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e13025 Background: H3B-6545, a highly Selective ERα Covalent Antagonist (SERCA), inactivates both wild-type and mutant ERα by targeting cysteine 530 and enforcing a unique antagonist conformation. At the dose of 450 mg daily, H3B-6545 has a manageable safety profile and demonstrated preliminary single-agent antitumor activity in heavily pretreated ER+, HER2- mBC patients (Hamilton et al, San Antonio Breast Cancer Symposium, 2020). Methods: The study evaluates the safety, pharmacokinetics (PK), and efficacy of H3B-6545 in combination with palbociclib in patients with ER+, HER2- metastatic breast cancer (MBC). The escalation phase enrolls patients with 2 or more prior therapies in the metastatic setting. Up to one prior chemotherapy and up to one prior CDK4/6 inhibitor were allowed. Results: As of January 31, 2021, 10 patients were enrolled; 7 in Cohort 1 (H3B-6545 300 mg QD and palbociclib 100 mg QD) and 3 in Cohort 2 (H3B-6545 300 mg QD and palbociclib 125 mg QD). One patient in Cohort 1 was not evaluable for dose limiting toxicity (DLT) assessment and no DLT was observed in the 6 evaluable patients. One patient discontinued study treatment because of progression and no patients discontinued study treatment due to adverse events (AE). Grade 3 or 4 neutropenia and thrombocytopenia were observed in 4 patients and 1 patient, respectively. One patient had grade 3 hypercalcemia, generalized muscle weakness, hypophosphatemia, fall, and anemia and one patient had grade 3 lipase increase. Four patients had grade 1 bradycardia or sinus bradycardia (asymptomatic) 1 patient had grade 2 sinus bradycardia (symptomatic, no intervention required). Preliminary PK analysis suggested no clinically relevant drug-drug interactions between H3B-6545 and palbociclib, to be confirmed with data from additional cohorts. Recruitment is currently ongoing in Cohort 2. Updated results will be presented. Conclusions: H3B-6545, in combination with palbociclib, was well-tolerated. Clinical trial information: NCT04288089.

1018 Background: H3B-6545, a selective, small molecule covalent antagonist of ERα demonstrated preclinical and preliminary clinical activity against ER+ breast cancer (Hamilton EP, SABCS, 2020). This study evaluated the activity and tolerability of H3B-6545 in patients (pts) with metastatic ER+, HER2-, breast cancer refractory to endocrine therapy. Methods: Patients received H3B-6545 once daily at the recommended phase II dose of 450 mg. The primary objective of the phase II is to estimate the objective response rate (ORR), progression-free survival (PFS), clinical benefit rate (CBR) and secondary objectives include safety. Results: 83 pts were treated with 450 mg in the phase II part of the trial. Additionally, 11 pts were treated with 450 mg in the phase I part of the trial and are included in this analysis. Median age was 62 years (range: 38 to 87 years), 81% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 8). Prior CDK4/6 inhibitors, aromatase inhibitors, fulvestrant, and chemotherapy were received by 85%, 80%, 72%, and 50% of the pts, respectively. 58 pts (62%) had detectable ESR1 mutations in liquid biopsies, including 10 (11%) and 19 pts (20%) who had clonal Y537S and clonal D538G mutation, respectively. As of January 29, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), fatigue (16%), nausea (17%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (38%), hemoglobin decrease (37%), bilirubin increase (12%), ALT increase (14%), AST increase (13%), and creatinine increase (11%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 34% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in the table below. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, CDK4/6 inhibitor, and/or chemotherapy in the metastatic setting. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was observed in pts with ESR1 mutations. Clinical trial information: NCT03250676 .[Table: see text]

e13043 Background: P90 ribosomal S6 kinase (RSK) is an actionable molecular target against metastatic triple negative breast cancer (mTNBC). RSK is a major convergence point in the integral TNBC signaling pathways, MAPK and PDK-1. PMD-026 is a first-in-class oral RSK inhibitor with high selectivity. The dose escalation portion of this study established the RP2D of PMD-026 as 200 mg Q12. PMD-026 demonstrated good plasma exposure following oral dosing, with a T1/2 of ̃ 6 h (range 4-8 h), and achieved the targeted preclinical efficacious concentrations using a Q12h dosing schedule. PMD-026 also demonstrated a tolerable safety profile and initial signs of efficacy in patients with metastatic breast cancer. The intensity of RSK2 activation ranged from an H Score of 110-268 based on a CLIA companion immunohistochemistry assay. We present initial data from the expansion cohort. Methods: The primary aim of this single-arm, open-label, first-in-human phase 1/1b study is to evaluate the safety of single agent PMD-026 in patients with mTNBC. Secondary endpoints are clinical activity, pharmacokinetics, and correlative biomarker expression on tumor specimens. Patients are dosed at 200 mg twice daily in 21-day cycles. Eligible patients have measurable disease as per RECIST v1.1 and have had disease progression on or after standard of care treatment. Tumor tissue is assessed to retrospectively correlate RSK2 activity by immunohistochemistry (IHC) with clinical outcomes. Pharmacokinetics are assessed along with a food effect (sub-study with n=12). In addition, a pharmacodynamic marker, YB-1 phosphorylation, is being explored in peripheral blood mononuclear cells before and during treatment. Results: As of February 16, 2021, 7 patients with mTNBC (median age 62 years, range 33-74) have been enrolled in the phase 1b Expansion (median of 7 prior lines of therapy). Notable prior therapies in the phase 1b include sacituzumab govitecan (n=4) and atezolizumab/nab-paclitaxel (n=1). Patients in escalation and expansion treated with the RP2D had median progression free survival of 30 vs 99 days for low vs high RSK2 expression, respectively. This cut-off will be further evaluated in the expansion phase of the study. Conclusions: Updated safety, clinical activity, pharmacokinetic, and biomarker analyses will be presented. Target accrual for phase 1b Expansion is a minimum of 20 patients with mTNBC. Clinical trial information: NCT04115306.

A Phase I study of A166, a Novel Anti-HER2 Antibody-Drug Conjugate (ADC), in Patients with Locally Advanced/Metastatic Solid Tumors. Purpose: A166 is an Antibody Drug Conjugate (ADC) targeting HER2-expressing cancer cells, aiming for post trastuzumab/TDM1 population and patients with HER2 expressing cancers not commonly treated with trastuzumab and TDM1. The antibody has the same amino acid sequence as trastuzumab, and it is designed to provide uniform distribution of payload molecules, using an innovative antibody-drug linker and duostatin-5 (an MMAF derivative) as payload. This ongoing phase I, open-label, first-in-human study is evaluating the safety, pharmacokinetics (PK), and dose-limiting toxicities (DLT) of A166 to determine the Maximum-Tolerated Dose (MTD) and/or recommended phase II dose (RP2D). Methods: Patients with advance solid tumors received escalating doses of A166 (0.3, 1.2, 3.6, and 4.8 mg/kg), administered intravenously (IV) every three weeks. Patients must have had documented HER2 positivity defined as positive, or amplified on in situ hybridization (ISH) or next-generation sequencing (NGS), or HER2 expression, defined as at least 1+ by validated immunohistochemistry (IHC) test or an activating HER2 mutation. Dose escalations were guided by a Bayesian logistic regression model (BLRM). Assessments include archival tumor molecular status, PK, and efficacy by Response Evaluation Criteria in Solid Tumors (RECIST). Results: 23 subjects [median age 68 (range 50-83), 17 female, 6 male, PS 0-1], have been treated. All patients had metastatic disease: 7 breast, 7 GC/GEJ/EC; 4 CRC, 5 other (lacrimal gland, vulvar, bladder, NSCLC, and ovarian). HER2 expression was available for all 23 patients: 12 (3+), 2 (2+ and amplified), 7 (amplified), 1 (1+), and 1 (HER2 mutated), and most had received previous HER2 targeted therapies (1-7 lines). No significant > Grade 3 AEs at doses below 3.6 mg/kg have been observed. Based on safety and efficacy outcomes, dose levels (DLs) 3.6 and 4.8 mg/kg were expanded to a total of 7 and 8 patients respectively. In these two cohorts, 4 patients experienced grade 2 ophthalmic toxicities involving the ocular surface (3 keratitis, 1 blurred vision), and 2 had Grade 3 keratitis. Treatment was discontinued (n=3) or delayed (n=3), and patients were treated with topical steroids and aggressive lubrication. All patients have resolved/resolving status of the ophthalmic toxicities, with a duration from onset to recovery/improvement of symptoms of 2-3 weeks. Other common drug-related and reversible Grade 1-2 AEs include blurry vision (n=4), peripheral neuropathy (n=3), anemia (n=2), leukopenia (n=2), thrombocytopenia (n=2). No cardiac or liver toxicities have been noted. Preliminary response assessment found that efficacy is evident at DL 3.6 and 4.8 mg/kg. Of 8 evaluable patients at 3.6-4.8 DL, 4/8 had PR, and 6/8 had DCR. Among PRs, 3 had prior anti-HER2 therapies, including 2/3 with prior TDM1. Conclusion: A166 has been well tolerated and shows promising anti-tumor activity in patients with heavily pre-treated HER2-positive cancers. The ophthalmic AEs have been reversible and manageable with supportive management. A detailed regimen for early diagnosis and intervention has been developed to further investigate the management of these toxicities in future cohorts, and three additional dose levels (6.0, 7.2, 8.4 mg/kg) will be added to the escalation phase. Citation Format: Diana M Lopez, Minal Barve, Judy Wang, Andrea J. Bullock, Eirini Pectasides, Ulka Vaishampayan, Alexander I. Spira, Susanna Ulahannan, Amita Patnaik, Rachel E. Sanborn, Dragan Cicic, Qiuqing Ang, Gregory Bergonio, Jordi Rodon Ahnert. A phase I study of A166, a novel anti-HER2 antibody-drug conjugate (ADC), in patients with locally advanced/metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B005. doi:10.1158/1535-7163.TARG-19-B005

3098 Background: Aurora kinase B (AURKB) represents a potential target for therapy in solid and hematological malignancies. AURKB inhibitor AZD1152 (barasertib) was previously investigated in solid tumor pts in a phase I setting. AZD2811-nanoparticle (np) is a novel, encapsulated slow release AURKB inhibitor offering several advantages over AZD1152 (Ashton S et al., Sci Transl Med 2016). We report the completed dose-escalation safety, pharmacokinetics (PK), preliminary activity and defined maximum tolerated dose (MTD) of AZD2811-np in pts with advanced solid tumors (NCT02579226). Methods: Adult pts with advanced solid tumors received AZD2811-np IV on Day 1 (D1) and 4 (D4) Q4 week (wk) in six cohorts 15-200 mg/infusion without the use of g-csf in cycle 1. D1 Q4wk and Q3wk schedules were investigated up to 600 mg/infusion (including cohorts with mandatory g-csf prophylaxis on day 8). A standard 3+3 design was used. PK was assessed in cycle 1. Results: 50 pts were recruited into 12 cohorts. D1, D4 Q4wk schedule: 24 pts (15, 25,38, 50, 100 mg/infusion (n=3/cohort), 200 mg/infusion (n=9)). All cohorts were tolerated. Transient grade 4 neutropenia was observed in 7/9 pts at 200 mg/infusion, including 1 DLT (gr4 > 7 days) D1 Q4wk: 200 mg(n=3) was tolerated. D1 Q3wk: 23 pts were evaluated (200/400 mg (n=3,7), and 400/600/500 mg with mandatory g-csf (n=3/5/6)). 400 mg without g-csf was not tolerated (1 gr3 mucosal inflammation & 1 gr4 neutropenia > 7 days). 600 mg with g-csf was not tolerated (gr3 febrile neutropenia & gr3 fatigue). 25/50 pts experienced AE ≥gr 3 (21 considered AZD2811-np-related, 19 neutropenia-related, no deaths within-DLT period). AZD2811-np caused transient gr1/2 fatigue, nausea, diarrhoea and mucosal inflammation. AZD2811 total blood PK appears dose proportional with a t1/2 of 30-50 hours irrespective of schedule. Released AZD2811 concentrations ~1% of total. 14 pts (28%) had disease stabilisation. 1 prostate ca. pt had a confirmed partial response (PR) (continued tx to 451 days). Conclusions: The MTD for AZD2811-np is 500 mg D1 Q3wk. AZD2811-np is now being investigated in a small cell lung cancer expansion. Clinical trial information: NCT02579226.

1059 Background: H3B-6545 inactivates both wild-type and mutant ERα by targeting cysteine 530 and enforcing a unique antagonist conformation. Methods: Women with locally advanced or metastatic HR+ BC are treated (tx) with H3B-6545 administered once daily orally over a 28 day cycle after progression on at least one hormonal therapy and at least one additional therapy/regimen. Dose escalation uses a 3+3 design with the option to backfill previously cleared doses and allows for intrapatient dose escalation. This phase 1 explores the safety, pharmacokinetics and pharmacodynamics of H3B-6545 in women with HR+ BC to identify the recommended Phase 2 dose. Results: As of 10-Dec-2018, 32 pts have been tx with H3B-6545 at doses of 100 to 450 mg/day; 97% had prior tx with a CDK4/6 inhibitor and 56% had received ≥3 lines of prior anti-cancer therapy. No dose-limiting toxicities and only one Grade 3 treatment related adverse event (TRAE) have been observed (lymphocyte count decrease). The most common (≥10%) TRAEs include asymptomatic sinus bradycardia, diarrhea, nausea, fatigue, anemia, decreased appetite, and hot flush. H3B-6545 was rapidly absorbed with a tmax of 2-4 h. Plasma concentration increased with dose from 100 to 450 mg, and was similar on C1D1 and C1D15. Consistent with the H3B-6545 mechanism of action and preclinical data, H3B-6545 inhibits ER target gene expression and shows a 50% decrease in Ki67 levels across all dose levels post-tx. ESR1 (60%) and PIK3CA (34%) mutations were detected in plasma at baseline and changes in mutant allele frequencies show correlation in response to tx. Stable disease was observed in 15 pts (47%) and 34% of pts completed at least 6 months of tx. Partial responses (PRs) were observed in 3 pts: 1 pt (mutant) received 2 prior lines of therapy and 2 pts (1 mutant and 1 wild-type) received >5 prior lines of therapy including fulvestrant and capecitabine; all 3 pts received a prior CDK4/6 inhibitor. Conclusions: H3B-6545 has been well-tolerated up to the 450 mg dose level with early signs of single-agent anti-tumor activity in a post CDK4/6 setting. Dose escalation continues in pts with advanced HR+ BC. Clinical trial information: NCT03250676.

Colorectal cancer (CRC) remains one of the commonest types of cancer in the USA. Effective treatment and potential curative resection is dependent on early detection, prior to the development of distant metastases. Radiologic and endoscopic evaluations are operator-dependent and limited by macroscopic detection when the relative cellular tumor burden is already high. Also, use of serum biomarkers such as carcinoembryonic antigen may not correlate with the extent of disease involvement. Circulating tumor cells (CTCs) continue be a prominent area of investigation, despite having been described first by Ashworth in 1869. As methods for detection expand and improve, CRC is increasingly characterized by the properties of CTCs and tumor-associated cellular elements (TACEs), such as circulating tumor DNA, cell-free DNA, and microRNA. This review serves to highlight the clinical implications of CRC CTCs and TACEs for prognostication, monitoring for disease recurrence, and response to therapy.

2579Background: CHK1 is a key kinase for DNA replication and repair. Prexasertib, a CHK1 inhibitor, enhanced the nonclinical activity of cisplatin and is predicted to potentiate the clinical activi...

3086Background: Agenus AGEN2034 is a fully-human IgG4 monoclonal antibody antagonist targeting Programmed Cell Death Protein-1 (PD-1). The objective was to assess safety, MTD, pharmacokinetic (PK) ...

e16235Background: MVT-5873, a fully human IgG1 mAb, targets sialyl Lewis A (sLea), an epitope on CA19-9. CA19-9 is expressed in PDAC and other GI and lung cancers, plays a role in tumor adhesion an...

2592Background: Aurora kinases represent potential targets for anticancer therapy in solid tumors and hematological malignancies. The aurora B kinase inhibitor AZD1152 (barasertib) has shown benefi...

The balance between tumor-promoting and tumor-suppressing immune responses and the difference between them ultimately determine whether a cancer escapes immune recognition mechanisms. Defining the complex relationships between the tumor itself, the tumor environment, and the immune system has been critical in facilitating the development of successful immunotherapies. This review explores the role of oncogenes in inducing cancer-associated inflammation, the local and systemic factors that lead to immune suppression, and immunotherapy approaches to overcome immune privilege.

2505 Background: ALRN-6924 is a cell-penetrating stapled alpha-helical peptide designed to equipotently disrupt the interaction between the p53 tumor suppressor protein and its endogenous inhibitors, murine double minute X (MDMX) and 2 (MDM2). For TP53 wild-type (WT) tumors, pharmacological disruption of this interaction offers a means to restore p53-dependent cell cycle arrest and apoptosis, resulting in antitumor efficacy via a novel mechanism. Methods: The study evaluated safety, PK, PD and anti-tumor effects of ALRN-6924 in patients (pts) with advanced solid tumors or lymphomas in a standard 3+3 design. Pts received ALRN-6924 IV once weekly for 3 consecutive wks on a 28-day cycle (arm A), or 2/wk for 2 consecutive wks on a 21-day cycle (arm B). Results: As of Dec 2016, 69 pts were enrolled with median age 61 yrs (25-78). Pts received a median of 2 (1-19) cycles in arm A [0.16-4.4 mg/kg] and 3 (1-19) cycles in arm B [0.32-2.7 mg/kg]. ALRN-6924 showed a t1/2 of 5.5 hours, dose-dependent PK, and an increase in serum macrophage inhibitory cytokine-1. Treatment-related AEs seen in 96% of pts were primarily grade 1 and 2; most frequent were GI side effects, fatigue, anemia, and headache. DLTs were G3 fatigue at 3.1 mg/kg, and G3 hypotension, G3 alkaline phosphatase elevation, G3 anemia and G4 neutropenia at 4.4 mg/kg all in 5 pts in arm A. No G3/4 thrombocytopenia was observed. All DLTs resolved with dose hold. Infusion-related reactions were seen in 7 pts, with 3 treatment discontinuations. The RP2D was determined to be at MTD: 3.1 mg/kg QW for 3 wks every 28 days. In 55 pts evaluable for efficacy, disease control rate (DCR) was 45%, including 2 CR (Peripheral T-cell Lymphoma [PTCL], Merkel Cell Carcinoma), 2 PRs (Colorectal Cancer, Liposarcoma) and 21 pts with SD. In WT TP53 pts who initiated ALRN-6924 at ≥0.8 mg/kg, DCR was 57%. 9 pts remain on treatment post data cutoff including 3 pts exceeding 1 year of treatment. Conclusions: ALRN-6924 was well tolerated and demonstrated intriguing anti-tumor activity in this first-in-human phase I trial. An expansion phase IIa cohort in PTCL opened in August 2016 using 3.1 mg/kg (arm A) and is currently enrolling. Clinical trial information: NCT02264613.

TPS2608 Background: Aurora kinase B performs key roles in the regulation of the cell cycle and represents a potential target for anticancer therapy. AZD2811, formerly designated AZD1152 hydroxy-quinazoline pyrazole anilide (AZD1152 hQPA), is a potent and selective inhibitor of Aurora B kinase activity and has been incorporated into a polymer nanoparticle carrier for intravenous (IV) administration. The phosphate pro-drug of AZD2811, known as AZD1152 (barasertib), reached Phase II of clinical development as a continuous IV infusion. While promising efficacy was seen with barasertib in elderly acute myeloid leukaemia (AML) patients ( Kantarjian HG et al., Cancer 2013;119:2611-19), continuous intravenous drug delivery precluded subsequent development in this disease setting and there were limited clinical responses in solid tumour patients due to dose-limiting myelotoxicity. AZD2811 nanoparticle has been designed to overcome these issues. Methods: Patients with relapsed advanced solid malignancies with no standard treatments are eligible for the part A dose escalation. Primary endpoint is to determine the maximum tolerated dose of AZD2811 nanoparticle using a 3+3 design. Patients with refractory/relapsed small cell lung cancer (SCLC) will be eligible for the part B expansion, where the safety, PK and anti-tumour activity of AZD2811 nanoparticle will be assessed as monotherapy and in combination with chemotherapy. Study enrolment is ongoing. Clinical trial information: NCT02579226.

4110 Background: MVT-5873, a fully human IgG1 monoclonal antibody (mAb), targets sialyl Lewis A (sLea), an epitope on CA19-9. CA19-9 is expressed in pancreatic (PDAC) and other GI cancers, plays a role in tumor adhesion and metastasis, and is a marker of an aggressive tumor phenotype. MVT-5873 is active as a single agent and with chemotherapy in murine xenografts. Methods: MVT-5873 was given IV every other week (Group 1) or weekly (Group 2). Eligible patients had progressive, locally-advanced or metastatic PDAC or other CA19-9+ malignancy and ECOG PS ≤1. Dose escalation followed a 3+3 design with a 10 patient expansion at MTD. Endpoints include safety, MTD, pharmacokinetics (PK) and efficacy. Exploratory endpoints include changes in serum CA19-9 levels. Results: As of 2-Feb 2017, data are available from N = 25 in Groups 1 (N = 9) and 2 (N = 16) at doses ranging from 1 to 3 mg/kg. Dose limiting toxicities of transient grade 3 elevations in AST, ALT, and total bilirubin were encountered at 3 mg/kg in both groups. Liver function laboratory abnormalities typically emerged and resolved within a week of dosing without significant clinical sequelae. Of toxicities deemed possibly related, most were low grade and included GI toxicity (abdominal pain/cramps/diarrhea/nausea) and infusion reactions. Infusion reactions were mitigated by using pre-medications and decreasing the infusion rate. Initial PK data demonstrate initial (20 hours) and terminal (211 hours) half-lives, comparable to other mAbs. Stable disease of > 4 months was observed in 24% of patients. CA19-9 levels were measured pre- and post-dose with each treatment. Immediate reductions showed dose-dependent reductions of up to 97% from baseline at 3 mg/kg. Downward trends of CA19-9 with successive doses were seen, with 48% and 22% of patients exhibiting ≥50% and ≥90% reductions in CA19-9 levels, respectively. Conclusions: Single agent MVT-5873 appears safe and tolerable at biologically active doses. DLTs included reversible serologic liver toxicity. The safety profile, efficacy, and reductions in serum CA19-9 levels over time support further development of MVT-5873 in this indication both as a single agent and in combination. Clinical trial information: NCT02672917.

Background: Treatment of IRI-resistant CRC lines with a DNA methyltransferase inhibitor (DNMTi) can induce IRI re-sensitization. We theorized that combination of next generation DNMTi GUA+IRI would overcome resistance in previously IRI-treated mCRC pts. Methods: mCRC pts with prior IRI exposure were enrolled in a 3+3 Phase I, dose escalation study to define the maximum tolerated dose (MTD) and dose limiting toxicities of GUA+IRI. Pharmacodynamics studies were planned on pre- and post-treatment tumor biopsies (C1D8); serial blood was also taken. Pts were enrolled to 4 dose levels (DL) of GUA SQ qd D1-5 with IRI 125mg/m2 D8 and 15: GUA 45mg/m2 (DL 1), 30mg/m2 (DL -1), 30mg/m2 with growth factor support (GFS) (DL -1G), and 45mg/m2 with GFS (DL 1G) of a 28 day cycle. Results: 22 heavily pre-treated pts were enrolled (DL 1 = 6, DL -1 = 3, DL -1G = 7, DL 1G = 6); the MTD was established at DL 1G. Grade (G) 3-5 toxicities attributed to therapy were hematologic [neutropenia (16), neutropenic fever (5), anemia (3), thrombocytopenia (2)]. Other G3-4 toxicities were diarrhea (3), fatigue (2), and dehydration (2). There was one death on study possibly due to study treatment (febrile neutropenia). There were some dose reductions of IRI (6) or GUA (3). Median cycles of therapy were 4 months (range 1-14). 15 pts had at least one restaging scan, 12:SD and 1:PR. LINE-1 methylation analysis on serial biopsies revealed mixed changes in global methylation on C1D8, but LINE-1 of circulating tumor DNA showed consistent, delayed, dose-dependent demethylation with peak demethylation at C2D15. Conclusions: GUA+IRI is well tolerated and demonstrates potentially compelling activity in mCRC pts with prior IRI exposure. Further testing of the combination is ongoing in a randomized phase II trial (2:1 randomization to GUA+IRI or TAS-102/Regorafenib - provider choice). Clinical trial information: NCT01896856. Supported by Astex Pharma and VARI SU2C/AACR Epigenetics Dream Team. Toxicity attributable to therapy in ≤ 10% of patientsAny GG1/G2G3/G4/G5N (%)N (%)N (%)HematologicNeutropenia16 (73)0 (0)16 (73)Anemia13 (59)10 (45)3 (14)Thrombocytopenia9 (41)7 (32)2 (9)InfectionNon-neutropenic infection6 (27)6 (27)0 (0)Febrile Neutropenia5 (23)0 (0)5 (23) 1 death DL-1GFever9 (41)8 (36)1 (5)GastrointestinalNausea/Vomiting16 (73)16 (73)0 (0)Abdominal discomfort4 (18)4 (18)0 (0)Diarrhea11 (50)8 (36)3 (14)Constipation4 (18)4 (18)0 (0)Increased AST4 (18)3 (14)1 (5)Increased alkaline phosphatase9 (41)8 (36)1 (5)Injection Site Reactions15 (68)15 (68)0 (0)GeneralFatigue10 (45)8 (36)2 (9)Anorexia/Weight loss9 (41)8 (36)1 (5)Alopecia7 (32)7 (32)0 (0)Lower extremity edema5 (23)5 (23)0 (0)Dehydration5 (23)3 (14)2 (9)Headache3 (14)3 (14)0 (0)Taste changes4 (18)4 (18)0 (0) Citation Format: Valerie Lee, Judy Wang, Anthony El Khoueiry, Henk Verheul, Elske Gootjes, Anup Sharma, Zachary Kerner, Peter Jones, Stephen Baylin, Ellen Lilly, Nita Ahuja, Thomas Brown, Nilofer Azad. A phase I study of guadecitabine (GUA) combined with irinotecan (IRI) in previously treated metastatic colorectal cancer (mCRC) patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT017.

11025 Background: Despite aggressive therapeutic interventions with pancreaticoduodenectomy and adjuvant chemo/chemoradiotherapy, recurrence rates remain high for patients with resectable pancreas ...

TPS797 Background: Studies have suggested that epigenetic modifications may play a role in oncogenesis and acquired chemoresistance in certain cancers including colorectal cancer (CRC). Our preclinical data has shown that DNA hypermethylation may confer acquired chemoresistance, and that combining a hypomethylating agent can re-induce tumor sensitivity to irinotecan in CRC cell lines. We propose a phase I study to assess the safety and tolerability of SGI-110 with irinotecan therapy in metastatic colon cancer previously treated with irinotecan. This will be followed by a randomized phase II study to evaluate efficacy of the combination. Methods: We will enroll 12-22 patients at two institutions with metastatic colon adenocarcinoma previously treated with irinotecan to our phase I study. Dose escalation will be performed in a traditional 3+3 design, where patients receive SGI-110 30-45mg/m2 SQ days 1-5 in combination with irinotecan 125mg/m2 days 1, 8, and 15 (depending on the dose level) every 28 days, with or without G-CSF. Patients will be monitored for safety and tolerance with laboratory studies, clinical exam, and periodic CT scans to assess response to therapy. In addition, pharmacokinetic studies on peripheral blood and paired tumor biopsies will be obtained to assess for global demethylation and evaluation of biomarkers. Major eligibility criteria include measureable disease with accessibility for paired tumor biopsies, and prior treatment with irinotecan without limit on number of total therapies. Current Enrollment: Dose level 1 enrolled 6 patients and encountered 1 DLT following expansion for safety assessment. Dose level -1 enrolled 3 patients and encountered 2 DLTs, which has since prompted amendments for additional dose levels with modifications to scheduled growth factor support. Dose level -1G enrollment began in September 2014. Clinical trial information: NCT01896856.