bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/Ib study of the PARP inhibitor olaparib (O) with carboplatin (C) in BRCA1/2 mutation carriers with breast or ovarian cancer (Br/OvCa) (NCT00647062).
Authors: Lee Jung-min , Annunziata Christina M. , Hays John L. , Noonan Anne M. , Minasian Lori M. , Zujewski JoAnne , Yu Minshu , Ji Jiuping Jay , Sissung Tristan , Houston Nicole D. , Kohn Elise C.
Published: March 2020

2514

Background: O capsules have single agent activity against Br/OvCa in BRCA1/2mut+carriers. Our goals were to define safety and explore predictive biomarkers for an OC regimen in these pts. Methods: 3x3 dose escalation optimized daily oral O (100 or 200mg q12h; DL1&2) with IV C/AUC3 on d8 and q21d, and on DL3-6, O d1-7 at 200 then 400mg q12h with C/AUC3-5 on d2. ≤ 8 OC cycles were given, followed by daily O until progression. Safety was assessed q cycle and response q2 cycles. PBMCs were collected for polymorphism analysis (PARP1; XRCC1), and serially for PAR incorporation by ELISA. Paired tumor biopsies (pre/postC1) were collected in phase Ib pts for protein microarray (RPPA) and TUNEL endpoints. Results: 45 women (37Ov/8Br) with BRCA1 (32), BRCA2 (11), 1 each BRCA1&2 and BRCApro 68% received OC. All OvCa pts previously received C (6-55mo prior, median 14). DLT was thrombocytopenia (O 200mg q12h, C/AUC3 2/5 pts). MTD was not reached on the intermittent schedule. RP2D is O 400mg q12hx14, C/AUC5 (1/6: g4 thrombocytopenia). Gr 3/4 AEs included neutropenia (42%), thrombocytopenia (20%), anemia (13%), C hypersensitivity (9%), and fatigue (7%). 7 pts discontinued C early for hypersensitivity reaction (4) or myelosuppression (3). Responses included 1 CR (BrCa, 17mo), PR in 15/34 OvCa (44%; 3-28+mo) and 6/8 BrCa (5-24+ mo), and stabilization in 14/34 OvCa (41%; 3-25+ mo) and a BrCa pt (11mo) for a clinical benefit rate of 85% OvCa, 100% BrCa. RPPA (N=10) showed high FOXO3 and NFκB1 preC1 correlated with time on study (r=0.822, p=0.0035; r=-0.832, p=0.0028, respectively). The change post-preC1 correlated with time on study for the combination of eIF4E/G, caspase 7, pPI3K, FOXO3a, p62, E-cadherin, PCNA, Bim, and Bcl2 (r=-0.855, p=0.0068). Post-preC1 TUNEL results trended to correlate with response (p=0.07). PBMC PAR concentrations and PARP1/XRCC1 polymorphisms did not correlate with response. Conclusions: O 400mg q12h x14 with C/AUC5 q21d is active and tolerable in Br/OvCa BRCAmut+ pts despite interactive marrow suppression. Exploratory translational studies indicate FOXO3 and NFkB1 may be predictive for response to therapy, requiring a prospective validation. Clinical trial information: NCT00647062.
First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M.
Authors: Sequist Lecia V. , Soria Jean-Charles , Gadgeel Shirish M. , Wakelee Heather A. , Camidge D. Ross , Varga Andrea , Fidias Panos , Wozniak Antoinette J. , Neal Joel W. , Doebele Robert Charles , Garon Edward B. , Jaw-Tsai Sarah S. , Stern Jennifer C. , Allen Andrew R. , Goldman Jonathan Wade
Published: March 2020

2524

Background: Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 50% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition, compromises tolerability. CO-1686 is an orally active TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest maximal efficacy when trough plasma concentrations exceed 200ng/ml. Methods: This is a first in human phase 1 (3+3) dose-finding study of oral CO-1686, administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. Endpoints include safety, pharmacokinetics (PK), and efficacy. All patients undergo a biopsy for genotyping before starting study drug. Results: As of 18 Jan 2013, 35 patients (18/28 (64%) T790M+; 7 pending) have been treated with CO-1686. Dosing started at 150mg QD and escalated in steps to 900mg QD, 600mg BID and 400mg TID, with a maximum tolerated dose not yet reached. A recommended phase 2 dose is expected to be reached soon. Related AEs of grade 3 or higher were hypoglycaemia (n=1) and hyperglycaemia (n=1). AEs typical of WT-EGFR inhibition (rash, diarrhea) have not been observed. Dose-proportional PK was observed; plasma half-life was 4-5 hrs and at 900mg QD Cmax=3000ng/ml but trough concentrations were < 200ng/ml. At ≥300mg BID and TID dosing, trough concentrations can exceed 200ng/ml. At 900mg QD, 2 of 3 patients showed clinical benefit after 2 cycles of CO-1686 including one with clinically-relevant tumor shrinkage (18%) and a second with stabilization of a pleural effusion that had previously required repeat thoracenteses at ~10 day intervals. At 300mg BID, one patient (Del(19)/T790M+) with PK trough concentration >200ng/ml exhibited significant tumor shrinkage (29%) after 2 cycles. Further efficacy data from BID/TID cohorts and centrally-confirmed genotypes will be presented at the meeting. Conclusions: CO-1686 offers potential for improved activity and better tolerability over current EGFR TKIs, particularly in the treatment of T790M+ disease, an area of high unmet clinical need. Clinical trial information: NCT01526928.
Phase I, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors.
Authors: Adjei Alex A. , LoRusso Patricia , Ribas Antoni , Sosman Jeffrey Alan , Pavlick Anna C. , Dy Grace K. , Zhou Xiaofei , Gangolli Esha A. , Walker Russell M , Kneissl Michelle , Faucette Stephanie , Neuwirth Rachel , Bozon Viviana
Published: March 2020

2528

Background: This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), MTD, and efficacy of TAK-733 – an oral, selective, allosteric inhibitor of MEK1/2 – in pts with advanced solid tumors (NCT00948467; completed study). Methods: Eligibility: age ≥18 y; ECOG PS 0–2; evaluable tumors. Pts received escalating doses of TAK-733 QD in a modified 3+3 design for 21 d in a 28-d cycle to determine the MTD based on DLTs in cycle 1. Plasma (PK) and peripheral blood samples (PD: pERK reduction in PBMCs) were obtained pre-dose (d 1, 8, 15, 21) and post-dose (d 1, 21) in cycle1. Results: 51 pts (median age 58 y; 51% M) received escalating doses of TAK-733 (0.2–22 mg; median 2 cycles, range 1–11 [5 pts ≥6 cycles]). 4 pts had DLTs: grade 3 acneiform dermatitis, 1 each at 11.8 and 16mg; grade 3 pustular rash and grade 2 rash/stomatitis (qualifying as a DLT) at 22mg, leading to the 16 mg dose being selected as MTD. 45 pts (88%) had a drug-related AE; most frequent was acneiform dermatitis (47%). 10 pts (20%) had a grade ≥3 drug-related AE; most frequent were creatine phosphokinase increase and acneiform dermatitis (each n=3, 6%). 7 pts discontinued due to AEs. TAK-733 exhibited a moderately fast absorption with a median Tmax of 3 hr. Steady-state exposure of TAK-733 (0.2–22mg) did not increase in a dose proportional manner based on the power model analysis. The mean terminal t1/2 (11.8, 16, and 22 mg) was 43 hr. Overall mean accumulation ratio was 3.5 following QD dosing for 21 d. On d 21, Emax of blood pERK modulation was 56–99%, and time-averaged modulation over the dosing interval at steady-state was 76–98% at MTD. This range correlates well to the 76–89% for pERK modulation associated with maximal efficacy in xenograft models. 1 pt (16 mg) with melanoma (BRAF L597R) had a confirmed partial response after 4 cycles (treated for 9 cycles). 15 pts had a best response of stable disease (4–11.7 months in 6 pts). Conclusions: From preliminary data, TAK-733 appears generally well tolerated, pharmacodynamically active and shows signs of anti-tumor activity in pts with advanced solid tumors. MTD was associated with significant pERK inhibition in peripheral blood. Clinical trial information: NCT00948467.
A phase I study of ombrabulin (O) combined with bevacizumab (B) in patients with advanced solid tumors.
Authors: Ong Michael , Del Conte Gianluca , Bahleda Rastislav , Mateo Joaquin , Damian Silvia , Perotti Antonella , Lassau Nathalie , Farace Françoise , Lovosgaldeano Jimena , Tunariu Nina , Hospitel Marie , Mariani Paola , Cohen Patrick , Capri Giuseppe , Soria Jean-Charles , Gianni Luca , Molife L Rhoda , Sessa Cristiana
Published: March 2020

2535

Background: O, a vascular-disrupting agent derived from combretastatin A4-phosphate, induces rapid tumor vascular shutdown via endothelial cell damage. Resistance to O may occur by surges in circulating endothelial progenitors (CEP) that repopulate the tumor vasculature. Experimental models suggest prolonged and synergistic antitumor activity when O is combined with VEGF-blockade, with reduction in CEP surge. This phase I study was performed to determine the maximum tolerated dose, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O combined with B. Methods: Patients (pts) with advanced treatment-refractory solid tumors, ECOG PS ≤1, and adequate organ function were eligible. O (mg/m²) was administered intravenously (IV) on day (d)1 with B (mg/kg) IV on d2 in 21d cycles (C). A Bayesian model informed dose escalation steps. PK sampling, dynamic contrast-enhanced ultrasound (DCE-US) for tumor perfusion, and CEP samples were collected. Results: 39 pts (M:F 10:29; median age 51 years [range 25-75]) were treated at 12 dose levels combining O [8 to 50mg/m2] with B [5, 10, or 15mg/kg]. Ovary (16/39, 41%) and colon (4/39, 10%) were the most common primary sites. No C1 dose-limiting toxicities occurred in 37 evaluable pts. Drug-related grade 3-4 treatment emergent adverse events (AE) were hypertension (6/39, 15%), intestinal perforation (2/39, 5%), headache (1/39, 3%), myocardial infarction (1/39, 3%), and pulmonary embolism (1/39, 3%). 36 pts (14 ovarian) were evaluable for response by RECIST 1.1. Antitumor activity was observed at O 20mg/m2+ B 10mg/kg and above, with confirmed partial responses in 2/14 pts with ovarian primary (14%), CA125 responses in 2 further ovary/endometrial cancers lasting ≥ 6 months, and stable disease in 15/36 pts (42%) lasting ≥ 6 months in 3 pts. PK indicated no interactions of O+B. Analyses of CEP levels post O and paired DCE-US data are ongoing. Conclusions: The maximum administered dose (MAD) was O 50mg/m2 with B 15mg/kg, with no dose-limiting toxicities and vascular toxicity that was manageable. Promising antitumor activity was observed at doses below the MAD and warrants further evaluation. Clinical trial information: NCT01193595.
Therapeutic p53 gene agent in the treatment of refractory cancer cases: A phase I study.
Authors: He Xia , Xu Jianhua , Wen Jie
Published: March 2020

2543

Background: To evaluate the benefit of adding therapeutic p53 gene agent into the standard treatment regimens for refractory cancer cases. Methods: Recombinant adenoviral human p53 gene (rAd-p53), was given intravenously at a dose of 2×1012 viral particles /day on 5 consecutive days one week before routine anti-cancer treatment start, and was repeated after an interval of 16 days. The inclusion criteria include: 1.Pathologically confirmed recurrent cancers; 2. Disseminated cases; 3. Patients with key organ metastasis; 4.Unresectable lesions; 5.Chemo- or radio-therapy resistant cases. The exclusion criteria include: 1.With severe liver, kidney, heart or hemotologic disorders; 2.Pregnancy; 3.Without informed consent. Efficacy was evaluated according to the results of contrasted MRI or CT. Results: A total of 16 patients entered the study with a median age of 59 years old (range 30-76 years), 13 were male and 3 were female. 5 were recurrent cases(4 HNSCC and 1 esophageal cancer), 5 were widely infiltrated unresectable HNSCC, esophageal carcinoma(2 cases) and undifferentiated thyroid carcinoma(1 case). 3 were disseminated cases(2 NPC and 1 Lung cancer). Two cases were breast cancer with multiple brain metastasis. One was refractory central nervous lymphoma. One patient did not finish the planned chemoradiation due to radiation-induced pneumotitis. Another one patient experienced chemotherapy delay due to A grade 4 hemotologic toxicity. 93.8% patients had shivering and fever after injection of rAd-p53. Other acute toxicities during the treatment included: leukopenia(Grade 3/4) 43.8%, thrombocytopenia (Grade 3/4) 25.0%, oral mucositis(Grade 3/4) 18.8%, vomiting(Grade 2 and above) 31.3%, ALT elevation (Grade 2 and above) 6.3%. No Cr elevation was observed. The acute toxicities were controllable and reversible. At the 3 months after treatment, PR, SD and PD rate were 56.3%, 25.0% and 18.7%, respectively. Conclusions: The therapeutic p53 gene agent can be intravenously safely added to routine anti-cancer regimens with controllable and reversible acute toxicities. A randomized controlled phase II is needed to make clear the role of the therapeutic p53 gene agent.
Efficacy of the Royal Marsden Score (RMS) to improve the selection patients (pts) considered for participation to dose-seeking phase I trial.
Authors: Favre Veronique , Meniai Fatima-Zhora , Cassier Philippe Alexandre , Gomez-Roca Carlos Alberto , Isambert Nicolas , Clisant Stephanie , Philippe Peggy , Levart Alice , Desmoulins Isabelle , Bouchet Juliette , Delord Jean-Pierre , Penel Nicolas
Published: March 2020

2548

Background: Selection of pts entering in phase trials remains difficult. An international network of expert centers had validated the efficacy of the RMS as selection tool in such context. Nevertheless, RMS have been developed (Arkenau EJC 2008) and validated (Olmos et al. JCO 2012) in cohorts of already enrolled pts, whereas that the question of eligibility is crucial at the time of screening. We have then implemented and measured the efficacy of the RMS in 453 pts entering in the screening process in 4 expert centers. Methods: We have analyzed pts having signed the PIS/IC. RMS (0 to 3) is sum of the following prognostic factors: LDH>ULN, met. sites>2 and albumin <35 g/L. We have established the rates of enrolled pts, of pts dying within 90 days, of pts having completed PK/PD analysis, with accurate tumor assessment, having to be replaced according to RMS value. Results: Score was as follows: 0 (122/453, 27.0%), 1 (147/453, 32.4%), 2 (79/453, 17.4%), 3 (20/354, 4.4%) & not assessable (84/453, 19.2%). OS according to RMS value were 615, 299, 239 & 136 days (p=0.0001). The rates of 90-day mortality were 5.3%, 12.6%, 26.6% & 41.1% (p=0.0001). The rates of enrolled pts were 79.5%, 77.5%, 60.7% & 50.0% (p=0.001). Among enrolled pts, the rates of pts having completed the PK/PD analysis were 87.6%, 79.8%, 70.8% & 50.0% (p=0.007). Among enrolled pts, the rates of tumor assessment available were 95.8%, 88.6%, 89.5% & 70.0% (p=0.006). The rates of pts having to being replaced 4.1%, 5.2%, 2.0% & 50.0% (p=0.04). The time under study was 118, 81, 56 and 62 days (p=0.005). Conclusions: We confirm that the RMS is a reliable, easily obtained tool for selecting pts in such context. The enrollment of pts with RMS=3 is associated with a high risk of attribution rate & risk to be replaced. The time under study was significantly lower in cases of RMS =[2-3].
A phase I dose-escalation study of volasertib (BI 6727) combined with nintedanib (BIBF 1120) in advanced solid tumors.
Authors: De Braud Filippo G. , Cascinu Stefano , Spitaleri Gianluca , Pilz Korinna , Clementi Laura , Liu Dan , Glomb Patricia , De Pas Tommaso
Published: March 2020

2556

Background: Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF, and FGF receptors. Both have shown clinical activity with a manageable safety profile in patients (pts) with advanced solid tumors. This study was designed to determine the maximum tolerated dose (MTD) of V combined with N in these pts. Methods: Cohorts of 3–6 pts received V (100–450 mg IV Q3W) + oral standard dose N (200 mg BID continuously, except V infusion day). Treatment continued until clinical progression. Up to 12 pts were treated at the MTD for additional safety data. Primary endpoint was the MTD; secondary endpoints were pharmacokinetics (PK), overall safety, and preliminary efficacy. Results: 30 pts were treated (median age, 56.5 yr; ECOG PS 0/1/2, 33%/60%/7%; ≥3 prior therapies, 87%). At V doses >200 mg, 7 pts experienced 13 dose-limiting toxicities (DLTs) during cycle 1: increased alanine aminotransferase [ALT] or aspartate aminotransferase [AST], neutropenia and thrombocytopenia. The MTD was V 300 mg (Table). At the MTD, the most common all grade (Gr) adverse events (AEs) were neutropenia (69%), asthenia and thrombocytopenia (62% each), increased ALT, increased AST and diarrhea (54% each). Median (range) duration on treatment was 4 (1–18) cycles. Treatment was discontinued due to progressive disease (80%), DLT (3%) and other non-AE related reasons (17%). 2 objective responses were observed (1 complete [breast cancer] and 1 partial [NSCLC]), both with the 300 mg dose. 6 pts had SD for ≥ 6 mo. PK data will be presented at the meeting. Conclusions: MTD of V + standard dose N (200 mg BID) was determined to be 300 mg Q3W (the same as the recommended phase II single agent dose of V in solid tumors). This combination had a manageable safety profile without unexpected or overlapping toxicities and showed preliminary antitumor activity. Clinical trial information: NCT01022853. [Table: see text]
A pharmacokinetic and dose-escalating study of paclitaxel injection concentrate for nano-dispersion (PICN) alone and with carboplatin in patients with advanced solid tumors.
Authors: Ma Wen Wee , Lam Elaine Tat , Dy Grace K. , Diamond Jennifer Robinson , Zhao Yujie , Bui Lynne A. , Fetterly Gerald J. , Abramowitz Wattanaporn , Harning Ronald , Pencheva Pepi , Bhowmik Shravanti , Divekar Ganesh Harishchandra , DiRaddo Ann Marie , Eckhardt S. Gail , Adjei Alex A. , Jimeno Antonio
Published: March 2020

2557

Background: PICN is a novel Cremaphor-free composite of paclitaxel nano-particles stabilized with polymer and lipid using Nanotecton Technology. The MTD of PICN alone was previously determined to be 295 mg/m2 iv every 3 weeks in a South Asian population. This study aimed to determine the pharmacokinetic (PK) profile of PICN alone and with carboplatin (C), and the MTD of PICN plus C. Methods: Patients (pt) with advanced solid malignancies and ECOG PS 0-1 were eligible. Part A was a PK study designed to examine cohorts of 3 pts, receiving PICN over 30 min at dose levels of 175, 260, and 295 mg/m2 every 3 weeks; PK were performed at pre-determined time-points. Part B used a ‘3+3’ dose escalation scheme, designed to determine the MTD of PICN (220, 260, and 295 mg/m2) when combined with C at AUC 6. Only standard anti-emetic pre-medications were used. Adverse events (AEs) were graded using CTCAE 4.0 and tumor response by RECIST 1.1. Results: A total of 18 evaluable pts (9 in Part A, 9 in Part B) were enrolled from 2 US academic centers. No infusion reactions were observed with PICN. No dose limiting toxicity (DLT) was observed in Part A. In Part B, the DLTs were G3 febrile neutropenia and G4 thrombocytopenia requiring platelet transfusion at PICN 260/C AUC 6. A total of 6 pts were treated at PICN 220/C AUC 6 with no DLT. G3 or worse AEs for all cycles were as follow: Part A, bilateral lower extremity weakness, neuropathy, anorexia and neutropenia; Part B, anemia, thrombocytopenia, neutropenia and empyema. Partial responses were observed in biliary(Part A; PICN 260 mg/m2), breast (Part B 220/6) and anal cancers (Part B 260/6). PK analysis showed dose-proportional increase in total plasma paclitaxel level. Conclusions: PICN alone was tolerable in the dose range evaluated. When administered with C AUC 6, the MTD of PICN was 220 mg/m2 administered every 3 weeks. Anti-cancer activity was observed in biliary, breast, and anal cancers. Final PK, toxicity and efficacy data of PICN alone and with C will be presented at the conference. Clinical trial information: NCT01304303.
Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with gemcitabine in patients with advanced cancer.
Authors: Kozloff Mark , Carbonero Rocio , Nadal Tamara , Gueorguieva Ivelina , Cleverly Ann , Desaiah Durisala , Lahn Michael M. F. , Pillay Sada , Blunt Al , Tabernero Josep , Macarulla Teresa
Published: March 2020

2563

Background: Based on animal studies, the combination of a TGF-β inhibitor and gemcitabine is expected to enhance antitumor activity of gemcitabine. Hence, we started a combination study of LY with gemcitabine to assess the safety of this combination therapy. Methods: Gemcitabine was administered as approved and LY was given daily as intermittent dosing (14 days on/14 days off=1 cycle). A dose escalation consisting of 3 cohorts (80 mg/day, 160 mg/day, and 300 mg/day) evaluated the safety of LY in combination with gemcitabine. Toxicity was assessed using the CTCAE, version 4. Pharmacokinetic (PK) profile of LY in combination with gemcitabine was determined. Results: A total of 14 patients were evaluated (cohort 1 [n=5, 4 adenocarcinoma of colon, 1 non-small cell lung cancer, cohort 2 [n=4, adenocarcinoma, 1 each of esophageal, well differentiated, pancreas, lung], cohort 3 [n=5, 3 pancreatic, 2 rectal cancer]) in this study. The median number of cycles was 2 (range (1-6). Regardless of causality, the following treatment-emergent adverse events (TEAEs) were observed in ≥25% of patients: anemia (n=10), nausea (n=8), thrombocytopenia (n=6), neutropenia (n=6), vomiting (n=6), anorexia (n=5), fatigue (n=5), diarrhea (n=5) asthenia (n=5), pyrexia (n=4), AST increased (n=4), and constipation (n=4). Possibly related to LY, (Grade, Gr, 3/4 as mentioned) TEAEs observed were: nausea (n=5), asthenia (n=4), fatigue (n=3, 1 Gr 3), neutropenia (n=3, 1 Gr 3), anemia (n=3, 2 Gr 3 ), and in 2 patients each, thrombocytopenia (both Gr 3), headache, edema peripheral, rash, anorexia, diarrhea (1 Gr 3), mucosal inflammation, vomiting and reversible rhabdomyolysis (n=1, Gr 4). No change in the PK profile of LY was shown when LY was combined with gemcitabine. Conclusions: There were no dose limiting toxicities observed and no clinically meaningful cardiotoxicities were detected. Because of the observed manageable safety profile, LY at 300 mg/day has been advanced into a randomized Phase 2 trial in pancreatic cancer in 1st line setting to assess the antitumor activity of the combination. Clinical trial information: NCT01373164.
ProGem1: Phase I first-in-human study of the novel nucleotide NUC-1031 in adult patients with advanced solid tumors.
Authors: Ghazaly Essam Ahmed , Joel Simon , Gribben John G. , Mohammad Tariq , Emiloju Oluwadunni , Stavraka Chara , Hopkins Tom , Gabra Hani , Wasan Harpreet , Habib Nagy A , Leonard Robert C. F. , McGuigan Christopher , Slusarczyk Magdalena , Blagden Sarah Patricia
Published: March 2020

2576

Background: NUC-1031 is a novel nucleotide (ProTide) that evades all three key cellular resistance mechanisms associated with gemcitabine (dFdC). NUC-1031 bypasses nucleoside transporters, is activated independent of deoxycytidine kinase and is resistant to cytidine deaminase-mediated degradation. NUC-1031 has demonstrated broad antiproliferative activity in vitro and in vivo. Methods: Patients with relapsed/refractory advanced solid tumors entered in sequential cohorts of up to 6 patients, with escalating doses of NUC-1031 administered as a 5-10 minute IV injection weekly or twice-weekly. Ongoing objectives are to determine recommended phase II dose, safety profile, pharmacokinetics (PK) and preliminary anti-tumor activity. Results: 8 patients (5 female, 3 male) with pancreatic (2), colorectal (2), breast (1), and ovarian (1) cancers; cholangiocarcinoma (1) and unknown primary (1) have been enrolled. Two dose levels - 500mg/m2 (4) and 1000mg/m2 (1) weekly and one dose level - 375 mg/m2(3) twice-weekly. No DLTs have been observed. Mean AUC (0 - 24 h) for NUC-1031 was 150.3 ± 84.8 µM/h (n=5). dFdC and dFdU were detected in plasma up to 24 h (range of 0 - 5.8 µM for dFdC and 0 - 14.9 µM for dFdU). NUC-1031 excreted in urine mainly as dFdU. The Table shows rapid elimination of NUC-1031 from plasma and high intracellular levels of the active gemcitabine triphosphate at 2 and 24 h. Stable disease achieved in 1 patient with rapidly progressing breast cancer. Two further patients had symptomatic relief and improved QOL, including a dramatic reduction in ascites and pain. Conclusions: PK data show NUC-1031 has ≥ 10x higher intracellular levels of the active compound, dFdCTP, and significantly lower plasma Cmax levels of the toxic metabolite, dFdU, compared to equivalent levels of gemcitabine. NUC-1031 has shown better intracellular delivery and toxicity profile than gemcitabine with some promising early indicators of clinical efficacy. Clinical trial information: NCT01621854. [Table: see text]
First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.
Authors: De Bono Johann Sebastian , Mina Lida A. , Gonzalez Michael , Curtin Nicola J. , Wang Evelyn , Henshaw Joshua W. , Chadha Manpreet , Sachdev Jasgit C. , Matei Daniela , Jameson Gayle S. , Ong Michael , Basu Bristi , Wainberg Zev A. , Byers Lauren Averett , Chugh Rashmi , Dorr Andrew , Kaye Stanley B. , Ramanathan Ramesh K.
Published: March 2020

2580

Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50<1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage dose-escalation study with 3-6 patients (pts)/dose level. In dose escalation (Stage 1) cycle 1 was 6 wks, with drug taken on days 1 and 8-35, for PK and PD assays, followed by daily continuous dosing in 4-wk cycles. Stage 2 (expansion at MTD) recruits pts with tumors defective in DNA repair: Ewing sarcoma, small cell lung cancer or tumors associated with BRCA mutation (mut). Results: 39 pts (33F/6M) were enrolled in 9 cohorts from 25 to 1100 µg/d that defined a MTD of 1000 µg/d. Median (range) age was 58 (19-81), PS 0 (0-1) and # of prior therapies 4 (1-13). Tumors (# with deleterious BRCA 1/2 mut) included 23 ovarian/primary peritoneal (17); 8 breast (6); 3 pancreas; 2 colon; 1 prostate (1), and 1 mullerian carcinosarcoma. 17 and 8 pts had BRCA 1 and 2 mut, respectively. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 µg/d, respectively. Potentially-related adverse events in >10% of pts (# grade 1 and 2/grade 3 and 4) included fatigue (10/0); nausea (10/0); flatulence (4/0); anemia (5/2); neutropenia (4/3); thrombocytopenia (1/3); and grade 1 alopecia (10). Inhibition of PARP activity in PBMCs was observed at doses ≥ 100 µg/d. BMN 673 plasma concentrations peaked 1-2 hrs post-dose; exposure increased dose proportionally. Steady state plasma concentrations were reached by the end of the 2nd week of daily dosing; mean Cmax: 0.30 - 25.4 ng/mL and AUC0-24: 3.96 - 203 ng-hr/mL across the 25 to 1100 µg/d dose range after 28d of daily dosing. RECIST and/or CA-125 responses occurred at doses ≥ 100 µg/d in 11/17 BRCA carrier ovarian/peritoneal cancer pts. Objective responses occurred in 2/6 BRCA-carrier breast cancer pts. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with BRCA mut with a single agent recommended Phase II trial dose of 1000 µg/d due to dose-limiting thrombocytopenia. Clinical trial information: NCT01286987.
Impact of UGT1A4, UGT2B7, and UGT2B15 pharmacogenetics on tamoxifen (TAM) metabolism.
Authors: Lim Joanne Siok-Liu , Ganchev Boian , Singh Onkar , Muerdter Thomas E , Yap Yoon Sim , Ng Raymond C.H. , Wong Nan Soon , Schwab Matthias , Chowbay Balram
Published: March 2020

2588

Background: The aims were to characterize the genetic profiles of UGT1A4, UGT2B7 and UGT2B15in Asian healthy populations (Chinese, Malay, Indians, N=80 each) and investigate the effects of these SNPs on the disposition of TAM in Asian breast cancer patients (N=202). Methods: Healthy Asian subjects and Asian breast cancer patients were genotyped for UGT1A4, UGT2B7 and UGT2B15 SNPs. Plasma levels of tamoxifen and its metabolites in Asian patients were determined via LC-MS/MS analysis. Genotypic-phenotypic differences were examined using non-parametric tests. Haplotypic effects were examined using haplotype-specific generalized linear model. Results: Screening of the 5′ upstream, exonic, exonic-intronic junctions and 3′ downstream regions identified 61, 77 and 47 SNPs in UGT1A4, UGT2B7 and UGT2B15respectively. A total of 16, 14 and 20 tag-SNPs were identified in these genes respectively and genotyped in patients. Haplotypic analysis revealed associations between LD block 1 (-1548A>G, -1531C>T, -419G>A, -219C>T, -163G>A, 142T>G, 448T>C, 804G>A, IVS1+196T>C, IVS1+346T>G, IVS1+414A>G, IVS2+307A>G) and higher plasma Tam-N-Gluc level and MRTAM-N-Gluc/TAM after adjustment for significant covariates. The median (range) MRTAM-N-Gluc/TAM was 2.1- and 1.9-fold higher among patients carrying one and two copies of H2 (GCATAGCACTGG), respectively, compared to patients who carried two copies of H1 haplotype (ACGCGTTGTTAA) [H1/H1 vs H1/H2 vs H2/H2: 0.35 (0.11 - 2.09) vs 0.74 (0.19 - 3.60) vs 0.66 (0.52 - 1.66), P < 0.0001]. Similar association was observed between H2 and Tam-N-Gluc level [H1/H1 vs H1/H2 vs H2/H2: 0.75 (0.15 - 4.45) vs 1.29 (0.19 - 9.20) vs 1.66 (0.62 - 2.83) ng/ml, P= 0.004]. UGT2B15 LD block 3 (1568A>C, *168C>T, *186A>T, *+630C>G and *+888A>G) was associated with modest decrease and increase in (E)-END and MRZ-NDM-4-O-GLUC/E-END, respectively. UGT2B7haplotypes were not associated with O-glucuronidations of 4-OHT and END. Conclusions: This study highlights the involvement of UGT1A4 haplotypes in the variability in TAM N-glucuronidation while UGT2B7 and UGT2B15 variants played limited role in the variabilities of O-glucuronidations of 4-OHT and END in Asian breast cancer patients. Clinical trial information: 0822570P.
Dose-dependent pharmacokinetic (PK) interaction of pegylated liposomal doxorubicin (PLD) with escalating doses of veliparib in a phase I study.
Authors: Pothuri Bhavana , Muggia Franco , Sparano Joseph A. , Blank Stephanie V. , Curtin John Patrick , Chuang Ellen , Hershman Dawn L. , Chen Alice , Liebes Leonard
Published: March 2020

2591

Background: PARP1 inhibition enhances the effects of DNA-damaging agents such as doxorubicin. We sought to investigate PK of PLD in a phase I study of veliparib (ABT-888, V) and PLD in patients (pts) with recurrent ovarian, fallopian tube, and primary peritoneal, and triple negative breast cancers. No prior PK interactions have been described in V clinical trials. Methods: Complete blood samples on day (D) 1 (pre-PLD and 1 hr post PLD), D 8, D 22 on cycle 1 and 2 of treatment in pts receiving PLD 40 mg/m2, day (D) 1 and V D1-14 at varying dose levels of 50,100,150, 200, 300, 350 mg twice daily, were collected in 25 of 31 pts enrolled to a previously reported dose finding phase I study of V and PLD (SGO2012). Plasma PLD levels were measured by HPLC methodology detailed by Gabizon et al Cancer Chemo Pharmacol 2008, 61:695. PK parameter estimates were obtained using non-linear modeling programs available in Winnonlin Ver 5.3. Affect of V dose on PK parameters was estimated with linear regression analysis. Due to a higher degree of GI toxicity with V dosages > 200 mg, we utilized a cut-off of 200 mg for V. PK parameters in the group with dosages greater than or equal to 200 mg (high V, n=18) and those less than 200 mg (low V, n=7) were compared, utilizing an unpaired, 2 sided t-test. Results: PLD clearance (CL) was reduced, half-life (hL) was increased, and AUC/mg was increased with higher dosages of V when compared to historical published data. We noted a positive correlation of the auc/mg dose, p=0.001 and a negative correlation with the CL, p=0.001 and increasing V dose. When analyzed as low and high V groups, the mean ± SEM hL (hrs) was significantly lower in the low V when compared to the high V group, 83.2 ± 11.7 vs 108.6 ± 6.0(p =0.042) , and the mean PLD clearance (ml/h)was greater in the low V versus the high V group 35.9 ± 5.6 vs 14.2 + 1.0, P<.0001. Similarly the AUC/mg dose (mg x h/L) was significantly lower in the low vs high V groups, 35.0 ±5.2 vs 74.9 ± 4.4, P<0.0001. Conclusions: Higher exposure of PLD is noted with V at doses greater than or equal to 200 mg twice daily. An expansion cohort with patients receiving PLD alone in cycle 1, and PLD + V 200 mg twice daily in subsequent cycles, will validate the presence of a PK interaction. Clinical trial information: NCT01145430.
Application of pharmacokinetic (PK)-guided 5-fluorouracil (FU) in clinical practice.
Authors: Patel Jai Narendra , Deal Allison Mary , O'Neil Bert H. , Ibrahim Joe , Sherrill Gary Bradley , Davies Janine Marie , Bernard Stephen A. , Goldberg Richard M. , Olajide Oludamilola A. , Atluri Prashanti , Inzerillo John J. , McLeod Howard L. , Walko Christine Marie
Published: March 2020

2595

Background: Body surface area (BSA)-based dosing of FU results in up to 100-fold inter-individual PK variability. PK-guided FU compared to BSA-based dosing resulted in higher response rates and decreased rate of toxicities in two randomized clinical trials. A paucity of data exists on PK-guided FU dosing in the clinical setting. Methods: A total of 70 colorectal cancer (CRC) patients (pts) from 6 academic and community sites received mFOLFOX6 (FU 2,400 mg/m2over 46 h every 2 wks) +/- bevacizumab. Peripheral blood was obtained 2-44 h after start of FU infusion and AUCs were estimated using an immunoassay at Myriad Genetics. FU doses for cycles 2-4 (C2-4) were adjusted algorithmically to target an area under the concentration-time curve (AUC) of 20-25 mg*h/L. The primary outcome was the % of pts within target AUC by C4, with a secondary outcome of toxicity rates compared to historical data. Comparisons between cycles were made using generalized linear models, accounting for repeated observations within pt. Results: The % of pts within target AUC post C1 and C4 was 30% (17/57, 95%CI: 18-43%) and 46% (24/52, 95%CI: 32-61%), respectively (OR=2.16, p=0.05). For each subsequent cycle, the odds of a pt being within range increases by 28% (p=0.04) (Table). The median dose needed to achieve target AUC at C4 was 2,580 (range 1,920-3,484) mg/m2. The median AUC post C1 and C4 was 19 and 21 mg*h/L, respectively. Less grade 3/4 mucositis and diarrhea were seen compared to historical data (3 v 15% and 6 v 12%, respectively); however, no difference in grade 3/4 neutropenia was noted (27 v 33%). Nine pts were non-evaluable by protocol for PK analysis, largely due to sampling/processing errors. Conclusions: PK-guided FU resulted in a greater number of pts achieving the targeted AUC and fewer pts under-dosed at C4 compared to C1. Individualization of FU dosing in the front-line, community and academic, setting is achievable for the treatment of CRC; however, larger clinical trials are needed to define the clinical utility of PK-guided FU. Clinical trial information: NCT01164215. [Table: see text]
A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors.
Authors: Arnedos Monica , Denlinger Crystal Shereen , Harb Wael A. , Rixe Olivier , Morris John Charles , Dy Grace K. , Adjei Alex A. , Pearlberg Joseph , Follows Sarah , Czibere Akos Gabor , Soria Jean-Charles
Published: March 2020

2609

Background: MM-121 is a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3. ErbB3 has been implicated in driving cancer growth and in the development of resistance to conventional chemotherapies across multiple malignancies. Here we present results of an open-label, Phase 1, multicenter, non-randomized, dose-escalation trial which recently completed enrollment evaluating MM-121 in combination with one of the following chemotherapies: Gemcitabine (Arm A, n=11), carboplatin (Arm B, n=11), pemetrexed (Arm C, n=10), or cabazitaxel (Arm D, n=11). Methods: Patients were treated in a dose escalation “3+3” design to assess the safety, tolerability and pharmacokinetics (PK) of MM-121 administered weekly in combination with anticancer therapies in subjects with advanced cancer. Doses were escalated until the maximum tolerated dose (MTD) was identified or the combination was shown to be tolerable at the highest planned doses. Secondary objectives included: Determining the objective response rate, clinical benefit rate, PK and immunogenicity of MM-121. Data summarized are as of 1/17/2013 from a live database. Results: Overall, 43 patients, [22 (51%) female and 21 (49%) male] have been treated with a median treatment duration of 57 days (range 1-302). The median age was 59 years (range 42-84) and patients had received a median of four prior lines of therapy (range 0-13). Common (>20%) adverse events of any grade and causality across all arms included diarrhea (74%), nausea (54%), fatigue (51%), anemia (44%), vomiting (33%), hypokalemia (30%), decreased appetite (26%), thrombocytopenia (26%), peripheral edema (23%), neutropenia (21%), and constipation (21%). Four DLTs were observed: Two in combination with carboplatin (G4 thrombocytopenia and G3 rash), one with gemcitabine (G4 thrombocytopenia), and one with pemetrexed (G4 hyperuricemia). Overall 38 (88%) patients were evaluable for response and the overall clinical benefit rate (PR or SD >18 weeks), is 32% (12/38). Conclusions: MM-121 can be combined at its recommended single agent dose with standard doses of gemcitabine, pemetrexed, and cabazitaxel and adapted doses of carboplatin. Clinical trial information: NCT01447225.
Phase I trial of sorafenib, bevacizumab, and temsirolimus in advanced solid tumors.
Authors: Westin Shannon Neville , Smart Melody L. , Pal Navdeep , Urbauer Diana L , Janku Filip , Wheler Jennifer J. , Piha-Paul Sarina Anne , Naing Aung , Tsimberidou Apostolia Maria , Fu Siqing , Falchook Gerald Steven , Hong David S. , Zinner Ralph , Subbiah Vivek , Culotta Kirk Salvatore , Lu Karen H. , Coleman Robert L. , Kurzrock Razelle
Published: March 2020

2611

Background: Pathway crosstalk and emergence of drug resistance have limited the activity of targeted therapies, including anti-angiogenic agents and mTORC1 inhibitors. However, this vulnerability may be addressed by rationally combining targeted therapies to improve outcomes. We sought to determine the MTD/recommended phase II dose and define the pharmacokinetics (PK) of the combination of sorafenib (S), bevacizumab (B), and temsirolimus (T) in patients with advanced solid tumors. Methods: S was given once or twice daily, B was given intravenously every three weeks, and T was given intravenously weekly. Doses were escalated in a stair-step dose escalation with 6 planned dose levels (DL) in a standard 3+3 design. Responses were defined using RECIST 1.1. Results: To date, 51 patients have been enrolled. Three patients withdrew consent after only one dose. One dose-limiting toxicity (DLT) occurred at DL 5 (grade 4 fatigue, pain) and one DLT occurred at DL 6 (G3 headache). However, 5/6 patients required dose reduction on DL6 (G2 nausea, fatigue, hand/foot syndrome, rash). Thus, DL5 (B 10mg/kg, T 20mg, S 200mg twice daily) is being explored in dose expansion (N=10) and tumor expansion cohorts as the recommended phase II dose. The most common adverse events (>10%) were fatigue (69%; G3/4 6%), nausea (38%, G3/4 2%), pain (35%, G3/4 10%), thrombocytopenia (33%, G3/4 8%), mucositis (33%, 0%), constipation (29%, G3/4 0%), hand/foot syndrome (23%, G3/4 0%), rash (19%, G3/4 0%), hypertension (17%, 0%), neuropathy (17%, G3/4 0%), diarrhea (15%, G3/4 6%), vomiting (15%, G3/4 2%), headache (12%, G3/4 2%), and hypertriglyceridemia (10%, G3/4 2%). Of 34 patients evaluable for response, 4 had PR including ovarian (-57%, +6m), gastric (-46%, +5m), colorectal (-32%, +5 m), and thyroid (-31%, +6m) cancer. Eight patients had SD for greater than 4 months including ovarian (0%, +7m), colorectal (-5%, +8m), endometrial (-26%, +5m; -16%, +4m; -15%, +6m), leiomyosarcoma (-5%, +6m), squamous lung cancer (-6%, +6m), and triple negative breast (-15%, +4m) cancer. Conclusions: The combination of S, B, and T is well tolerated and demonstrates preliminary evidence of tumor activity in a variety of solid tumors. PK studies at the recommended phase II dose are ongoing. Clinical trial information: NCT01187199.
A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors.
Authors: Herbst Roy S. , Gordon Michael S. , Fine Gregg Daniel , Sosman Jeffrey Alan , Soria Jean-Charles , Hamid Omid , Powderly John D. , Burris Howard A. , Mokatrin Ahmad , Kowanetz Marcin , Leabman Maya , Anderson Maria , Chen Daniel S. , Hodi F. Stephen
Published: March 2020

3000

Background: Tumor PD-L1 mediates cancer immune evasion. Therefore, inhibition of PD-L1 binding represents an attractive strategy to restore tumor-specific T-cell immunity.MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: A study was conducted with MPDL3280A administered IV q3w in pts with locally advanced or metastatic solid tumors, including 3+3 dose-escalation and expansion cohorts. ORR was assessed by RECIST v1.1 and includes u/cCR and u/cPR. Results: As of Jan 10, 2013, 171 pts were evaluable for safety. Administered doses include ≤1 (n=9), 3 (n=3), 10 (n=35), 15 (n=57) and 20 mg/kg (n=67). Pts in the dose-escalation cohorts did not experience DLTs. No MTD was identified. Pts had received MPDL3280A for a median duration of 127 days (range 1-330). 39% of pts reported G3/4 AEs, regardless of attribution. AEs of special interest included hepatitis, rash and colitis. No G3-5 pneumonitis was observed. MPDL3280A PK was linear at doses ≥1 mg/kg. 122 pts enrolled prior to Jul 1, 2012 were evaluable for efficacy. RECIST responses were observed in multiple tumor types including NSCLC, RCC, melanoma, CRC and gastric cancer. An ORR of 21% (25/122) was observed in nonselected solid tumors, including several pts who demonstrated tumor shrinkage within days of initiating treatment. Additional pts had delayed responses after apparent radiographic progression (not included in the ORR). Some responders demonstrated prolonged SD prior to RECIST responses. The 24-week PFS was 44%. Pts with PD-L1–positive tumors (from archival samples) showed an ORR of 39% (13/33) and a PD rate of 12% (4/33). In contrast, patients with PD-L1–negative tumors showed an ORR of 13% (8/61) and a PD rate of 59% (36/61). As of the cutoff date, all responses are ongoing or improving. Updated data will be presented. Conclusions: MPDL3280A was well tolerated, with no pneumonitis-related deaths. Durable responses were observed in a variety of tumors. PD-L1 tumor status appears to correlate with responses to MPDL3280A. PK supports q3w dosing at 15 mg/kg or fixed-dose equivalent. Clinical trial information: NCT01375842.
Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: Survival and long-term safety in a phase I trial.
Authors: Topalian Suzanne Louise , Sznol Mario , Brahmer Julie R. , McDermott David F. , Smith David C. , Gettinger Scott N. , Taube Janis M. , Drake Charles G. , Pardoll Drew M. , Powderly John D. , Carvajal Richard D. , Sosman Jeffrey Alan , Atkins Michael B. , Antonia Scott J. , Spigel David R. , Lawrence Donald P. , Kollia Georgia , Gupta Ashok Kumar , Wigginton Jon M. , Hodi F. Stephen
Published: March 2020

3002^

Background: Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression (Topalian et al., NEJM 2012). Here we present long-term safety and efficacy outcomes from a phase I study of nivolumab, a PD-1 blocking mAb, in patients (pts) with advanced solid tumors. Methods: Pts enrolled between 2008-2012 received nivolumab (0.1−10 mg/kg IV Q2W) during dose escalation and/or cohort expansion. Tumors were assessed by RECIST 1.0 after each 4-dose cycle. Pts received ≤12 cycles until unacceptable toxicity, confirmed progression, or CR. Results: 304 pts with non-small cell lung cancer (NSCLC, n=127, squamous and nonsquamous), melanoma (MEL, n=107), renal cell (RCC, n=34), colorectal (n=19) or prostate cancer (n=17) were treated. Durable ORs (CR/PR) were observed in MEL, NSCLC and RCC (Table); in 54 responders with ≥1 yr follow-up, 28 lasted ≥1 yr. Median OS in these heavily pretreated pts (47% with 3-5 prior systemic therapies) compared favorably with expected outcomes as of July 2012. Drug-related AEs (any grade) occurred in 72% (220/304) and G3/G4 AEs in 15% (45/304) of pts. Drug-related pneumonitis occurred in 3% (10/304), including G3/G4 in 1% (3/304), resulting in 3 deaths early in the trial, which led to increased clinical monitoring and an emphasis on management algorithms. Nivolumab-related pneumonitis characteristics and management will be summarized. Updated survival and safety data from Feb 2013 (≥1 yr follow-up all pts) will be presented, including OS at 3 yr. Conclusions: Nivolumab produced sustained survival with a manageable long-term safety profile in advanced MEL, NSCLC and RCC, supporting its ongoing clinical development in controlled phase III trials with survival endpoints. Clinical trial information: NCT00730639. [Table: see text]
Effect of algenpantucel-L immunotherapy for pancreatic cancer on anti-mesothelin antibody (Ab) titers and correlation with improved overall survival.
Authors: Rossi Gabriela R. , Hardacre Jeffrey M , Mulcahy Mary Frances , Talamonti Mark S. , Obel Jennifer Carrie , Rocha Lima Caio Max S. , Safran Howard , Lenz Heinz-Josef , Chiorean E. Gabriela , Vahanian Nicholas N. , Link Charles J. ,   NLG0205
Published: March 2020

3007

Background: Hyperacute rejection of tissues expressing the carbohydrate α(1,3)Gal xenoantigen is a potent innate immune defense mechanism that was leveraged to treat resected pancreatic cancer patients by immunization with genetically modified allogeneic tumor cells expressing αGal moieties (algenpantucel-L). We propose that adding algenpantucel-L to SOC adjuvant therapy may improve survival and induce immunological biomarkers that positively correlate with improved median overall survival (OS). Methods: Open-label, multicenter phase II study evaluating algenpantucel-L+SOC (RTOG-9704: gemcitabine + 5-FU-XRT) for resected pancreatic cancer patients. Endpoints: 1°) disease-free survival (DFS) at 1 year; 2°) OS, toxicity and immunologic analysis. Biomarkers were evaluated including total IgG, complement, CA19-9 levels, anti-αGal Ab, anti-CEA Ab, and anti-membrane-bound recombinant mesothelin (MSLN) Ab. Results: Patients received gemcitabine with 5-FU modulated radiation therapy plus algenpantucel-L. The primary endpoint, 12-month DFS, was 62% and 12-month OS was 86%. All evaluable patients have been in follow-up for ≥ 3 years. We now report OS rates at 3 years of 39% and DFS of 26% at 3 years. Evaluable patients (n=64) were tested for the induction of anti-MSLN Ab where ≥ 25% increase in the anti-MSLN Ab compared to baseline was considered significant (p<0.001). Twenty of 64 patients (31%) had increased anti-MSLN Ab. Patients responding with anti-MSLN Ab had a median OS of 42 months compared to 20 months for patients without sero-conversion. The positive correlation between increased anti-MSLN Ab and improved median OS was statistically significant (p=0.027). Conclusions: The addition of algenpantucel-L to SOC for resected pancreatic cancer may improve survival. In 20/64 patients, algenpantucel-L-induced anti-MSLN Ab responses that correlates with improved survival (median OS 42 vs 20 months). Immunological monitoring of algenpantucel-L immunotherapy with this biomarker is feasible and might predict patient response to therapy. A multi-institutional, phase III study is currently underway (ClinicalTrials.gov NCT01072981). Clinical trial information: NCT00569387.