Citations

TPS505 Background: TH-302 is a hypoxia-activated, nitroimidazole-linked prodrug of bromo-isophosphoramide mustard (Br-IPM), which is released under hypoxic conditions. TH-302 is currently being studied in combination with gemcitabine (G) in a phase III trial in patients (pts) with advanced pancreatic adenocarcinoma (PDAC) (NCT01746979). Encouraging preclinical activity of TH-302 plus nab-paclitaxel (nab-P) and G provides a rationale for further study of this triplet (Sun JD et al, AACR Special Conference on Pancreatic Cancer 2014; abstract #B88). Methods: Clinical trial: NCT02047500. Open-label, phase I, dose-escalation trial of TH-302 plus nab-P and G in pts with previously untreated locally advanced or metastatic PDAC. Dose escalation: 3 + 3 design with one of 3 planned dose levels of TH-302 (170, 240 and 340 mg/m2) on days 1, 8, and 15 of a 28-day cycle, plus nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Expansion cohort (n≥15): TH-302 at the recommended phase II dose (RP2D) with nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Treatment will be continued until disease progression or intolerable toxicity. Primary objectives: To evaluate safety and tolerability, define the maximum tolerated dose and determine the RP2D of TH-302 in combination with nab-P/G. The primary endpoint is no. of pts with dose-limiting toxicities during the first 28 days. Secondary objectives: To evaluate overall safety of the triplet regimen, metabolic response rate using EORTC criteria for 18F-FDG PET, CA19–9 response rate (defined as >50% decline from baseline), and RECIST response rate of TH-302 plus nab-P/G. The pharmacokinetic (PK) profile of TH-302 and Br-IPM in the plasma of pts will also be evaluated, as will the effect of TH-302 on the PK of nab-P, and vice versa. Exploratory analyses include the association of pharmacogenomic markers, such as CYP2C9, BRCA1 and BRCA2, with PK, safety and efficacy. The association of potential hypoxia biomarkers (CA IX, GLUT1, VEGF, osteopontin) with antitumor activity will also be explored. The trial is in progress; 7 of an estimated 48 planned pts have been recruited (trial start Jan 2014, estimate end Aug 2016). Clinical trial information: NCT02047500.

335 Background: CCA is a hepatobiliary malignancy with poor prognosis and few treatment options following cytotoxic therapy in the first-line metastatic setting. The fibroblast growth factor receptor (FGFR) axis may promote CCA tumorigenesis. FGFR2 fusions (in up to 17% of intrahepatic CCAs) may predict FGFR inhibitor sensitivity. A prior phase 1 trial of the selective pan-FGFR inhibitor BGJ398 showed antitumor activity in a pt with CCA harboring an FGFR2 fusion. Methods: This ongoing phase 2, open-label study is evaluating oral BGJ398 125 mg once daily on a 3-week-on/1-week-off schedule (28-day cycle) in pts with advanced or metastatic CCA with FGFR2 fusions (n ≈ 40) or other FGFR genetic alterations (n ≤ 15) who progressed after cisplatin/gemcitabine or are cisplatin intolerant (NCT02150967). The primary endpoint is investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival, best overall response (BOR), disease control rate (DCR), overall survival, safety, and pharmacokinetics. Results: As of 10 July 2015, 26 pts with CCA harboring FGFR2 fusions (n = 22) or other FGFR alterations (n = 4), pretreated with 1 to ≥ 4 prior regimens, were enrolled. Common adverse events (AEs; ≥ 20% of pts), were hyperphosphatemia (50%), fatigue (42%), constipation (38%), cough (23%), and nausea (23%). Grade 3/4 AEs occurring in ≥ 2 pts were hyper/hypophosphatemia, lipase increase, and hyponatremia. AEs were manageable, reversible, and rarely led to treatment discontinuation. Among 22 pts evaluable for BOR, 3 achieved partial response and 15 had stable disease, including 10 with tumor reductions (-41%, n = 1; -2% to -29%, n = 9). Overall DCR was 82%. As of the cutoff date, 18 pts remained on therapy, of which 13 were on for > 120 days. Kaplan-Meier estimated lower limit (95% CI) of median time on study was 143 days. Conclusions: BGJ398 shows impressive anti-tumor activity and a manageable safety profile in pts with advanced FGFR-altered CCA, an indication of high unmet medical need. Updated data including additional responses post data cutoff will be presented. Clinical trial information: NCT02150967.

248 Background: Improved understanding of TME in CCA may allow for development of novel therapeutics targeting stromal components. Hyaluronic acid (HA) is a polysaccharide that has been found in the TME of a number of solid tumors characterized by desmoplastic stroma, such as pancreatic cancer. Elevated HA levels were prognostic in these malignancies. HA prevalence and association with clinic-pathological features in CCA is unknown. Methods: A retrospective study was conducted using clinically annotated formalin-fixed paraffin embedded tissue from resected intrahepatic CCA samples. Specimens were analyzed for HA, scored using a positive pixel count algorithm (Aperio Imagescope) and positivity was calculated as % of total pixel count. Clinical variables were examined by chi-square or ANOVA F-test. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier method and compared via log-rank test. Multivariate analysis was conducted using Cox proportional hazards regression models. Results: 142 patient samples were stained for HA. HA was identified in all samples (100%), with a range of HA positivity of 32.8 – 91.8%. Median HA value was 67.1% and 95% of patients had HA positivity ≥ 45%. Factors associated with higher than median HA ( > 67%) included perineural invasion (PNI) (40% vs. 21%, p = 0.011), necrosis (67% vs. 41%, p = 0.003), lymph node positivity (32% vs. 14%, p = 0.027), and small tumor size ( < 6.8 cm vs. > 8.4cm, p = 0.014). Stratification of HA staining by median positivity value was not an independent predictor of survival based on multivariate analysis. OS for patients with HA > 67% was 40.1 months (mo) vs 48.5 mo with HA ≤ 67%, p = 0.537. PFS for patients with HA > 67% was 14.4 mo vs. 25.7 mo with HA ≤ 67%, p = 0.177. Conclusions: Prevalence of HA staining in resected CCA is higher than seen in many solid tumors and is ubiquitous in our study. Absence of statistically significant association with OS and PFS might be attributable to ubiquitous prevalence, narrow signal range, and association with known negative prognostic factors. Further pre-clinical and clinical evaluation would be warranted.

327 Background: The use of preoperative therapy for pancreatic cancer remains controversial. This study reviews our experience using neoadjuvant chemotherapy and chemoradiation (CRT) followed by surgery with intraoperative electron irradiation (IOERT) for patients with borderline resectable (BR) or unresectable (UR) tumors. Methods: A retrospective review identified 48 patients (pts) with primary BR/UR pancreas adenocarcinoma treated with preop CRT with intent to proceed to curative surgery with IOERT. Seventeen patients did not undergo attempted resection and are excluded (disease progression, 12; medically inoperable, 3; declined surgery, 2). Thirty-one patients proceeded to resection attempt and are the subject of this analysis. Kaplan-Meier survival analysis was performed using log rank test for significance. Median follow up was 19 months (mo). Results: Complete resection (R0) was achieved in 11 pts, R1 in 5, and R2 or not resected (IOERT alone) in 15 patients. Twenty-six pts died (23 of disease, 2 unrelated causes, 1 uncertain). Median overall survival (OS) was 19 mo for all pts. Local progression was detected in only 5 patients (16%) while distant disease developed in 24 (77%). Resection status significantly correlated with OS; R0/R1 patients had a median survival of 23 mo vs. 10 mo for R2/unresected tumors (p = 0.002). Three-year OS was 35% vs. 0%, respectively. Survival was not influenced by tumor location, CA19-9 baseline or response, tumor size, or initial judgment of resectability (BR vs. UR). BR tumors were resectable after neoadjuvant therapy in 9 of 11 patients (R0, 8; R1, 1) while 8 of 20 initially UR tumors underwent resection (R0, 3; R1, 4; R2, 1). Conclusions: Neoadjuvant therapy combined with IOERT has the possibility to improve patient selection for surgical resection and to optimize local therapy. Although the prognosis for locally advanced pancreatic cancer remains poor, survival was superior among patients for whom R0 or R1 resection was achieved. Distant metastasis remained the dominant pattern of failure, and novel systemic agents are needed. Prospective evaluation of the impact of neoadjuvant chemotherapy, CRT, and IOERT is warranted.

249 Background: HA, a glycosaminoglycan in the tumor matrix, accumulates in 20-30% of solid tumors and ≥28%, ≥42% and ≥87% of colon, gastric and pancreatic ductal adenocarcinoma (PDA) tumors, respectively. Tumors that accumulate HA can develop high interstitial fluid pressure (IFP) and are resistant to chemotherapy. HA in human PDA is associated with disease progression and poor prognosis. In animal models, PEGPH20 reduced tumor-associated HA, tumor IFP and tumor growth, and increased efficacy of chemotherapy. Pharmacodynamic (PD) activity of PEGPH20 is being evaluated in Phase 1 (Ph1) trials. Methods: Two Ph1 studies in pts with advanced solid tumors refractory to prior therapy examined the safety, tolerability, PK, PD and MTD of single-agent IV PEGPH20. Dosing in Study 1 was 2x/wk and then reduced to q21d and in Study 2 is 1-2x/wk x 4wks and 1x/wk thereafter with dexamethasone pre-medication regimen. Biomarkers evaluated: Histochemistry to detect depletion of tumor HA, serum HA catabolites, Dynamic Contrast Enhanced (DCE)-MRI and FDG-PET. Results: In Study 1, the first 3 pts demonstrated musculoskeletal events (MSE; 2 pts dosed with 50 µg/kg 2x/wk, severe; 1 pt dosed with 0.5µg/kg 2x/wk, moderate) not predicted from GLP safety studies. The frequency of drug administration was reduced to q21d and the next 10 pts tolerated ≤1.5 µg/kg. In Study 2, dexamethasone pre-medication regimen was evaluated while dosing at 1-2x/wk. Nine pts were dosed ≤5.0 µg/kg. Doses ≤3.0 µg/kg administered 2x/wk were tolerated with intermittent Grade 1-2 MSE. Activity of PEGPH20 was reflected by increased HA serum catabolites. Pre- and post-dose biopsies from 2 colon pts demonstrated a 23-60% reduction in tumor HA after 4 wks of PEGPH20 dosing. DCE-MRI of PDA and FDG-PET of lung metastases increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 dose and was still apparent after 4 wks of treatment with PEGPH20. Conclusions: Ongoing Ph1 studies have shown in vivo activity of PEGPH20 through HA plasma catabolites, tumor HA depletion, DCE-MRI and FDG-PET.

265 Background: Gemcitabine (G) is the standard treatment for first- line PanC. PanC is one of the most hypoxic solid tumors. TH-302 is an inert prodrug of brominated isophosphoramide mustard and undergoes selective activation in deep hypoxia. As a single agent, tumor responses were reported in patients (pts) with metastatic melanoma, SCLC, and head/neck cancer at TH-302 weekly doses of 480-575 mg/m2. Methods: Eligible pts for the PanC expansion of this phase I/II study ( NCT00743379 ) had ECOG <1, locally advanced or metastatic PanC previously untreated with systemic chemotherapy other than adjuvant G, 5FU, and/or radiation. IV TH-302 was dosed at 240-575 mg/m2 (240 or 340 in expansion) with standard dose G (1000 mg/m2) on days 1, 8 and 15 of a 28-day cycle. Serum protein and microRNA hypoxia biomarkers were analyzed at baseline, start of cycle 3 and end of study. Results: 46 PanC subjects (12 locally advanced, 34 distant mets); median age: 63 (range 41-83); 24 male; ECOG 0/1 in 29/17 pts; RECIST response rate (RR) of 21%, median PFS of 6.1 mo (95%CI 4.8, 7.7) and median survival of 11.4 mo (95%CI 6.0, not reached) were observed. RR was 23% with median survival of 7.4 mo in pts with distant mets. 52% of pts had a >50% decrease in CA19-9. Common adverse events were skin or mucosal toxicity, nausea, fatigue and vomiting; most grade 1/2. Grade 3/4 neutropenia, thrombocytopenia and anemia in 68%, 64%, and 20% of pts respectively. The dose intensities at 240 mg/m2 and 340 mg/m2 were similar and related to hematologic toxicities. Skin toxicities were less common at 240 mg/m2. A TH-302 dose response was present with higher RR and PFS at 340 mg/m2. Initial serum hypoxia biomarkers did not identify a preferential pt population. Conclusions: The activity and clinical benefits of the combination of TH-302 with G in first line PanC are promising as compared to previous studies of G alone. TH-302 adds to the hematologic toxicity of G, but the regimen is well tolerated. The safety and activity provided rationale for comparing TH-302 plus G versus G alone in a randomized phase II trial ( NCT01144455 ) and indicate TH-302 may complement G by penetrating into the hypoxic regions of the PanC tumors where activation induces cytotoxicity. No significant financial relationships to disclose.

Pancreatic cancer is a highly aggressive and lethal cancer characterized by high invasiveness, local and extensive dissemination at time of diagnosis and resistance to treatment. Few therapies have shown efficacy in the past and even standard of care therapies yield only modest improvements in the mortality of patients with advanced or metastatic disease. Efforts have been undertaken to study the pancreatic tumor microenvironment and have established its complex and immunosuppressive nature which could explain the high resistance to chemotherapy. Novel therapies targeting the tumor microenvironment with an aim to decrease this resistance, improve immune tolerance and increase the efficacy of the current treatment have shown some promising preliminary results in preclinical and clinical trials. We review the current advances in the field of immunotherapy and their effectiveness as a potential treatment strategy in the pancreatic cancer.

Abstract Background: MRX34 is a liposomal nanoparticle formulation with an encapsulated mimic of the naturally occurring microRNA-34 (miR-34), which is lost or expressed at reduced levels in many tumors. miR-34 inhibits key oncogenic pathways by repressing multiple important oncogenes including BCL2, E2F3, HDAC1, MET, MEK1, CDK4/6, PDGFR-ɑ/β, SIRT1, WNT1/3, NOTCH-1, β-catenin, CD44, Nanog and AXL. miR-34 also represses the expression of PD-L1 and DGKζ, thereby possibly triggering an anti-tumor immune response and cancer cell death. A multicenter Phase 1 clinical trial of MRX34 is being conducted in patients with advanced malignancies. Methods: Eligible patients were enrolled in a standard 3 + 3 dose escalation study and were given a MRX34 starting dose of 10 mg/m2, administered intravenously (IV) twice weekly (BIW) for 3 weeks in 28-day cycles. Enrollment is ongoing into a second MRX34 dosing schedule, daily x 5 (QD x 5) in 21-day cycles. The primary objectives are to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for the two dosing schedules. Secondary objectives include assessments of safety, tolerability and the pharmacokinetic profile of MRX34 after intravenous dosing as well as to assess any biological and clinical activity. Results: As of July 2015, 75 patients with advanced solid tumors were enrolled and evaluable: 44 Caucasians, 47 males, a median age of 61 years and a median of 4 prior treatments. Histologies included 30 hepatocellular carcinoma (HCC), 7 pancreatic cancer, 4 cholangiocarcinoma, 3 each of bladder, breast, colorectal, cervix and lung. The remaining 19 patients represented various other malignancies &lt;3 patients each. The 110 mg/m2 was deemed to be the MTD for the BIW dosing schedule. The MTD has not been determined yet for the QD x 5 schedule and dose escalation is continuing. The current dose levels are 70 mg/m2 QD x 5 for HCC and 93 mg/m2 QD x 5 for other solid tumors. The following treatment-emergent, all-causality adverse events (AEs) were most frequent among 47 patients in BIW cohorts vs 28 patients in QD x 5 cohorts: fever (64% vs 61%), fatigue (57% vs 39%), chills (57% vs 36%), back pain (55% vs 36%), nausea (49% vs 39%), diarrhea (43% vs 11%), headache (34% vs 14%), vomiting (32% vs 11%), anorexia (26% vs 14%), abdominal pain (23% vs 21%), dyspnea (23% vs 14%), insomnia (23% vs 14%), and dehydration (23% vs 4%). Most frequent grade 3/4 laboratory abnormalities were: lymphopenia (36% vs 71%), neutropenia (26% vs 36%), hyponatremia (26% vs 7%), AST elevation (26% vs 29%), leukopenia (23% vs 36%), hyperglycemia (19% vs 36%), thrombocytopenia (17% vs 29%), anemia (11% vs 21%), alkaline phosphatase elevation (11% vs 21%), and ALT elevation (9% vs 21%). One patient with HCC and another patient with melanoma achieved confirmed partial responses per RECIST. Conclusions: MRX34 has a manageable safety profile with confirmed partial responses in two patients with advanced HCC and melanoma. Due to better tolerability, QD x 5 schedule has been chosen for further study. Following MTD determination, enrollment will soon begin into the QD x 5 expansion cohorts for selected tumors. Citation Format: Muhammad Shaalan Beg, Andrew Brenner, Jasgit Sachdev, Samuel Ejadi, Mitesh Borad, Yang-Kon Kang, Ho Lim, T-Y Kim, Andreas Bader, Jay Stoudemire, Susan Smith, Sinil Kim, David Hong. Safety, tolerability, and clinical activity of MRX34, the first-in-class liposomal miR-34 mimic, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C43.

Abstract DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2–2.8 mg/kg; q3w) or weekly (0.8–1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n = 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n = 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer. Mol Cancer Ther; 15(3); 439–47. ©2016 AACR.

Abstract Background: Genomic assessment of cancer has been revolutionized by Next-Generation sequencing and is increasingly being applied to guide clinical prognostic and therapeutic decision-making. Initial clinical applications have been limited to gene panels and whole exome based strategies due to challenges with time to reporting of results, specimen quantity, analyte quality, and ethical-legal-social issues (ELSI). Methods: Excisional or core tumor biopsies or bone marrow biopsies were obtained from consenting participants. Nucleic acid was extracted from fresh or frozen samples followed by WGS/WES/RNASeq on the Illumina HiSeq2000 or HiSeq2500 and bioinformatics analysis. Therapeutic targets were then prioritized by a multi-disciplinary Genomic Tumor Board (GTB) and CLIA validated using Sanger sequencing, RT-qPCR, FISH and/or IHC. Treatment was delivered using on/off-label FDA approved drugs, available clinical trials and single patient INDs. Results: We consented 64 and enrolled 35 patients with advanced, treatment-refractory cancers. Median age was 59 (range 27-91) with 62% male. The majority had ECOG scores of 1 (94%). A median of 79 (range 28-8891) potentially functional somatic point mutations were identified in each case. One to two mutations/case were further identified as therapeutically targetable in 60% of the cases. The median time from tissue acquisition to CLIA validated results was 116 days (range 42-282) with CLIA validation of targets achieved in 21 of 22 patients. Genomic, target directed treatment was ultimately instituted in 13 patients utilizing: on/off label FDA approved drugs (n = 9), clinical trial (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in 5 patients (2 PR, 3 SD). Integration of WES, long-insert WGS and RNA-Seq identified a case with an ERRFI1 mutant allele present in only 11% of the DNA reads while 82% of the RNA-Seq reads had the mutant transcript. The patient was treated with erlotinib and achieved a partial response by RECIST criteria. In another case, a fusion between FGFR2-MGEA5 was observed in WES and RNA-Seq data leading to prioritization as a drug target. Reasons for patients not receiving targeted therapy included: inability to access treatment (n = 1), death prior to intended treatment (n = 3), results returned after death (n = 3), no targets identified (n = 2) and decision to pursue alternate therapy (n = 5). Conclusions: Integrating whole genome analysis in a CLIA setting is not only feasible, but also valuable, in the prioritization and selection of potential targeted therapies for patients with advanced tumors. Continued barriers to broad application include the need for shorter time to reporting as well as broad availability of therapies through basket studies. Citation Format: Mitesh J. Borad, Jan Egan, Mia Champion, Katherine Hunt, Robert McWilliams, Ann McCullough, Jessica Aldrich, Sara Nasser, Winnie Liang, Michael Barrett, David Craig, Ramesh Ramanathan, John Carpten, A. Keith Stewart, Alan Bryce. Implementation of CLIA enabled integrated whole genome (WGS)/exome (WES)/transcriptome (RNAseq) next-gen sequencing to identify therapeutically relevant targets in advanced cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT112. doi:10.1158/1538-7445.AM2015-CT112