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Objective: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors. Cohort C will enroll triple-negative breast cancer (TNBC) patients. Background: Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aberrant NOTCH signaling is associated with chemotherapy resistance, tumor plasticity, enhanced metastatic potential, promotion of a cancer stem cell phenotype, and immune evasion. In TNBC, aberrant NOTCH expression is associated with poor prognosis, making targeting of this pathway an attractive therapeutic strategy. Additionally, NOTCH may mediate resistance to angiogenesis inhibition. While VEGF inhibitors are approved for the treatment of multiple solid tumors, observed anti-tumor activity is limited in breast cancer. Pre-clinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway targeting. We postulate that navicixizumab will demonstrate anticancer efficacy against TNBC. Methods: Eligible TNBC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 4 prior lines of standard therapy for metastatic disease, including immunotherapy (for PD-L1 positive TNBC patients), and sacituzumab govitecan. TNBC is defined as ER and PR < 1%, and HER2-negative (IHC 0, 1+, or 2+ and negative fluorescence in situ hybridization [FISH]). Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap™ ExTra with the Xerna TME Panel™ to classify patient samples into one of four tumor microenvironment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each TNBC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort C1) or in combination with paclitaxel (80 mg/m2 on Days 1, 8, and 15 of a 28-day cycle) (Cohort C2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of < 5% and a 20% PFS rate at 4 months, with targets of 15% and 40% respectively considered promising for this study. Interim efficacy assessments will be at 10-patient increments following the time patients have had at least 1 post-baseline scan. Cohort continuation and future evaluation decisions will be guided by the boundaries identified by a sequential monitoring procedure. Secondary efficacy endpoints include overall survival, time to response, disease control rate, duration of response, and the relationship between antitumor activity of navicixizumab and Xerna TME Panel™ biomarker subtypes. Citation Format: Amelia B. Zelnak, Heinz-Josef Lenz, Kerry Culm, Lukas Makris, Valerie Chamberlain Santos, Hagop Youssoufian, Colleen Mockbee, Kathy D. Miller. ONCX-NAV-G201: A phase 2, basket study of navicixizumab monotherapy or in combination with chemotherapy in patients with select advanced solid tumors: Triple-negative breast cancer cohort (trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-01.

PURPOSE This phase Ib study evaluated the safety and efficacy of paclitaxel plus navicixizumab, a bispecific antiangiogenic antibody to vascular endothelial growth factor and delta-like ligand 4, against platinum-resistant ovarian cancer. PATIENTS AND METHODS This open-label, nonrandomized, dose-escalation and -expansion study included 44 patients with previously treated, recurrent, platinum-resistant grade 2/3 ovarian cancer. Treatment was intravenous navicixizumab (3 mg/kg or 4 mg/kg once every 2 weeks) plus paclitaxel (80 mg/m2 intravenously on days 0, 7, and 14 of 28-day cycles). The primary and secondary objectives were to evaluate the safety and efficacy of navicixizumab plus paclitaxel. An RNA-based diagnostic panel was retrospectively used to test the hypothesis that tumors with high angiogenesis or immune-suppressed tumor microenvironment (TME) subtypes (biomarker-positive) are more likely to respond to navicixizumab than those with immune-active/-desert TME subtypes (biomarker-negative). RNA expression was analyzed in available pretreatment tumor tissue to classify 33 patients' TME subtypes, and TME panel findings were correlated with tumor response. RESULTS The dose-escalation cohorts enrolled patients at navicixizumab doses of 3 mg/kg once every 2 weeks (n = 3) and 4 mg/kg once every 2 weeks (n = 2); 3 mg/kg was selected for expansion (n = 39). No dose-limiting toxicities occurred. The most common grade 3/4 treatment-related adverse events were hypertension (40.9%), neutropenia (6.8%), and thrombocytopenia (4.5%). Pulmonary hypertension occurred in 18.2% (grade 1-2). The overall objective response rate was 43.2% (95% CI, 28.3 to 59.0): 33.3% (95% CI, 17.3 to 52.8) in patients previously treated with bevacizumab, 64.3% (95% CI, 35.1 to 87.2) in bevacizumab-naive patients, and 62% (95% CI, 31.6 to 86.1) in biomarker-positive patients. The median duration of response was 6 months (95% CI, 5.4 months to not estimable). CONCLUSION Navicixizumab plus paclitaxel demonstrated promising clinical activity in bevacizumab-treated and -naive patients with platinum-resistant ovarian cancer, with manageable toxicity.

Supplementary Data from Anti–Transforming Growth Factor β Receptor II Antibody Has Therapeutic Efficacy against Primary Tumor Growth and Metastasis through Multieffects on Cancer, Stroma, and Immune Cells

The distributions of mRNA gene expression levels IGF-1R, Total IR, IR-A, and IR-B

Supplemental Section for Resubmission - Clean Version

Figure S2C displays probability of progression-free survival over time in subgroups of patients with and without bulky disease

Purpose:In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% (P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial.Patients and Methods:Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety.Results:As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%).Conclusions:Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab.

Figure S2 displays a graph of the plasma concentrations of total docetaxel for patients dosed with 60/mg/m2 of BIND-014 on the Q3W schedule.

Supplemental Figure Legend

Supplementary Figure from Safety and Activity of PolyPEPI1018 Combined with Maintenance Therapy in Metastatic Colorectal Cancer: an Open-Label, Multicenter, Phase Ib Study

Purpose: This phase II trial evaluated the efficacy and safety of cixutumumab, a human anti–insulin-like growth factor receptor 1 (IGF-1R) monoclonal IgG1 antibody, and explored potential biomarkers in postmenopausal women with hormone receptor–positive breast cancer.Experimental Design: Patients with hormone receptor–positive breast cancer that progressed on antiestrogen therapy received (2:1 randomization) cixutumumab 10 mg/kg and the same antiestrogen (arm A) or cixutumumab alone (arm B) every 2 weeks (q2w). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety. Correlative analyses of IGF-1R, total insulin receptor (IR), and IR isoforms A (IR-A) and B (IR-B) expression in tumor tissue were explored.Results: Ninety-three patients were randomized (arm A, n = 62; arm B, n = 31). Median PFS was 2.0 and 3.1 months for arm A and arm B, respectively. Secondary efficacy measures were similar between the arms. Overall, cixutumumab was well tolerated. IGF-1R expression was not associated with clinical outcomes. Regardless of the treatment, lower IR-A, IR-B, and total IR mRNA expression in tumor tissue was significantly associated with longer PFS [IR-A: HR, 2.62 (P = 0.0062); IR-B: HR, 2.21 (P = 0.0202); and total IR: HR, 2.18 (P = 0.0230)] and OS [IR-A: HR, 2.94 (P = 0.0156); IR-B: HR, 2.69 (P = 0.0245); and total IR: HR, 2.72 (P = 0.0231)].Conclusions: Cixutumumab (10 mg/kg) with or without antiestrogen q2w had an acceptable safety profile, but no significant clinical efficacy. Patients with low total IR, IR-A, and IR-B mRNA expression levels had significantly longer PFS and OS, independent of the treatment. The prognostic or predictive value of IR as a biomarker for IGF-1R–targeted therapies requires further validation. Clin Cancer Res; 22(2); 301–9. ©2015 AACR.

Supplementary Figure Legends for Figures S1 and S2

Kaplan-Meier curves of PFS and OS in pooled group and arm A dichotomized by insulin receptor-A (IR-A) expression (high vs. low) using the 75th percentile of marker distribution as cutpoint.

Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)–targeted nanoparticle, containing docetaxel.Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m2 and 15 to 45 mg/m2, respectively.Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non–small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors.Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m2 every three weeks or 40 mg/m2 weekly. Clin Cancer Res; 22(13); 3157–63. ©2016 AACR.

Figure S3 displays probability of overall survival over time in the study population

Supplementary Table from Safety and Activity of PolyPEPI1018 Combined with Maintenance Therapy in Metastatic Colorectal Cancer: an Open-Label, Multicenter, Phase Ib Study

•Table S1 shows a summary of prior anticancer therapies received by all patients in the study •Table S2 shows best overall response, overall response rate, and duration of response by investigator in the study population of patients while receiving ofatumumab in the parent DUO study before crossover •Table S3 shows rates of all serious TEAEs and individual hematologic and non-hematologic serious TEAEs in {greater than or equal to} 2% of patients in the study population • Table S4 shows rates of all TEAEs leading to death in patients in the study population •Table S5 shows a summary of patient disposition information

Purpose: Transforming growth factor β (TGFβ) is a pleiotropic cytokine that affects tumor growth, metastasis, stroma, and immune response. We investigated the therapeutic efficacy of anti–TGFβ receptor II (TGFβ RII) antibody in controlling metastasis and tumor growth as well as enhancing antitumor immunity in preclinical tumor models.Experimental Design: We generated neutralizing antibodies to TGFβ RII and assessed the antibody effects on cancer, stroma, and immune cells in vitro. The efficacy and mechanism of action of the antibody as monotherapy and in combination with chemotherapy in suppression of primary tumor growth and metastasis were evaluated in several tumor models.Results: Anti–TGFβ RII antibody blocked TGFβ RII binding to TGFβ 1, 2, and 3, and attenuated the TGFβ-mediated activation of downstream Smad2 kinase, invasion of cancer cells, motility of endothelial and fibroblast cells, and induction of immunosuppressive cells. Treatment with the antibody significantly suppressed primary tumor growth and metastasis and enhanced natural killer and CTL activity in tumor-bearing mice. Immunohistochemistry analysis showed cancer cell apoptosis and massive necrosis, and increased tumor-infiltrating T effector cells and decreased tumor-infiltrating Gr-1+ myeloid cells in the antibody-treated tumors. Fluorescence-activated cell sorting analysis indicated the significant reduction of peripheral Gr-1+/CD11b+ myeloid cells in treated animals. Concomitant treatment with the cytotoxic agent cyclophosphamide resulted in a significantly increased antitumor efficacy against primary tumor growth and metastasis.Conclusions: These preclinical data provide a foundation to support using anti–TGFβ RII antibody as a therapeutic agent for TGFβ RII–dependent cancer with metastatic capacity. Clin Cancer Res; 16(4); 1191–205

Figure S1 displays probability of progression-free survival over time in the study population and in the subgroup of patients with del(17p) and/or TP53 mutations that received ofatumumab while participating in the parent DUO study before crossover

Purpose:Although chemotherapy is standard of care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a “cold” tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC.Patients and Methods:Eleven patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study, 5 patients received a single dose; in Part B, 6 patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety; secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor level, and immune correlates.Results:PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. Eighty percent of patients had CD8+ T-cell responses against ≥3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients’ liver biopsies, combined with increased expression of immune-related gene signatures. Three patients had objective response according to RECISTv1.1, and 2 patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs. 4.6 months; P = 0.017) suggested a dose–efficacy correlation. The host HLA genotype predicted multi-antigen–specific T-cell responses (P = 0.01) indicative of clinical outcome.Conclusions:PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting.

Purpose: Although chemotherapy is standard of care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a “cold” tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC. Patients and Methods: Eleven patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study, 5 patients received a single dose; in Part B, 6 patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety; secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor level, and immune correlates. Results: PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. Eighty percent of patients had CD8+ T-cell responses against ≥3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients’ liver biopsies, combined with increased expression of immune-related gene signatures. Three patients had objective response according to RECISTv1.1, and 2 patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs. 4.6 months; P = 0.017) suggested a dose–efficacy correlation. The host HLA genotype predicted multi-antigen–specific T-cell responses (P = 0.01) indicative of clinical outcome. Conclusions: PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting.

TPS263 Background: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors (NCT05453825). Cohort A will enroll colorectal cancer (CRC) patients. Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aggressive CRC remains difficult to treat owing to the aberrant activation of oncogenic signaling pathways including the NOTCH pathway. Preclinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway inhibition. We postulate that navicixizumab will demonstrate anticancer efficacy against CRC. Methods: Eligible CRC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 3 prior lines of standard therapy for metastatic disease, including an anti-VEGF monoclonal antibody. Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap ExTra with the Xerna TME Panel where patient samples will be classified into one of four tumor microenviroment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each CRC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort A1) or in combination with irinotecan (180 mg/m2 on Days 1 and 15 of a 28-day cycle, Cohort A2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of

TPS283 Background: Colorectal cancer (CRC) is among the top three most commonly occurring cancers globally. CRC is now routinely classified as MSI-high (MSI-H) or microsatellite-stable (MSS) based on the detection or absence of molecular markers of genetic instability, respectively. The efficacy of checkpoint inhibitor immunotherapy in MSI-H CRC has not been replicated in MSS CRC. Therefore, additional interventions are needed to convert immunologically “cold” MSS CRC to “hot” tumors resembling MSI-H tumors. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 cancer testis antigens (CTAs) frequently expressed in patients with CRC. PolyPEPI1018 successfully restored and boosted pre-existing anticancer immunity of MSS mCRC subjects and triggered recruitment and infiltration of cytotoxic T cells into the tumor. In first line metastatic MSS CRC, PolyPEPI1018 in combination with fluoropyrimidine/bevacizumab vaccine was safe and demonstrated early evidence of clinical activity. Therefore, we hypothesized that the combination of PolyPEPI1018 and atezolizumab will convert a “cold” MSS mCRC to a “hot” tumor and may increase the likelihood of inducing favorable antitumor immunity and subsequent clinical benefit. Methods: The study is a phase 2, multicenter, single-arm clinical trial of PolyPEPI1018 vaccine (1.2 mg, sc, every 3 weeks) and atezolizumab (1200 mg, iv, every 3 weeks) for patients with advanced or metastatic MSS CRC who have progressed on 2 or 3 lines of prior standard regimens. 28 patients will be enrolled at 3 US sites with a primary objective to assess the safety and tolerability of multiple doses of PolyPEPI1018 in combination with atezolizumab. Secondary endpoints include objective response rate (ORR) assessed by RECIST v1.1, vaccine induced immunological response rate (IRR), progression-free survival and overall survival. Correlative aims include assessing blood and tissue biomarkers (PD-L1, Immunoscore®IC, ctDNA, clinical tumor markers) for association with clinical benefit. An exploratory study is being conducted for co-development of a companion diagnostic based on HLA-genotype and computational personal epitope (PEPI) prediction test. A Simon 2-stage design will be used for the initial assessment of ORR. If pre-specified activity goal for the first stage of accrual (n = 18) is met, additional 10 participants will be enrolled to the second stage. A formal review of safety will be performed after the initial 6 participants have received at least 2 cycles of study therapy. The study is open with 10 patients enrolled at time of submission. Clinical trial information: NCT05243862 .

e20609 Background: ACSS2 catalyzes the ligation of acetate with Co-enzyme A to generate Acetyl-CoA. Selection to an acetate dependent state has been demonstrated and is associated with the induction of ACSS2 gene expression in certain human cancers. The ACSS2 gene is amplified in human breast cancers, and its expression is up-regulated in human colorectal, breast, ovarian and lung cancers. MTB-9655 is a potent (IC50 = 0.15nM in biochemical, and EC50 = 3nM in cellular assays) oral inhibitor of ACSS2 and induces anti-tumor effects in xenograft mouse models of human colorectal, breast and lung cancers that express high levels of ACSS2. Methods: Using a combined accelerated (single patient for the first two dose levels) and 3+3 dose escalation and dose expansion design, MTB-9655 was administered on a once daily (QD) schedule in 21-day cycles in a Phase 1 trial to assess safety, tolerability, PK and potential anti-tumor activity in patients with advanced solid tumors. Re-staging was performed every 2 cycles. Results: To-date, 10 subjects have received MTB-9655 at doses up to 225mg. MTB-9655 was absorbed rapidly post oral dosing with a half-life of 6-12 hours. Dose proportional exposure was observed on day 1 of the first dosing cycle, and steady-state exposure was noted between day 8 and day 1 of the second dosing cycle. Dose limiting toxicities or Grade 3 treatment-related adverse events (AEs) have not been observed up to the 225mg dose level. The most common AE was nausea (29%). Low grade increase in bilirubin levels was observed in 1 patient at 225mg dose, without changes in other liver enzyme levels. Increased bilirubin levels were readily reversed with dose interruption. As MTB-9655 is a 729nM inhibitor of the UGT1A1 enzyme, the increase in bilirubin levels is likely attributed to off-target UGT1A1 inhibitory activity. Conclusions: MTB-9655 has been well tolerated, and the safety profile was predictable based on preclinical studies in rodents and non-human primates. Dose proportional plasma drug levels were observed and predicted to have reached biologically active levels. Expected increase in bilirubin levels was observed in 1 patient, which may be used as a marker of significant drug exposure. MTD has not reached up to the 225mg dose and the dose escalation is continuing. Development of MTB-9655 is planned as a single agent, and based on animal model studies, in combination with standard of care platinum-based agents and gemcitabine. Clinical trial information: NCT04990739.

581 Background: The prognosis for advanced metastatic pancreatic adenocarcinoma remains dismal with median survival of 12-15 months in most recent trials, highlighting the urgent need for novel therapeutic agents. mFOLFIRINOX remains the standard of care for the first line treatment of advanced disease, with historical objective response rate (ORR) of ̃31%. Eryaspase, L-asparaginase (ASPNase) encapsulated in red blood cells (RBCs), is an investigational product under development. Following infusion, asparagine is actively transported in RBCs where it is hydrolyzed by encapsulated ASPNase. The reduction in plasma concentration of this essential amino acid leads to cancer cell death. A second line pivotal randomized phase III trial (Trybeca-1), which compares chemotherapy (Gemcitabine + Nab-Paclitaxel or 5-Fluorouracil + Irinotecan) with or without Eryaspase, has completed enrollment with results pending (NCT03665441). Methods: Patients with locally advanced or metastatic biopsy-proven pancreatic adenocarcinoma were treated with the combination of mFOLFIRINOX plus Eryaspase. The design was a standard 3 +3 dose escalation. mFOLFIRINOX was given as 5-Fluorouracil 2400 mg/m2 over 46 hours, Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2 plus Eryaspase 75 units/kg at dose level 0 or 100 units/kg at dose level 1. Key eligibility criteria include performance status of 0 or 1, locally advanced or metastatic disease, and adequate organ function. The primary objectives were to determine the maximum tolerated dose (MTD) and to determine the safety of this combination. Results: To date, nine patients have been enrolled with a mean age of 70. Four patients had locally advanced disease and five had metastatic disease. Three patients were enrolled at dose level 0 and six at dose level 1, with no dose limiting toxicities (DLT). Eight patients have had imaging to evaluate response: the ORR was 50% with four partial responses (PRs); 50% (N = 4) had stable disease (SD); disease control rate (PR + SD) was 100%. There were no grade 4 adverse events (AEs). The most common grade 3 AEs were hypokalemia (33%), fatigue (11%), and hypotension (11%); but they were beyond the DLT period of 28 days. The most common grade 1/2 AEs were neuropathy (78%), elevated liver enzymes (78%), nausea (78%), anemia (66%), fatigue (66%), diarrhea (66%), and mucositis (44%). Conclusions: The novel combination of mFOLFIRINOX plus Eryaspase was well tolerated with no DLT and has encouraging signs of clinical activity. The MTD has been declared with 5-FU 2400 mg/2, Oxaliplatin 85 mg/2, Irinotecan 150 mg/m2, and Eryaspase 100 units/kg. We plan to expand enrollment to further look at efficacy and are in the process of designing a larger randomized study in the first line setting pending results from the Trybeca-1 trial. Clinical trial information: NCT04292743.

518 Background: Eryaspase, asparaginase encapsulated in red blood cells is an investigational product under development. The encapsulated asparaginase induces the degradation of asparagine and glutamine, crucial for cancer cell growth and survival. An earlier Phase 2b study in patients with advanced pancreatic cancer showed an improvement in overall survival (OS) and progression free survival (PFS) with eryaspase plus chemotherapy. Methods: TRYbeCA-1 was a randomized, open-label Phase 3 trial of eryaspase combined with chemotherapy in patients with advanced adenocarcinoma of the pancreas who have progressed on only one prior line of systemic anti-cancer therapy. Patients were randomized in a 1:1 ratio to gemcitabine/nab-paclitaxel or irinotecan/fluorouracil (5FU) therapy (depending on first-line received) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria included progression on or following first-line systemic treatment, ECOG performance status 0 or 1, stage III-IV disease, documented evidence of disease progression, available tumor tissue and adequate organ function. The primary endpoint was OS. A total of 412 events were required for 90% power to detect a treatment effect hazard ratio (HR) of 0.725 at a two-sided significance level of 5%. Results: A total of 512 patients were included. Baseline characteristics were well balanced between the treatment arms. The study did not meet the OS primary endpoint [HR: 0.92 (95% confidence interval (CI), 0.76-1.11), p-value 0.375]. The median OS for patients treated with eryaspase plus chemotherapy was 7.5 mo (95% CI, 6.5-8.3), compared to 6.7 mo (95% CI, 5.4-7.5) for chemotherapy alone. There was a trend of nominal OS benefit in 107 patients treated with eryaspase and irinotecan-5FU compared to 109 patients in control subgroup, with a median OS of 8.0 mo versus 5.7 mo, respectively [HR: 0.81 (95% CI: 0.60- 1.09)]. Treatment effect was consistent across various prognosis factors. Median PFS was 3.7 mo vs. 3.5 mo in the eryaspase and control arms, respectively [HR: 0.89 (95% CI: 0.73-1.07), p-value 0.215]. Disease control rate was 57.6% and 49.0% (p-value 0.047) in the eryaspase and control arms, respectively. The most common adverse events were in the eryaspase arm were asthenia, diarrhea, and anemia (Grade 3-4: 16.9%, 7.66% and 17.3%, respectively). Eryaspase did not appear to enhance toxicity of chemotherapy. Conclusion: This large prospective study did not meet it primary endpoint of improving OS in patients treated with eryaspase. The addition of eryaspase demonstrated nevertheless a well-tolerated profile and an encouraging survival benefit in the irinotecan/5FU subgroup, warranting further investigation. Clinical trial information: NCT03665441.