bluuebunny/crossref_metadata_2025 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.
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.
Phase I pharmacokinetic study of dasatinib (BMS-354825) in patients with advanced malignancies and varying levels of liver dysfunction: S0711, a SWOG early therapeutics committee study.
Authors: Sarantopoulos John , Hoering Antje , Synold Timothy W. , Mahalingam Devalingam , Wang Ding , Lenz Heinz-Josef , O'Rourke Pat , Sexton Rachel , Van Veldhuizen Peter J. , Mita Monica M. , Wong Lucas , Mita Alain C. , El-Khoueiry Anthony B. , Chung Vincent M. , Gandara David R. , Tejwani Sheela , Takebe Naoko , Takimoto Chris H.M. , Ivy S. Percy , Kurzrock Razelle
Published: March 2020

3078

Background: Dasatinib (D) is a first in class Src kinase inhibitor, and inhibits BCR-Abl, c-Kit, PDGFR-beta, EPHA2 and Src family kinases including Src, Lck, Yes, Fyn at nanomolar concentrations. Initially FDA approved for use in imatinib resistant CML. It is a small molecule targeted therapy hepatically metabolized primarily by CYP3A4. We conducted a phase I study to determine maximum tolerated dose (MTD) and pharmacokinetics (PK) of D in patients (pts) with liver dysfunction (LD). Methods: Pts with advanced solid tumors or lymphoma, Zubrod ≤2, no baseline ascites or pleural effusions, adequate renal and bone marrow function, received PO D daily. Cycles q28 days. Pts stratified into 4 LD groups: normal, mild, moderate, severe, using Child-Pugh classification (CPC). Data also collected for NCI ODWG Organ Dysfunction Working GroupCriteria. D dose was escalated in sequential cohorts of pts within each LD category. Blood analysis for D concentrations were determined during cycle 1 using a validated LC-MC/MS assay. Study objectives included characterizing safety, tolerability, PK, identifying the MTD and obtaining preliminary evidence of efficacy. Results: 54 registered pts, 51 pts received 51 cycles of D at doses starting at 100 mg in mild LD (50-140 mg). Median age 60, male 55%, Zubrod 1 70%. CRC 27%. Groups: normal-17, mild-20, moderate-13, severe-1 pt(s). Related AEs include fatigue 35%, diarrhea 27%, anemia 27%, nausea 25%, vomiting 21%, lymphopenia 13%, rash 13%, pleural effusion 8%. 1 DLT of increased CK in a pt in moderate LD with past history of similar episode with previous sorafenib. Previous linear PK disposition, and no accumulation. No apparent PK differences between normal and mild groups. Cycle 1 Day 1 D 140 mg Normal Group: Cmax 129 ng/mL. Mild Group 140mg: Cmax 157 ng/mL. Prolonged disease stabilization (≥4 cycles) in 6 pts, 3 CRC (4,5,8); 1 Pancreas, HCC, Bladder (4,5,6). Conclusions: Recommended dose for Dasatinib given PO QD for pts with mild, moderate, or severe LD using clinical criteria with CPC and no baseline ascites, are 140 mg, 70 mg, insufficient pts, respectively. Dose adjustment not necessary in pts with mild LD.