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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

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...

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.

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.