , Gulley James L. , Arlen Philip M. , Parnes Howard L. , Pierpoint Ann , Kohler David R. , Trepel Jane B. , Price Douglas K. , Steinberg Seth M. , Figg William Douglas , Dahut William L. 
Published: March 2020

3043 Background: Pre−clinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate (ORR) and overall survival (OS). Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Six cohorts of patients, on escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10, 15, or 20 mg/kg IV every 2 weeks (cohorts 1, 2, 3, 5, and 6) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with imaging studies every 2 months for the first four months and then every 3 months thereafter. Results: Sixteen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range 0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range 8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with measurable soft tissue disease achieved stable disease for at least two cycles. Conclusions: TRC105 is tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. An additional cohort (6), with dosage of 20 mg/kg, is currently under investigation. Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of this study.
SORAVE: Phase I study for the treatment of relapsed solid tumors with the combination of sorafenib and everolimus.
Authors: Nogova Lucia , Mattonet Christian , Scheffler Matthias , Bos Marc Christiaan Allardt , Gardizi Masyar , Papachristou Irini , Muthen Noemi , Rokitta Denis , Kinzig Martina , Soergel Fritz , Fuhr Uwe , Kahraman Deniz , Kobe Carsten , Rhiem Kerstin , Mallmann Peter , Schnell Roland , Katay Ildiko , Schlaak Max , Dietlein Markus , Wolf Juergen 
Published: March 2020

3044 Background: Dual inhibition of signaling pathways interfering with angiogenesis and cell proliferation may increase anti-tumor efficacy. We evaluated the combination of the VEGFR inhibitor sorafenib (S) and the mTOR inhibitor everolimus (E) and used FDG-PET to assess pharmacodynamic (PD) activity of E. Methods: Patients with relapsed solid tumors were treated with escalating doses of E 2.5-10.0mg/d p.o. in a 14 days monotherapy run in phase followed by combination therapy with a fixed dose of S 400mg bid from day 15. The primary aim was to define a safe and feasible combination treatment regimen for a subsequent phase II trial. DLT was defined as any drug related toxicity of CTC IV° or toxicity requiring hospitalization or interruption of therapy for more than 2 weeks within the first 29 days of treatment. Pharmacokinetic (PK) analyses were performed on day 5, 14 and 29 combined with explorative PD assessment of E by FDG-PET on days 1, 5 and 14 of treatment. Results: Nineteen patients were treated with the combination of E and S. The DLT was not reached according to protocol definition. However, at a dose level of E 10mg/d p.o. the following adverse events (AE) occurred in the non-DLT interval: Pneumonia III°, treatment delay due to leucopoenia/thrombopenia III° and sudden cardiac death probably due to arrhythmia. Based on these observations, the dose level of 7.5mg/day E p.o. in combination with 400mg S bid was defined as the MTD. The steady state of E alone was reached after 5 days of treatment and did not change until day 14. However, on day 29 everolimus plasma concentrations (AUC and Cmax) showed a significant 30 % reduction when co-administered with S. A metabolic response of the hottest lesion in PET on day 5 defined as ≤ 80% of baseline was seen in 4 of 15 evaluable patients. Median PFS and OS were 4.2 and 5.4 months, respectively. A patient with neuroendocrine carcinoma reached the longest PFS of 16.6 months. Conclusions: Treatment of patients with relapsed solid tumors with a combination of E 7.5mg/day and 400mg S bid is safe and feasible. The extension phase for confirmation of safety data, further PK and PD modeling and preliminary exploration of efficacy in KRAS mutant cancer patients will be performed at this dose level.
A dose-escalation phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 28 days on/14 days off schedule.
Authors: Grilley-Olson Juneko E. , Weiss Glen J. , Rajagopalan Prabhu , Henderson David Andrew , Kornacker Martin , Govindan Ramaswamy 
Published: March 2020

3046 Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting CDKs 1, 2, 4, 7, and 9 in the low nanomolar range. A phase I dose escalation multicenter study was initiated to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) in patients (pts) with advanced solid tumors. Methods: BAY was administered twice daily as an oral solution on a 28 days on / 14 days off schedule (cycle length 42 days, 3+3 design). PK was evaluated on cycle 1 day 1, 2, and 15. Response rate was assessed according to RECIST 1.1. Results: Ten pts were treated at doses of 0.6 (4 pts) and 1.0 (6 pts) mg per day. Tumor types included 3 non-small cell lung, 2 colorectal, 2 melanoma and 3 others. CTCAEv4 grade 1/2 drug related adverse events (AEs) occurring in more than 3 patients were nausea (5 pts), hot flashes (4), vomiting, diarrhea, dyspepsia, and fatigue (3). The median interval between start of treatment and occurrence of hot flashes was 23 days. Drug-related grade 3 AEs were hyponatremia (2 pts) and edema, lymphopenia, myalgia, fatigue, and hypokalemia in 1 pt each. Hyponatremia in one and hypokalemia in another patient were dose limiting toxicities in cohort 2. Enrollment has been stopped. BAY PK was dose proportional and T1/2 was 13 hours; major metabolite levels were low. One pt with metastatic malignant melanoma pretreated with interferon, talimogene laherparepvec, and ipilimumab (best prior response: progressive disease) achieved stable disease (SD) lasting for 5 months. Three pts had SD lasting for 2.5 - 3 months (thyroid, colorectal, squamous esophageal). Conclusions: BAY administered for 28 days on / 14 days off demonstrated a limited tolerability. This is in contrast to the ongoing 3 days on / 4 days off trial which is currently at a dose level of 20 mg per day. Hot flashes were an infrequent AE in the other dosing schedule but occurred in 4 of the 10 pts presented here. The long interval between start of treatment and occurrence of hot flashes suggests that the 28 days of continuous treatment contributed to the lower tolerability observed in this trial. The 3 days on / 4 days off schedule will be used in the further clinical development of BAY.
Safety and efficacy results from two randomized expansions of a phase I study of a tablet formulation of the PARP inhibitor, olaparib, in ovarian and breast cancer patients with BRCA1/2 mutations.
Authors: Molife L Rhoda , Mateo Joaquin , McGoldrick Trevor , Krebs Matthew , Drew Yvette , Banerjee Susana N. , Nicum Shibani , Ranson Malcolm , Rustin Gordon J. S. , Sessa Cristiana , Plummer Ruth , Leunen Karin , Friedlander Michael , Swaisland Helen , Burke Wendy , McCormack Peter , Pemberton Kristine , Tchakov Ilian , Kaye Stanley B. , Gourley Charlie 
Published: March 2020

3048 Background: We previously reported the comparative bioavailability of the capsule (CAP) formulation of olaparib and the more convenient new tablet (TAB) formulation (Molife et al ASCO 2010). We subsequently performed two separate dose expansions (DE1 and DE2) to explore comparative safety and efficacy of the TAB (NCT00777582). Methods: Patients with breast or ovarian cancer and BRCA1/2 mutations, ECOG PS 0–2 and adequate organ function were randomized to receive: DE1: 200 TAB or 400 CAP; DE2: 300 TAB, 400 TAB or 400 CAP (all mg BID). Endpoints included safety, pharmacokinetics and exploratory analysis of efficacy (change in tumor size at 8 weeks by RECIST 1.0). Groups were compared using analysis of covariance, including baseline tumor size and treatment as covariates; results are presented using least square (LS) means. Results: 24 patients (ovarian n=15, breast n=9) entered DE1 and 53 patients (ovarian n=38, breast n=15) entered DE2. Baseline characteristics including age, BRCA mutation status and tumor histology were balanced. The table shows key toxicity-related information and change in tumor size at 8 weeks by cohort. Conclusions: These data suggest a dose-response effect for tolerability and, possibly, efficacy with the new TAB between 200 and 400 mg BID. Further studies will require dosing according to patient tolerability within this dose range. [Table: see text]