Korn, Ronald L.

Abstract Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.

4525 Background: Pancreatic cancer cells and surrounding stroma are known to overexpress SPARC (secreted protein acid rich in cysteine), which is associated with poor clinical outcomes. nab-P, an albumin-bound nanoparticle form of paclitaxel increased tumor accumulation of paclitaxel through binding of albumin to SPARC. This disease specific phase 1 study was designed to evaluate the safety and efficacy of G + nab-P and the correlation of response with tumor SPARC and serum CA19–9 levels. Methods: nab-P doses (100–150 mg/m2) + (G) (1000 mg/m2) were given on days 1, 8, and 15 of a 28-day cycle to pts with metastatic pancreatic adenocarcinoma and with no prior chemotherapy for their metastatic disease. Level 3 SPARC staining by immunohistochemistry was considered positive. Results: 63 pts received treatment. The most common grade 3 and 4 adverse event that occurred in >20% of pts was neutropenia. Nine (18%) pts and 4 (8%) pts had a grade 3/4 event, respectively. Neuropathy was also observed. One combination-associated death due to sepsis occurred at the 150 mg/m2 nab-P level. Serial PET scans of 53 pts with outside adjudication to date showed 12 (23%) complete responses, 29 (55%) partial responses (PRs) and 4 (8%) stable disease (SD). By RECIST criteria, of the 49 pts evaluable to date, 1(2%) had CR, 12 (24%) had PR, and 20 (41%) had SD. The median survival was 9 months to date. SPARC data were available for 35 pts, of which 10 (29%) were SPARC+ and 25 (71%) were SPARC-. Of these, 27 pts had evaluable response data. Pts that were SPARC+ (8/27) were more likely to be responders (6/8, 75%) than pts who were SPARC- (5/19, 26%), P = 0.03, Fisher's exact test. Median progression-free survival (PFS) increased from 4.8 months for SPARC- pts (22 pts) to 6.2 months for SPARC+ pts (9 pts); however, these data are still immature. Of 45 pts with elevated CA19–9 at baseline, 42 (93%) had maximum decrease of >40% with a median maximum decrease of 92%. Conclusions: The combination of nab-P and G was generally well tolerated and had substantial enough antitumor activity in patients with pancreatic cancer to warrant a phase III clinical trial. SPARC+ status in these patients was associated with higher response rate and longer PFS. [Table: see text]

358 Background: Effective therapy for the treatment of PDAC remains one of the greatest unmet oncology clinical needs. The addition of C to G and AP has shown promising clinical data in a previously reported study [J Clin Oncol 35, 2017 (suppl 4S; abstract 341)]. In preclinical work, vitamin D (Vit D) analog therapy decreases myeloid derived suppressor cells and regulatory T cells, turning PDAC into a more immune-friendly microenvironment. This trial combines AP/C/G with Vit D analog P and the anti-PD-1 antibody N as a combination therapy for patients with previously untreated metastatic PDAC. This trial evaluates the efficacy and safety of NAPPCG in that patient population (NCT02754726). Methods: Eligibility criteria include Stage IV PDAC, no prior chemotherapy for systemic disease, KPS ≥ 70, and measurable disease. Doses are AP 125 mg/m2 undiluted, G 1000 mg/m2 in 250 ml of normal saline (NS), each infused over 30 minutes with C 25 mg/ m2 in 500 ml of NS infused over 60 minutes on days 1, 8, 22, and 29 of a 42-day cycle. N is given at a fixed dose of 240 mg as a 60 minute infusion on days 1, 15, and 29. P is given at a fixed dose of 25 µg IV twice weekly. Primary objective is to determine the efficacy of the combination for patients with previously untreated metastatic PDAC through determining CR, ORR, PFS, and OS. The secondary objective is to evaluate safety in patients with previously untreated metastatic PDAC. Results: Trial was initiated May 2016 and10 patients have been enrolled in the initial phase of the study and are evaluable (baseline and ≥1 follow up CT scan). Most common drug-related grade (Gr) 3-4 adverse events (AE’s), n = 10, are thrombocytopenia 100% (gr 3 = 50%, gr 4 = 50%) with no serious bleeding events, anemia 50% (gr 3 = 50%, gr 4 = 0%), and colitis 20% (gr 3 = 20%, gr 4 = 0%). By RECIST 1.1 criteria, the best response is 8 PR and 2 SD, yielding an 80% ORR. Median PFS is 8.2 months. Median OS has not been reached. Conclusions: Although a small study, the high response rate is encouraging. This regimen is being expanded to 25 patients with plans to include exploratory inflammatory biomarkers. Clinical trial information: NCT02754726.

Abstract Archival tumor samples present a rich resource of annotated specimens for genomics research. However, standard variant calling approaches require a matched normal sample from the same individual, which is often not available with archival tissue. Without a matched normal sample, it is very difficult to distinguish between true somatic variants and germline variants that are private to the individual. Archival FFPE sections often contain adjacent normal tissue, but this normal tissue is often contaminated with infiltrating tumor cells. Comparative somatic variant callers are designed to exclude variants present in the normal sample, so a novel approach is required to leverage sequencing of adjacent normal tissue. Here we present LumosVar 2.0, a software package designed to jointly analyze multiple samples from the same patient. The approach is based on the concept that the allelic fraction of somatic variants, but not germline variants, would be diluted by the presence of normal tissue. Given the allele specific copy number state and expected tumor fraction of each sample, one can model the expected allelic fractions of somatic and germline variants. LumosVar estimates allele specific copy number and tumor sample fractions from the data, and uses the model to call somatic and germline variants. LumosVar is also able to detect sub clonal events and spatial heterogeneity between samples. To evaluate this approach, we used a glioblastoma dataset, where enhancing (high tumor content) and non-enhancing (low tumor content) samples were available for each patient, as well as the matched normal sample to define the true somatic variants. We show that both sensitivity and positive predictive value are improved by analyzing the high tumor and low tumor jointly compared to analyzing the samples individually or in silico pooling of the two samples. Finally, we apply this approach to a set of breast and prostate archival FFPE tumor samples where normal samples were not available for germline sequencing. Citation Format: Rebecca F. Halperin, Winnie S. Liang, Erica Tassone, Jonathan Adkins, Megan Russell, Nhan Tran, Nicole Hank, James Newell, Sandeep Gupta, Michael Berens, Ronald Korn, David W. Craig, Sara A. Byron. Leveraging spatial heterogeneity in tumor purity for improved somatic variant calling of archival tumor-only samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-007. doi:10.1158/1538-7445.AM2017-LB-007

TPS511 Background: Despite decades of basic and clinical research, effective therapy for the treatment of patients with pancreatic ductal adenocarcinoma (PDAC) remains one of the greatest unmet clinical needs in oncology today. Albumin-bound paclitaxel (AP) and gemcitabine (G) reported on an improvement in overall survival in metastatic (m) PDAC [NEJM 2013; 369:1691-1703]. The addition of cisplatin (C) has shown promising clinical data in previously reported studies [Cancer Res 2015; 75(15 Suppl):Abstract nr LB-003]. Through further preclinical work, vitamin D analog therapy decreases myeloid derived suppressor cell (MDSC) and regulating T cells (Tregs) thus turning PDAC into a more immune friendly microenvironment. This trial combines AP/C/G with the vitamin D analog paricalcitol (P) and the antibody-PD-1 drug Nivolumab (N) as a combination therapy for individuals with previously untreated metastatic PDAC. This trial evaluates the efficacy and safety of NAPPCG in patients in that population (NCT02754726). Methods: Key eligibility criteria include Stage IV PDAC, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. Key exclusion criteria include prior PD-1 or PD-L1 therapy. Doses are AP 125 mg/m2 undiluted, G 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes with C 25mg/ m2 in 500 ml of NS infused over 60 minutes on days 1, 8, 22, and 29 of a 42 day cycle. N is given at a fixed dose of 240 mg as a 60 minute infusion on days 1, 15, and 29. P is given at a fixed dose of 25 µg IV on days 1,4,8,12,15,22,26,29,32,36,and 39. Primary objective is to determine the efficacy of the combination NAPPCG for patients with previously untreated metastatic PDAC through determining CR, ORR, PFS, and OS. The secondary objective is to evaluate the safety of NAPPCG in patients with previously untreated metastatic PDAC. The study initiated accrual in April of 2016. If 4 of the first 10 patients are determined to have a PR the trial will expand to a total of 25 patients. Clinical trial information: NCT02754726.

341 Background: Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations indicating DNA repair abnormalities associated with sensitivity to DNA damaging agents such as the platinums. Cisplatin was added to a nab-paclitaxel + gemcitabine regimen, which has been determined to improve survival over gemcitabine alone (NEJM 2013; 369:1691-1703). The objectives are to determine the efficacy and safety of nab-paclitaxel and gemcitabine plus cisplatin in patients with Stage IV pancreatic cancer. Methods: Eligibility criteria included Stage IV adenocarcinoma of the pancreas, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. Doses are nab-paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. The maximum tolerated dose and phase II dose of cisplatin is 25 mg/m2. Results: 25 pts were treated; 24 were evaluable (baseline and ≥ 1 follow up CT scan). The most common drug related grade (gr) 3 - 4 adverse events (AEs), n = 25, were thrombocytopenia 76% (gr 3 = 36%, gr 4 = 40%) with no serious bleeding events, anemia 32% (gr 3 = 32%, gr 4 = 0%), neutropenia 24% (gr 3 = 20%, gr 4 = 4%), infection 20% (gr 3 = 16%, gr 4 = 4%), and diarrhea 16% (gr 3 = 16%, gr 4 = 0%). Peripheral neuropathy ≥ gr 3 was seen in only 1 pt (gr 3 = 4%). Grade 5 AEs were infection (1), cardiac arrest (1), and stroke (1). Median time on therapy was 5.5 months, range (1 – 9.5). By RECIST 1.1 criteria, 2 pts had complete response (8.3%), 15 partial response (62.5%), 4 stable disease (16.7%), and 3 progressive disease (12.5%). Median overall survival to date as of 11/10/16 is 16.5 months. Conclusions: Although a small study, the high response rate and landmark evolving median survival are very encouraging. This regimen is being expanded in patients with stage IV pancreatic cancer, neoadjuvant and adjuvant settings. Clinical trial information: NCT01893801.

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.

Abstract Background: The genomes of metastatic pancreatic cancers contain a myriad of intrachromosomal aberrations indicating a likely high prevalence of DNA repair deficiencies indicating sensitivity to DNA damaging agents such as the platinum’s. Because of this, the drug cisplatin was added to an albumin-bound paclitaxel + gemcitabine regimen, which has already been determined to improve survival over gemcitabine alone in a randomized phase III trial (NEJM 2013; 369:1691-1703). Objectives: To determine the efficacy and safety of albumin-bound paclitaxel and gemcitabine plus cisplatin for patients with advanced pancreatic cancer Methods: Eligibility criteria included Stage IV pancreatic cancer, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. The doses were albumin-bound paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. Results: To date, 10 patients have been entered on study with all patients being evaluable, (baseline and at least one follow up CT scans completed). There have been 2 complete responses (20%), 6 partial responses (PR), (60%), 1 stable disease (10%), and 1 patient with progressive disease (10%), by RECIST 1.1 criteria. An exponential decrease in CA19-9 correlating with the t1/2 of the marker was noted. Response was seen rapidly with PR observed at the first staging evaluation at 9 weeks in 7 of 10 patients. The 8th patient achieved a PR at 18 weeks. Serious adverse events occurred in 4 patients: non-neutropenic sepsis/pneumonia (n = 1), and non-neutropenic bacteremia (n = 1) in the cisplatin 25 mg/m2 cohort; clostridium difficile colitis (n = 1) with cisplatin 37.5 mg/m2; and neutropenic fever/pneumonia (n = 1) with cisplatin 50mg/m2. Discussion: The study has completed phase Ib and will be expanded at the phase II dose of cisplatin 25 mg/m2 for a total of 25 patients. If this favorable response rate is confirmed, this 3 drug regimen could be further developed both for patients with advanced disease as well as in neoadjuvant and adjuvant settings. Supported by grants from the Seena Magowitz Foundation and the SU2C Dream Team Citation Format: Gayle S. Jameson, Erkut Borazanci, Elizabeth Poplin, Michael T. Barrett, John Crowley, Adam Rosenthal, Amy Stoll-D'Astice, Karen L. Ansaldo, Steven Boone, Leticia Lebron, Ramesh K. Ramanathan, Ronald L. Korn, Daniel D. Von Hoff. High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer. [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 LB-003. doi:10.1158/1538-7445.AM2015-LB-003

Abstract Enzymatic degradation of hyaluronan (HA), a key component of the extracellular matrix (ECM), can enhance tumor perfusion, improve delivery of chemotherapeutics, and enhance the effects of anti-tumor agents. HA accumulation has been correlated with local invasion, the presence of distal metastasis, higher tumor grade, and poorer overall survival. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational therapeutic agent under clinical development for the treatment of patients with solid tumors that may accumulate HA. Preclinical studies have demonstrated that sustained HA removal, accomplished with PEGPH20, inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Twenty-six patients with advanced solid tumors were enrolled in a Phase 1 multi-center trial. Patients received weekly or twice weekly doses of IV PEGPH20 (0.5 - 5 μg/kg) for the first 4-week cycle, followed by once-weekly dosing for the subsequent 4-week cycles. Serial blood samples were drawn from each patient, and plasma concentrations were measured by an ultrasensitive hyaluronidase activity assay to assess PEGPH20 pharmacokinetics (PK). Plasma levels of HA catabolites were measured using a quantitative HPLC method to characterize PEGPH20 pharmacodynamics (PD). Other measures of PD activity were evaluated in selected patients, including DCE-MRI, DW-MRI, 18FDG-PET, textural analysis on CT, and histochemical staining of HA in tumor biopsies collected both before and after PEGPH20 treatment. Peak plasma PEGPH20 concentrations increased with dose, and plasma pharmacokinetics (PK) were well described by a linear PK model. Pre-treatment plasma HA levels were typically <1 μg/mL and increased in a dose-dependent fashion after PEGPH20 treatment. Increased plasma HA corresponded with decreased HA staining in patients with available tumor biopsies. DCE-MRI analysis indicated early (24-48 hr) and rapid increase in tumor perfusion compared to baseline in 4 patients with serial MRI assessments. Pharmacodynamic activity was also demonstrated when pre-treatment 18FDG-PET scans were compared with images collected at scheduled times after PEGPH20 dosing. Reduction in FDG uptake exceeding 25% was demonstrated in 3 of 4 patients after one cycle of treatment, consistent with a partial metabolic response. These data are consistent with the mechanism of action reported in preclinical models, and results support continued evaluation of PEGPH20 in combination with anti-tumor agents via modification of the ECM. Citation Format: Ping Jiang, Daniel C. Maneval, Ramesh K. Ramanathan, Jeffrey R. Infante, Mitesh Borad, Alberto Bessudo, Patricia LoRusso, Barry J. Sugarman, Deborah Carson, Marie A. Printz, Curtis B. Thompson, Paneer Selvam, Joy Zhu, Ronald Korn, H Michael Shepard, Gregory I. Frost. Phase 1 pharmacodyamic activity of multiple-dose PEGylated hyaluronidase PH20 (PEGPH20) in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3375. doi:10.1158/1538-7445.AM2013-3375