Khanh Tu

3092 Background: mRNA-2752 is a novel mRNA-based therapeutic agent encoding OX40L T cell co-stimulator, IL-23 and IL-36γ pro-inflammatory cytokines. Here we present findings from a first-in-human study of iTu mRNA-2752 in solid tumor patients as monotherapy or in combination with durvalumab (durva). At the time of presentation, data will encompass the monotherapy escalation MTD/RDE along with the supporting translational work, and the available data in combination. Methods: iTu mRNA-2752 was administered every 2 weeks for up to 7 doses as monotherapy or in combination with durva in patients with advanced solid malignancy or lymphoma. Biomarker analyses include measurement of IL-23, IL-36γ and pro-inflammatory cytokine proteins in pre- and post-treatment tumor biopsies and plasma. PD-L1 immunohistochemistry was used to further characterize baseline status and changes to the TME with treatment. Results: As of 20 December 2019, 23 solid tumor patients have been treated either with mRNA-2752 alone (n = 14) or in combination (n = 9) and has been well tolerated with no dose limiting toxicities or related grade 3/4 toxicities. Of the 17 patients evaluated per RECIST and iRECIST, 1 had a PR (iRECIST), 6 had SD, and 10 had PD. The patient with a PR (52% tumor reduction) received 0.5 mg mRNA-2752 with durva, and had aPD-1/L1 naïve squamous-cell bladder carcinoma. Tumor shrinkage was observed in an additional 5 patients in injected and/or uninjected lesions in both monotherapy and combination. Preliminary biomarker data showed increased IL-23 and IL-36γ protein expression after 6-24 hours, and increased levels of downstream cytokines IL-22 and IL-6, respectively. Pro-inflammatory cytokines (e.g. IFN-γ, TNF-α) were also significantly increased at 1 day and 1-week post-treatment. Significant increases in PD-L1 expression predominantly in tumor-associated immune cells were observed after first dose and persisted up to 29 days after treatment. Conclusions: iTu mRNA-2752 given as monotherapy and in combination with durva is tolerable at all dose levels studied, and administration can be associated with tumor shrinkage. Analyses of tumor and plasma biomarkers suggest a sustained immunomodulatory effect of treatment that includes elevated IFN-γ, TNF-α, and PD-L1 levels. These data support the ongoing testing of the mRNA-2752/durva combination in the dose escalation part of the study. Clinical trial information: NCT03739931 .

11006 Background: CMB305 is an active immunotherapy regimen designed to generate and expand anti-NY-ESO-1 T cells. It consists of LV305, a dendritic cell targeting lentiviral vector encoding NY-ESO-1, and a boost with G305, an NY-ESO-1 recombinant protein plus GLA-SE, a TLR-4 agonist. An LV305 phase 1 study demonstrated a 1-yr survival of 81% and induction of anti-NY-ESO-1 T cells in sarcoma patients (pts). This first-in-human study of CMB305 examined safety, immunogenicity, and efficacy in pts with NY-ESO-1 positive (+) solid tumors. Methods: Adults with previously treated NY-ESO-1 + sarcomas, NSCLC, ovarian cancer were enrolled in a 3+3 dose-escalation with an expansion phase 1 study. The CMB305 regimen included 4 intradermal injections of LV305 at 10 9 or 10 10 vector genomes, alternating with 3 intramuscular G305 injections at 250 µg for 3 months, then bimonthly G305 injections up to 1 yr. Results: As of 31Dec2016, 25 pts with STS (15 synovial (SS), 8 myxoid/round cell liposarcoma (MRCL), 2 other) were evaluable for safety; 23 SS/MRCL pts were evaluable for immune response (IR) and efficacy. All SS and MRCL pts received prior therapy for locally advanced/metastatic disease, 67% > = 2 prior chemo regimens. No DLTs were observed; treatment related AEs were grade 1 and 2, except 1 pt with grade 3 SAE (prostatic pain). Of 11 SS/MRCL pts tested, 64% pts developed NY-ESO-1 specific T cells and 72% pts anti-NY-ESO-1 antibodies. T cell receptor sequencing indicated increased clonality, and antigen spreading after CMB305. Best response by immune related response criteria was stable disease in 8/15 (53%) SS pts and 6/8 (75%) MRCL pts. The 3 month PFS rate was 74% and 75% for SS and MRCL pts. Median survival has not been reached with 1-yr survival rate of 86% and 100% for SS and MRCL pts. Conclusions: CMB305 is safe, well tolerated, and demonstrates a survival rate that is favorable when compared with approved agents for recurrent STS. CMB305 resulted in a stronger and broader integrated IR than LV305, including antigen spreading. These data warrant further investigation of CMB305 as a monotherapy in a randomized clinical study in STS. A randomized study of CMB305 in combination with atezolizumab in SS/MRCL pts is ongoing. Clinical trial information: NCT02387125.

3529 Background: The RAF/MEK/ERK and PI3K/AKT signaling pathways are commonly deregulated in CRC. Each can serve as a compensatory mechanism mediating resistance to single pathway blockade. Combined inhibition with MK-2206 and selumetinib (AZD6244) could enhance antitumor activity. Tolerable doses for the combination in solid tumors (ASCO 2011, abstr 3004) are less than single agent MTDs. We conducted a biomarker driven trial of MK-2206 and selumetinib at the established combination doses to determine extent of pERK and pAKT inhibition in tumor biopsies (bx), using new, clinically validated immunoassays for pERK and pAKT. Methods: Patients (pts) with advanced CRC, refractory to standard therapy, ECOG ≤ 2, adequate organ function, and disease amenable to bx were treated with oral MK-2206, 90 mg QW and selumetinib, 75 mg daily, stratified for KRAS mutation status (+ or WT). For each strata, pAKT and pERK levels from paired tumor bx, baseline and 3-6 hrs post-dose in 3 pts each on C1D1 or C1D22, were measured using a quantitative, chemiluminescence immunoassay (dilution linearity R 2 = 0.985 pERK, 0.995 pAKT; % CV at 0 < 6). 70% inhibition was considered biologically significant based on levels observed in preclinical models that demonstrated antitumor activity. Results: 11 pts enrolled to date (KRAS +, 6 pts; WT, 5 pts). 2/9 pts had SD after 2 cycles. Gr 1/ 2 toxicities: rash, reversible retinal detachment, liver abnormalities, hypoalbuminemia, lymphopenia. Target protein inhibition data are available for 8 paired bx samples (Table). Conclusions: Although 4/8 pts demonstrated biologically significant inhibition in one marker, at the MTD for this combination no pt had ≥ 70% inhibition of both targets. If repeated dosing does not produce the desired inhibition of pERK and pAKT, we will conclude that the dose reductions for each agent necessitated by the toxicity of the agents used in combination preclude the possibility of providing adequate dual pathway inhibition. Loss of PTEN and DNA mutation analyses (KRAS, BRAF, PIK3Ca, AKT) are planned. [Table: see text]

3104 Background: Enhancer of Zeste homolog 2 (EZH2) is a histone methyltransferase and the catalytic subunit of Polycomb Repressive Complex 2 (PRC2). EZH2 is frequently overexpressed in cancers and correlates with poor prognosis. CPI-0209 is an oral, small molecule, second-generation, selective inhibitor of EZH2 designed to achieve comprehensive target coverage through extended on-target residence time. The compound demonstrates more potent anti-tumor activity in preclinical cancer models, compared to first-generation EZH2 inhibitors. CPI-0209 is currently being evaluated in a Phase 1/2, open-label, FIH study (NCT04104776). Methods: Patients (pts) with advanced tumors were enrolled in a 3+3 design. Primary objective is to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of CPI-0209. Secondary objectives are to evaluate the safety, PK, and PD in pts who received CPI-0209 QD in 28 days cycles (C). Results: As of December 16, 2020, 33 pts were treated: pancreatic cancer (n = 6), mesothelioma, breast, colorectal, and ovarian cancer (n = 5 each), leiomyosarcoma, melanoma, cholangiocarcinoma, prostate, bladder, endometrial clear cell and gastric cancer (n = 1 each). Pts received CPI-0209 at 50 mg (n = 4), 100 mg, 137.5 mg, and 187.5 mg (n = 6 each), 225 mg (n = 7), and 275 mg (n = 4) daily dose. Median treatment duration was 43 days (range 1-239); 4 pts are ongoing. Median age was 64 yrs (range 24-79); 15 (45%) pts were male. Patients were heavily pretreated, with 67% of pts had ≥ 3 prior lines of therapy. No dose limiting toxicities have been observed. The most frequent treatment-emergent adverse events (TEAEs) (≥10%) were fatigue (27%), diarrhea (24%), nausea (21%), abdominal pain, alopecia, anemia, thrombocytopenia, and dysgeusia (15% each), and vomiting, headache, decreased appetite, and alkaline phosphatase increased (12% each); usually grade 1 or 2 in severity. Thrombocytopenia was dose-dependent and not associated with bleeding or clinical sequalae. Three pts (9%) discontinued CPI-0209 due to TEAEs. Comprehensive target engagement (assessed by global reduction in H3K27me3 levels in monocytes) was observed within the first cycle at all dose levels. CPI-0209 also increased the expression of PRC2-controlled gene sets in blood in a dose-dependent manner. Updated safety, PK, PD, and preliminary efficacy results from Phase 1 will be presented. Conclusions: CPI-0209 achieved robust PD effects and a PK-PD relationship has been established. CPI-0209 monotherapy was generally well tolerated, and treatment related AEs were manageable and reversible. The MTD has not been reached. Clinical trial information: NCT04104776.

2549 Background: Ataxia-telangiectasia-related (ATR) protein kinase is central to the repair of damaged DNA through the homologous recombination (HR) pathway, activating phosphorylation cascades that culminate in cell cycle arrest to allow time for DNA damage repair (DDR). M6620 is an ATR inhibitor with antitumor activity across a range of cell lines. Veliparib (ABT-888), an oral poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor, plays a pivotal role in DDR response through the base excision repair pathway, with clinical evidence of antitumor activity in combination with cisplatin in BRCA mutation carriers. As DNA damage and antitumor activity of platinum results from DNA cross-links that stall replication forks and halt transcription, this trial evaluates if veliparib together with M6620 impair DNA repair by inducing a “BRCA null”-like phenotype that potentiates the antitumor activity of cisplatin. Methods: Open label phase I trial of the M6620+veliparib+cisplatin combination; 3+3 design, 21-day cycle: cisplatin 40mg/m2 intravenously (IV) Day 1 [Day 8 added from dose level (DL)3]; M6620 (M) IV Days 2+9; Veliparib (V) orally twice daily Days 1-3 and 8-10. Prior platinum, PARPi therapy permitted. Response: RECIST 1.1. Results: 23 patients(pts) enrolled, 22pts evaluable for response. 3/22pts confirmed partial responses (PR) lasting > 4cycles (range 4-15): 1pt with BRCA-wildtype ovarian cancer (DL3), 1pt with esophageal cancer/biallelic loss of ATM (DL4); 1pt with NSCL cancer/ATM mutation (DL5); all remain on study. 12/22pts have stable disease: median time on study 5 cycles (range 3-10). DL3+4 expanded for dose limiting toxicity: grade 4 hypophosphatemia and thrombocytopenia respectively (1pt, 4%). Other adverse events: grade 3 thrombocytopenia (6pts, 27%), leucopenia (5pts, 22%), lymphopenia (4pts, 18%). Maximally tolerated dose (MTD) not reached for the combination, currently enrolling DL7: V 200mg, M 210mg/m2. Conclusions: combination is safe and shows anti-tumor activity in HR-compromised tumors. Planned biomarker assessment at MTD includes γH2AX, RAD51, pNbs1, and pATR in tumor biopsies and circulating tumor cells using a validated, quantitative immunofluorescence assay. Clinical trial information: NCT02723864.