BackgroundThe Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin’s lymphoma population, primarily consisting of patients with DLBCL.MethodsPatients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells.ResultsThirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance.ConclusionsAZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing.Trial registrationRegistered at ClinicalTrials.gov: NCT01563302. First submitted 2/13/2012.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0436-5) contains supplementary material, which is available to authorized users.

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3085 Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription and additional mechanisms. AZD5153 is a novel, reversible BRD4 inhibitor with bivalent mechanism of action and enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), and pharmacodynamics (PD). We report here preliminary, unvalidated data from AZD5153 monotherapy in pts with RR solid tumor, including lymphoma. Methods: Adult pts received oral AZD5153 QD/BID to determine the MTD. During dose escalation, a continual reassessment model was used to estimate toxicity and all final decisions were made by the Safety Review Committee. PK and PD were characterized using standard methods. Results: As of 1 Nov 2018, 28 pts (78.6% female, median age 66.5 y) were treated in 7 cohorts: 2 mg QD (3 pts), 5 mg QD (3 pts), 10 mg QD (3 pts), 10 mg BID (5 pts), 15 mg BID (4 pts), 20 mg BID (7 pts), and 30 mg QD (3 pts). Treatment was ongoing in 8 pts at data cut-off. Safety findings showed 50% of pts experienced treatment-related AEs. 25% of pts experienced treatment-related Grade ≥3 AEs, which were thrombocytopenia and fatigue (7.1% each), and anemia, diarrhea, and platelet count decreased (3.6% each). SAEs were observed in 25% of pts; none of the SAEs was attributable to AZD5153 alone. Dose-limiting toxicities of thrombocytopenia (1 pt) and diarrhea with herpetic rash leading to discontinuation (1 pt) occurred at 20 mg BID. 53.6% of pts discontinued due to disease progression. Total median treatment duration was 1.3 mo (range up to 8.9 mos). Dose proportional increase in Cmax and AUC were observed across the dose range tested. Tmax ranged from 0.5 to 3 h and t1/2 was 6 h. Dose-dependent changes in expression of target genes (eg, HEXIM1, HIST2H2BF, CD274, and CCR2) and platelet counts were observed in the peripheral blood. Conclusions: AZD5153 monotherapy is safe and tolerated at doses up to 30 mg QD and 15 mg BID. Linear increase in PK was observed. Additional safety and efficacy updates will be reported at the annual meeting. Clinical trial information: NCT03205176.

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3086 Background: BDTX-189 is an orally available, ATP-competitive and irreversible inhibitor directed against families of allosteric HER2 and EGFR oncogenic mutations. In preclinical studies BDTX-189 achieved potent inhibition of 48 allosteric HER2 and EGFR/HER2 exon 20 insertion mutant variants with selectivity versus EGFR wild-type (WT) and demonstrated tumor growth inhibition and regression in vivo. The primary objective of the Ph 1 portion of this trial (NCT04209465) is to determine the RP2D and schedule of monotherapy BDTX-189 in pts with advanced solid tumors. Methods: Eligibility includes pts with relapsed or refractory locally advanced or metastatic solid tumors with no standard therapy available whose tumor harbors an allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplification or overexpression; or EGFR exon 19 deletion or L858R mutation. BDTX-189 is dosed continuously orally in 3-wk cycles QD and BID in separate dose escalation cohorts. A separate cohort is also evaluating the high- and low-fat food-effect (FE) on BDTX-189 PK. Results: As of 1/11/21, 46 pts have been dosed, with 36 in the QD (fasting) schedule (25-1200 mg), including pts from the FE cohort who received 800 mg QD fasting after FE evaluation: 58% female; 67% white; median age 63.5 yrs; 53% received ≥ 3 prior tx lines. Cancer types: 12 NSCLC, 5 breast, 4 ovary, 3 biliary, and 12 other. Genomic alterations: 23 HER2 amplification and the following mutations: 11 allosteric HER2, 5 EGFR exon 20 insertion, 5 HER2 exon 20 insertion, 3 EGFR exon 19 del./L858R, and 2 HER3. At ≥ 800 mg QD, 3 and 2 pts had EGFR or HER2 exon 20 mutations, respectively. The maximum tolerated dose (MTD) for QD (fasting) was 800 mg, with 2/6 pts with DLTs at 1200 mg. DLTs: gastrointestinal (G3 diarrhea; G1/2 nausea/vomiting). The most frequent (≥20%) related adverse events were diarrhea (36%, 8% G3), nausea (28%, 0% G3), and vomiting (25%, 3% G3). The rate of skin disorders was 11% with the highest severity of G2 in 1 pt. Dose-dependent exposure increases were observed, with the exposure at 800 mg QD fasting within the projected efficacious range. Pilot FE data suggest possible increased exposure with food. 27 pts were evaluable for efficacy, 15 at ≥ 800 mg QD, with 2 partial responses observed: 1 PR confirmed and ongoing (800 mg QD, CUP, HER2 amp, 3 prior lines of chemo) and 1 PR unconfirmed (NSCLC with brain mets, 1200 mg QD, HER2 amp + exon 19 del., 2 prior EGFR TKIs). 3 pts had a best response of SD and 10 with progressive disease. Conclusions: BDTX-189 has a generally manageable safety profile with early evidence of anti-tumor activity. Enrollment is ongoing in non-fasting QD and BID cohorts, and the FE cohort, prior to RP2D identification. Clinical trial information: NCT04209465.