bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot study of sirolimus (S) in subjects with Cowden syndrome (CS) with germ-line mutations in PTEN.
Authors: Komiya Takefumi , Blumenthal Gideon Michael , Ballas Marc S. , Dechowdhury Roopa , Manu Michell , Fioravanti Suzanne , Hornyak Thomas J , Wank Stephen , Weinstein Douglas , Morris Jennifer , Hewitt Stephen M. , Memmott Regan , Dennis Phillip A. , Morrow Betsy 
Published: March 2020

2532 Background: CS is characterized by germline PTEN mutations. Because tumors from CS patients show increased activation of the PI3K/Akt/mTOR pathway, mTOR inhibitor such as S might have activity in such patients. Methods: Eligibility: subjects with germline PTEN mutation who meet international diagnostic criteria for CS, age 18, ECOG PS 0-2, and adequate organ function. Subjects were treated with a 56-day course of daily oral S (2 mg). Objective: Inhibition of the mTOR pathway in benign skin/GI lesion, as assessed by IHC (P-AKT, Total S6, P-S6, P-4E-BP1, score 0-4), changes in benign or malignant tumor by CT/MRI/PET, digital dermoscopy/endoscopy, and changes in cerebellar testing by modified SARA (Neurology 2006). Protocol was amended to allow up to 20 subjects. Results: A total of 18 pts/16 families were enrolled. Median age 42 (range 19-69). Male/Female: 9/9. Involvement in skin, thyroid, GI polyps, breast, CNS, and all of the five organs was observed in 18, 15, 13, 8, 18, 5 subjects, respectively. 7 had h/o malignancies: 3 renal cell, 4 breast, 3 thyroid, 4 others. 3 cerebellar gangliocytomas and 2 others were measurable by CT or MRI. PTEN mutations: 6 families in Exon 1-2, 1 in Exon 4, 9 in Exon 5-8. All but one (D24H) were truncating mutations. 11 of 16 pts who completed a 56-day course reported subjective improvement in energy, mood, focus or skin lesion. Pts with Ex6-8 mutation (n=4) had a median SUV decrease of 29.4%. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Cerebellar evaluation showed a significant improvement in a total SARA score at 1 month (n=9, p=0.034). 3 pts were treated for only 28 days due to voluntary withdrawal. IHC analysis in skin and GI benign lesions showed a decrease in average P-S6K, P-S6, Total S6, P-S6/Total S6 in response to S. P-S6K/Total S6 ratios at d14 and d56 were significantly lower than at baseline (p=0.0026, 0.0391, respectively). The most common AEs (all grades >25%) were LFTs/Hb (39%), fatigue/hypercholesterolemia (28%). Grade 3 AEs: 1 pt hypophosphatemia/lymphopenia. Conclusions: A 56-day course of S was well tolerated in subjects with CS and was associated with improvement in symptoms, skin/GI lesions, cerebellar function and decreased mTOR signaling. Clinical trial information: NCT00971789.
Pharmacodynamic study using FLT PET/CT in patients treated with axitinib.
Authors: Liu Glenn , Scully Peter , Kolesar Jill , Bruce Justine Yang , Eickhoff Jens C. , Perlman Scott , Carmichael Lakeesha , Heideman Jennifer , Jeraj Robert 
Published: March 2020

2537 Background: Axitinib (AX) is a potent VEGFR2 TKI. The objective of this study was to characterize tumor vascular and proliferative changes in patients treated with AX. Methods: Thirty pts with solid malignancies with at least one target lesion appropriate for FLT PET/CT imaging were enrolled. Pts were treated in Cycle #1 (C1) with AX at 5 mg BID x 2 wks, followed by a 1 wk drug holiday. Subsequent cycles continued the AX BID on a continuous basis until progression or unacceptable toxicity. In cohort A, FLT PET/CT was obtained at baseline, C1D14 (during AX) and C1D21 (AX withdrawal). Cohort B used the same treatment schedule, but FLT PET/CT was obtained on C1D14, C1D16 and C1D21. At each imaging time, peak FLT Standardized Uptake Values (SUVpeak), AX pharmacokinetics and plasma VEGF levels were obtained. Results: Of the 30 total pts, 28 had at least 1 PET/CT scan with 24 completing all planned PET/CT scans (13 in Cohort A; 11 in Cohort B). Strong proliferative flare (36% increase in SUVpeak from C1D14 to C1D21) was observed in majority of pts with most of the flare occurred within two days after AX withdrawal (25% increase in SUVpeak from C1D14 by C1D16). A robust vascular flare paralleled proliferative flare (R=0.57). A trend linking short progression free survival with high withdrawal flare was seen (44% increase in SUVpeak for PFS ≤ 6mo vs 11% increase in SUVpeak for PFS > 6 mo; p=0.14). VEGF levels and AX PK levels increased during treatment, followed by decrease during withdrawal. Conclusions: The observed AX pharmacodynamics is consistent with our prior observation with another VEGFR TKI and suggests that acute AX withdrawal results in a robust withdrawal flare. This information suggests that the timing of cytotoxic chemotherapy during the flare may increase the therapeutic index, as opposed to concurrent administration which may be antagonistic. This study also shows the power of quantitative molecular imaging, which can simultaneous evaluate treatment response heterogeneity, as well as compensatory effects that may lead to early treatment failure. Clinical trial information: NCT00859118.
Phase I dose escalation study of the protein kinase C iota inhibitor aurothiomalate for advanced non-small cell lung cancer, ovarian cancer, and pancreatic cancer.
Authors: Mansfield Aaron Scott , Fields Alan P. , Jatoi Aminah , Qi Yingwei , Adjei Alex A. , Erlichman Charles , Molina Julian R. 
Published: March 2020

2551 Background: Protein kinase C iota (PKCi) is overexpressed in non-small cell lung (NSCLC), ovarian and pancreatic cancers and promotes tumorigenesis. The gold compound aurothiomalate (ATM) inhibits downstream activation of Rac1 by PKCi. We sought to determine the maximum tolerated dose (MTD) of ATM. Methods: We conducted a phase I dose escalation trial of ATM in patients with NSCLC, ovarian or pancreatic cancer. In the dose escalation cohort patients received ATM IM weekly for three cycles (cycle duration 4 weeks) at 25 mg, 50 mg or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Up to 9 subjects were allowed to enroll in the expansion cohort at the MTD. Blood samples were analyzed for elemental gold levels. Patients were evaluated for response every eight weeks with computed tomography using modified response evaluation criteria in solid tumors. Results: Fifteen patients, all pretreated, enrolled in this study. There were ten patients with NSCLC, four with ovarian cancer and one with pancreatic cancer. Six patients were treated at the 25 mg dose, 6 patients at 50 mg, and 2 at 75 mg. There was 1 dose limiting toxicity (DLT) at 25 mg (hypokalemia), 1 DLT at 50 mg (urinary tract infection), and none at 75 mg. There were 3 grade 3 hematologic toxicities in the dose escalation cohort. The recommended MTD of ATM is 50 mg, and 1 subject was treated in the expansion cohort at 50 mg. Patients received treatment for a median of 2 cycles (range 1-3). The best response observed was stable disease in 2 subjects. There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold with concentrations exceeding 20 µM after one month of therapy with 75 mg of ATM and after 2 months of therapy with 50 mg of ATM, consistent with linear pharmacokinetics. Conclusions: In summary, this phase I study was successful in identifying ATM 50 mg IM weekly as the MTD. In this heavily pre-treated group of patients in who we observed at best stable disease, it remains unclear whether future investigations that target PKCi should focus on single agent ATM, combination therapy with ATM, or other PKCi inhibitors that are currently in development. Clinical trial information: NCT00575393.
PHI-55: (NCI#7427): A phase I study of halichondrin B analog (E7389) in combination with cisplatin (CDDP) in advanced solid tumors: A CCC, NCI/CTEP-sponsored trial (grant U01 CA 062505).
Authors: Koczywas Marianna , Lenz Heinz-Josef , Mortimer Joanne E. , El-Khoueiry Anthony B. , Frankel Paul Henry , Gandara David R. , Cristea Mihaela C. , Chung Vincent M. , Lim Dean , Reckamp Karen L. , Lau Derick H. M. , Ye Wei , Doyle L. Austin , Carroll Mary I. , Newman Edward M. 
Published: March 2020

2564 Background: E7389 is a structurally simplified synthetic macrocyclic ketone analog of the marine sponge natural product Halichondrin B, which inhibits microtubule dynamics via a novel mechanism characterized by suppression of microtubule growth, lack of effect on microtubule depolymerization, and sequestration of tubulin into nonfunctional aggregates. Methods: The goals of this trial were to determine the DLT, the MTD, and PK of E7389 (administered on days 1, 8 and 15 every 28 days) in combination with CDDP (administered on day 1 every 28 days) in patients (pts) with advanced solid tumors. The protocol was amended after dose level 4 (E7389 1.4 mg/m2, CDDP 60 mg/m2) when it was not feasible to administer E7389 on day 15 due to neutropenia; the treatment schedule was changed to E7389 days 1 and 8 and CDDP day 1 every 21 days. Eligibility criteria included normal organ function and < 2 prior chemotherapy regimens. Results: To date, 36 pts have been treated (E7389 0.7-1.4 mg/m2 and CDDP 60-75 mg/m2). Median age 61 years; 19 males; the most common tumor types were lung (8), pancreatic (5), head and neck (6). 36% ECOG 0, 56% ECOG 1, 8% ECOG 2; Median number of cycles was 3 (1 – 8). There were 3 pts with DLT’s on the 28-day cycle: gr 4 febrile neutropenia (1.0/60); gr 3 anorexia/fatigue/hypokalemia (1.2/60); and gr 3 stomatitis/fatigue (1.4/60). There were 3 pts with DLTs treated on the 21-day schedule: gr 3 hypokalemia/hyponatremia (1.4/60); gr 4 mucositis (1.4/60); and gr 3 hypokalemia (1.2/75). With 2 DLTs out of 6 pts at E7389 1.4 mg/m2 and CDDP 60 mg/m2, E7389 was reduced, CDDP was escalated, and the MTD was determined to be E7389 1.2 mg/m2 and CDDP 75 mg/m2(1 patient out of 6 with a DLT). At the MTD, protocol defined dose modifications or delays were required in 2 of the 6 patients by cycle 2. Notably, all DLTs were observed in patients exposed to at least 2 prior lines of chemotherapy. Two pts had an unconfirmed PR (pancreatic, breast) and 2 had a PR (esophagus, transitional bladder). Conclusions: On a 21 day schedule,E7389 in combination with CDDP appears well tolerated and showed preliminary activity. The MTD was determined to be E7389 1.2 mg/m2 and CDDP 75 mg/m2. Clinical trial information: 00400829.
A first-in-human (FIH) dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous BAL101553, a novel microtubule inhibitor, in adult patients with advanced solid tumors.
Authors: Calvert Alan Hilary , Gonzalez Michael , Ganguli Sushila , Ng Matthew , Benafif Sarah , Capelan Marta , Goldstein Robert , Shah Krunal , Jarvis Claire , Flynn Michael , Forster Martin , Anderson Stephanie , Schmitt-Hoffman Anne , Lane Heidi , Engelhardt Marc , Hannah Alison L. , Tzankov Alexandar , Bachmann Felix , Molife L Rhoda , Kristeleit Rebecca 
Published: March 2020

2566 Background: BAL101553, a pro-drug of the small molecule BAL27862, is a novel microtubule targeting agent (MTA) with cytotoxic and vascular disrupting properties. Pre-clinical data showed anti-proliferative activity in several in vitro and xenograft tumour models, including tumours refractory to conventional MTAs through diverse resistance mechanisms. Primary objectives of this FIH study were determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included the evaluation of PK, PD and anti-tumour activity. Methods: An accelerated titration dose-escalation design was used. Eligible patients (pts) with advanced solid tumours, who had failed standard therapy, received BAL101553 as a 2-h intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Adverse events (AEs) were assessed according to CTCAEv4. Disease response was assessed by RECIST 1.1 every 2 cycles. Results: 16 pts (7 male; median age 52 years; range 29-80) with solid tumours were treated at 4 dose levels (15, 30, 45 and 60 mg/m2). DLTs were observed at 60 mg/m2 and included rapidly reversible grade (G) 3 hypertension (HTN) and G3 reduced mobility/ dizziness. DLT criteria for HTN were subsequently modified. Frequent drug-related AEs were injection site reactions, nausea, vomiting (all G1-2), and G2-3 HTN (transient during the infusion; responding to nifedipine). One pt experienced G2 peripheral neuropathy at 60 mg/m2. PK analyses indicated conversion of BAL101553 to the active BAL27862, dose proportional exposure for both compounds and a half-life of BAL27862 in a range of 11 to 27 h. Preliminary tumour PD data comparing pre/post biopsies showed loss of CD34+ capillaries and focally decreased proliferation. A confirmed partial response was demonstrated in 1 pt with ampullary (pancreaticobiliary) cancer maintained on treatment for >16 cycles with intra-pt dose escalation. 2 pts (laryngeal and rectal cancer) demonstrated stable disease >16 weeks. Conclusions: BAL101553 is well tolerated up to 60 mg/m2 with evidence of anti-tumour activity. Dose escalation continues to determine the MTD. Clinical trial information: NCT01397929.
A genotype-directed study to optimize dosing of irinotecan according to the UGT1A1 genotype.
Authors: Innocenti Federico , Salgia Ravi , Ramirez Jacqueline , Janisch Linda A. , Undevia Samir D. , House Larry , Das Soma , Wu Kehua , Turcich Michelle , Marsh Robert de Wilton , Karrison Theodore , Maitland Michael L. , Schilsky Richard L. , Ratain Mark J. 
Published: March 2020

2570 Background: The risk of severe neutropenia from irinotecan (I) is in part related to UGT1A1*28, a polymorphism that reduces the elimination of SN-38, the active metabolite of I. We aimed to identify the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of I in advanced solid tumor patients (pts) stratified by*1/*1, *1/*28, and *28/*28 genotypes. We hypothesized that *1/*1 pts would tolerate a higher MTD than the standard 350 mg/m2 dose and that *28/*28 pts would require dose reduction. Methods: 68 pts (30 lung, 30 gastrointestinal, 8 other cancers) received q3w, flat-dose I. Genotype frequencies were 46% (*1/*1), 41% (*1/*28), and 13% (*28/*28). Pts (66% males, median age 68 years) had 0-1 PS (only one pt had PS 2). 82% were Caucasians, 13% African Americans, and 4% Hispanics. The I starting dose was 700 mg in *1/*1 and *1/*28 pts, and 500 mg in *28/*28 pts. Pharmacokinetics was obtained at cycle 1. DLT at cycle 1 was defined as grade (G) 4 neutropenia (N) for ≥4 days, G≥3N on a treatment day, G≥3 febrile N, G4 anemia or thrombocytopenia, or G≥3 non-hematological toxicity. Results: In *1/*1 pts, the MTD was 850 mg (4 DLTs/16 pts), and 1000 mg was not tolerated (2 DLTs/6). In *1/*28 pts, the MTD was 700 mg (5 DLTs/22) and 850 mg was not tolerated (4 DLTs/6). In *28/*28 pts, the MTD was 400 mg (1 DLT/6) and 500 mg was not tolerated (3 DLTs/3). DLTs were mainly G4N, G≥3 febrile N, and G3 diarrhea. I clearance followed linear kinetics. I and SN-38 AUCs were associated with decreased log10ANC nadir (r2 0.27 and 0.30, respectively, p<0.0001). At the MTD, I AUC in *28/*28 pts was 50% and 62% lower than that of *1/*28 and *1/*1 pts (16.8±4.4, 33.4±11.9, 44.2±11.3 h*ug/ml [mean±SD], respectively). At the MTD, SN-38 AUC in *28/*28 pts was 30% and 26% lower than that of *1/*28 and *1/*1 pts (620±407, 881±715, 841±888 h*ng/ml). 3 PRs were observed (NSCLC-700 mg-*1/*28, gastric-850 mg-*1/*1, small bowel-850 mg-*1/*28). Conclusions: In a heavily pretreated population, UGT1A1*28 information can be used to individualize dosing of I. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in pts receiving I. Clinical trial information: NCT00708773.
Phase I study of inotuzumab ozogamicin (INO) combined with R-GDP for relapsed CD22+ B-cell non-Hodgkin lymphoma (B-NHL).
Authors: Sangha Randeep S. , Davies Andrew John , Dang Nam H. , Ogura Michinori , Paccagnella M. Luisa , Ananthakrishnan Revathi , Vandendries Erik , Tee Goh Yeow 
Published: March 2020

2574 Background: CD22 is expressed on most B-NHL. INO, an anti-CD22 antibody linked to calicheamicin, has activity in refractory B-NHL. This study hypothesized that INO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) for relapsed CD22+ B-NHL was safe and tolerable. Methods: Patients (pts) with relapsed CD22+ B-NHL treated with ≥1 prior R-chemo regimen were enrolled using an up-and-down independent dose-escalation schema for G and P. INO (0.8 mg/m2 day 2) was combined with R-GDP (R 375 mg/m2, G, and P day 1; oral D 40 mg days 1-4) on a 21-d cycle for up to 6 cycles. Dose-limiting toxicity (DLT) included febrile neutropenia, grade (Gr) 4 ANC lasting ≥7 d, Gr 4 platelets ≥7 d, Gr ≥3 platelets with bleeding and transfusion support, Gr ≥3 QTc prolongation, Gr 4 AST/ALT, Gr 2 bilirubin ≥7 d, G-CSF during cycle 1, Gr ≥3 clinically significant or drug-related nonhematologic toxicity ≥7 d, and Gr ≥2 drug-related nonhematologic toxicity causing dose delay of ≥7 d. Results: Thirty-seven pts were treated: 15 DLBCL, 11 FL, 7 MCL, 1 MZL, 1 SLL, and 2 indolent B-NHL. Characteristics: aged 33 to 81 y (median 65 y); 34 with ECOG PS £1; median of 2 prior chemo regimens (range 1-6); 5 refractory to prior therapy. No DLTs were observed at the starting dose of G 500 mg/m2, P 37.5 mg/m2 (n = 6); 2 DLTs (febrile neutropenia, Gr 2 platelets) at G 1000 mg/m2, P 37.5 mg/m2 (n = 3); no DLTs at G 1000 mg/m2, P 0 mg/m2 (n = 6); 2 DLTs (febrile neutropenia; Gr 4 ANC ≥7 d) at G 500 mg/m2, P 50 mg/m2 (n = 8); and 2 DLTs (Gr 3 hypokalemia, Gr 4 neutropenic sepsis) at G 500 mg/m2, P 75 mg/m2 (n = 4). In a maximum tolerated dose (MTD) confirmation cohort of 10 additional pts, 3 pts had DLTs (2 with Gr 4 platelets, 1 with febrile neutropenia); thus MTD was determined to be INO 0.8 mg/m2, R 375mg/m2, G 500 mg/m2, D 40 mg, P 50 mg/m2. Gr ≥3 adverse events included thrombocytopenia (68%), neutropenia (54%), lymphopenia (32%), anemia (27%), leukopenia (24%), hypokalemia (22%), fatigue (11%), and febrile neutropenia (11%). Median treatment cycle was 4 (range 1-6). There were 8 complete and 9 partial responses. Conclusions: INO 0.8 mg/m2 with R-GDP is tolerable at reduced doses of G (500 mg/m2) and P (50 mg/m2). Preliminary efficacy is being explored in the ongoing MTD expansion cohort. Clinical trial information: NCT01055496.
A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Ciprotti Marika , Tebbutt Niall C. , Lee Fook Thean , Lee Sze Ting , McKee Dave C. , O'Keefe Graeme J. , Gong Sylvia J. , Chong Geoffrey , Gan Hui Kong , Hopkins Wendie , Chappell Bridget , Scott Fiona Elizabeth , Brechbiel Martin W. , Tse Archie N. , Jansen Mendel , Matsumura Manabu , Watanabe Rira , Beckman Robert A. , Greenberg Jonathan , Scott Andrew Mark 
Published: March 2020

2583 Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody (Ab) to human DR5 created by CDR grafting of the murine Ab TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative tumor uptake and anti-tumor response in pts with mCRC. Methods: Pts with mCRC were treated with weekly IV CS-1008 in 5 non-sequential cohorts (Co). Different loading doses were used on days 1 and 8 (0.2 to 6 mg/kg), followed by a weekly dose of 2 mg/kg. D1 and D36 doses were trace-labeled with 111In, followed by whole-body planar and regional SPECT imaging over 10 days. Primary endpoints: initial biodistribution, pharmacokinetic (PK) and tumor uptake following single infusion; changes in biodistribution, PK and tumor uptake following sequential doses. Secondary endpoints: tumor response; changes in tumor metabolism by FDG-PET; serum apoptosis biomarkers and tumor response markers. Results: 19 pts (median age 64 yrs; M:F 11:8; 2-6 prior chemotherapy regimens) were enrolled as follows: Co 1, n=2; Co 2, n=4; Co 3, n=5; Co 4, n=3; and Co 5, n=5. Tumor uptake was variable: 7 pts had no uptake, 11 pts had uptake in all sites of disease but liver, 1 pt showed liver uptake. Tumor uptake and PK were not affected by dose or repeated drug administration. No anti-CS-1008 Ab responses were detected. DR5 expression in archived samples did not correlate with uptake or response. 111In‐CS‐1008 biodistribution showed gradual blood pool clearance and no abnormal uptake in normal tissue. Mean % change in SUVmax from baseline in lesions with uptake was higher than in those with no uptake. There were 8 SD, 1 PR and 10 PD. Duration of PR was 3.7 months (mo). Mean duration of SD was 4 mo. Disease control rate (SD + PR) in pts with uptake was 58% vs 28% of pts with no uptake. Lesions with no uptake were more likely to progress, with a PD risk of 3.4 times higher than those lesions with uptake. Conclusions: Tumor DR5 expression, assessed by 111In-CS-1008 imaging, revealed real-time heterogeneous DR5 expression and appeared to be a promising predictive imaging biomarker of clinical benefit in pts with mCRC receiving CS-1008. Clinical trial information: NCT01220999.
Phase I study of the HDAC inhibitor vorinostat in combination with capecitabine in a biweekly schedule in advanced breast cancer.
Authors: James Edward Samuel , Chung Gina G. , DiGiovanna Michael , Sanft Tara Beth , Hofstatter Erin Wysong , Sowers Noelle , Clark Mary Beth , Lilian Rebecca , Chmael Susan , Cappiello Michelle , Abraham Gineesha , Israel Gary M , Pusztai Lajos , Harris Lyndsay , Abu-Khalaf Maysa M. 
Published: March 2020

2587 Background: Synergy between histone deacetylase inhibitors and 5-fluorouracil is thought to be due to down regulation of thymidylate synthase. Study objectives are to assess maximum tolerated dose (MTD), dose limiting toxicities (DLT) and objective response rate of vorinostat (V) in combination with capecitabine (C). Secondary aims are pharmacodynamics of V. Methods: Cohorts of 3-6 patients (pts) were enrolled on a 3+3 dose-escalation phase to assess MTD of escalating doses of oral C (1500/1800/2000mg) with V 200 mg BID on days 1-7 and 15-21 of a 28 d cycle. 10 pts enrolled on dose expansion phase and treated at MTD. Pts received a “run in” treatment of V for 5 d and pre/post V biopsy (bx) collected when feasible. DLT was defined as ≥ grade 3 non hematological toxicity, grade 4 thrombocytopenia, grade 4 neutropenia > 5 d, grade 4 febrile neutropenia requiring hospitalization, QTc >500ms,or treatment delay > 2 weeks from toxicity. Microarray analysis was performed using Illumina HT-12 gene arrays on pre/post bx from 4 pts. Results: 23 ptswith median age 51 (range 33-69) were treated: 8 pts at 1500/200mg, 5 pts at 1800/200mg, and 10 pts treated on dose expansion phase at 1500/200mg. Median # of prior lines of chemotherapy was 2 (range 0-7). 3 pts are still on study. Median # of cycles on study were 2 (range 1-42). Cycle 1 DLT was grade 3 fatigue in 2 pts treated on 1800/200mg, and in 1 pt treated on 1500/200mg. Other grade 3/4 toxicities are summarized in the Table. 14 pts are evaluable for response (12 pts at 1500/200mg and 2 pts at 1800/200mg). No objective responses were seen, 3 pts had stable disease > 6 months (1 pt completed 42 cycles). Changes in pathways involved in extracellular matrix and TGFb pathway were noted. Conclusions: DLT of C concomitant with V was fatigue. MTD was 1500 mg C combined with 200 mg V BID. Combination has modest clinical activity. Consistent modulation of pathways involved in extracellular matrix and TGFb pathway, suggesting biomarkers of response to V. Clinical trial information: NCT00719875. [Table: see text]