Infante, Jon

AbstractBackground and purposeClinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.MethodsTo evaluate total tau (t‐tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and neurofilament light‐chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD‐1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t‐tau and phosphorylated tau (p‐tau181). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t‐tau levels.ResultsPlasma t‐tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non‐Ataxia Signs was associated with t‐tau in ataxic patients (p = 0.004). Pre‐ataxic carriers showed higher cerebrospinal fluid t‐tau and p‐tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t‐tau was elevated in MJDTg mice compared to wild‐type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).ConclusionOur results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.

Background: Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528; LCAR-B38M CAR-T cells) is a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies designed to confer avidity. In the phase 1 LEGEND-2 study in China, LCAR-B38M yielded deep, durable responses with a manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (R/R MM). The phase 1b/2 CARTITUDE-1 study (NCT03548207) is further evaluating cilta-cel in this pt population in the US. We present updated data from the phase 1b portion along with initial phase 2 data. Methods: Eligible pts (aged ≥18 y) were diagnosed with MM per International Myeloma Working Group (IMWG) criteria and had measurable disease, Eastern Cooperative Oncology Group performance status ≤1, received ≥3 prior regimens or were double-refractory to a proteasome inhibitor and immunomodulatory drug, and received an anti-CD38 antibody. After apheresis, bridging therapy was permitted. Cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 d were used for lymphodepletion. A single infusion of cilta-cel at a target dose of 0.75×106 (range 0.5-1.0×106) CAR+ viable T cells/kg was administered 5-7 d after start of lymphodepletion. The primary objective of the phase 1b portion was to characterize cilta-cel safety and establish the recommended phase 2 dose; the primary objective of the phase 2 portion was to evaluate cilta-cel efficacy. Response was assessed per IMWG criteria and minimal residual disease (MRD) by next-generation sequencing. Adverse events (AEs) were graded using CTCAE v5.0. In the phase 1b portion, cytokine release syndrome (CRS) was graded by Lee et al (Blood 2014) and neurotoxicity by CTCAE v5.0; in the phase 2 portion, CRS and neurotoxicity were graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria. In this combined analysis, Lee et al and CTCAE v5.0 were mapped to ASTCT criteria for CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Results: As of the May 20, 2020 clinical cutoff, 97 pts (58.8% male; median age 61.0 y [range 43-78]) with R/R MM received cilta-cel (29 in phase 1b; 68 in phase 2). Median follow-up duration was 8.8 mo (range 1.5-20.4). Pts had received a median of 6 prior lines of therapy (range 3-18); 83.5% were penta-exposed, 87.6% were triple-refractory, 41.2% were penta-refractory, and 97.9% were refractory to last line of therapy. Overall response rate per independent review committee (primary endpoint) was 94.8% (95% CI 88.4-98.3), with a stringent complete response rate of 55.7% (95% CI 45.2-65.8), very good partial response rate of 32.0% (95% CI 22.9-42.2), and partial response rate of 7.2% (95% CI 3.0-14.3). All pts achieved a reduction in M-protein. Median time to first response was 1.0 mo (range 0.9-5.8; 80.4% ≤1.0 mo), and median time to complete response or better was 1.8 mo (range 0.9-12.5; 74.1% ≤3.0 mo); responses deepened over time (Figure). Median duration of response was not reached (NR). Of 52 MRD-evaluable pts, 94.2% were MRD-negative at 10-5. The 6-mo progression-free survival (PFS) and overall survival (OS) rates (95% CI) were 87.4% (78.9-92.7) and 93.8% (86.7-97.2), respectively; median PFS and OS were NR. Ten deaths occurred during the study; 8 were due to AEs (both related and unrelated; CRS/hemophagocytic lymphohistiocytosis, neurotoxicity, respiratory failure, sepsis, septic shock, pneumonia, lung abscess, and acute myelogenous leukemia [n=1 each]), and 2 due to progressive disease. AEs reported in &gt;70% of pts were CRS (94.8%; grade [gr] 3/4 4.1%), neutropenia (90.7%; gr 3/4 90.7%), anemia (81.4%; gr 3/4 68.0%), and thrombocytopenia (79.4%; gr 3/4 59.8%). Median time to CRS onset was 7.0 d (range 1-12) and median duration 4.0 d (range 1-27, excluding n=1 with 97 d). CAR-T cell-related neurotoxicity was reported in 20.6% of pts (gr 3/4 10.3%). Cilta-cel CAR+ T cells showed maximum peripheral expansion at 14 d (range 9-43). Among pts with 6 mo' individual follow-up, 67% had cilta-cel CAR+ T cells below the level of quantification (2 cells/µL) in peripheral blood. Conclusions: Preliminary phase 1b/2 data from CARTITUDE-1 indicate a single low-dose infusion of cilta-cel leads to early, deep, and durable responses in heavily pretreated pts with MM with a safety profile consistent with LEGEND-2. Further investigation of cilta-cel in other MM populations is underway. Disclosures Madduri: Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Berdeja:Teva: Research Funding; Bluebird: Research Funding; Bioclinica: Consultancy; Celgene: Consultancy, Research Funding; EMD Sorono: Research Funding; Kite Pharma: Consultancy; Prothena: Consultancy; Cellularity: Research Funding; Karyopharm: Consultancy; Servier: Consultancy; Legend: Consultancy; Poseida: Research Funding; Lilly: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Janssen: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Kesios: Research Funding; Novartis: Research Funding. Usmani:Celgene: Other; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Abbvie: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: Patents/Intellectual property licensed, Research Funding. Stewart:Janssen, BMS, Sanofi-Aventis, GSK: Honoraria; Tempus, Inc., Genomics England LLC: Membership on an entity's Board of Directors or advisory committees. Hari:Amgen: Consultancy; BMS: Consultancy; GSK: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy. Htut:City of Hope Medical Center: Current Employment. Munshi:OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; AbbVie: Consultancy; C4: Current equity holder in private company. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; GenMab: Consultancy, Honoraria. Singh:Janssen: Current Employment. Zudaire:Janssen: Current Employment. Yeh:Janssen: Current Employment. Allred:Janssen: Current Employment. Olyslager:Janssen: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Schecter:Janssen: Current Employment. Jackson:Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Deraedt:Janssen: Current Employment, Current equity holder in publicly-traded company. Zhuang:Janssen: Current Employment. Infante:Janssen: Current Employment. Geng:Legend Biotech USA Inc.: Current Employment. Wu:Legend Biotech USA Inc.: Current Employment. Carrasco:Legend Biotech USA Inc.: Current Employment. Akram:Legend Biotech USA Inc.: Current Employment. Hossain:Legend Biotech USA Inc.: Current Employment. Rizvi:Legend Biotech USA Inc.: Current Employment. Fan:Legend Biotech USA Inc.: Current Employment. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Lin:Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:AMGEN: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; GSK: Consultancy; Sanofi: Research Funding.

Abstract Purpose: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. Patients and Methods: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. Conclusions: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

2519 Background: PT-112 is a novel platinum-pyrophosphate agent designed to avoid the toxicity and drug resistance mechanisms of conventional chemotherapy. Pre-clinical models show effects on multiple cell signaling components: p16 mediated G1/S cell cycle arrest; modulation of MDM2/p53 expression; extrinsic apoptosis initiation; and immunogenic cell death (ICD) induction. This Phase I first-in-human, multicenter, open label study assesses PT-112’s safety and pharmacokinetic (PK) profile in advanced solid tumor patients (pts), to determine the RP2D and signals of activity. Methods: Pts with advanced solid tumors and acceptable marrow / organ function received PT-112 IV over 1-hr on days 1, 8, and 15 every 4 wks in a 3+3 dose escalation design. Intra-subject escalation was allowed. PK samples from cycles 1-2 were analyzed by ICP-MS and LC-MS/MS. Results: 44 pts have been treated across dose levels (DL) from 12-300mg/m2. Cumulative dosing ranged from 1 to 60 infusions, and cumulative exposure from 96 to 5,244 mg/m2. PK parameters were dose proportional. Target Cmax and AUC levels were achieved, with constant VD. DLTs were observed at 150mg/m2 (G3 pancytopenia); 250mg/m2 (G2 renal injury in a cervical ca pt with hydro-nephrosis); and 300mg/m2 (G3 rash). The most common treatment-related AEs were G1-2 fatigue (26% pts), nausea (23%), vomiting (14%), constipation (12%), and diarrhea (12%). Numerous signals of activity were observed at DLs ≥ 125mg/m2. These include a confirmed PR in a NSCLC pt with 6 prior lines of therapy and no response to TKI inhibition or PD-1 blockade; PFS > 6 months (7-18 months) in 3 pts; metabolic response via PET scan in bone and liver mets (basal cell and pancreatic ca.); biomarker responses in ovarian and prostate ca.; and nodal/metastatic volumetric reduction in 3 pts. Conclusions: PT-112 is a well-tolerated novel agent with a pleiotropic mode of action and feasibility for long-term and combination treatment. Numerous signals of anti-cancer efficacy in heavily pre-treated pts suggest lack of cross-resistance with conventional agents. MTD has not yet been reached. PT-112’s profile makes it an attractive candidate for further development, including in combination with immunotherapy. Clinical trial information: NCT02266745.

9505 Background: D (BRAF inhibitor) + T (MEK inhibitor) combination therapy is associated with rapid clinical responses and has improved clinical outcomes in pts with BRAFV600–mutant MM, but long-term (˃ 3 y) clinical efficacy and safety data are limited. The longest follow-up to date of a randomized trial evaluating D+T at the approved dose (150 mg BID/2 mg QD [150/2]) was of the phase II study BRF113220 (part C; median, 45.6 mo) in which durable outcomes were achieved in some pts with BRAFV600–mutant MM (3-y OS, 38%). Here, we report updated 5-y landmark analyses to further characterize the impact of D+T in MM. Methods: Pts with BRAFV600–mutant mm enrolled in BRF113220 part C (NCT01072175) were randomized 1:1:1 to receive monotherapy D (150 mg BID), D+T (150 mg BID/1 mg QD), or D+T (150/2). Pts who progressed on D alone could cross over to the D+T 150/2 arm. Pt disposition, pt demographics, and 4- and 5-y efficacy and safety were analyzed for both the D-alone and D+T (approved 150/2 dose) arms. Results: This updated analysis represents an additional ≈ 2 y of follow-up (D and D+T arms; n = 54 each). As of 13 Oct 2016, 45 pts (83%) on D alone had crossed over to D+T. 20 pts were ongoing (D, n = 7 [13%]; D+T, n = 13 [24%]); 80% of D pts and 70% of D+T pts had died. D+T OS remained superior to D alone. The 4- and 5-y OS rates with D+T were 30% and 28%, respectively, demonstrating a stabilization of the OS curve. The PFS curve for D+T also remained stable (4- and 5-y: both 13%). Consistent with earlier results, the best OS for pts who received D+T was seen in pts with normal LDH (5-y, 45%) and normal LDH with disease in < 3 organ sites (5-y, 51%). At the 5-y landmark, 1 additional pt who received D+T improved from a partial to a complete response. Additional follow-up revealed no new safety signals with D+T. Detailed analyses of D crossover pts, responders, and post-progression therapy will be presented. Conclusions: This longest follow-up to date of BRAF + MEK inhibitor combination therapy in pts with BRAFV600–mutant mm revealed stable OS and PFS lasting ≥ 5 y with consistent tolerability. These results demonstrate that some pts with mm can achieve durable benefit with D+T therapy. Clinical trial information: NCT01072175.

Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity—grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation—chemokine induction, T-cell stimulation, regulatory T cell depletion—was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.

368 Background: SGN-75 is an antibody-drug conjugate composed of a humanized anti-CD70 mAb conjugated to the microtubule-disrupting agent MMAF via a plasma-stable linker. Upon binding to CD70, SGN-75 internalizes and releases cys‑mcMMAF which binds tubulin and induces G2/M arrest and apoptosis. Methods: A phase 1, dose-escalation, multicenter study was initiated to investigate the safety, tolerability, PK, and antitumor activity of SGN-75 monotherapy in pts with CD70-positive metastatic RCC or relapsed/refractory NHL (ClinicalTrials.gov #NCT01015911). SGN-75 was administered IV in cohort-specific doses using 2 schedules [every 3 weeks (q3wk) or weekly (days 1, 8, 15 q28 days)] at doses of 0.3-4.5 mg/kg. Pts were eligible to receive treatment until PD. Results: A total of 58 pts (39 RCC/19 NHL) with a median age of 60.5 yrs (range 30-82) were treated. The MTD was 3 mg/kg q3wk; 2 pts had DLTs at 4.5 mg/kg q3wk (NHL pt had neutropenia and RCC pt had proteinuria). Weekly dosing (N=11) was terminated at the 0.6 mg/kg dose level after 2 pts with NHL developed idiopathic thrombocytopenic purpura. At the MTD, adverse events (AEs) in ≥30% of RCC pts (N=21) were fatigue (52%), dry eye (48%), nausea (38%), constipation (33%), and corneal epithelium defect (33%). AEs ≥ Grade 3 in >10% of RCC pts treated at the MTD were corneal epithelium defect (19%) and thrombocytopenia (14%). PK analysis suggested that SGN-75 exposure was approximately dose-proportional with a mean terminal half-life of 6-11 days. Among the 32 pts with RCC treated in the q3wk schedule, all had prior nephrectomy and a median of 3 prior therapies (range 1-6). All pts had clear cell RCC, with the exception of 2 pts who had papillary RCC. Most pts had high CD70 expression by central IHC analysis (2 or 3+, 80-100% of cells). The best clinical responses of RCC pts treated q3wk were 2 PR, 12 SD, 12 PD, and 6 were not evaluable. Durations of response for the 2 responding pts were 23 and 41 weeks. The median duration of disease control (PR and SD) was 46.4 weeks [95% CI (12, 46)]. Conclusions: SGN-75 monotherapy was generally well tolerated in pts with metastatic RCC. Evidence of antitumor activity was observed in heavily pretreated RCC pts and further studies of SGN-75 in RCC are warranted. Clinical trial information: NCT01015911.

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.

Abstract Background. nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. Materials and Methods. Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. Results. Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. Conclusion. The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials.