bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine (CEA-vac) in patients (pts) with pancreatic adenocarcinoma (PC).
Authors: Geynisman Daniel M. , Zha Yuanyuan , Kunnavakkam Rangesh , Aklilu Mebea , Catenacci Daniel Virgil Thomas , Polite Blase N. , Rosenbaum Cara Ann , Namakydoust Azadeh , Karrison Theodore , Gajewski Thomas , Kindler Hedy Lee 
Published: March 2020

2561 Background: CEA is expressed in >90% of PC and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC pts to determine the appropriate CEA-vac peptide dose required to induce an optimal cytotoxic T lymphocyte (CTL) response. Methods: Eligible pts, PS 0-1, expressed HLA-A2 and had CEA-expressing, histologically-confirmed, previously-treated PC. Randomization: 10 μg (arm A), 100 μg (arm B) or 1000 μg (arm C). CEA-vac was given Q 2 weeks until disease progression (amended 4/09 to a 24 dose maximum). Results: From 2/06-9/09 66 pts were screened for HLA-A2; 19 pts randomized to Arms A/B/C 5/8/6 are evaluable for toxicity; 14 pts (5/5/4) who received at least 3 doses of CEA-vac are evaluable for the primary immunologic endpoint. Median age: 60 (range 27-86), female: 68%, PS 0: 58%. Disease stage: metastatic (M) 74%, locally advanced (LA) 5%, resected (R) 21%. Cycles: median 4 (range 1-81). Mean CTL response by ELISPOT (spots per 104 CD8+ cells, Arm A/B/C): 37/126/248. (A vs. C, p=0.037). CTL responses developed in 20%/60%/100% of pts in Arms A/B/C. 1 LA pt in Arm C had a complete radiologic response, a strong CTL response, and remains alive at 71 mo. 1 M pt in Arm B had SD for 11 mo, a strong CTL response, and is alive at 39 mo. Toxicity: no grade 3/4 toxicities, 58% grade 1/2 skin toxicity. Conclusions: CTL response was dose-dependent in this randomized phase I trial; the 1 mg peptide dose elicited the most robust CTL response. Clinical activity was demonstrated at the higher doses. Further evaluation of 1 mg CEA-vac with stronger adjuvants, combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts. Supported by UCCCSG P30CA14599.
A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors.
Authors: LoRusso Patricia , Shapiro Geoffrey , Pandya Shuchi Sumant , Kwak Eunice Lee , Jones Cheryl , Belvin Marcia , Musib Luna C. , de Crespigny Alex , McKenzie Meghan , Gates Mary R. , Chan Iris Tan-Chi , Bendell Johanna C. 
Published: March 2020

2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either agent alone dosed continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. Pts received: concurrent GDC-0973 + GDC-0941 once daily (qd) on a 21 day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 qd on a 21/7 schedule (MEK int); or GDC-0973 + GDC-0941 qd on a 7 day on /7 day off schedule (7/7). Starting doses were 20 mg GDC-0973 + 80 mg GDC-0941 (21/7), 100 mg GDC-0973 + 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 + 130 mg GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n=1), G4 CPK elevation (n=1). Compared to the 21/7 MTD of 40 mg GDC-0973 + 100 mg GDC-0941, higher doses of GDC-0973 + GDC-0941 were tolerated on the MEK int schedule. Overall, adverse events related to the study drug combination in ≥ 20% pts were diarrhea, rash, nausea, fatigue, vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary analysis indicated PK of GDC-0973 and GDC-0941 are not altered when dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial metabolic response (≥ 20% decrease in mean SUVmax from baseline) at ≥1 time points. Partial responses were observed in 3 pts (mBRAF melanoma, mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease ≥ 5 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules continues and updated data will be presented.
Cellular function of the mononuclear phagocyte system (MPS) as a phenotypic probe for pharmacokinetics (PK) and pharmacodynamics (PD) of PEGylated liposomal doxorubicin (PLD) in patients with recurrent ovarian cancer.
Authors: Caron Whitney Paige , Lay John C. , Kumar Parag , Fong Alan M. , La-Beck Ninh My , Newman Suzanne E. , Clarke-Pearson Daniel L. , Brewster Wendy R. , Van Le Linda , Bae-Jump Victoria Lin , Gehrig Paola A. , Zamboni William 
Published: March 2020

2591 Background: A phenotypic probe is a test that can be administered to a patient as a potential indicator of a drug’s PK/PD which can then be used to individualize therapy. Since nanoparticles are cleared via the MPS, including blood monocytes (MO), we hypothesize that circulating MO could potentially play a major role in, and be a surrogate marker of nanoparticle clearance (CL). Furthermore, we postulate that the ability to measure MO functional activity in blood samples can be used to predict CL and subsequently PD endpoints such as progression free survival (PFS) and hand-foot syndrome (HFS), in patients (pt). Methods: PLD 30/40 mg/m2 IV x 1 with or without carboplatin (AUC = 5 mg/mL/min) was administered to pts (n=10) with recurrent ovarian cancer. Serial PK samples were obtained at time 0 to day 28 post dose. Plasma was processed to measure encapsulated and released doxorubicin using solid phase separation and HPLC. Data was analyzed with WinNonlin to obtain PK parameters. MO and granulocyte phagocytic function (uptake of FITC-labeled opsonized E. Coli) and oxidative burst activity (intracellular oxidation of dihydrorhodamine 123) were assessed via flow cytometry at 0, 48, 96 h, and on day 28. For both assays, changes in mean fluorescence intensity of the gated MO population, following incubation of whole blood with the appropriate substrate, served as an index of activity. Pts were followed from the first dose of PLD until time of disease progression. Results: There was a direct linear relationship between encapsulated doxorubicin CL and both phagocytosis (R2 = 0.87) and oxidative burst activity (R2 = 0.64) in blood MO. Similarly, phagocytosis (R2 = 0.77) and oxidative burst probes correlated with PFS (R2 = 0.67) in the 4 pts who progressed while on PLD. Oxidative burst also correlated with degree of HFS (R2 = 0.56). There was no relationship between phagocytosis and oxidative burst in granulocytes and PK/PD of PLD. Conclusions: These findings indicate that probes of MPS function predict PLD CL, HFS and PFS and thus may be useful for individualizing PLD therapy in ovarian cancer and other malignancies.
A randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain.
Authors: Currow David C , Hardy Janet , Quinn Stephen , Fazekas Belinda , Plummer John , Eckermann Simon , Agar Meera , Spruyt Odette , Debra Rowett 
Published: March 2020

2604 Background: The dissociative anaesthetic ketamine is widely used for cancer related pain. A Cochrane review concluded that insufficient evidence was available to support its use in this setting. Methods: This phase III, multisite, double-blind, dose escalation, placebo, randomised controlled study aimed to determine whether ketamine, delivered subcutaneously over three to five days is more effective than placebo, when used in conjunction with adjuvant therapy in the management of chronic uncontrolled cancer pain. Ketamine would be considered to be of net benefit if it provided a reduction in average pain scores by ≥2/10 points from baseline, with limited breakthrough analgesia and acceptable toxicity. Results: For the 185 participants, there was no significant difference between the proportion of positive outcomes (0.04 (-0.10, 0.18) p=0.55) in the placebo and intervention arms (response rates 27% (25/92) and 31% (29/93)). Pain type (nociceptive versus neuropathic) was not a predictor of response. There was almost twice the incidence of adverse events worse than baseline in the ketamine group after day 1 (IRR = 1.95 (1.46, 2.61), p<0.001) and throughout the study. Those receiving ketamine were more likely to experience a more severe grade of adverse event/day (OR=1.09 (1.00, 1.18), p=0.039). The number needed to treat for one additional patient to get a positive outcome from ketamine was 25 (6, ∞). The number needed to harm, because of toxicity-related withdrawal was 6 (4, 13). Conclusions: Ketamine does not have net clinical benefit when used as an adjunct to opioids and standard co-analgesics in cancer pain.
Phase I/II dose-finding study of crizotinib (CRIZ) in combination with erlotinib (E) in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Ou Sai-Hong Ignatius , Govindan Ramaswamy , Eaton Keith D. , Otterson Gregory Alan , Gutierrez Martin , Mita Alain C. , Argiris Athanassios , Brega Nicoletta , Usari Tiziana , Tan Weiwei , Ho Steffan Nicholas , Robert Francisco 
Published: March 2020

2610 Background: c Met expression is common in NSCLC tumors and has been implicated in the development of resistance to EGFR inhibitors. CRIZ is an ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies, combining CRIZ with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell lines that were either sensitive or resistant to EGFR inhibition. The phase I portion of a phase I/II study (A8081002; NCT00965731) investigated the combination of E (EGFR TKI) and CRIZ in pts with advanced NSCLC. Methods: Pts had advanced NSCLC, 1 or 2 prior chemotherapy regimens, and no previous MET-directed therapy. Endpoints included maximum tolerated dose (MTD) determination, safety, and pharmacokinetics (PK). Pts received CRIZ 150 or 200 mg BID combined with E 100 mg QD (150/100 and 200/100, respectively). Results: Twenty-five pts have been treated to date. Median duration of combination therapy in 150/100 (n=18) was 6.6 weeks (0.1–25.3); for 200/100 (n=7) was 6.9 weeks (3.0–64.7). Five pts had dose-limiting toxicities (grade [G] 2 and unable to receive at least 80% of the planned dose or ≥G3), all of which resolved: 3 pts at 150/100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and dehydration; and at 200/100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts (92%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were diarrhea (72%), rash (56%) and fatigue (44%). Six pts discontinued therapy due to TRAEs (150/100: G3 diarrhea, G3 dehydration, and G2 rash in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n=1 each; 200/100: G3 dry eyes, G1 esophagitis, n=1 each). One partial response (200/100; duration 61 weeks) and 9 stable diseases (n=7 150/100, n=2 200/100; duration 7–54 weeks) were observed overall. Co-administration of both doses of CRIZ with E increased E AUC by 1.8 fold, while CRIZ PK parameters appeared to be unaffected. Plasma exposure to E 100 mg QD with CRIZ was comparable to that of 150 mg QD from historical data. Conclusions: E plus CRIZ at the MTD was well tolerated, with no unexpected AEs, and showed signs of activity in a pre-treated population. E 100 mg QD plus CRIZ 150 mg BID was defined as MTD.
Effect of baseline QTc interval prolongation on oncology clinical trial enrollment.
Authors: Moreno Carolina , Weber Jill M. , Guglin Maya , Roy Larry , Strosberg Jonathan R. 
Published: March 2020

2612 Background: An increasing number of clinical trials in oncology require normal or near-normal intervals of electrocardiographic corrected QT (QTc) as an eligibility criterion. However the normal QTc reference range (conventionally defined as ≤450ms) has been developed in broad populations of patients, and it is unclear whether average QTc intervals are higher in adult cancer patients. Methods: All electrocardiograms (ECGs) performed for any indication at the Moffitt Cancer Center during a one-week period were reviewed. The QTc interval for each patient was calculated according to the Bazett and Fridericia formulas. Mean and median QTc intervals were calculated along with standard deviations. The percentage of QTc intervals above 450ms, 470ms, and 500ms were calculated and graded accordingly to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). The effects of gender on the QTc interval were also evaluated. Results: 257 patients underwent ECGs over a one-week period. A total of 90 patients (35%) had abnormally prolonged QTc. 50 patients (20%) had QTc prolongation >450 (≥ grade 1), 32 (12%) had QTc prolongation > 470 (≥grade 2) and 8 patients (3%) had QTc prolongation >500ms (≥grade 3) using the Bazett formula. The corresponding numbers according to the Fridericia formula were 23 (9%), 13 (5%) and 2 (1%) . The median QTc interval was 441 (Bazett) and 422 (Fridericia) with a standard deviation of 30 and 28 respectively. Women had a mean QTc of 438 (Bazett) versus 443 for men. Conclusions: A very large percentage of patients seen at a comprehensive cancer center have QTc intervals above the normal reference range on routine ECGs. The growth in number of trials requiring a normal QTc interval as an eligibility criteria suggests that an ever-larger number of patients are excluded from trial participation. Regulatory agencies may need to reconsider eligibility criteria that substantially restrict trial enrollment and that accrue patients who are not reflective of the general patient population.
Phase I clinical and pharmacologic study of the focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with advanced solid tumors.
Authors: Soria Jean-Charles , Gan Hui Kong , Arkenau Hendrik-Tobias , Blagden Sarah Patricia , Plummer Ruth , Ranson Malcolm , Evans T.R. Jeffry , Zalcman Gerard , Bahleda Rastislav , Hollebecque Antoine , Lemech Charlotte , Brown Jennifer , Peddareddigari Vijay Gopal Reddy , Gibson Diana , Murray Sharon Cornell , Nebot Noelia , Mazumdar Jolly , Fleming Ronald Alan , Millward Michael 
Published: March 2020

3000 Background: FAK has an important role in cancer invasion and metastasis. FAK and phospho-FAK (pFAK) are increased in advanced cancer and are correlated with poor prognosis. GSK2256098 is a potent and specific small molecule inhibitor of FAK. Methods: This is a first-time in cancer pts, dose escalation study (NCT01138033) to identify the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity. Part 1 used a modified accelerated titration procedure switching to standard 3+3 design based on toxicity during the first 21 days of treatment. Pts were treated with GSK2256098 orally twice daily (BID) with food. Safety was established in cohorts of 1-6 pts. After MTD determination, Parts 2 and 3 were opened to further evaluate safety, PK and PD. Serial PK samples were obtained over 24 h on Days 1 and 15. Pre- and post-dose skin, hair and tumor tissue biopsies were analyzed for pFAK. Results: 57 pts with advanced solid tumors have been treated at escalating doses ranging from 80 mg to 1500 mg BID: median age=58.8 (range 21-84). The most common tumor types include: mesothelioma (23), ovary (7), colon (3), kidney (3), and pancreas (3). MTD was determined to be 1000 mg BID. DLTs were Gr 2 proteinuria (1000 mg), Gr 2 nausea, vomiting, fatigue (1250 mg) and Gr 3 asthenia (1500 mg). Most frequent toxicities were nausea (32 pts, 56%), diarrhea (31 pts, 54%), vomiting (25 pts, 44%), decreased appetite (18 pts 32%) and asthenia (11 pts, 19%). The majority of toxicities were Gr 1-2; Gr 3 drug-related events included hypertriglyceridemia (n=2), hyperlipasemia (2), asthenia (1), increased amylase (1), and loss of consciousness (1). Few dose reductions and interruptions have occurred. Minor responses/stable disease (SD) were observed in pts with mesothelioma (-12%, 27 wks), melanoma (-26%, 54 wks), and naso/pharyngeal cancer (-31% target lesion, 30 wks) and SD in renal cell (48+ wks). In preliminary analysis of single-dose PK, exposure generally increased in a dose-proportional manner, and the geometric mean t½ was 4.2 h. Accumulation was not observed with repeat dosing. Conclusions: GSK2256098 is well tolerated with evidence of clinical activity. PK supports BID dosing.
A phase lb, open-label, multicenter, dose-escalation study of the oral pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 inhibitor GSK1120212 in patients (pts) with selected advanced solid tumors.
Authors: Bedard Philippe , Tabernero Josep , Kurzrock Razelle , Britten Carolyn D. , Stathis Anastasios , Perez-Garcia Jose Manuel , Zubel Angela , Le Ngocdiep T. , Carter Kirsten , Bellew Kevin M. , Gallarati Chiara , Niazi Faiz , Demanse David , De Buck Stefan S. , Sessa Cristiana 
Published: March 2020

3003 Background: MAPK and PI3K/AKT signaling pathways regulate proliferation, differentiation and cell death in human cancers. Known interaction between the 2 pathways provides the rationale for combining both inhibitors in a phase I study. Methods: The objective is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for oral, daily administered, BKM120 + GSK1120212, mainly in pts with tumors with RAS/RAF mutations (mt). A Bayesian logistic regression model with overdose control guides the dose escalation of the treatment. Secondary objectives include safety, tolerability, PK and efficacy. Results: As of 22.09.11, 49 pts were treated with BKM120 + GSK1120212 as follows: 30mg + 0.5mg, 60mg + 0.5mg, 60mg + 1.0mg, 60mg + 1.5mg, 60mg + 2.0mg, 70mg + 1.5mg, 80mg + 1.0mg, 80mg + 1.5mg. 6 pts had dose-limiting toxicities (DLTs); all were reversible. Grade 3 DLTs were: 3 x stomatitis, 1 x dysphagia, 1 x LVEF decrease, 1 x CK increase, 1 x nausea, 1 x anorexia, 1 x decreased oral intake. MTD and/or RP2D for the combination have not been reached. Most common adverse events (AEs) (>25%), all grades and causality, were dermatitis acneiform, diarrhea (51% each); nausea (41%); vomiting (37%); rash (33%); asthenia (31%); CK increase, decreased appetite, pyrexia or stomatitis (29% each) and hyperglycemia (27%). There were 4 on-treatment deaths unrelated to treatment. AEs led to treatment discontinuation, 17 pts (35%) and interruptions/dose reductions, 25 pts (51%). Apparent steady-states of BKM120 and GSK1120212 were reached by day 28. Plasma concentrations of BKM120 in combination with GSK1120212 were lower than for monotherapy. Exposure to GSK1120212 with BKM120 was similar to that observed in monotherapy studies. 3 confirmed partial responses have been observed in pts with KRAS mt ovarian cancer; 2 lasting >9 months. 2 patients with BRAF mt melanoma, who had previously progressed on BRAF inhibitors, had stable disease, for 1 of whom treatment is still ongoing in cycle 6. Conclusions: BKM120 and GSK1120212 can be safely combined. Signs of clinical activity have been seen in pts with RAS/RAF mt tumors.
First-in-human phase I study of LY2780301, an oral P70S6K/AKT inhibitor, in patients with refractory solid tumors.
Authors: Calvo Emiliano , Benhadji Karim Adnane , Azaro Analia , Duran Ignacio , Argiles Guillem , Boni Valentina , Ohnmacht Ute , Wallin Johan , Bumgardner William Mark , Rodon Ahnert Jordi 
Published: March 2020

3005 Background: LY2780301is an oral potent, highly selective ATP competitive inhibitor against p70S6 kinase and AKT. We report on safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity from the first-in-men study of LY2780301 in solid tumors. Methods: Eligible pts (ECOG≤1) had relapsed solid tumors, adequate hematologic, renal, and hepatic functions. Using a predictive pre-clinical PK/PD model and non-clinical toxicology data, a total daily dose of 100-1000 mg, was selected. LY2780301 was given either once or twice daily for 28-day cycle until disease progression. Dose escalation (3+3 design) was based on CTCAE V4 toxicities. The primary objective was to define the recommended phase 2 dose of LY2780301. Secondary objectives were PK, PD (pS6 in skin), and preliminary antitumor activity. Results: 32 patients were treated at dose levels from 100mg – 500mg total daily dose. LY2780301 was well tolerated at all dose levels No dose-limiting toxicities were observed in cycle 1. Common toxicities potentially related to study therapy included: constipation (7pts), fatigue (5pts), nausea (4pts), diarrhea (3pts), and vomiting (3pts). Grade 3/4 toxicities potentially related to study therapy were: anemia (3pts), increased ALT/AST (1pt), and increased GGT (1pt). Average number of cycles received across all dose levels was 2. There were no partial or complete responses; best response observed was prolonged stable disease for 6.5 cycles. Plasma exposures of LY278030 exceeded predicted efficacious dose in all pts (AUC 0-24H >25000 ng*hr/mL). Increase in exposure with dose was observed (QD or BID) with significant inter-pt variability. The exposure increase was less than linear with dose. Preliminary PK parameters are CL/F 4.5L/h and t1/2 of 24 hours. pS6 assessment in skin showed inhibition in > 50% of pts receiving 400-500 mg per day. Positive correlation with the exposure of the didesmethyl metabolite was observed. Conclusions: LY2780301displayed favorable safety profile, and high PK exposures in the range of efficacious dose. The recommended dose will be defined in the range between 300 and 500 mg. Further exploration of PK/PD effect in mesothelioma is ongoing.