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Introduction: For women with advanced ovarian cancer survival outcomes with standard cytotoxic chemotherapy are poor and are thought to reflect the existence of drug-resistant ovarian cancer stem cells. TRX-E-002-1 (Cantrixil), a novel third generation benzopyran molecule has been shown to be effective in a mouse model of recurrent chemotherapy-resistant ovarian cancer. We present the final results of a phase I progressive design trial (Part A dose escalation, Part B dose expansion) of Cantrixil (NCT02903771). The objectives were to establish maximum tolerated dose (MTD) when given in combination with chemotherapy, and to evaluate safety, tolerability and anti-tumour activity of intraperitoneal (IP)-administered Cantrixil. Methods: Women who had completed ≥2 prior regimens and whose disease was platinum-refractory, platinum-resistant or who had documented intolerance to platinum therapy, were eligible. Treatment comprised up to eight 3-week cycles. In the first 2 cycles, patients were dosed weekly with Cantrixil as monotherapy after which investigators were allowed to initiate pre-defined standard intravenous chemotherapy regimens (cycles 3-8). All patients were followed up for 3 months after the end of treatment. Results: Of 32 patients enrolled, 25 received ≥1 Cantrixil dose; 6 patients (24%) completed all 8 treatment cycles. Patients (92% Caucasian, mean age 62.5 years) had a median of 2 prior lines of platinum therapy and a median of 3 prior lines of anticancer therapies (including anti-VEGF; n=13, 52% and PARPi; n=6, 24%). Platinum sensitivity: refractory (n=3,12%), resistant (n=17, 68%), sensitive (n=5, 20%). In Part A (n=11), an MTD of 5mg/kg was established on the dose-limiting toxicity of ileus (n=2) and safety signals of bowel obstruction (n=3) and abdominal pain (n=2). The pharmacokinetic profile was multi-exponential, with rapid increases in systemic concentration and distribution and a slower elimination phase. Drug accumulation was minimal and was not influenced by co-administration of chemotherapy. Analysis of weight and dose-normalized (to 1 mg/kg) data found no notable trends. Across Parts A and B, 16 patients received ≥1 Cantrixil dose and had a post-baseline efficacy measurement available. The overall response rate was 18%, including one complete response (platinum-resistant; who remains in remission 37.05 months since starting treatment) and two partial responses (one platinum-resistant, one platinum refractory). The median progression free survival was 3.06 months (95% CI:1.28,∞). Conclusion: IP-administered Cantrixil, a first-in-class, dual acting, anti-cancer therapy has encouraging activity in a cohort of difficult to treat patients with persistent epithelial ovarian, fallopian tube or primary peritoneal cancer who have demonstrated resistance to a range of prior treatments. Disease response compares favorably to a figure of 10% for historical controls. Citation Format: Jermaine Coward, Ganessan Kichenadasse, Paul Harnett, Kathleen Moore, Minal Barve, James Garner, Mary Lopresti, Don S. Dizon. TRX-E-002-1 in treatment-refractory ovarian cancer: Final phase 1 study results from the dose-escalation and dose-expansion cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT012.

Background: Engineered toxin bodies (ETBs), composed of an engineered Shiga-like Toxin A subunit genetically fused to an antibody-binding domain, can force receptor internalization, induce potent cell-kill via enzymatic and permanent inactivation of ribosomes, and may not be subject to resistance mechanisms of other targeted agents. MT-5111, a de-immunized 55 kD ETB targeting HER2 in solid tumors, also binds to an epitope distinct from trastuzumab and pertuzumab, which may permit combination strategies with other HER2 targeting agents. Methods: The primary objective is to determine maximum tolerated dose (MTD) of MT-5111 monotherapy in adult patients (pts) with advanced HER2+ solid tumors. Secondary objectives are PK, efficacy, and immunogenicity. Using a modified 3+3 design, the dose-escalation part of the study includes the following 7 cohorts: 0.5, 1, 2, 3, 4.5, 6.75, and 10 µg/kg. Three dose-expansion cohorts will follow for HER2+ breast cancer, gastro-esophageal cancer, and any other HER2+ tumors. All pts will receive MT-5111 weekly as a 30-min IV infusion in each 21-d treatment (tx) cycle (C) until disease progression (PD), unacceptable toxicity, death, or withdrawn consent (NCT04029922). Results: As of the data cut in December 2020, 16 pts were treated; cancer types included breast (n=6), gastric (n=1), colon (n=1), gallbladder (n=5), and other solid tumors (n=3). Mean age was 64 years (range, 34-78); 37.5% were male. Pts received a median of 4 prior lines of systemic therapies (range, 1-8). No G4 or G5 TEAEs occurred. Six pts had 11 G3 TEAEs; the most common were increased AST and dyspnea (both n=2). Three pts had tx-emergent serious adverse events (abdominal distension [n=1]; dyspnea [n=2]). Tx-related TEAEs occurred in 8 (50%) pts; the most common was fatigue (n=5, 31.3%) and all were ≤ grade 2 in nature, except for one grade 3 event of dyspnea. No cardiac TEAEs, clinically significant changes in cardiac biomarkers (troponin, electrocardiogram, left ventricular ejection fraction), or cases of capillary leak syndrome were observed. Fifteen pts discontinued with PD; 1 pt in cohort 5 (4.5 µg/kg) is on tx with stable disease. To date, no DLTs have been observed and the MTD has not been reached. One pt in cohort 2 (1 µg/kg) had resolution of all hepatic lesions (sub-centimeter lesions pre-tx) at the end of C8; however, the pt came off study due to clinical progression at the end of C10. PK data for the first 5 cohorts matched simulations based on non-human primate studies. Conclusions: MT-5111 was well tolerated with no clinically significant cardiotoxicity. Continued dose escalations are ongoing. Citation Format: Zev A. Wainberg, Monica M. Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel Ahn, Joleen Hubbard, Jason Starr, Christine Burnett, Joshua Pelham, Eric T. Williams, Banmeet S. Anand, Thomas Strack, Andrés Machado Sandri, Brian A. Van Tine. Phase 1 study of the novel immunotoxin MT-5111 in patients with HER-2+tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT130.

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Summary Background Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. Methods An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG ( NCT02650401 ; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov , NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001). Findings Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. Interpretation Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. Funding Ignyta/F Hoffmann-La Roche.

Purpose:Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors.Patients and Methods:A 3 + 3 dose escalation for different mivebresib dosing schedules [daily, Monday/Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity.Results:Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2–3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8–1.9).Conclusions:On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.

2526 Background: T3011 is a genetically modified, next-generation oncolytic HSV-1 with 2 exogenous genes encoding the active heterodimer human interleukin 12 (IL-12) and the Fab fragment of an anti-human PD-1 antibody. Locally produced IL-12 induces the synthesis of interferon-gamma (IFN-γ) production, enhancing cytolytic activity of natural killer cells and cytotoxic T lymphocytes. The anti PD-1 antibody blocks checkpoint inhibition of T effector cells. Extensive preclinical studies demonstrate that T3011 (and murine equivalent T3855) has potent antitumor activities. Methods: This phase 1 multicenter, open-label, dose escalation study evaluates the safety of intratumoral (IT) T3011 given once every other week (Q2W) in patients (pts) with advanced cutaneous or subcutaneous malignancies. The primary objective is to determine the Recommended Phase 2 Dose of T3011 based on the overall safety, pharmacokinetic and pharmacodynamic profile. Eligible pts are ≥ 18 years, have cutaneous or subcutaneous advanced cancer that has progressed on standard treatment and at least 1 measurable tumor lesion (≥ 10 mm) suitable for T3011 IT injection. Part 1 of the study uses a 3+3 design to evaluate the safety and tolerability of T3011 monotherapy in 4 escalating doses (1 × 106, 1 × 107, 5 × 107, and 1 × 108 PFU/mL). Up to 4 mL of T3011 may be injected based on tumor size. Total enrollment will be determined by toxicities observed. Results: As of Feb. 14, 8 pts have received IT T3011 (Q2W): 3 in Cohort 1 (1 × 106), 3 in Cohort 2 (1 × 107), and 2 in Cohort 3 (5.0 × 107 PFU/ml). Maximum doses per pt was 11. Enrollment continues in Cohort 3. T3011 was well tolerated with no ≥ Grade 3 treatment-related adverse events (AEs), no DLTs or treatment-related SAEs reported to date. Common AEs were pain at injection site, leukopenia, anemia, hypocalcemia, nausea, fever, headache, dermatitis, and diaphoresis. Viral shedding was analyzed in blood, urine and saliva at various times during the study. No Viral DNA was detected in blood or urine samples (first 3 pts analyzed) to date. Biopsy samples taken from injected tumors from 2 melanoma pts (Cohort 1) revealed significant reduction of viable tumor cells after 4 injections (Week 9) compared with baseline. In particular, one post-treatment biopsy contained 45% tumor necrosis area with dramatic increases of CD8 + and NKT cells. CD3+ and CD4+ cells as well as PD-1 expression were increased in post-treatment biopsies of both pts. Conclusions: T3011 IT injection was well tolerated at the first 2 dose levels. Post treatment biopsies from 2 pts (Cohort 1) demonstrated significantly reduced tumor cell viability as well as increased lymphocyte infiltration indicating on-target anti-tumor activities of T3011. To date, 5 out of 6 evaluable pts had SD as best response and 6 enrolled pts remain on study. Dose escalation is continuing. Clinical trial information: NCT04370587.

2510 Background: SAR439459 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. In preclinical models, combining SAR439459 with an anti-PD-1 showed improved anti-tumor activity compared to single agent. Here we report preliminary results of SAR439459 ± cemiplimab in a first in human study. Methods: This is an open-label study (dose escalation and expansion) of SAR439459 ± cemiplimab administered intravenously in adult patients with advanced solid tumors to determine safety and tolerability, the maximum tolerated dose (MTD) and/or maximum administered dose (MAD) of SAR439459 ± cemiplimab, pharmacokinetics (PK); pharmacodynamic (PD) and preliminary clinical benefit. In Part 1A, SAR439459 (0.05-15 mg/kg) was administered as monotherapy Q2W in an adaptive Bayesian design with overdose control. In Part 1B, SAR439459 doses cleared from monotherapy were administered in combination with fixed dose of cemiplimab (3 mg/kg Q2W or 350 mg Q3W) in a 3+3 design. Results: As of 31 January 2020, 28 (1A) and 24 (1B) patients with ECOG performance status of 0-1 with a median age of 60.5 and 63 years respectively were enrolled. In Part 1A, 25 patients (89.3%) had at least one treatment emergent adverse event (TEAE) and 15 (53.5%) experienced grade (G)≥ 3 events. In Part 1B, 22 patients (91.7%) had at least one TEAE and 14 (58.3%) experienced G ≥ 3 events. Dose-limiting toxicities (DLTs) were evaluable in 24 and 21 patients respectively. In 1A, 2 DLTs were reported in 2 of 8 evaluable patients in dose level (DL) 4: G5 brain stem hemorrhage in a patient on concomitant low molecular weight heparin treatment and G3 myocardial infarction in a patient with diabetes, chronic kidney disease, chronic obstructive pulmonary disease, and hypertension. In 1B, 1 of 6 evaluable patients in DL5 had DLTs (G3 ALT and AST increase). MTD was not reached in either part. Ten patients had best overall response of stable disease: 6 in 1A and 4 in 1B. The PK of SAR439459 was dose proportional over the dose range tested with no evidence of cemiplimab effect on SAR439459 PK, when given in combination. Treatment with SAR439459 ± cemiplimab led to rapid reduction in total plasma TGFβ level in all dose levels tested and induced CD8 & NK cells expansion and Th1 cytokines production, suggesting peripheral T cell activation. Preliminary results from paired tumor biopsies collected from patients treated with SAR439459 ± cemiplimab in expansion showed trend of TGFβ signaling pathway inhibition and conversion from excluded to inflamed tumor-immune phenotype. Conclusions: SAR439459 ± cemiplimab showed an acceptable tolerability profile overall. MTD was not reached. Peripheral and tumor target engagement and modulation of key immune cells was observed in treated patients. Dose expansion cohorts are currently enrolling selected solid tumor patients. Funding: Sanofi. Clinical trial information: NCT03192345.

4139 Background: Nearly all stage IV pancreatic adenocarcinoma (PAC) patients progress after first-line treatment, and second-line options are limited. SGT-53 is an investigational product for tumor-targeted TP53 gene therapy that has completed phase Ia/Ib trials [Senser et al (2013), Mol Ther 21:1096; Pirollo et al (2016) Mol Ther 24:1697]. Methods: Here we provide an interim analysis of a Phase II trial (SGT53-02-1; NCT02340117) combining SGT-53 with gemcitabine/nab-paclitaxel (GEM/ABX). Eligible were first-line patients or those who had progressed after FOLFIRINOX (FFX) and/or gemcitabine-based therapy (second-line). In a 7-week treatment cycle, SGT-53 (3.6 mg DNA) was given once or twice weekly with GEM/ABX (1000 mg/m2/wk and 125 mg/m2/wk, respectively, for 3 of 4 weeks). Progression-free survival (PFS) and objective response rate (ORR) are primary endpoints.Overall survival (OS) and PFS are estimated by Kaplan-Meier analysis. Results: Of all evaluable patients (n=20), best response in 7 patients was determined to be partial response (PR) and 13 had stable disease (SD); none had progressive disease. In the second-line patients (n=11) there were 5 PR and 6 SD after 9 had failed FFX treatment, 3 had failed gemcitabine-based treatment and 1 had failed both. For patients with elevated CA19-9, SGT-53 + GEM/ABX resulted in marked reductions in the tumor marker. Published data for patients with PAC after therapy failure [Mita et al (2019) J Clin Med 8: 761; Portal et al (2015) Br J Cancer 113:989; Wang-Gillam et al (2016) Lancet 387:545] are shown for comparison. Notably, mPFS in our second-line patients was 7.4 months versus 3.1 months for the approved second-line therapy [Wang-Gillam et al (2016)]. This improvement in PFS exceeds the benchmark proposed to predict a clinically meaningful Phase III trial [Rahib et al (2016) Lancet Oncol 2:1209]. Conclusions: Our data suggest a clinically meaningful benefit of adding SGT-53 to GEM/ABX particularly for second-line PAC patients, most of whom had failed prior FFX treatment. Clinical trial information: NCT02340117. [Table: see text]

2594 Background: NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 which can increase the number and functionality of T cells in the peripheral blood (PB) of patients (pts). The combination of NT-I7 and pembrolizumab (pembro), a PD-1 Checkpoint Inhibitor (CPI), may augment and broaden the efficacy of CPIs. Methods: This is an open-label, phase 1b/2a study in pts with relapsed/refractory (R/R) advanced solid tumors. In the phase 1b (Dose Escalation), which followed the 3+3 design, pts received NT-I7 intramuscularly (IM) at 3 dose levels (DLs): 480, 960, and 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously (IV) Q3W. The objectives of the phase 1b were to evaluate Dose Limiting Toxicity (DLT), determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D), and assess pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity. Results: As of 12 January 2021, 12 pts were enrolled in the phase 1b: DL1 (n=3), DL2 (n=3) and DL3 (n=6). Median age 58.0 years [43-77], ECOG PS 0 (50%), PS 1 (50%), median number of prior therapies 4 [1-8]. MTD was not reached. One DLT (Grade [G] 3 ALT increased) was reported in DL3. Treatment-related adverse events (AEs) occurred in 11 (91.7%) pts, 11 (91.7%) G1-2 and 4 (33.3%) G3; no G4 or G5 AEs reported. Common treatment-emergent AEs were injection site reaction (n=8, 66.7%), chills (n=7, 58.3%), nausea (n=6, 50%) and pyrexia (n=6, 50%). Preliminary PK analysis showed Tmax = 24 hours and T1/2 = 123 hours for NT-I7 at DL3. NT-I7 + pembro induced dose-dependent lymphocyte proliferation in the PB, with ̃ 3-fold increase at DL3, and a corresponding decrease in neutrophil to lymphocyte ratio at 14 days after the 1st treatment. Importantly, increased number of T cells in the tumor microenvironment (TME) was also observed (Table). One pt with metastatic mucosal melanoma who had not responded to prior combination of nivolumab and ipilimumab had a rapid, confirmed partial response with 46% tumor reduction. Patient follow-up continues and updated data will be presented. The combination of NT-I7 1200 µg/kg IM Q6W + pembro 200 mg IV Q3W has been selected as the RP2D. Conclusions: The combination of NT-I7 + pembro was well tolerated in pts with R/R advanced solid tumors. NT-I7 + pembro significantly increased T cell numbers in both the TME and the PB, and there was encouraging antitumor activity with the combination in this pt population. These results support continued evaluation of NT-I7 in combination with pembro in pts with R/R advanced solid tumors. The phase 2a of the study is enrolling pts with either CPI-pretreated or CPI-naïve solid tumors (NCT04332653). Clinical trial information: NCT04332653. [Table: see text]

1563 Background: Clinical trials that require patients to have specific actionable mutations based on next generation sequencing (NGS) present unique problems, such as recruiting patients with rare mutations, low enrollment rates, and distance between patients and trial sites. Such barriers can slow the pace of trial enrollment and delay the development of new therapeutic options. Methods: Tempus Labs has partnered with experienced research sites and pharmaceutical companies with molecularly targeted clinical trials to create the TIME Trial Network. The study portfolio includes pharmaceutical sponsored phase I-III clinical trials across solid tumors and hematological malignancies, targeting actionable mutations. This network was established to ensure rapid just-in-time (JIT) activation of trials by streamlining start-up activities (i.e., execution of CTAs and study budgets/financial exhibits, regulatory paperwork, SIV planning and conduct, drug and study supply shipments, submission to the central IRB, and sponsor-specific requirements). Rapid activation begins upon receipt of an activation form from a site partner. “Site Activated” describes a site that has fulfilled all regulatory, documentation, contracting requirements, and has sponsor approval to screen and enroll patients. Results: In Q4 2020, JIT activations were completed for 6 unique interventional clinical trials across 10 sites in 8 US states in the TIME Trial Network. On average, sites were activated in 9.4 business days. Patients enrolled had rare NGS mutations and were from geographically diverse locations. In one urgent case, trial activation, patient consent, screening, and treatment were achieved in 5 business days. In total, 91.7% of patients consented to trial. The average timeline from activation to consent was 4.5 days (range 0 - 24 days), with half of patients consenting within 1 business day. 45.5% of patients who consented to trial received the study drug within 1 day of consent; 2 patients dosed on day of consent. Conclusions: Over a 3-month period, on average, TIME Trial sites were activated in 9.4 days (compared to the 20+ week industry-wide average), and patient consent was completed in 4.5 days. Rapid JIT activations through the TIME program provide significant improvements in trial enrollment timelines and increase access to therapies nationwide. JIT activations may be especially useful for rural, underserved communities, as sites can enroll diverse patient populations and help address the equity gap in clinical trials across ethnic groups.[Table: see text]

TPS3146 Background: Transforming growth factor-beta 1 (TGFβ1) is a key mediator of primary resistance to programmed cell death protein 1 (PD-1) pathway blockade. SRK-181 is a fully human, highly potent and selective monoclonal antibody that inhibits latent TGFβ1 activation. SRK-181 has minimal or no binding to latent TGFβ2 and TGFβ3 isoforms or to active TGFβ growth factors. In mouse tumor models (bladder, melanoma, and breast cancer), SRK-181 in combination with anti-PD1 therapy overcame primary anti-PD-1 resistance and showed survival benefit. No cardiotoxicities (valvulopathy) were observed with SRK-181 in 4-week GLP nonclinical toxicology studies. Thus, the potency and selectivity of SRK-181 may overcome PD-1 inhibitor resistance and toxicity of non-selective TGFβ pathway approaches. Methods: The DRAGON trial NCT04291079 is an ongoing multicenter, open-label, phase 1 study of SRK-181 administered by IV infusion every 3 weeks (Q3W) alone or in combination with anti-PD-(L)1 in patients (pts) with locally advanced or metastatic solid tumors. The study comprises 3 parts: Part A of the study follows a standard 3+3 dose escalation trial design to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of SRK-181 alone (Part A1) or in combination with the anti-PD-(L)1 agent that is approved for the respective tumor indication (Part A2). Part A1 and Part A2 will determine maximum tolerated dose (MTD) or maximum administered dose and Recommended Phase 2 Dose (RP2D) for Part B. Part B (expansion phase) will evaluate combination treatment of SRK-181 with anti-PD-(L)1 in pts with non-small cell lung cancer, urothelial carcinoma (UC), melanoma or other advanced solid tumors, to confirm the tolerability of the RP2D and to evaluate the antitumor activity of combination treatment. Pts in Part A2 and Part B must have previously received an anti-PD-(L)1 therapy approved in their tumor indication and considered non-responders (best response of stable disease or disease progression) to anti-PD-(L)1 monotherapy. Pts in Part B must have received the most recent dose of the prior anti-PD-(L)1 within 6 months of study enrollment (9 months for UC cohort). Safety, PK, PD and efficacy data will be collected and monitored throughout the study. Detailed translational PD and predictive biomarker studies for SRK-181 will include a novel digital pathology analysis of CD8 to assess the alteration of immune profile in tumor microenvironment and TGFb pathway biomarkers, such as quantitative analysis of tumor phospho-Smad2 and circulating levels of TGFb1 ligand. As of Feb 01 2021, dose escalation has proceeded to the highest planned dose of 2400 mg Q3W in Part A1 (monotherapy) and to 800 mg Q3W in Part A2 (anti-PD-(L)1 combination). Additional planned doses in Part A2 are 1600 mg and 2400 mg Q3W. Clinical trial information: NCT04291079.

5502 Background: In the VITAL (NCT02346747) trial, maintenance therapy with Vigil, an autologous tumor cell vaccine transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin for TGFβ expression control, following frontline platinum-based chemotherapy led to a recurrence-free survival (RFS) benefit in patients with advanced high-grade ovarian cancer (HR=0.69, 90% CI 0.44–1.07, p=0.078) and significantly in BRCA-wt patients (HR=0.51, 90% CI 0.30-0.88, p=0.020) ( Rocconi et al. Lancet Oncol. 2020). Here we report post-hoc HR deficiency (HRD) subgroup analysis and identification of an additional molecular subgroup sensitive to Vigil therapy involving STRING analysis. Methods: This double-blind, placebo-controlled, Phase 2b study randomized 92 patients with newly diagnosed stage III/IV ovarian cancer with a complete clinical response (CR) to frontline surgery and chemotherapy. Patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses or disease progression. RFS was the primary endpoint assessed by blinded independent central review. HRD status was determined according to the Myriad Genetics myChoice CDx assay (HRD score < 42 for proficient). Using tumor annotated DNA polymorphism data, a protein-protein interaction network was constructed using the STRING database. Properties of this network including topological distance and the identification of hub genes were used to predict a target molecular population sensitive to Vigil. Results: In the per-protocol population (PP, n=91), 62 BRCA-wt patients were tested for HRD status. Forty-five patients were HR proficient (HRP) and 17 patients were HR deficient (HRD). No HRP patients in the Vigil group reported treatment related Grade 3 or higher adverse events. From the time of study randomization median RFS was improved with Vigil (n=25) in HRP patients compared to placebo (n=20) (Table 1). Similarly, overall survival (OS) benefit was observed in the Vigil group compared to placebo (Table 1). Improved RFS was demonstrated for a subset of patients with STRING predicted molecular profile. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed clinical benefit in both BRCA-wt and HRP molecular profile patients. Results suggest a unique molecular network that enhances sensitivity to Vigil therapy. Clinical trial information: NCT02346747. [Table: see text]

TPS258 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action & are capable of forcing internalization, self-routing through intracellular compartments to the cytosol & inducing potent cell-kill via the enzymatic & permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2+ solid tumors. Its novel mechanism of action, via enzymatic ribosome inactivation, may not be subject to resistance mechanisms that exist for tyrosine kinase inhibitors, antibody-drug conjugates, or antibody modalities. MT-5111 binds an epitope on HER2, distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2-targeting agents. MT-5111 is a 55 kilodalton protein & may have improved tumor penetration capability. The objective of this trial will be to determine the safety, tolerability, & maximum tolerated dose (MTD) of MT-5111 in patients (pts) with advanced HER2+ solid tumors. Methods: This Phase 1, first-in-human, open-label, dose escalation & expansion study will evaluate MT-5111 monotherapy in pts with HER2-positive solid tumors. The primary objective is to determine the MTD; secondary objectives include pharmacokinetics, tumor response & immunogenicity. Part 1 consists of MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10µg/kg/dose) based on a modified 3+3 design (n≤42 pts); Part 2 (dose expansion) will evaluate MT-5111 at the MTD in ≤98 pts. All pts will be administered MT-5111 over 30 min via IV infusion on Days 1, 8, & 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent, or another reason for withdrawal. Part 1 will include pts with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastric or gastroesophageal junction adenocarcinomas (collectively referred as gastroesophageal adenocarcinomas [GEA]) & other HER2+ solid cancers. Immunohistochemistry (IHC) status must be 2+ or 3+, regardless of in situ hybridization (ISH) results; if no IHC is available for pts with BC or GEA, ISH criteria per the American Society of Clinical Oncology College of American Pathologists guidelines will be used. In metastatic cases, HER2 positivity must be demonstrated on metastatic lesions. Pts with HER2+ BC should have had ≥2 lines of HER2-directed therapy; pts with HER2+ GEA should have received or been intolerant to trastuzumab. Pts with evaluable disease may be included in Part 1; in Part 2, all pts must have ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors v1.1. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment, which began in September 2019, is ongoing. Clinical trial information: NCT04029922.

Ewing's sarcoma is a devastating rare pediatric cancer of the bone. Intense chemotherapy temporarily controls disease in most patients at presentation but has limited effect in patients with progressive or recurrent disease. We previously described preliminary results of a novel immunotherapy, FANG (Vigil) vaccine, in which 12 advanced stage Ewing's patients were safely treated and went on to achieve a predicted immune response (IFNγ ELISPOT). We describe follow-up through year 3 of a prospective, nonrandomized study comparing an expanded group of Vigil-treated advanced disease Ewing's sarcoma patients (n = 16) with a contemporaneous group of Ewing's sarcoma patients (n = 14) not treated with Vigil. Long-term follow-up results show a survival benefit without evidence of significant toxicity (no ≥ grade 3) to Vigil when administered once monthly by intradermal injection (1 × 10e(6) cells/injection to 1 × 10e(7) cells/injection). Specifically, we report a 1-year actual survival of 73% for Vigil-treated patients compared to 23% in those not treated with Vigil. In addition, there was a 17.2-month difference in overall survival (OS; Kaplan-Meier) between the Vigil (median OS 731 days) and no Vigil patient groups (median OS 207 days). In conclusion, these results supply the rational for further testing of Vigil in advanced stage Ewing's sarcoma.

Introduction: The poor outcomes associated with current therapies for recurrent epithelial ovarian cancer (EOC) are thought to reflect the existence of drug-resistant ovarian cancer stem cells (OCSCs). The introduction of emerging therapies such as anti-angiogenic monoclonal antibodies and PARP inhibitors have added to the treatment armamentarium but have generated new resistance mechanisms to contend with. TRX-E-002-1 is a novel, 3rd generation benzopyran molecule that induces caspase-dependent and -independent apoptosis in CD44 +ve ovarian cancer stem-like cells and CD44 -ve ovarian somatic cancer cells. The dose escalation phase of a progressive design trial investigating intraperitoneal (IP)-administered TRX-E-002-1 monotherapy and in combination with standard of care for recurrent EOC (NCT02903771) has been completed with a Maximum Tolerated Dose (MTD) of 5 mg/kg established. Methods: Women with platinum-resistant relapsed disease, platinum refractory disease, or documented intolerance to platinum therapy were enrolled into the study. Patients had completed at least 2 or more prior regimens (including adjuvant therapy) prior to enrolment. Patients were dosed weekly with single agent TRX-E-002-1 IP for the first 2 cycles after which addition of pre-defined standard intravenous chemotherapy regimens was allowed cycles 3-8. Patients were followed up for 3 months after the end of treatment. Assessments included disease response, based on CA-125 and Response Evaluation Criteria in Solid Tumours or GCIG criteria along with circulating epithelial tumour cells (CETC) and stem cell markers. Results: For the 11 evaluable patients, on average, 4 prior lines of therapy, across a range of current and emerging treatments were completed. A total of 9 subjects were evaluable for MTD analysis with 5 patients showing stable disease on monotherapy per RECIST 1.1 criteria and 4 completing 8 cycles (6 months) of treatment; 2 remained progression-free at the 3-month endpoint post-treatment. Preliminary data on activity includes 2 partial responses (PR) per RECIST 1.1 criteria observed at follow-up. With no measurable disease per RECIST 1.1 criteria, 1 patient demonstrated a complete response (CR) during combination treatment which was maintained through-out follow-up, as per GCIG criteria in patients without initial measurable disease. Median progression free survival shown to be 5.5 months. CETC data for responders shows growth of circulating cancer stem cells no longer detected during cultivation of epithelial-antigen +ve cells indicating that the epithelial antigen cells present are not capable of clonal expansion. Conclusion: IP administered TRX-E-002-1 as a first-in-class, dual acting, anti-cancer therapy has preliminary activity for the treatment of platinum resistant ovarian cancer for patients who have demonstrated resistance to a range of prior treatments. Citation Format: Jermaine Coward, Ganessan Kichenadasse, Paul Harnett, Kathleen Moore, Minal Barve, Daniel Berg, James Garner, Don Dizon. TRX-E-002-1 in treatment-refractory ovarian cancer - 3-month follow-up results from a phase I study dose escalation phase [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT166.

e15567 Background: Engineered toxin bodies (ETBs), composed of a Shiga-like Toxin A subunit genetically fused to antibody-like binding domains, can force receptor internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-5111, a de-immunized 55 kD ETB targeting HER2 in solid tumors, binds to an epitope distinct from and non-competitive with trastuzumab and pertuzumab. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of MT-5111 monotherapy in adults with advanced HER2+ solid tumors. Secondary objectives are pharmacokinetics, efficacy, and immunogenicity. Part 1 will identify the MTD via MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10 µg/kg/dose) according to a modified 3+3 design. Part 2 will further evaluate the safety of MT-5111 at the recommended phase 2 dose (RP2D) in 3 separate cohorts of subjs with a HER2 immunohistochemistry score ≥2 in a metastatic lesion of primary breast, gastroesophageal, or other cancers. All subjs receive MT-5111 as a 30-minute IV infusion on Days 1, 8, and 15 of each 21-day treatment (tx) cycle (C) until disease progression, unacceptable toxicity, death, or withdrawn consent. Details can be found on clinicaltrials.gov (NCT04029922). Results: The first cohort (0.5 µg/kg/dose) enrolled 4 subjs (metastatic breast cancer, n = 2; metastatic cholangiocarcinoma, n = 2). Three subjs were female and the mean age was 69 years (median 65, range 64-78). Subjs received a mean of 5 prior lines of therapy (median 4.5, range 3-8). Three subjs completed C1 of tx without dose-limiting toxicities; 1 subj was inevaluable. Two subjs had progressive disease in C2. A total of 23 AEs occurred in 4 subjs; all were grade (G) 1-2 except one G3 event of hypertension in a subj with a history of hypertension. There were 2 tx-related AEs (G1 chills; G2 aspartate aminotransferase increased in the setting of progressive liver metastases). There was 1 serious, non-tx-related AE (G2 dyspnea) that occurred in the inevaluable subj. No cardiac AEs were noted, nor clinically significant changes in cardiac biomarkers, an important safety parameter given non-human primate toxicity. Conclusions: MT-5111 appears to be well tolerated at the lowest dose with no apparent cardiotoxicity to date. Drug concentrations are expected to be below the level required for in vitro tumor cell killing. Safety and efficacy data from subsequent dose escalation cohorts are expected by May 2020. Clinical trial information: NCT04029922.

3549 Background: XMT-1536 is a first-in-class ADC targeting the sodium-dependent phosphate transport protein NaPi2b, broadly expressed in NSCLC and ovarian cancer. XMT-1536 utilizes the Dolaflexin platform to deliver 10-12 DolaLock auristatin payload molecules per antibody. In the dose-escalation portion of the Phase I study (NCT03319628), XMT-1536 showed clinical activity at doses >20mg/m2 with confirmed responses and prolonged stable disease in heavily pretreated OC and NSCLC patients, without preselection for NaPi2b expression. XMT-1536 was generally well-tolerated without the severe toxicities observed with other ADC platforms such as neutropenia, peripheral neuropathy, or ocular toxicity (Tolcher et al., ASCO 2019; Richardson et al., SGO 2020). Here, we report on the expansion (EXP) cohort, which included patients with fewer prior lines of therapy, in the ongoing Phase I study. Methods: Doses administered intravenously every 4 weeks (q4w) of 36 and 43 mg/m2 were evaluated in two cohorts (1) high grade serous ovarian, fallopian tube, or primary peritoneal cancer (OC) with up to 4 prior lines of therapy and (2) NSCLC adenocarcinoma; prior treatment with a platinum-based therapy, immune checkpoint inhibitor, and TKI, if indicated. Archival tumor tissue and tissue from a new tumor biopsy were required for retrospective evaluation of NaPi2b expression. Results: As of 10 February 2020, 23 patients (19 OC and 4 NSCLC) were enrolled in the EXP cohort: 16 dosed at 36 mg/m2 and 7 dosed at 43 mg/m2. Adverse events were generally similar to those previously reported, including transient AST elevation, fatigue, nausea, and pyrexia. Clinical responses and stable diseases have been observed. Efficacy data (objective response rate) and initial correlation of NaPi2b score with clinical response will be reported. Available data from all patients with data cutoff in May 2020 will be included. Conclusions: Overall, XMT-1536 treatment demonstrated clinical activity in high grade serous ovarian cancer and NSCLC adenocarcinoma and was generally well-tolerated with no new safety signal trends identified in the EXP. Clinical efficacy and the relevance of NaPi2b expression for treatment with XMT-1536 will be presented. Clinical trial information: NCT03319628 .

6017 Background: Vigil is an autologous tumor cell vaccine constructed from autologous harvested tumor tissue transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin thereby creating TGFβ expression control. Methods: A randomized double-blind placebo-controlled trial of Vigil vs. placebo was performed in advanced stage frontline OC patients. Relapse-free survival (RFS) and safety were endpoints. Patients who achieved complete clinical response were randomized [1:1 to placebo (control group, CG) or Vigil (Vigil group, VG)] after completion of frontline surgery and chemotherapy. All patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses. Results: Ninety-two patients were randomized with 91 patients in the per-protocol population (PP), (VG n=46; CG n=45). 62 patients were tested for BRCA1/2 status. VG showed no added overall toxicity compared to CG and no grade 4/5 toxicities were observed. Grade 2/3 toxic events were observed in 18% of CG patients (most common bone pain, fatigue) compared to 8% of VG patients (most common nausea, musculoskeletal pain). From time of randomization median RFS for all 91 patients was favorable in the VG (HR 0.69, one-sided p 0.088).Stratified by BRCA status, an advantage in RFS was seen in the BRCA1/2-wt patients in VG (19.4 mo) compared to CG (8 mo) (HR 0.51, 90% CI 0.26 – 1.01, one-sided p 0.050) from time of randomization and HR of 0.49 (90% CI 0.25 – 0.97, one-sided p 0.038) from time of surgery. Median time from surgery to randomization was 208.5 days (6.9 mo) in VG vs. 200 days (6.6 mo) in CG. 37.5% BRCA1/2-wt Vigil treated patients relapsed compared to 71% of placebo at time of data snap for analysis (HR 0.51, one-sided p 0.05), (median follow-up of 34.3 mo for all n=91 subjects). Germline and somatic BRCA1/2 molecular testing via central third party is underway on all 91 patients under continued blinded conditions to validate activity in BRCA1/2-wt. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed RFS clinical benefit, particularly in BRCA1/2-wt disease. Clinical trial information: NCT02346747. [Table: see text]

3606 Background: Pemigatinib (INCB054828) is a selective fibroblast growth factor receptor (FGFR) 1–3 inhibitor with demonstrated efficacy as monotherapy in phase 1/2 (FIGHT-101) and phase 2 (FIGHT-201, -202, -203) trials in pts with advanced cancer. Here, we present preliminary safety, efficacy, and pharmacokinetic (PK) data for pemigatinib (PEMI) combined with pembrolizumab (PEMBRO), a programmed cell death protein-1 (PD-1) inhibitor, in pts with refractory advanced malignancies enrolled in the ongoing FIGHT-101 trial (NCT02393248). Methods: FIGHT-101 includes monotherapy (part 1 and 2) and combination therapy (part 3) cohorts. This analysis is based on pts enrolled in the PEMI + PEMBRO combination dose finding (3a) and dose expansion (3b) cohorts. Eligible adults had advanced malignancies who had progressed after prior therapy and for whom PEMBRO treatment was relevant; pts in part 3b had FGF/FGFR alterations. Pts received oral PEMI at 9 mg or 13.5 mg QD on an intermittent dosing (ID) schedule (21-day cycle, 14-day on/7-day off), or 13.5 mg QD on a continuous dosing (CD) schedule, plus PEMBRO 200 mg IV on day 1 of each 21-day cycle. Results: At data cutoff (August 30, 2019), 23 pts had received PEMI + PEMBRO; 22 (96%) had discontinued therapy (disease progression, 70%). Most frequent tumors were NSCLC (n = 3), bladder (n = 3), pancreatic, testicular, and sarcoma (each n = 2). Of 19 enrolled pts with baseline FGF/FGFR data; 5 had FGFR mutations or rearrangements. No dose-limiting toxicities occurred with PEMI + PEMBRO. The recommended PEMI dose combined with PEMBRO was 13.5 mg QD. Most frequent all-cause, all-grade (Gr) adverse events for ID (n = 17) were hyperphosphatemia (n = 14 [82%]; Gr ≥3, n = 0), anemia (n = 9 [53%]; Gr ≥3, n = 3 [18%]), and decreased appetite (n = 9 [53%]; Gr ≥3, n = 0); for CD (n = 6), hyperphosphatemia (n = 5 [83%]; Gr ≥3, n = 0), and dry mouth (n = 4 [67%]; Gr ≥3, n = 0). One pt discontinued, 2 reduced dose, and 13 interrupted dose due to AEs (none for hyperphosphatemia; dose interruption mainly for gastrointestinal AEs [n = 5]). One fatal AE occurred (suicide, not treatment-related). PK parameters for PEMI in the PEMI + PEMBRO combination were comparable with those for PEMI monotherapy. Five pts had partial response (3 had FGFR rearrangements or mutations); 5 pts had stable disease. Conclusions: PEMI + PEMBRO combination therapy was tolerable with no new safety signals, and demonstrated preliminary antitumor activity in pts with advanced malignancies including those with FGF/FGFR alterations. Clinical trial information: NCT02393248 .

TPS3163 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects are being enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy (Part 1a) or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of February 4, 2020, Phase 1 dose escalation has been completed and a recommended Phase 2 dose chosen for both FLX475 monotherapy and combination therapy with pembrolizumab. Enrollment into Phase 2 expansion cohorts has been initiated. Clinical trial information: NCT03674567 .

TPS465 Background: Engineered toxin bodies (ETBs) are proprietarily engineered from a Shiga-like Toxin A subunit fused to antibody-like binding domains. ETBs can force receptor internalization, self-route to the cytosol, and induce cell-kill via inactivation of ribosomes. MT-5111 is a 55 kDa de-immunized ETB targeting HER2, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibodies. It binds a HER2 epitope distinct from trastuzumab or pertuzumab, could be combined with other HER2 targeting agents, and may have improved tumor penetration. Methods: MT-5111 is evaluated as monotherapy in subj with confirmed HER2+ locally advanced or metastatic cancers. The primary objective is to determine the maximum tolerated dose in subjects (subj) with advanced HER2-positive tumors. Secondary endpoints are PK, tumor response and immunogenicity. Part 1 will escalate doses to identify MTD in up to 42 subj. Part 2 will further evaluate MT-5111 at the MTD in up to 98 subj. All subj will receive MT-5111 on Days 1, 8, and 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent or another reason for withdrawal. Part 1 will include subj with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastroesophageal cancer (GEA), and other HER2+ solid cancers. HER2+ must be demonstrated on metastatic lesions in case of metastases. Tumors tested by immunohistochemistry (IHC) must have IHC status of 2+ or 3+, regardless of in-situ hybridization (ISH) results; for BC and GEA, if no IHC is available, ISH per ASCO-CAP guidelines is used. Subj with HER2+ BC should have had at least 2 lines of HER2-directed therapy; subj with HER2+ gastric cancer should have received trastuzumab or have been intolerant to trastuzumab. Subj with evaluable disease may be included in Part 1; in Part 2, all subj must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac function should be adequate. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment has begun in September 2019. Clinical trial information: NCT04029922.

PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate “flu-like” symptoms. Among the 9 patients naïve to anti–PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti–PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions. Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250–7. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195

Background The poor outcomes associated with current therapies for recurrent epithelial ovarian cancer (EOC) are thought to reflect the existence of drug-resistant ovarian cancer stem cells (OCSCs). TRX-E-002-1 is a novel, third generation benzopyran molecule that induces caspase-dependent and -independent apoptosis in CD44 positive ovarian cancer stem-like cells and CD44 negative ovarian somatic cancer cells. The dose escalation phase of a progressive design trial investigating intraperitoneal (IP)-administered TRX-E-002-1 monotherapy and in combination with standard of care for recurrent EOC (NCT02903771) has been completed with a Maximum Tolerated Dose (MTD) of 5 mg/kg established. Methods Women with platinum resistant, persistent or recurrent EOC were enrolled into the dose escalation phase of the study (Part A) in which TRX-E-002-1 monotherapy was administered IP weekly for 2 three-week cycles, after which combination with standard intravenous chemotherapy was allowed to a maximum of 8 cycles. Subjects were followed up for 3 months after the end of treatment. The study objectives were to establish the MTD and to evaluate safety, tolerability, pharmacokinetics and anti-tumour activity of TRX-E-002-1. Results A total of 9 subjects were evaluable for efficacy. Four of 9 patients completed 8 cycles (6 months); 2 remained progression-free at the 3-month endpoint post-treatment (9 months). Preliminary data on activity include 1 partial response (during combination treatment) and 5 patients with stable disease on monotherapy per RECIST criteria. The most common drug-related adverse events, not generally dose limiting, were abdominal pain (27%), fatigue (13%), vomiting (10%) and nausea (10%). There was limited accumulation of TRX-E-002-1 with multiple dosing across multiple concentration‐time points. PK profiles were comparable between all subjects with plasma concentrations progressively declining to Conclusions IP administered TRX-E-002-1 as a first-in-class, dual acting, anti-cancer therapy has demonstrated preliminary activity for the treatment of platinum resistant ovarian cancer. Clinical trial identification NCT02903771. Editorial acknowledgement Dr Caroline Markey, Markey Medical Consulting. Legal entity responsible for the study Kazia Therapeutics Limited. Funding Kazia Therapeutics Limited. Disclosure J. Coward: Honoraria (institution): Takeda Pharmaceuticals; Research grant / Funding (self): AstraZeneca; Leadership role, Overseas Trainee Sub-committee member: Royal Australasian College of Physicians. K. Moore: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Immunogen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Tesaro; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy: Aravive; Advisory / Consultancy, Research grant / Funding (institution): OncoMed; Advisory / Consultancy: Samumed; Advisory / Consultancy: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Janssen; Advisory / Consultancy: Cue; Research grant / Funding (self): Lilly; Research grant / Funding (self): PTC Therapeutics; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Agenus; Leadership role, Chair: NRG Oncology OVarian Committee; Leadership role, Associate Director: GOG Partners. D. Berg: Full / Part-time employment: Kazia Therapeutics Limited. J. Garner: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Kazia Therapeutics Limited. D. Dizon: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Kazia Therapeutics; Honoraria (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self): Regeneron; Advisory / Consultancy: iMab. All other authors have declared no conflicts of interest.

Stathmin1 (STMN1) is a microtubule modulator that is expressed in multiple cancers and correlates with poor survival. We previously demonstrated in vivo safety of bifunctional (bi) shRNA STMN1 bilamellar invaginated vesicle (BIV) and that systemic delivery correlated with antitumor activity. Patients with superficial advanced refractory cancer with no other standard options were entered into trial. Study design involved dose escalation (four patients/cohort) using a modified Fibonacci schema starting at 0.7 mg DNA administered via single intratumoral injection. Biopsy at baseline, 24/48 hours and resection 8 days after injection provided tissue for determination of cleavage product using next-generation sequencing (NGS) and reverse transcription quantitative polymerase chain reaction (RT-qPCR), 5′ RLM rapid amplification of cDNA ends (RACE) assay. Serum pharmacokinetics of circulating plasmid was done. Twelve patients were entered into three dose levels (0.7, 1.4, 7.0 mg DNA). No ≥ grade 3 toxic effects to drug were observed. Maximum circulating plasmid was detected at 30 seconds with less than 10% detectable in all subjects at 24 hours. No toxic effects were observed. Predicted cleavage product was detected by both NGS (n = 7/7 patients analyzed, cohorts 1, 2) and RLM RACE (n = 1/1 patients analyzed cohort 3). In conclusion, bi-shRNA STMN1 BIV is well tolerated and detection of mRNA target sequence-specific cleavage product confirmed bi-shRNA BIV mechanism of action.

Therapies for advanced hepatocellular carcinoma (HCC) are limited. We carried out a phase I trial of a novel autologous whole-cell tumor cell immunotherapy (FANG™), which incorporates a dual granulocyte macrophage colony-stimulating factor (GM-CSF) expressive/bifunctional small hairpin RNA interference (bi-shRNAi) vector. The bi-shRNAi DNA targets furin, which is a proconvertase of transforming growth factors beta (TGFβ) 1 and 2. Safety, mechanism, immunoeffectiveness, and suggested benefit were previously shown [Senzer et al.: Mol Ther 2012;20:679-689; Senzer et al.: J Vaccines Vaccin 2013;4:209]. We now provide further follow-up of a subset of 8 HCC patients. FANG manufacturing was successful in 7 of 8 attempts (one failure due to insufficient cell yield). Median GM-CSF expression was 144 pg/106 cells, TGFβ1 knockdown was 100%, and TGFβ2 knockdown was 93% of the vector-transported cells. Five patients were vaccinated (1 or 2.5 × 107 cells/intradermal injection, 6-11 vaccinations). No FANG toxicity was observed. Three of these patients demonstrated evidence of an immune response to the autologous tumor cell sample. Long-term follow-up demonstrated survival of 319, 729, 784, 931+, and 1,043+ days of the FANG-treated patients. In conclusion, evidence supports further assessment of the FANG immunotherapy in HCC.

Background SL-801 is a novel, oral, small molecule that reversibly inhibits Exportin-1 (XPO-1), a nuclear export protein, overexpressed in a variety of solid and hematologic malignancies. XPO-1 is a mediator of nuclear-cytoplasmic transport of over 200 nuclear proteins and has been associated with aggressive tumor behavior and poor prognosis. SL-801 has demonstrated potent in vitro and in vivo activity. Interim results from the dose-escalation stage are reported. Methods STML-801-0115 is a first-in-human, multicenter dose and schedule finding study in patients with localized unresectable, or metastatic solid tumors that are refractory to or are relapsed after treatment with standard therapy. Objectives are to identify the maximum tolerated dose or optimal dose/schedule, and assess pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity. SL-801 was initially orally administered on days 1-4 and 8-11 of a 21-day cycle (Schedule A). The dosing schedule has been amended to potentially allow a longer recovery time between dosing periods while maintaining dose intensity. Patients are now receiving SL-801 once daily on days 1-2, 8-9, 15-16 and 22-23 of a 28-day cycle (Schedule B). The starting dose in the study was 5 mg/day in Schedule A; current study dose level is 70 mg/day in Schedule B. Results 45 patients received 5-65 mg/day of SL-801 in Schedule A (median age 63 YO [range: 39-83], 51% females, median number of prior systemic therapies, 4 [range: 2-10]; 57% received 3 or more. Common treatment-emergent adverse events (TEAEs) were nausea (62%), vomiting (64%), fatigue (44%), decreased appetite (33%), and diarrhea (29%). Grade 3 TEAEs included nausea (9%), anemia (7%), and fatigue, diarrhea, hyponatremia and hypophosphatasemia (each 4%). Most TEAEs were grade 1-2; no grade 4-5 toxicities reported. 12 patients (27%) had stable disease (SD) and remained on study for 2-11 months including 5 with SD for 4+ months. 1 patient with basal cell carcinoma had SD for 11 months. 3 patients had radiographic tumor shrinkage of 14-20% in target lesions. Conclusions SL-801 reversibly binds XPO1, a clinically validated target in oncology. To date 27% of heavily pre-treated patients have achieved SD as best response. Enrollment and dose escalation continue. Clinical trial identification NCT02667873. Legal entity responsible for the study Stemline Therapeutics. Funding Stemline Therapeutics. Disclosure J. Wang: Speaker Bureau / Expert testimony: AstraZeneca. E. Chiorean: Research grant / Funding (institution): Boehringer-Ingelheim, Merck, BMS, Lilly, Stemline, Ignyta/Roche, Incyte, Halozyme; Advisory / Consultancy: AstraZeneca, Array, Ipsen, Eisai, Halozyme, Seattle Genetics, Vicus, Five Prime. P. LoRusso: Advisory / Consultancy: abbvie; Advisory / Consultancy, data safety monitoring board: agios; Advisory / Consultancy: alexion; Advisory / Consultancy: ariad; Advisory / Consultancy, data safety monitoring committee: Five prime; Advisory / Consultancy: GenMab; Advisory / Consultancy: Glenmark; Advisory / Consultancy, data safety monitoring: Halozyme; Advisory / Consultancy: Menarini; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: CytomX; Advisory / Consultancy: Omniox; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Takeda; Advisory / Consultancy: Sotio; Advisory / Consultancy, data safety monitoring committee: Tyme. K. Courtney: Advisory / Consultancy: Janssen; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Aragon; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (institution): PSMA Development; Research grant / Funding (institution): Stemline; Research grant / Funding (institution): Peloton; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Proacta; Spouse / Financial dependant, Receives patent royalties: Athena Diagnostics, Inc. D. Qi: Advisory / Consultancy: stemline. J. Bullington: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. M. Sardone: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. J. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. C. Brooks: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. S. Shemesh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Stemline. T.M. Bauer: Full / Part-time employment: Tennessee Oncology; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Loxo; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medpacto, Inc; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MabVax; Research grant / Funding (institution): Stemline Therapeutics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Amgen. All other authors have declared no conflicts of interest.

3017 Background: Entrectinib potently inhibits kinases encoded by the NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated data (31 May 2018 cut-off) from 3 Phase 1/2 entrectinib trials (ALKA-372-001, EudraCT 2012-000148-88; STARTRK-1, NCT02097810; STARTRK-2, NCT02568267) for a large cohort of adults with ROS1 fusion-positive NSCLC ( ROS1+) or NTRK fusion-positive solid tumors ( NTRK+), with/without baseline CNS metastases. Methods: Pts had locally advanced/metastatic NTRK+ or ROS1+ tumors by nucleic acid-based confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were at wk 4, then every 8 wk by blinded independent central review (RECIST v1.1). Primary endpoints: ORR, DOR. Secondary endpoints: CBR, PFS, OS, intracranial efficacy and safety. Results: Most pts had ≥1 prior therapy; 33% had baseline CNS metastases. Outcomes for the ROS1+ NSCLC (n = 53) and NTRK+ solid tumors (n = 54; 24% sarcoma, 18% NSCLC) efficacy evaluable data sets are shown (table). Entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2. Conclusions: Entrectinib induced clinically meaningful durable responses in pts with ROS1+ NSCLC or NTRK+ solid tumors with or without CNS disease. Clinical trial information: NCT02097810; NCT02568267. [Table: see text]

2505 Background: CPI-006 inhibits CD73, a nucelotidase that converts AMP to adenosine and functions as a lymphocyte adhesion molecule. CPI-006 is a humanized IgG1 FcγR binding-deficient antibody that binds to CD73+ T and B lymphocytes leading to activation of B cells and expression of CD69. This study investigates the immunobiology, safety, and efficacy of CPI-006 monotherapy and in combination with CPI-444, an adenosine A2A receptor (A2AR) antagonist (NCT03454451). Methods: Patients with relapsed solid tumors were treated in a 3 + 3 escalation study with 1, 3, 6 or 12 mg/kg CPI-006 (Q3w IV infusion) monotherapy or in combination with CPI-444 (100 mg, PO, BID). Flow cytometry was performed on blood samples for lymphocyte subset analysis and receptor occupancy. Results: 17 patients were enrolled; 11 monotherapy and 6 combination. CPI-006 was associated with Grade 1 infusion reactions occuring within 30 minutes of the first infusion and were eliminated by premedication with non-steroidals. No DLTs with monotherapy or combination therapy were seen. Receptor occupancy on peripheral lymphocytes was maintained for the full dosing interval at 12 mg/kg. Pharmacodynamic effects suggesting immune modulation were observed within 1 hr of infusion at all dose levels and included a decrease in peripheral blood CD73pos B cells (mean reduction 86%, p < 0.05), increased CD73neg CD4 T cells (mean increase 37%, p < 0.01), and decreased CD8 T cells (mean reduction 20%, p < 0.01) compared to baseline. Overall, CD4:CD8 ratios were increased. Tumor regression was observed in a prostate cancer patient after 5 cycles of monotherapy at 6 mg/kg; peripheral B cells partially returned by the second cycle and reached a new homeostatic level through subsequent cycles. No change in serum immunoglobulins were observed. Conclusions: CPI-006 induces a rapid lymphocyte redistribution, including a transient reduction of circulating CD73pos B cells suggesting redistribution to lymphoid tissues, and an increased CD4:CD8 ratio, consistent with increased TH effector/memory cells in the blood. The treatment has been well-tolerated, and there is early evidence of anti-tumor activity of CPI-006 monotherapy. Clinical trial information: NCT03454451.

9534 Background: SD-101 is a synthetic CpG TLR9 agonist. Pembrolizumab is a PD-1 inhibitor. SYNERGY-001/KEYNOTE-184 assesses the safety and preliminary efficacy of the combination of SD-101 and pembrolizumab in patients naïve to anti-PD-1/L1 therapy with unresectable stage IIIC-IV melanoma. Methods: SD-101 was evaluated as 2 mg/lesion injected into 1 to 4 lesions and 8 mg/lesion in 1 lesion as 4 weekly doses followed by 7 doses Q3W. Pembrolizumab was administered as 200 mg IV Q3W. CT scans were performed every 9 weeks. Responses were assessed per investigator using RECIST v1.1. Responses and post-hoc Kaplan-Meier analyses of PFS in the ITT population were compared for patients who received 2 mg/lesion with 8 mg/lesion. Results: 86 patients (2 mg: N = 45; 8 mg: N = 41) have been enrolled with similar baseline characteristics: median age = 66 years; male = 67%; ECOG stage 0 = 67%; disease stage: IIIC = 21%; IVM1a/b = 50%; IVM1c = 28%; LDH ≤ ULN = 71%; treatment naïve = 73%. Median follow up to date is 8.1 months in 2 mg group and 8.3 months in 8 mg group. SD-101 safety profile comprises flu-like symptoms with most frequent grade ≥3 SD-101-related AEs of headache (7%), fatigue (7%), malaise (5%), myalgia (4%), and chills (4%). Immune-related AEs were reported in 19%. ORR in 2 mg group = 71% (95% CI: 57, 82) (CR: 13%) and in 8 mg group = 49% (95% CI: 33, 65) (CR: 7%) with responses in both injected and non-injected lesions, including visceral. DOR = not reached (NR) in either group. ORR by baseline PD-L1 expression in 62 patients, 53% of whom were PD-L1 positive: 2 mg = 80%/79% (PD-L1 positive/negative); 8 mg = 62%/40% (PD-L1 positive/negative). PFS was higher in 2 mg group with median PFS in 2 mg = NR (95% CI: Not estimable [NE], NE) and in 8 mg = 10.4 months (95% CI: 4.2, NE), HR = 0.45 (95% CI: 0.21, 0.98), p = 0.036. 6 month PFS rate in 2 mg = 81% and in 8 mg = 60%. 6 month OS rate in 2 mg = 98% and in 8 mg = 92%. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab has been well-tolerated, and is showing promising high response rates and PFS, regardless of PD-L1 expression, particularly in patients who received 2 mg SD-101. Clinical trial information: NCT02521870.

9555 Background: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells - activating T cell anti-tumor responses. Pembrolizumab has demonstrated activity in melanoma. SYNERGY-001/KEYNOTE-184 study assesses the safety and preliminary efficacy of the combination of intratumoral SD-101 and intravenous pembrolizumab in PD1/PDL 1 resistant unresectable stage IIIC- IV melanoma. A prior phase 2 study with SD-101 at 8 mg per injection resulted in a 21.4% ORR in this population (Abstract 3781, ESMO 2018). We report preliminary data in this ongoing phase 2 trial evaluating efficacy at a lower SD-101 dose of 2 mg per injection. Methods: PD1/PDL 1 resistant melanoma patients received 2 mg of SD-101 intratumorally per lesion in 1-4 lesions (weekly x 4 doses followed by Q3W x 7). Pembrolizumab was administered at a dose of 200 mg intravenously Q3W. Scans were performed Q9W. Responses were assessed per RECIST v1.1. Results: 23 patients have been enrolled with baseline characteristics: median age 65 years; male: 77%; stage at screening: IIIC = 26%; IV = 57%, unknown = 17%; LDH > ULN: 36%. Lines of prior therapy: 1: 52%; 2: 22%; > 2: 26%. Prior anti CTL-A4 therapy: 39%. Best overall response on prior antiPD-1/PD-L1: PD: 88%, PR/CR: 8%, SD: 4%. Safety: Grade ≥3 treatment-related AEs: pneumonia and constipation (8%). No immune-related AEs reported. 2 non-treatment related SAEs reported from 2 patients: pneumonia and intussusception. 4 patients discontinued treatment early: 1 post SAE, per patient’s request, 3 due to PD. 1 patient died due to malignant pleural effusion after 1 dose of SD 101 and Pembrolizumab. No treatment related deaths. Efficacy: Mean duration on treatment: 39 days (1 - 169). mITT population: six patients at time of first CT scan at day 64: PR: 1, SD: 1, PD:3; non-evaluable: 1. 17 patients on study have not yet had first CT scan. Conclusions: The TLR9 innate immune stimulant, SD-101, in combination with pembrolizumab is well tolerated. Mature efficacy data, with additional first and second follow-up CT scans, will be presented at the meeting. Clinical trial information: NCT02521870.

TPS2646 Background: CD73 expression is elevated in tumors and contributes to increasing levels of immunosuppressive adenosine in the tumor microenvironment. CD73 knockout mice exhibit reduced tumor growth and resistance to experimental metastasis. Inhibition of CD73 activity with an anti-CD73 antibody blocks adenosine production, shown to inhibit tumor growth in syngeneic models. CPI-006 is a humanized IgG1 FcγR binding-deficient anti-CD73 antibody now being investigated in this Phase 1/1b multicenter, open label trial as single agent (SA) or combination with CPI-444, an oral, small molecule, selective A2aR antagonist or in combination with pembrolizumab, an anti-PD1 indicated for the treatment of patients across a number of malignancies (NCT03454451). Methods: Up to 462 subjects will be enrolled at approximately 35 sites in the US, Canada and Australia. Eligible patients must have: non-small cell lung, renal cell carcinoma, urothelial bladder, cervical, colorectal, ovarian, pancreatic, prostate, head and neck, triple-negative breast, endometrial, select sarcomas and non-Hodgkin lymphoma malignancies relapsed, refractory or intolerant to 1 to 5 standard therapies; aged ≥ 18 yo; adequate organ function and measurable disease. The objectives of the study are 1) evaluate the safety and tolerability of SA CPI-006, in combination with CPI-444 and in combination with pembrolizumab, 2) evaluate the pharmacokinetics of each regimen and 3) identify potential biomarker signals predictive of response. Study design in table. Study Design. Clinical trial information: NCT03454451. [Table: see text]

Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions.

TAG vaccine is a novel 'triad vaccine' that involves transfection of autologous tumor with a dual plasmid, TGFβ2 antisense gene and GM-CSF gene. Patients with advanced cancer who failed standard therapy were treated. IFN-γ ELISPOT analysis (Enzyme-Linked Immunospot Assay for Interferon Gamma) using TAG autologous vaccine target cells was performed prior to vaccination and at week 12 after the third vaccination. The purpose of this assessment was to correlate the IFN-γ ELISPOT immune response with long-term survival of advanced cancer patients who received TAG vaccination. Twenty-three of 28 patients received ≥ 3 TAG vaccinations (two patients withdrew consent and three had disease progression prior to the third vaccination). Eleven patients demonstrated a positive ELISPOT response (10 spots and ≥ 2 × baseline) at week 12 and 12 patients did not (P=0.002). Median survival from time of treatment between ELISPOT-positive and -negative groups was significantly different (550 vs 159 days, P=0.036), as was median survival from the time of procurement (627 vs 257 days, respectively, P=0.043). In conclusion, the IFN-γ ELISPOT assay may provide an effective measure of immune response following treatment with 'triad vaccines', but additional patient numbers and/or other immune modulatory parameters are necessary for future testing.

Objectives The majority of women with Stage III/IV ovarian cancer who achieve clinical complete response with frontline standard of care will relapse within 2years. Vigil immunotherapy, a GMCSF/bi-shRNA furin DNA engineered autologous tumor cell (EATC) product, demonstrated safety and induction of circulating activated T-cells against autologous tumor in Phase I trial Senzer et al. (2012, 2013) . Our objectives for this study include evaluation of safety, immune response and recurrence free survival (RFS). Methods This is a Phase II crossover trial of Vigil (1.0×10 7 cells/intradermal injection/month for 4 to 12 doses) in Stage III/IV ovarian cancer patients achieving cCR (normal imaging, CA-125≤35units/ml, physical exam, and no symptoms suggestive of the presence of active disease) following primary surgical debulking and carboplatin/paclitaxel adjuvant or neoadjuvant chemotherapy. Patients received Vigil or standard of care during the maintenance period. Results Forty-two patients were entered into trial, 31 received Vigil and 11 received standard of care. No≥Grade 3 toxicity related to product was observed. A marked induction of circulating activated T-cell population was observed against individual, pre-processed autologous tumor in the Vigil arm as compared to pre-Vigil baseline using IFNγ ELISPOT response (30/31 negative ELISPOT pre Vigil to 31/31 positive ELISPOT post Vigil, median 134 spots). Moreover, in correlation with ELISPOT response, RFS from time of procurement was improved (mean 826days/median 604days in the Vigil arm from mean 481days/median 377days in the control arm, p=0.033). Conclusion In conjunction with the demonstrated safety, the high rate of induction of T-cell activation and correlation with improvement in RFS justify further Phase II/III assessment of Vigil.

We performed a phase I trial of FANG vaccine, an autologous tumor-based product incorporating a plasmid encoding granulocyte-macrophage colony-stimulating factor (GMCSF) and a novel bifunctional short hairpin RNAi (bi-shRNAi) targeting furin convertase, thereby downregulating endogenous immunosuppressive transforming growth factors (TGF) β1 and β2. Patients with advanced cancer received up to 12 monthly intradermal injections of FANG vaccine (1 × 10(7) or 2.5 × 10(7) cells/ml injection). GMCSF, TGFβ1, TGFβ2, and furin proteins were quantified by enzyme-linked immunosorbent assay (ELISA). Safety and response were monitored. Vaccine manufacturing was successful in 42 of 46 patients of whom 27 received ≥1 vaccine. There were no treatment-related serious adverse events. Most common grade 1, 2 adverse events included local induration (n = 14) and local erythema (n = 11) at injection site. Post-transfection mean product expression GMCSF increased from 7.3 to 1,108 pg/10(6) cells/ml. Mean TGFβ1 and β2 effective target knockdown was 93.5 and 92.5% from baseline, respectively. Positive enzyme-linked immunospot (ELISPOT) response at month 4 was demonstrated in 9 of 18 patients serially assessed and correlated with survival duration from time of treatment (P = 0.025). Neither dose-adverse event nor dose-response relationship was noted. In conclusion, FANG vaccine was safe and elicited an immune response correlating with prolonged survival. Phase II assessment is justified.

This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed.Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression.Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (150μg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated.Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts.

Background: This phase 1b trial evaluates the safety and antitumor efficacy of the combination of SD-101, a synthetic CpG-oligonucleotide that stimulates Toll-like receptor 9 (TLR9), and pembrolizumab in patients with recurrent Stage IIIC/IV malignant melanoma. Methods: Dose escalation of SD-101 used a modified 3+3 design. SD-101 was injected in a single tumor lesion (weekly x 4 doses then every 3 weeks x 7 doses over 6 months) at 1, 2, 4, or 8 mg and pembrolizumab was administered intravenously at 200 mg every 3 weeks up to 2 years. Tumor responses were assessed per investigator using RECIST v1.1 taking into account both injected and non-injected lesions. Results: Of the 22 patients, 9 were naïve to anti-PD-1/L1 therapy at baseline and 13 had progressive disease while receiving prior anti-PD-1/L1 therapy. Treatment was well tolerated with no Grade 3 or higher treatment-related AEs in longer term follow up. Among the 9 patients who were anti-PD-1/L1 naïve, best objective responses were CR: 2, PR: 5, PD: 1, not evaluated [NE]: 1. Median PFS, duration of response, and OS have not been reached. Estimated 12 month PFS was 88% and OS was 89%. After a median of 18 months of follow-up, 86% of responses were ongoing. One patient with a PR developed progressive disease after 20 months of treatment. Among patients who had received prior anti-PD-1/L1 therapy, best objective responses were PR: 2, SD: 5, PD: 5, NE: 1. One patient with stable disease and 1 patient with a PR continued on combination therapy without progression for at least 10.5 months. The other 10 patients developed progressive disease ranging from 1.5 to 8 months after enrollment. Percent change in tumor size from baseline in injected and non-injected lesions will also be presented. Conclusion: These early results suggest that combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially provide more clinical responses that are meaningfully durable than PD-1 blockade alone based on historical data. Citation Format: Antoni Ribas, Theresa Medina, Shivaani Kummar, Asim Amin, Joseph J. Drabick, Minal Barve, Gregory Daniels, Deborah L. Wong, Emmett V. Schmidt, Abraham C. Leung, Robert Janssen. Durability of responses to the combination of SD-101 and pembrolizumab in advanced metastatic melanoma: Results of a phase Ib, multicenter study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT139.