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BACKGROUND: Elotuzumab plus lenalidomide and dexamethasone has shown improved progression-free and overall survival versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. We aimed to assess these regimens in patients with newly diagnosed multiple myeloma who are ineligible for haematopoietic stem-cell transplantation (HSCT). METHODS: ELOQUENT-1 is an open-label, multicentre, randomised, phase 3 trial conducted at 185 hospitals, oncology practices, and research centres in 19 countries. Eligible patients were aged 18 years or older with newly diagnosed, untreated, symptomatic myeloma and not candidates for high-dose therapy plus HSCT, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Patients were randomly assigned (1:1) to receive elotuzumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone using an interactive voice response system, stratified by the International Staging System (ISS; stage I-II vs III), age (

Metastatic uveal melanoma (UM) is a devastating disease with few treatment options. We evaluated the safety, tolerability and preliminary activity of arginine depletion using pegylated arginine deiminase (ADI-PEG20; pegargiminase) combined with pemetrexed (Pem) and cisplatin (Cis) chemotherapy in a phase 1 dose-expansion study of patients with argininosuccinate synthetase (ASS1)-deficient metastatic UM. Eligible patients received up to six cycles of Pem (500 mg/m

Effects of ADI-PEG20 on the folate pathway

Purpose:Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed.Patients and Methods:We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16–06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy.Results:Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti–ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5–20.8) and overall survival was 6.3 months (95% CI, 1.8–9.7).Conclusions:In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.

Background Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models. Methods This was a global, multicenter, open-label, single-arm, phase 2 trial of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child-Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression-free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 36 mg/m2 . Results In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30-85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%-15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression-free survival was 3.8 months (95% CI, 1.8-6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6-20.9 months). The most common grade ≥3 treatment-related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%). Conclusions Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued. Lay summary Arginine is an important nutrient for hepatocellular carcinoma (HCC). The depletion of arginine with pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial. To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI-PEG 20 and FOLFOX in the treatment of patients with refractory HCC. The study showed limited activity of ADI-PEG 20 and FOLFOX in advanced HCC and was stopped early.

Background Arginine depletion interferes with pyrimidine metabolism and DNA damage-repair pathways, and pairing arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG20) with platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. Methods This single-centre, Phase 1 trial was conducted using a 3 + 3 dose escalation designed to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of ADI-PEG20. Results We enrolled 99 patients with metastatic argininosuccinate synthetase 1 (ASS1) deficient malignancies. We observed no dose-limiting toxic effects or treatment-related mortality. Three percent of patients discontinued treatment because of toxicity. After treatment, 5% (5/99) of patients had partial responses, and 41% had stable disease. The median progression-free and overall survival durations were 3.62 and 8.06 months, respectively. Substantial arginine depletion and citrulline escalation persisted in most patients through weeks 24 and 8, respectively. Tumour responses were associated with anti-ADI-PEG20 antibody levels at weeks 8 and 16 (p = 0.031 and p = 0.0357, respectively). Conclusion Concurrently administered ADI-PEG20 and cisplatin had an acceptable safety profile and had shown antitumour activity against metastatic ASS1-deficient solid tumours. Further evaluation of this treatment combination is warranted.

Background: Arginine deprivation with ADI-PEG20 (pegargiminase) alone or combined with chemotherapy displayed antitumor activity in early phase clinical trials of argininosuccinate synthase 1 (ASS1)-deficient cancers, including pleural mesothelioma (PM). The non-epithelioid subtype of mesothelioma is particularly aggressive and arginine-auxotrophic due to frequent ASS1 loss. ATOMIC-meso is a pivotal phase 2-3 trial comparing standard of care (SOC) chemotherapy plus pegargiminase or placebo for patients (pts) with non-epithelioid PM. Methods: In this double-blind, placebo-controlled, phase 2-3 trial, we randomly assigned ECOG PS 0-1 pts with chemonaïve non-epithelioid PM in an intention-to-treat 1:1 ratio to receive q3 week SOC chemotherapy with pemetrexed (500mg/m2 i.v.) and cisplatin (75mg/m2 i.v.) with q1 week pegargiminase (36 mg/m2 i.m.) or placebo i.m. up to 6 cycles. Carboplatin (AUC5) was permitted in the phase 3 portion instead of cisplatin. Maintenance therapy with pegargiminase or placebo was continued until progression, toxicity or 24 months. The primary end point was median OS (mOS) and secondary end points included median PFS (mPFS), safety, pharmacodynamics and immunogenicity. ORR was assessed by blinded independent central review (BICR) for the phase 2 portion only using modified RECIST or RECIST v1.1. Results: 249 pts with non-epithelioid PM (median age 71, range 28-86; male 82.7%; 48.2% biphasic and 51.8% sarcomatoid) from 5 countries were randomized between Aug 2017 and Aug 2021: 125 pts were assigned to the pegargiminase-chemotherapy group and 124 pts to the placebo-chemotherapy group. The experimental arm showed a superior mOS respect to SOC: 9.3 months (95% confidence interval [CI], 7.9-11.8) vs. 7.7 months (95% CI, 6.1-9.5) (hazard ratio [HR], 0.71; 95% CI, 0.55-0.93; p=0.023). Also, the mPFS was higher in the experimental vs. control arm: 6.2 months (95% CI, 5.8-7.4) vs. 5.6 months (95% CI, 4.14-5.91) ([HR], 0.65; 95% CI, 0.46-0.90; p=0.019). The ORR by BICR was 13.8% in the pegargiminase-chemotherapy group vs. 13.5% in the placebo-chemotherapy group (p=0.95) with more stable disease in the former (71.3% vs. 62.9%). Plasma arginine declined with a reciprocal increase in citrulline. Anti-ADI-PEG20 antibodies were detected in 97.4% of patients by week 25 on pegargiminase. Grade ≥ 3 treatment-related adverse events to pegargiminase occurred in 28.8% and to placebo in 16.9%; grade ≥ 3 drug hypersensitivity and skin reactions occurred in 3.2% and 1.6% in the experimental arm, respectively, and none on placebo. Post-study drug treatment was comparable in both arms (45.6% post-pegargiminase vs. 46.8% post-placebo). Conclusions: In this first randomized trial of an arginine-depleting chemotherapy in cancer, the pegargiminase-pemetrexed-platinum triplet prolonged survival and had a favorable safety profile in pts with non-epithelioid PM (ClinicalTrials.gov Identifier NCT02709512) Citation Format: Peter W. Szlosarek, Ben Creelan, Thomas Sarkodie, Luke Nolan, Paul Taylor, Olga Olevsky, Federica Grosso, Diego Cortinovis, Meenali Chitnis, Amy Roy, David Gilligan, Hedy Kindler, Dionysis Papadatos-Pastos, Giovanni L. Ceresoli, Aaron Mansfield, Anne Tsao, Ken O’Byrne, Anna K. Nowak, Jeremy Steele, Michael Sheaff, Amanda Johnston, John Bomalaski, Marjorie Zauderer, Dean A. Fennell. Phase 2-3 trial of pegargiminase plus chemotherapy versus placebo plus chemotherapy in patients with non-epithelioid pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT007.

Mislocalization of TAR DNA binding protein 43 kDa (TARDBP, or TDP-43) is a principal pathological hallmark identified in cases of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As an RNA binding protein, TDP-43 serves in the nuclear compartment to repress non-conserved cryptic exons to ensure the normal transcriptome. Multiple lines of evidence from animal models and human studies support the view that loss of TDP-43 leads to neuron loss, independent of its cytosolic aggregation. However, the underlying pathogenic pathways driven by the loss-of-function mechanism are still poorly defined. We employed a genetic approach to determine the impact of TDP-43 loss in pyramidal neurons of the prefrontal cortex (PFC). Using a custom-built miniscope imaging system, we performed repetitive in vivo calcium imaging from freely behaving mice for up to 7 months. By comparing calcium activity in PFC pyramidal neurons between TDP-43 depleted and TDP-43 intact mice, we demonstrated remarkably increased numbers of pyramidal neurons exhibiting hyperactive calcium activity after short-term TDP-43 depletion, followed by rapid activity declines prior to neuron loss. Our results suggest aberrant neural activity driven by loss of TDP-43 as the pathogenic pathway at early stage in ALS and FTD.

Introduction: Chemotherapy remains the cornerstone in the management of solid organ malignancies (SOM) and hematological malignancies (HM). Although life-prolonging, it is not without cost, with heart failure and arrhythmia becoming increasingly recognised complications of treatment. Although there is significant overlap in the chemotherapeutic management of SOM and HM, epidemiological information on the differential prevalence of baseline cardiovascular risk factors and outcomes in these populations is scarce. Hypothesis: A differential cardiovascular risk profile and clinical course will be appreciated in patients with SOM and HM undergoing chemotherapy. Methods: Retrospective observational study design. Patients admitted to our institution undergoing chemotherapy for SOM (2014-2018) or HM (2012-2015) were reviewed. Baseline demographic and clinical data was collated and patients were followed for up to five years following chemotherapy for occurrence of major adverse cardiac events (MACE) defined as the development of new-onset heart failure or arrhythmia. Results: 545 hematology and 435 oncology patients with malignancy were assessed. Compared to those with HM, those treated for SOM had a poorer cardiovascular risk profile (table 1). At mean follow-up period of 22.8±17.8 months, no significant difference in the incidence of the composite endpoint (9.4% vs 9.0%, p=0.45) or its components was observed. Higher rates of anthracycline therapy was observed in patients with HM (100% vs 17%, p < 0.01), however its use did not have a differential effect on MACE (12% vs 9%, p=0.25). Conclusions: Compared to patients treated for HM, patients with SOM had a greater burden of cardiovascular risk factors and lower use of anthracycline chemotherapy. Despite this, MACE occurred at similar rates in both groups. The use of anthracyclines was not associated with the development of MACE, suggesting alternative pathways contributing to its development.

Introduction Pegargiminase (ADI-PEG 20; ADI) degrades arginine and potentiates pemetrexed (Pem) cytotoxicity in argininosuccinate synthetase 1 (ASS1)–deficient malignant pleural mesothelioma (MPM). We conducted a phase 1 dose-expansion study at the recommended phase 2 dose of ADI-PEG 20 with Pem and cisplatin (ADIPemCis), to further evaluate arginine-lowering therapy in ASS1–deficient MPM and explore the mechanisms of resistance. Methods A total of 32 patients with ASS1–deficient MPM (11 epithelioid; 10 biphasic;11 sarcomatoid) who were chemonaive received weekly intramuscular pegargiminase (36 mg/m2) with Pem (500 mg/m2) and cisplatin (75 mg/m2) intravenously, every 3 weeks (six cycles maximum). Maintenance pegargiminase was permitted until disease progression or withdrawal. Safety, pharmacodynamics, immunogenicity, and efficacy were determined. Biopsies were performed in progressing patients to explore the mechanisms of resistance to pegargiminase. Results The treatment was well tolerated. Most adverse events were of grade 1/2, whereas four nonhematologic grade 3/4 adverse events related to pegargiminase were reversible. Plasma arginine decreased whereas citrulline increased; this was maintained by 18 weeks of ADIPemCis therapy. The disease control rate in 31 assessed patients was 93.5% (n = 29 of 31; 95% confidence interval [CI]: 78.6%–99.2%), with a partial response rate of 35.5% (n = 11 of 31; 95% CI: 19.2%–54.6%). The median progression-free and overall survivals were 5.6 (95% CI: 4.0–6.0) and 10.1 (95% CI: 6.1–11.1) months, respectively. Progression biopsies on pegargiminase revealed a statistically significant influx of macrophages (n = 6; p = 0.0255) and patchy tumoral ASS1 reexpression (n = 2 of 6). In addition, we observed increased tumoral programmed death-ligand 1—an ADI-PEG 20 inducible gene—and the formation of CD3-positive T lymphocyte aggregates on disease progression (n = 2 of 5). Conclusions The dose expansion of ADIPemCis confirmed the high clinical activity and good tolerability in ASS1–deficient poor-prognosis mesothelioma, underpinning an ongoing phase 3 study (ClinicalTrials.gov NCT02709512). Notably, resistance to pegargiminase correlated with marked macrophage recruitment and—along with the tumor immune microenvironment—warrants further study to optimize arginine deprivation for the treatment of mesothelioma.

Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients with argininosuccinate synthetase 1 (ASS1)-deficient small-cell lung cancer (SCLC).Patients were enrolled into either a 'sensitive' disease cohort (≥ 90 days response to first-line chemotherapy) or a 'refractory' disease cohort (progression while on chemotherapy or 90 days afterwards or ≥ third-line treatment). Patients received weekly intramuscular pegargiminase, 320 IU/mBetween January 2011 and January 2014, 22 patients were enrolled: 9 in the sensitive disease cohort and 13 in the refractory disease cohort. At a pre-planned interim analysis, the best overall response observed was stable disease in 2 patients in each cohort (18.2%). Owing to the lack of response and slow accrual in the sensitive disease cohort, the study was terminated early. Pegargiminase treatment was well-tolerated with no unexpected adverse events or discontinuations.Although pegargiminase monotherapy in SCLC failed to meet its primary endpoint of RECIST-confirmed responses, more recent molecular stratification, including MYC status, may provide new opportunities moving forward.

2057 Background: ADI-PEG 20 exploits the different metabolic ability for synthesizing arginine (Arg) between normal and neoplastic cells to reduce tumor cell growth. Preclinical and clinical studies have shown that cancers which are either Arg auxotrophic, with silencing of argininosuccinate synthetase ( ASS1), or Arg non-auxotrophic, respond to ADI-PEG 20 monotherapy or ADI-PEG 20 combined with various chemotherapies, respectively. ADI-PEG 20 has shown efficacy as monotherapy in ASS1 negative mouse glioblastoma (GBM) models and the combination of ADI-PEG 20 with temozolomide (TMZ) and with radiation (RT) in both ASS1 negative and ASS1 positive mouse GBM models. Based on these rationales, ADI-PEG 20 was added to standard RT + TMZ in patients with newly diagnosed GBM. This is the first clinical trial combining ADI-PEG 20 with RT. Methods: This phase IB, open-label, single-arm, standard 3+3 dose escalation with a recommended phase 2 dose (RP2D) expansion study (NCT04587830) was initiated in June 2020. Weekly ADI-PEG 20 is added to concurrent RT + TMZ and to 6 cycles of adjuvant TMZ (Stupp protocol). ADI-PEG 20 could be continued for up to 2 years. RANO criteria are used to determine response by evaluating MRI at 1, 3 and 6 months after RT, and every 3 months thereafter. Major eligibility criteria are age 20-75 years with newly diagnosed, histologically confirmed GBM with Karnofsky performance status ≥ 60. Endpoints include safety, pharmacodynamics, immunogenicity, progression free survival (PFS) and overall survival (OS). Results: Cohorts 1 (18 mg/m2) and 2 (36 mg/m2) were completed without dose limiting toxicity (DLT). Enrollment to cohort 3 (RP2D phase, 36 mg/m2) is ongoing with 23/26 patients. The major adverse events (AEs) were fatigue (52%), constipation (39%) and neutrophil decrease (39%). Dermatologic or allergic reactions occurred in 12/23 (52%), and all were grade 1-2 except for anaphylactic shock in 1 and vasculitis/rash in 1. 22/23 are alive, with median PFS = 9.5 months. The first 6 study patients are all alive for at least 11 months, with the longest at 1.5 years. 10 are off treatment due to progressive disease in 6, severe AE in 2, consent withdrawal in 1, and medical decision in 1. Mean peripheral blood Arg levels were suppressed ( < 10uM) for 4-6 weeks in most subjects, with a reciprocal elevation of citrulline levels. Anti-ADI-PEG 20 antibodies tended to increase as peripheral Arg levels increased. Conclusions: The addition of ADI-PEG 20 to RT + TMX was safe, and no DLT was observed. The RP2D of ADI-PEG 20 was determined to be 36mg/m2. AEs were those typically seen with RT + TMZ, with perhaps an increase in rash reported with the addition of ADI-PEG 20. Anaphylaxis and vasculitis were seen (1 subject with each), and have been observed previously with ADI-PEG 20. The preliminary OS data are encouraging. A registration phase 2/3 trial of this triplet is being considered. Clinical trial information: NCT04587830.

Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) being much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aims at investigating the safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy, ADI-PEG 20. Nine patients were enrolled in this pilot study. The combination therapy was safe and tolerable with an absence of immune-related adverse events (irAE) of special interest, but with four of nine patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of the treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at the baseline in metastases.

Introduction R-mini-CHOP is an established standard of care in elderly patients with DLBCL, with a 2yr OS of 59% and PFS of 47% (Peyrade et al, Lancet Oncol 2011). The addition of ibrutinib to full dose R-CHOP in younger pts with DLBCL has efficacy, but significant toxicity limits the ability to complete therapy in pts ≥60 yrs (Younes et al, JCO 2019). We previously demonstrated the deliverability of ibrutinib with R-mini-CHOP in 80 pts ≥75yrs with DLBCL with a median average relative total dose of 97%; 77% of pts received 6 cycles of R-mini-CHOP despite SAEs in 62% (Verner et al, Haematol Oncol 2019). Here we present the primary efficacy endpoint and key secondary and exploratory endpoints. Methods This was a prospective, multicenter, single-arm, phase 2 study of patients aged ≥75yrs with newly diagnosed DLBCL. Pts received six 21-day cycles of ibrutinib 560mg/d and R-mini-CHOP (Rituximab 375mg/m 2, cyclophosphamide 400mg/m 2, doxorubicin 25mg/m 2, vincristine 1mg on day 1 & prednisone 40mg/m 2 or 100mg/d x 5) followed by an additional two 21-day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). The efficacy primary endpoint was 2yr OS. Sample size calculations were made using a one-sample two-sided approach to detect a 15% improvement on the fixed reference OS (59%) and PFS (47%) rates (Peyrade et al, Lancet Oncol 2011). Results Eighty pts were recruited from Nov 2015 to Dec 2018. One died prior to receiving treatment and is not included in the analysis. Median age was 82yrs (75-95); 51% female, 81% stage III/IV and 63% IPI 3-5: 47% had a CIRS-G score of ≥6 (range 0-17). On centralized immunohistochemistry (IHC), 57% (45/79) were non-Germinal Centre B cell-like (GCB) subtype; 43% (34/79) were GCB. At a data cut-off of 6June 21, median follow-up was 29.5 months (m) (0.2 to 66.3). Two-year OS was 68% (95% CI 55-77%), not differing significantly from the null hypothesis of 59% (p=0.10), (Figure 1A). Median OS was not reached (NR) (95% CI 34m to NR), and was longer in those with lower IPI (IPI 1-3: NR, IPI 4: 35m, IPI 5: 19m). Two-year PFS was 60% (95% CI 47-70%), significantly different from the reference 47% (p At least one adverse event (AE) occurred in 99% pts (78/79): 30% (24/79) grade 1-2, 64% (49/79) grade 3-4, and 6% (5/79) grade 5. Most common grade ≥3 AEs were lung infection (13%), other infections (11%), anemia (11%), febrile neutropenia (9%), thrombocytopenia (9%), and atrial fibrillation (8%). Serious AEs occurred in 67%: most commonly lung infection (11%), atrial fibrillation (9%), fever (9%), and other infection (9%). 12/14 pts with atrial fibrillation/flutter were new onset. Ibrutinib was temporarily ceased in 62% of patients, and permanently ceased in 25%, mostly due to adverse events. As previously reported, the overall response rate on an intention to treat basis was 57/80 (71%) (Verner et al, ASH 2019). Response rates did not differ by cell of origin (COO) (ORR: non-GCB 76%, GCB 68% p=0.44). When recorded, pt's EORTC-QLQ-C30 global health status significantly improved between screening [n=78; mean (SD) 58(25)], end of treatment [n=57; 63(23)] and 18mo post-treatment [n=29; 74(19)] p=0.007. Significant reductions in fatigue, nausea and vomiting, pain, insomnia, appetite loss, constipation and diarrhea were also observed in respondents. There was no impact of CIRS-G score on disease response rate or risk of death. Conclusion The addition of ibrutinib to R-mini-CHOP was deliverable and improved 2-yr PFS compared to R-mini-CHOP alone. However, while there was a trend towards improvement in 2-yr OS, a target 15% increase was not achieved in this small sample size. Despite considerable and not unexpected toxicity in this elderly cohort, the QOL and functional improvements in survivors are also promising. These data support further study of the addition of ibrutinib to R-mini-CHOP in elderly patients with DLBCL. Figure 1 Figure 1. Disclosures Verner: Janssen-Cilag Pty Ltd: Research Funding. Hawkes: Merck KgA: Research Funding; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Specialised Therapeutics: Consultancy; Antigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee: Roche: Honoraria; BeiGene: Membership on an entity's Board of Directors or advisory committees. Cheah: BMS: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ascentage Pharma: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding. Purtill: Novartis: Honoraria; Gilead: Honoraria; BMS Celgene: Honoraria. Enjeti: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Honoraria; Sanofi: Honoraria; Astra Zeneca: Honoraria. Curnow: Bayer: Consultancy, Research Funding; Pfizer/BMS: Consultancy, Honoraria; Mylan: Consultancy; Norgine: Consultancy, Honoraria. Butcher: WriteSource: Current Employment, Other: Medical writing for Pharma companies. Not pertinent to this abstract for which author is study Statisticiam. Trotman: JANSSEN: Research Funding; TAKEDA: Research Funding; BMS: Research Funding; PCYC: Research Funding; roche: Research Funding; beigene: Research Funding. OffLabel Disclosure: Ibrutinib is not approved for use in DLBCL

Background: Adaptive resistance mechanisms leading to treatment failure have been identified in older patients receiving venetoclax (VEN) in combination with either azacitidine or low dose cytarabine (LDAC) as frontline therapy for acute myeloid leukemia (AML). These include the expansion or secondary emergence of kinase activating mutations, including FLT3-ITD in patients with non-adverse karyotype (NON-ADV), as well as TP53 mutations among patients with adverse karyotype (ADV)(DiNardo & Tiong et al, Blood 2020). INTERVENE is a phase 2 study evaluating the safety and efficacy of the "risk-stratified" addition of a novel third agent to VEN-LDAC, delivered in tandem to LDAC to minimize the risk of myelotoxicity (Figure 1A). To mitigate VEN resistance associated with activated kinases in NON-ADV risk AML, midostaurin (MIDO), a FLT3/multi-kinase inhibitor, was incorporated in combination with VEN. To address VEN resistance associated with TP53 defects in ADV risk AML, a HDAC inhibitor pracinostat (PRAN) was incorporated in accordance with pre-clinical studies suggesting synergistic induction of TP53 independent cell death with VEN plus HDAC inhibition (Salmon et al, ASH 2018). We hereby report the results of the dose-finding safety run-in phase of the study. Methods: Eligibility: Patients with treatment naïve AML (excluding APL), aged ≥60 years and unfit for intensive chemotherapy were included. Prior hypomethylating agents for antecedent myeloid neoplasms were permitted with a 14-day washout. Patients were stratified according to cytogenetic risk, as per Medical Research Council 2010 criteria. Treatment: VEN D1-28 (with dose ramp-up in cycle 1) was combined with LDAC (20mg/m 2 SC D1-10), with the third agent starting after/on the last day of LDAC (Fig 1A). Each cycle was 28 days. In the NON-ADV stratum (VEN-LDAC-MIDO), 2 dose levels were explored: (L1) VEN 400mg + LDAC + MIDO 50mg BD D11-28; (L2) VEN 600mg + LDAC + MIDO 50mg. In the ADV stratum (VEN-LDAC-PRAN), 3 dose levels were tested: (L1) VEN 400mg + LDAC + PRAN 45mg starting D10 and given 3x/week orally for a total of 9 doses; (L2) VEN 600mg + LDAC + PRAN 45mg; (L3) VEN 600mg + LDAC + PRAN 60mg. Azole antifungals were prohibited in cycle 1 but allowed from cycle 2 with VEN dose modification. Endpoints (safety run-in): Primary: occurrence of dose-limiting toxicities (DLT) during cycle 1 and determination of recommended phase 2 doses (RP2D) using a Bayesian Logistic Regression Model. Secondary: Preliminary response rates. Molecular studies: Next generation sequencing using a custom 48-gene Roche KAPA HyperCapture myeloid panel and FLT3-ITD targeted amplicon sequencing were performed on baseline bone marrow samples. First patient enrolled: 7SEP2020. Data cut-off: 29JUN2021. Results: 32 patients were enrolled: 18 in NON-ADV and 14 in ADV strata, respectively. Two patients in the NON-ADV stratum withdrew within the first 7 days due to non-therapy related reasons (1=personal, 1=incidental lung lesion) and were not DLT/response evaluable. Median age was 77 years (68-87; 69% ≥75 years). 43.8% (14/32) had secondary/therapy related AML. Although gastrointestinal adverse events (AE) during cycle 1 were more common in VEN-LDAC-PRAN arm with nausea (57 vs 17%), vomiting (36% vs 6%) and diarrhea (50% vs 22%), grade 3+ toxicities were uncommon (0-7%)(Table 2). Occurrence of febrile neutropenia was similar between the two arms. 30-day mortality was 0% and 14% (2/14: 1=infection, 1=disease progression) for NON-ADV and ADV strata, respectively. No DLTs were observed in either stratum across all dose levels, thus the RP2D was the highest dose level explored for both triplet combinations. The intention-to-treat overall response rate CR+CRi+CRh was 72.2% (13/18) in the NON-ADV arm and 57.1% (8/14) in ADV arm. The expanded response rate including PR and MLFS was 77.8% (14/18) and 71.4% (10/14) in the NON-ADV and ADV strata, respectively. Median time to best response was 1 cycle (range 1-6). Updated response and survival outcomes will be presented at the meeting. Conclusion: The addition of MIDO or PRAN to VEN-LDAC was tolerable in older/unfit patients with treatment naïve AML. Preliminary efficacy with this risk-stratified approach compared favorably to prior studies with VEN-LDAC alone (Wei et al Blood 2020: CR+CRi 56% in NON-ADV, 28% in ADV). The randomized phase 2 part of this tandem triplet strategy with the goal of preventing adaptive resistance is underway. Figure 1 Figure 1. Disclosures Chua: Abbvie: Other: Conference travel and accommodation . Reynolds: Alcon: Current equity holder in publicly-traded company; Abbvie: Research Funding; Novartis AG: Current equity holder in publicly-traded company. Enjeti: Astra Zeneca: Honoraria; Sanofi: Honoraria; AbbVie: Honoraria; Roche: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hiwase: AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Marlton: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Queensland Health: Current Employment; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Grove: Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cooney: Amgen: Other: Travel, accommodation, expenses ; Roche: Other: Travel, accommodation, expenses ; Novartis: Other: Online conference registration . Beligaswatte: Astellas: Membership on an entity's Board of Directors or advisory committees. Anstee: Walter and Eliza Hall Institute: Patents & Royalties: Dr Anstee was a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax. Perera: Abbvie: Speakers Bureau; BMS: Speakers Bureau. Ritchie: Takeda: Research Funding; BMS: Research Funding; Novartis: Honoraria; CRISPR Therapeutics: Research Funding; Amgen Inc: Honoraria, Research Funding; CSL: Honoraria. Wei: Genentech: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: This presentation will focus on the ALLG INTERVENE clinical trial combining venetoclax+LDAC+midostaurin or venetoclax+LDAC+pracinostat. Although venetoclax and midostaurin are individually FDA-approved in some indications, the combinations examined in this clinical trial have not been approved by FDA.

BACKGROUND ADI-PEG 20 is a pegylated form of the arginine-depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI-PEG 20 selectively targets malignant cells, which lack ASS1. METHODS A single-arm, nonrandomized, open-label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose-escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) for 3 of 4 weeks and intramuscular ADI-PEG 20 at 18 mg/m2 weekly (cohort 1) or at 36 mg/m2 weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI-PEG 20 in combination with nab-paclitaxel and gemcitabine. RESULTS Eighteen patients were enrolled. No dose-limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI-PEG 20 was 36 mg/m2 weekly in combination with standard-dose gemcitabine and nab-paclitaxel. The overall response rate among patients treated at the RP2D in the first-line setting was 45.5% (5 of 11).The median progression-free survival time for these patients treated at the RP2D was 6.1 months (95% confidence interval, 5.3-11.2 months), and the median overall survival time was 11.3 months (95% confidence interval, 6.7 months to not reached). CONCLUSIONS ADI-PEG 20 was well tolerated in combination with gemcitabine and nab-paclitaxel. Activity was observed in previously treated and untreated patients with advanced pancreatic cancer and in patients with ASS1-deficient and -proficient tumors. Cancer 2017. © 2017 American Cancer Society.

Background Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the most common indolent and aggressive B-cell lymphomas, respectively. Although the combination of anti-CD20 therapies rituximab (R) or obinutuzumab (G) with chemotherapy has led to improved patient (pt) outcomes, R/R disease remains a challenge, with a high unmet need. The potent and selective MDM2 antagonist idasanutlin (idasa) activates the p53 pathway, leading to anti-tumor activity. The BCL-2 inhibitor venetoclax (ven) has shown clinical activity in hematologic diseases including R/R NHL. In a Phase Ib/II study (NCT02624986), idasa could be safely combined in a doublet treatment (tx) regimen with R or G in R/R FL or DLBCL pts. Here we report the tolerability, safety and preliminary efficacy of the triplet tx regimen of idasa plus ven and G in R/R NHL pts. Methods BH39147 (NCT03135262) was an open-label, multicenter, non-randomized, Phase Ib/II study with a dose-escalation phase followed by an expansion phase. The dose-escalation phase evaluated idasa and ven combined with G in all pts (FL and DLBCL) until the maximum tolerated dose (MTD) was reached. Idasa and ven dose escalations started at 100 and 200 mg PO QD, respectively, on days 1-5 of each 28-day cycle (safety cohort); in subsequent cohorts, ven was given on days 1-10 of each cycle. G was given at a fixed dose of 1000 mg IV on days 1, 8 and 15 of cycle 1 and day 1 of subsequent cycles. Pts received 6 cycles of induction tx. The primary objective of the dose-escalation phase was to determine recommended Phase II doses for idasa and ven in combination with G. Efficacy objectives included evaluating the complete response (CR) rate at the end of induction (EOI) per investigator based on PET-CT. The trial was stopped prior to initiation of the expansion phase; results are presented for the dose-escalation cohorts evaluating idasa plus ven and G. Results Of the 29 pts enrolled, 14 each had a diagnosis of FL or DLBCL at study entry, and 1 had an unknown diagnosis at study entry that was later confirmed as FL. The median age was 70 y (range, 25-82), 58.6% of pts were male, and 67.9% had an ECOG PS of 1 or 2. The majority of pts had advanced-stage disease at enrollment, with 58.6% having received ≥ 3 lines of prior anti-lymphoma therapy; 17.2% and 24.1% of pts had received 1 and 2 prior lines of tx, respectively. Median (range) tx durations during induction were 1.3 mo (0-6) for idasa, 1.5 mo (0-7) for ven and 1.5 mo (0-6) for G; post-induction median (range) tx durations (n = 4) were 3.8 mo (0-4), 3.8 mo (0-4) and 8.4 mo (0-11), respectively. The safety-evaluable population was composed of 29 pts. Grade 3/4 adverse events (AEs) occurred in 86.2% of pts, with neutropenia (79.3%), thrombocytopenia (62.1%), leukopenia (27.6%) and anemia (20.7%) as the most common. No Grade 5 AEs were reported. Serious AEs occurred in 48.3% of pts and were most commonly neutropenia (10.3%). AEs led to treatment discontinuation in 41.4% of pts, with thrombocytopenia (17.2%) and neutropenia (13.8%) being the most common. AEs related to idasa, ven and G were reported in 86.2%, 89.7% and 79.3% of pts, respectively. Dose-limiting toxicities were reported in 4 pts (13.8%): neutropenia (n = 3; 10.3%), hyperbilirubinemia (n = 1; 3.4%) and transaminitis (n = 1; 3.4%). The MTD for idasa was determined to be 150 mg in combination with 200-mg ven and G and 100 mg in combination with 400-mg ven and G. Preliminary efficacy data are shown in the table. Among all pts, 20.7% (FL, n = 5; DLBCL, n = 1) had a CR at EOI per investigator (PET-CT) based on modified Lugano 2014 criteria. Per investigator based on Lugano 2014 criteria, the CR rate at EOI (CT) was 13.8% (FL, n = 3; DLBCL, n = 1), and the complete metabolic response rate at EOI (PET-CT) was 24.1% (FL, n = 6; DLBCL, n = 1). Conclusions This study successfully showed the combinability of idasa and ven with an anti-CD20 agent. MTDs were determined for idasa and ven in combination with G in FL and DLBCL pts. No new safety signals related to any of the study drugs were identified, and the observed safety profiles were consistent with those of each individual study drug. While the combination is feasible and promising, other agents and approaches in the field make this combination less likely to proceed further. As a consequence, this trial has been discontinued following the dose-escalation/proof-of-concept phase to focus on new tx combinations. Figure Disclosures Kamdar: Roche:Research Funding.Augustson:Roche:Other: Support of parent study and funding of editorial support.Edwards:Roche:Other: Support of parent study and funding of editorial support.Hertzberg:Roche:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support;Gilead:Membership on an entity's Board of Directors or advisory committees;MSD:Membership on an entity's Board of Directors or advisory committees;Abbvie:Honoraria;BMS:Honoraria;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees.Johnston:Roche:Other: Support of parent study and funding of editorial support.Kim:Alexion Pharmaceuticals Inc.:Honoraria, Research Funding.Kroschinsky:Riemsser:Research Funding;Roche:Consultancy, Honoraria, Other: Support of parent study and funding of editorial support;BMS/Celgene:Consultancy, Honoraria;Sandoz:Research Funding;Gilead:Consultancy.Smith:TG Therapeutics:Consultancy, Research Funding;Genentech/Roche:Consultancy, Other: Support of parent study and funding of editorial support, Research Funding;BMS:Consultancy;Karyopharm:Consultancy, Research Funding;FortySeven:Research Funding;Pharmacyclics:Research Funding;Acerta:Research Funding;Janssen:Consultancy;Celgene:Consultancy, Research Funding.Stevens:Amgen, MorphoSys:Consultancy.Monnet:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Zhao:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Nouet:Roche:Current Employment, Other: Support of parent study and funding of editorial support.Marinova:Roche:Current Employment, Other: Support of parent study and funding of editorial support.

Objective: Cardiac catheterization procedures provide tremendous benefits to modern healthcare and the benefit derived by the patient should far outweigh the radiation risk associated with a properly optimized procedure. With increasing utilization of such procedures, there is growing concern regarding the magnitude and variations of dose to patients associated with procedure complexity and techniques parameters. Therefore, this study investigated radiation dose to patients from six cardiac catheterization procedures at our facility and suggest possible initial dose values for benchmark for patient radiation dose from these procedures. This initial benchmark data will be used for clinical radiation dose management which is essential for assessing the impact of any quality improvement initiatives in the cardiac catheterization laboratory. Methods: We retrospectively analyzed the dose parameters of 1000 patients who underwent various cardiac catheterization procedures: left heart catheterization (LH), percutaneous coronary intervention (PCI), complex PCI, LH with complex PCI, LH with PCI and cardiac resynchronization therapy (CRT) pacemaker in our cardiac catheterization laboratories. Patient’s clinical radiation dose data [kerma–area–product (KAP) and air-kerma at the interventional reference point (Ka,r)] and technique parameters (fluoroscopy time, tube potential, current, pulse width and number of cine images) along with demographic information (age, height and weight) were collected from the hospital’s RIS (Synapse), Sensis/Syngo Dynamics and Siemens Sensis Stats Manager electronic database. Statistical analysis was performed with the IBM SPSS Modeler v. 18.1 software. Results: The overall patient median age was 67.0 (range: 26.0–97.0) years and the median body mass index (BMI) was 28.8 (range: 15.9–61.7) kg/m2 . The median KAP for the LH, PCI, LH with complex PCI, complex PCI, LH with PCI and CRT-pacemaker procedures are 44.4 (4.1–203.2), 80.2 (18.9–208.5), 83.7 (48.0–246.1), 113.8 (60.9–284.5), 91.7 (6.0–426.0) and 51.1 (7.0–175.9) Gy-cm2 . The median Ka,r for the LH, PCI, LH with complex PCI, complex PCI, LH with PCI and CRT-pacemaker procedures are 701.0 (35.3–3794.0), 1384.7 (291.7–4021.8), 1607.0 (883.5–4448.3), 2260.2 (867.4–5311.9), 1589.3 (100.2–7237.4) and 463.8 (67.7–1695.9) mGy respectively. Conclusion: We have analyzed patient radiation doses from six commonly used procedures in our cardiac catheterization laboratories and suggested possible initial values for benchmark from these procedures for the fluoroscopy time, KAP and air-kerma at the interventional reference point based on our current practices. Our data compare well with published values reported in the literature by investigators who have also studied patient doses and established benchmark dose levels for their facilities. Procedure-specific benchmark dose data for various groups of patients can provide the motivation for monitoring practices to promote improvements in patient radiation dose optimization in the cardiac catheterization laboratories. Advances in knowledge: We have investigated local patients’ radiation doses and established benchmark radiation data which are essential for assessing the impact of any quality improvement initiatives for radiation dose optimization.

11508 Background: Soft tissue sarcoma (STS) is dependent on extracellular arginine as it often lacks expression of argininosuccinate synthase 1 (ASS1), the urea cycle enzyme needed to produce intracellular arginine. PEGylated arginine deiminase (ADI-PEG 20) is an extracellular arginine-degrading enzyme that causes ASS1 deficient tumors to enter the starvation state. Preclinical data demonstrated that addition of docetaxel (D) with ADI-PEG20 upregulates expression of the transporter for gemcitabine (G), overcoming transporter level resistance, and causing increased cell death. In vivo modeling demonstrated that the combination of ADI-PEG20 with G+D was superior to G+D alone. Therefore, we performed a phase 2 trial testing the addition of ADI-PEG20 to G+D. Methods: We performed an investigator-initiated, phase 2, multicenter, multi-arm clinical trial of ADI-PEG20 with G (90minute infusion)+D in STS, Ewing’s, osteosarcoma and small cell lung cancer. We are reporting Arm A, the STS arm. Eligible patients had STS that would be standardly treated with G+D that had progressed on at least one prior line of therapy with measurable disease by RECIST1.1 and had adequate organ function Based on a historic median PFS of 6.2 months for G+D, we targeted to enroll N = 75 patients in cohort A to detect a 2.8 month improvement with 80% power at a 5% alpha level. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), clinical benefit rate (CBR), safety, tolerability, cancer related mortality, and correlation with ASS1 expression by IHC. We evaluated PFS by Kaplan-Meier method and estimated overall response rate (ORR). Results: 75 patients were treated and deemed evaluable. The trial underwent two dose reductions by the data safety monitoring board due to prolonged neutropenia and thrombocytopenia preventing the use of day 8 G+D, consistent with preclinical mechanism of action data showing that ADI-PEG 20+D enhanced G uptake. Originally, the G dose was 900mg/m2 reduced first to 750mg/m2 then to 600mg/m2. D was dose reduced at the time of the second dose reduction from 75mg/m2 to 60mg/m2. ADI-PEG20 was given at a fixed intramuscular dose (36 mg/m2) weekly. The need for two dose reductions affected the PFS. The PFS/OS (months) were for the 600mg/m2 group (n = 31) was 6.0/N.D., leiomyosarcoma (LMS) (N = 33) 7.2/22.5, liposarcoma 5.1/17.4, and other (N = 36) 2.8/15.0. Responses were 8% complete (6/75) (3 LMS, 1 synovial and 2 angiosarcoma), 17% partial (13/75), and 43% stable disease (32/75), for an ORR of 25% (19/75) and CBR of 68% (51/75). There was a trend for ASS1 negative tumors to benefit more than ASS1 positive tumors. Conclusions: The combination of ADI-PEG20 with G+D can be safely and effectively given at a dose of 600mg/m2 G and 60mg/m2 D. Future randomized trials of ADI-PEG20 with G+D are planned. Clinical trial information: NCT03449901.

Purpose: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. Patients and Methods: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16–06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy. Results: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti–ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5–20.8) and overall survival was 6.3 months (95% CI, 1.8–9.7). Conclusions: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme - arginine deiminase - conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and Patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives. Results: 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials (NCT 01287585).