2650 Background: REGN6569 is a fully human immunoglobulin G1 monoclonal antibody (mAb) that is highly specific for glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR). GITR is expressed on several immune cell subtypes, notably regulatory T cells (Tregs), and activated natural killer (NK) cells. REGN6569 demonstrated greater in vitro antibody-dependent cell-mediated cytotoxicity against GITR-expressing Tregs, as compared to GITR-expressing CD8+ T cells. Mouse studies showed that REGN6569 + cemiplimab (anti-PD-1) combination treatment achieved longer-term tumor responses compared with either drug alone. Methods: This is a first-in-human study (NCT04465487) evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of REGN6569 administered intravenously (IV) every 3 weeks (Q3W) + cemiplimab 350 mg IV Q3W, in pts with advanced solid tumors for which immune checkpoint inhibitor therapies have not been approved or are not available. The study includes a dose-escalation part with 5 dose levels (DL1-DL5) for REGN6569 (“4+3” design), with an initial dose of REGN6569 monotherapy given as a safety lead-in followed by REGN6569 + cemiplimab in subsequent doses. Results: As of the data cutoff date Oct 20, 2023, the dose-escalation part has been completed. 29 pts (median age 58.0 years, 62.1% male) were treated with REGN6569 + cemiplimab, up to the 1200 mg dose level (DL5), across many solid tumor types. The most common tumor type was colorectal cancer (34.5%). One pt (40 mg DL2) experienced a dose-limiting toxicity (Grade 3 hepatic failure); maximum tolerated dose was not reached. Twelve pts (41.4%) had a Grade ≥3 treatment-emergent adverse event (TEAE) and 16 pts (55.2%) had a treatment-related TEAE (any grade). The most frequent TEAEs (any grade) were arthralgia (24.1%), infusion-related reactions, and abdominal pain (20.7% each). There were no treatment-related deaths; 19 (65.5%) pts had disease progression leading to death. Two pts achieved ongoing partial responses by investigator assessment with REGN6569 + cemiplimab treatment: 1 pt with mucoepidermoid tumor of the parotid gland treated with 120 mg (DL3) REGN6569 and 1 pt with B3 thymoma treated with 400 mg (DL4) REGN6569, with duration of responses, 5.6 and 10.4 months, respectively. Full receptor occupancy on circulating Tregs was observed in all dose cohorts following REGN6569 treatment. Increased frequency (~10–50%) of proliferating NK cells in peripheral blood was observed post REGN6569 treatment across all dose cohorts. Conclusions: In this dose-escalation study, REGN6569 was administered up to 1200 mg (DL5) in combination with cemiplimab with one dose-limiting toxicity. The study has progressed to dose-expansion cohorts in anti–PD-1-resistant head and neck cancer, with pts treated with REGN6569 (DL5) + cemiplimab. Clinical trial information: NCT04465487 .

Supplemental Methods, Figures S1-S5, Tables S1-S7

Activation of apoptosis in malignant cells is an established strategy for controlling cancer and is potentially curative. To assess the impact of concurrently inducing the extrinsic and intrinsic apoptosis-signaling pathways in acute myeloid leukemia (AML), we evaluated activity of the TRAIL receptor agonistic fusion protein eftozanermin alfa (eftoza; ABBV-621) in combination with the B-cell lymphoma protein-2 selective inhibitor venetoclax in pre-clinical models and human patients. Simultaneously stimulating intrinsic and extrinsic apoptosis-signaling pathways with venetoclax and eftoza, respectively, enhanced their activities in AML cell lines and patient-derived ex vivo/in vivo models. Eftoza activity alone or plus venetoclax required death receptor 4/5 (DR4/DR5) expression on the plasma membrane but was independent of TP53 or FLT3-ITD status. The safety/tolerability of eftoza as monotherapy and in combination with venetoclax was demonstrated in patients with relapsed/refractory AML in a phase 1 clinical trial. Treatment-related adverse events were reported in 2 of 4 (50%) patients treated with eftoza monotherapy and 18 of 23 (78%) treated with eftoza plus venetoclax. An overall response rate of 30% (7/23; 4 complete responses [CRs], 2 CRs with incomplete hematologic recovery, and 1 morphologic leukemia-free state) was reported in patients who received treatment with eftoza plus venetoclax and 67% (4/6) in patients with myoblasts positive for DR4/DR5 expression; no tumor responses were observed with eftoza monotherapy. These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT03082209.

Background/Aim: The therapeutic potential of bromodomain and extra-terminal motif (BET) inhibitors in hematological cancers has been well established in preclinical and early-stage clinical trials, although as of yet, no BETtargeting agent has achieved approval. To add insight into potential response to mivebresib (ABBV-075), a broadspectrum BET inhibitor, co-clinical modeling of individual patient biopsies was conducted in the context of a Phase I trial in acute myeloid leukemia (AML). Materials and Methods: Co-clinical modeling involves taking the patient’s biopsy and implanting it in mice with limited passage so that it closely retains the original characteristics of the malignancy and allows comparisons of response between animal model and clinical data. Procedures were developed, initially with neonate NOD/Shi-scid-IL2rγnull (NOG) mice and then optimized with juvenile NOG–EXL as host mice, eventually resulting in a robust rate of engraftment (16 out of 26, 62%). Results: Results from the co-clinical AML patient-derived xenograft (PDX) modeling (6 with >60% inhibition of bone marrow blasts) were consistent with the equivalent clinical data from patients receiving mivebresib in monotherapy, and in combination with venetoclax. The modeling system also demonstrated the activity of a novel BD2-selective BET inhibitor (ABBV-744) in the preclinical AML setting. Both agents were also highly effective in inhibiting blast counts in the spleen (10/10 and 5/6 models, respectively). Conclusion: These findings confirm the validity of the model system in the co-clinical setting, establish highly relevant in vivo models for the discovery of cancer therapy, and indicate the therapeutic value of BET inhibitors for AML and, potentially, myelofibrosis treatment.

Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5–15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25–7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. ( Trial registration number : NCT03082209 (registered: March 17, 2017)).

BACKGROUND:Acute myeloid leukemia (AML) is a heterogenous malignancy driven by genetic and epigenetic factors. Inhibition of bromodomain and extraterminal (BET) proteins, epigenetic readers that play pivotal roles in the regulation of genes relevant to cancer pathogenesis, constitutes a novel AML treatment approach.METHODS:In this first-in-human study of the pan-BET inhibitor mivebresib as monotherapy (MIV-mono) or in combination with venetoclax (MIV-Ven), the safety profile, efficacy, and pharmacodynamics of mivebresib were determined in patients with relapsed/refractory AML (ClinicalTrials.gov identifier NCT02391480). Mivebresib was administered at 3 monotherapy dose levels (1.5, 2.0, or 2.5 mg) or in combination with venetoclax (400 or 800 mg).RESULTS:Forty-four patients started treatment: of 19 who started MIV-mono, 5 went on to receive MIV-Ven combination therapy after disease progression and a washout period. Twenty-five patients started MIV-Ven, resulting in a total of 30 patients treated with the combination. The most common mivebresib-related treatment-emergent adverse events were dysgeusia (74%), decreased appetite (42%), and diarrhea (42%) in the MIV-mono group and decreased appetite (44%), vomiting (44%), and nausea (40%) in the MIV-Ven group. Serious adverse events occurred in 14 patients (74%) who received MIV-mono and in 22 patients (88%) who received MIV-Ven. In the MIV-mono group, responses were complete remission with incomplete blood count recovery in 1 patient and resistant disease in 15 patients. In the MIV-Ven group, responses were complete remission in 2 patients, partial remission in 2 patients, morphologic leukemia-free state in 2 patients, resistant disease in 12 patients, and aplasia in 1 patient. The pharmacodynamic effects of mivebresib were proportional to dose and drug exposure.CONCLUSIONS:Mivebresib was tolerated and showed antileukemic effects as monotherapy and in combination with venetoclax in patients with relapsed/refractory AML.LAY SUMMARY:Mivebresib is a novel drug that influences the way cancer cells read genetic information. Mivebresib was tested together with venetoclax in patients with acute myeloid leukemia after standard medicines failed and the disease returned, or when standard medicine was unavailable. Adverse effects were described for different drug doses, and the dose that is tolerable was determined. In some patients, their leukemia improved for some time. More studies are necessary to determine whether mivebresib can be used to treat acute myeloid leukemia.

Aims Evaluate pharmacokinetic (PK) profile of Eftozanermin alfa (ABBV-621; eftoza) as monotherapy (eftoza-mono) or eftoza and venetoclax (eftoza-VEN); assess safety and tolerability, preliminary antitumor activity, and exploratory biomarkers. Methods In this phase 1 study, adults with relapsed/refractory (RR) acute myeloid leukemia (AML) or diffuse large B-cell lymphoma (DLBCL) received intravenous eftoza, 1.25, 3.75, or 7.5 mg/kg in AML eftoza-mono and 3.75 or 7.5 mg/kg in AML and DLBCL eftoza-VEN cohorts days 1, 8, and 15 of a 21-day cycle. VEN dose was 400 mg or 800 mg daily (oral). Results As of September 2019, 34 patients enrolled: 4 in AML eftoza-mono(median age 75 yrs; 1.25 [n=1], 3.75 [n=1], or 7.5 [n=2] mg/kg eftoza), 19 in AML eftoza-VEN(median age 72 yrs; 3.75 [n=10] or 7.5 [n=9] mg/kg eftoza), and 11 in DLBCL eftoza-VEN cohorts (median age 64 yrs; 3.75 [n=3] or 7.5 [n=8] mg/kg eftoza). Patients received eftoza for median 1 (AML eftoza-mono), 3 (AML eftoza-VEN), and 2 (DLBCL eftoza-VEN) cycles. Four patients in AML eftoza-VEN cohorts completed ≥5 cycles. Percentage of patients with treatment-emergent adverse events (TEAEs) was 100% for AML eftoza-mono/VEN, and 91% for DLBCL eftoza-VEN. Grade ≥3 TEAEs were in all AML eftoza-mono/VEN patients and 27% in DLBCL eftoza-VEN. Most common grade ≥3 TEAEs were increased alanine (n=4, AML eftoza-VEN) and aspartate (n=4, AML eftoza-VEN; n=1, DLBCL eftoza-VEN) aminotransferase. Serious eftoza-related AEs were in 5 patients (AML eftoza-VEN); none in >1 patient. Eftoza exhibited dose-proportional kinetics at weekly 1.25- to 7.5-mg/kg doses; PK was not affected by VEN. No responses were seen in AML eftoza-mono or DLBCL eftoza-VEN cohorts. Overall response rate in AML eftoza-VEN cohorts was 4/19 (21%), with 3 complete responses (CR; 3.75 mg/kg [n=2], 7.5 mg/kg [n=1]), and 1 CR with incomplete hematologic recovery (7.5 mg/kg); 4 had RD (3.75 mg/kg [n=2], 7.5 mg/kg [n=2]) and 3 PD (3.75 mg/kg [n=3]). Eftoza binding to death receptors on neutrophils was saturated by 2h post-dose in AML and DLBCL cohorts. There was time-dependent desaturation of the receptors for eftoza binding. In 63% of patients with RR AML ≥3, molecular aberrations were observed, with IDH1/2 and RAS being the most frequently mutated genes. Conclusions Eftoza-mono and eftoza-VEN were tolerated in patients with RR AML and DLBCL. Antitumor activity was observed in patients with AML treated with eftoza-VEN at 3.75- or 7.5-mg/kg doses. Abstract was previously published at EHA25. Evaluate pharmacokinetic (PK) profile of Eftozanermin alfa (ABBV-621; eftoza) as monotherapy (eftoza-mono) or eftoza and venetoclax (eftoza-VEN); assess safety and tolerability, preliminary antitumor activity, and exploratory biomarkers. In this phase 1 study, adults with relapsed/refractory (RR) acute myeloid leukemia (AML) or diffuse large B-cell lymphoma (DLBCL) received intravenous eftoza, 1.25, 3.75, or 7.5 mg/kg in AML eftoza-mono and 3.75 or 7.5 mg/kg in AML and DLBCL eftoza-VEN cohorts days 1, 8, and 15 of a 21-day cycle. VEN dose was 400 mg or 800 mg daily (oral). As of September 2019, 34 patients enrolled: 4 in AML eftoza-mono(median age 75 yrs; 1.25 [n=1], 3.75 [n=1], or 7.5 [n=2] mg/kg eftoza), 19 in AML eftoza-VEN(median age 72 yrs; 3.75 [n=10] or 7.5 [n=9] mg/kg eftoza), and 11 in DLBCL eftoza-VEN cohorts (median age 64 yrs; 3.75 [n=3] or 7.5 [n=8] mg/kg eftoza). Patients received eftoza for median 1 (AML eftoza-mono), 3 (AML eftoza-VEN), and 2 (DLBCL eftoza-VEN) cycles. Four patients in AML eftoza-VEN cohorts completed ≥5 cycles. Percentage of patients with treatment-emergent adverse events (TEAEs) was 100% for AML eftoza-mono/VEN, and 91% for DLBCL eftoza-VEN. Grade ≥3 TEAEs were in all AML eftoza-mono/VEN patients and 27% in DLBCL eftoza-VEN. Most common grade ≥3 TEAEs were increased alanine (n=4, AML eftoza-VEN) and aspartate (n=4, AML eftoza-VEN; n=1, DLBCL eftoza-VEN) aminotransferase. Serious eftoza-related AEs were in 5 patients (AML eftoza-VEN); none in >1 patient. Eftoza exhibited dose-proportional kinetics at weekly 1.25- to 7.5-mg/kg doses; PK was not affected by VEN. No responses were seen in AML eftoza-mono or DLBCL eftoza-VEN cohorts. Overall response rate in AML eftoza-VEN cohorts was 4/19 (21%), with 3 complete responses (CR; 3.75 mg/kg [n=2], 7.5 mg/kg [n=1]), and 1 CR with incomplete hematologic recovery (7.5 mg/kg); 4 had RD (3.75 mg/kg [n=2], 7.5 mg/kg [n=2]) and 3 PD (3.75 mg/kg [n=3]). Eftoza binding to death receptors on neutrophils was saturated by 2h post-dose in AML and DLBCL cohorts. There was time-dependent desaturation of the receptors for eftoza binding. In 63% of patients with RR AML ≥3, molecular aberrations were observed, with IDH1/2 and RAS being the most frequently mutated genes. Eftoza-mono and eftoza-VEN were tolerated in patients with RR AML and DLBCL. Antitumor activity was observed in patients with AML treated with eftoza-VEN at 3.75- or 7.5-mg/kg doses. Abstract was previously published at EHA25.

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by uncontrolled inflammation and fibrotic deposition in the extracellular bone marrow space, resulting in cytopenias, constitutional symptoms, and splenomegaly. A minority of patients are eligible for allogeneic hematopoietic stem cell transplant (allo-HSCT), which can be curative but is associated with substantial risks. Janus-associated kinase inhibitors (JAKi), including ruxolitinib (Rux), are approved for treatment of MF but do not reliably alter the disease course or generate durable responses. The limited treatment options for MF after Rux failure highlight a clear unmet need. In murine models of MPN, bromodomain and extra-terminal family protein inhibitors (BETi) reduced inflammatory cytokine levels and, combined with JAKi, reduced MF disease burden (Kleppe et al, 2018). BETi also modulated key nodes in the intrinsic apoptosis pathway and synergized with the B-cell lymphoma-2 (BCL-2) family inhibitor navitoclax (Nav) in solid tumor models (data on file). Pan-BETi have shown activity in patients with MF, including reduction in spleen volume and improvements in symptom burden, anemia, and bone marrow fibrosis as monotherapy and in combination with Rux (Mascarenhas et al, 2019). Selective BETi may reduce off-target toxicity relative to pan-BETi. The studies described here aim to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of ≥2 dosing regimens of 2 novel BETi: mivebresib, an oral pan-BETi that demonstrated antitumor activity in preclinical models of malignancy, and ABBV-744, a novel, potent small molecule that selectively inhibits bromodomain II of the BET family. Both BETi will be investigated as monotherapy and in combination with Nav or Rux in patients with MF. Methods: The 2 Phase 1b, multicenter, open-label studies will recruit patients with MF to receive ABBV-744 (NCT04454658) or mivebresib (NCT04480086), respectively, as monotherapy or in combination with Nav or Rux. Patients ≥18 years with intermediate-2 or high-risk MF, measurable splenomegaly (intermediate-1 with palpable splenomegaly ≥5 cm below costal margin eligible for Segment A) and Eastern Cooperative Oncology Group Performance Status <2 who are not candidates for allo-HSCT will be enrolled into 4 segments (Figure). Segment A: JAKi-experienced and BETi-naïve patients will receive 1 of 2 dosing regimens of ABBV-744 or 1 of 2 dosing regimens of mivebresib. Segment B: BETi-naïve patients currently receiving Rux will receive ABBV-744 or mivebresib plus Rux; Segment C: JAKi-experienced, and BETi-naïve, and/or BCL-XL/BCL-2 inhibitor-naïve patients will receive ABBV-744 or mivebresib plus Nav; Segment D: JAKi-naïve and BETi-naïve patients will receive ABBV-744 or mivebresib plus Rux. A dose regimen will be stopped if ≥3 of the first 9 dose-limiting toxicity (DLT)-evaluable patients given that dose in Segment A experience a DLT, or if the DLT rate is ≥33% at any point thereafter. Segments B and C will begin only once a dose regimen is deemed safe in Segment A. Segment D will commence after safety is established in Segment B. Treatment may continue until ≥1 discontinuation criterion has been met. The primary endpoint in both studies is adverse events (AEs) defined by the Common Terminology Criteria for AEs v5, including DLTs at a dose considered tolerable in patients with MF. Key secondary endpoints include the proportion of patients with spleen volume reduction of ≥35% at Weeks 12 and 24, PK parameters, proportion of patients with ≥50% reduction in Total Symptom Score at Week 24, and objective response rate (complete remission + partial remission). Key exploratory endpoints include change from baseline in allelic frequency, improvement in bone marrow fibrosis grade, and cytokine modulation. The planned sample size is approximately 130 patients per study. Analyses will include all patients who received ≥1 dose of study drug. Safety will be assessed by study drug exposure, AEs (including DLTs), serious AEs, deaths, and changes from baseline in laboratory determinations and vital sign parameters. AEs will include treatment-emergent events with an onset after first dose and ≤30 days after the last dose of study drug. Efficacy analyses will include summary statistics for categoric and continuous variables. Confidence intervals will be derived from the Clopper Pearson method. First dosing is planned for Q4 2020. Disclosures Mascarenhas: Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy. Saab:AbbVie: Current Employment, Other: may own stock or stock options. Brackman:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Modi:AbbVie: Current Employment, Other: may own stock or stock options. Abraham:AbbVie: Current Employment, Other: may own stock or stock options. Ward:AbbVie: Current Employment, Other: may own stock or stock options. Verstovsek:Celgene: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding; ItalPharma: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding.

e15668 Background: Eftozanermin alfa (eftoza; formerly known as ABBV-621), a 2nd-generation tumor necrosis factor-related apoptosis-inducing ligand receptor agonist, is being evaluated in previously treated solid and hematologic malignancies (NCT03082209). In a dose-expansion cohort, patients (pts) with KRAS-mutant colorectal cancer (n = 24) and pancreatic cancer (n = 24) were evaluated at 3 dose levels with 12 mandatory paired biopsies per tumor type (pretreatment [Tx] and on-Tx collection). Following eftoza dosing, RNA and protein expression including posttranslational modifications were assessed in tumor biopsies to understand the target engagement and downstream pathway activation. Plasma was evaluated for changes in somatic mutant allele frequency and M30, M65 (circulating apoptotic markers). Methods: Biopsies were collected anytime during the screening period (pre-Tx) and 24±4 h following 2nd or 3rd infusion (on-Tx). Of the requested 4–6 fresh biopsy cores, 1–2 cores were collected as formalin fixed paraffin embedded (FFPE) and the rest were frozen tissue. FFPE tissue was analyzed by multiplex immunohistochemistry (IHC) and RNAseq; reverse phase protein array was used for frozen cores. Plasma was collected at cycle 1 predose and 2, 8, 24, 48, and 168 h postdose and analyzed for M30, M65 (by ELISA) and circulating tumor DNA (64-gene PlasmaSELECT assay). Results: Twenty-five pts consented to biopsies; paired biopsies were obtained from 16 pts at a 64% success rate: FFPE (n = 15) and frozen cores (n = 12). Tumor cells were detected in 11/15 (73%) FFPE and 4/12 (33%) frozen cores. Increase in M30, activated caspases, and cleaved PARP levels was observed in on-Tx biopsy samples compared with pre-Tx, thus serving as evidence for apoptosis induction in tumors following eftoza dosing. Changes in the tumor microenvironment were observed post-Tx by RNAseq and multiplex IHC (eg, CD68 level). Downregulation of prosurvival signaling pathways (eg, AKT/MEK) was also observed following eftoza dosing. Thirteen out of 16 pts showed transient increase in mutant allele fractions post eftoza Tx that correlated with increased plasma circulating tumor markers M30 and M65 at similar time points, suggesting activation of apoptosis pathway. Increase in M30, M65 levels also preceded increase in liver enzymes (ALT/AST) at 2, 48 hr post-Tx. Conclusions: Pharmacodynamic effect of eftoza was successfully demonstrated in blood and tumor tissue, including induction of apoptosis and modulation of PI3K and MEK signaling pathways. Clinical trial information: NCT03082209.

Introduction: Despite some long-term remissions, eventual drug resistance in most patients remains a critical obstacle in the treatment of multiple myeloma (MM). The development of new drugs/drug combinations with novel mechanisms of action are needed for continued improvement in patient outcomes. Initiation of tumor cell death via activation of the intrinsic (mitochondrial) and/or extrinsic (death receptor) apoptotic signaling pathways has been shown to be an effective therapeutic strategy in MM. Venetoclax (Ven) is a selective, small-molecule inhibitor of BCL-2 that exhibits clinical activity in MM cells, particularly in patients harboring the t(11;14) translocation. Navitoclax (Nav) is a small-molecule that targets multiple antiapoptotic BCL-2 family proteins, including BCL-XL, BCL-2, and BCL-W to initiate the intrinsic apoptotic pathway. Eftozanermin alfa (Eftoza) is a novel, second generation TRAIL receptor agonist that induces cell death via death receptor pathways and is under investigation in multiple solid and heme malignancies. In addition, the pan-BET inhibitor mivebresib (Miv) and the BDII selective BET inhibitor ABBV-744 have shown synergistic activity with Ven in cell line models of multiple heme malignancies. Results reported here describe ex vivo drug sensitivities and functional genomic analyses of Ven, Nav, Eftoza, Miv, and ABBV-744 alone or in combination with standard-of-care agents, including bortezomib, carfilzomib, panobinostat, daratumumab, or pomalidomide. Methods: A high-throughput ex vivo drug screening assay using a coculture system of bone marrow (BM)-derived MM and stromal cells was used to assess the sensitivity of MM patient tumor cells (Figure 1A). Paired whole exome sequencing (WES) and RNA sequencing (RNA-seq) analyses were performed. Results: Primary MM patient specimens (n=52) were evaluated in the ex vivo platform, including treatment-naïve, early relapse (1-3 prior lines), and late relapse (4-8 prior lines) patients treated with proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. As expected, t(11;14)-positive MM patient specimens were more sensitive than wildtype to Ven ex vivo (D AUC, -18.6, P=0.002), however MM cells harboring amp(1q) were more resistant than wildtype (D AUC, +5.07, P=0.032), suggesting MCL1 (1q21 gene locus) is a key resistance factor to Ven single-agent activity in MM. Gene set enrichment analysis identified B-cell receptor signaling (normalized enrichment score (NES), 1.96, adjusted P=0.010) and MYC pathway (NES, 1.95, adjusted P=0.010) overexpression as predictors of increased sensitivity to Ven ex vivo. A t(11;14) gene expression signature was also generated using a penalized regression model approach in an additional MMWG/ORIEN MM patient cohort (n=155). The t(11;14) predictive gene expression signature was confirmed by correlation with Ven AUC in the ex vivo model. Additional pathway analyses were performed to identify potential predictive markers of sensitivity/resistance for each single agent and drug combination. Although ex vivo activity of Nav was higher in t(11;14) specimens compared to non-t(11;14) (D AUC, -17.8, P=0.011), ex vivo activity in non-t(11;14) specimens was also observed, indicating additional anti-MM activity by cotargeting of BCL-XL and BCL-2. Both Miv and ABBV-744 showed single-agent activity ex vivo, however Miv demonstrated higher activity (median LD50=88.4nM), suggesting that pan-BET inhibition is more effective than BDII-specific BET inhibition in MM. Finally, a novel drug-combination effect analysis was used that identified novel synergistic ex vivo combinations including Ven and panobinostat (P=0.0013) and Eftoza with bortezomib (P=1.8E-7) or carfilzomib (P=7E-4). Additionally, single-agent induction of macrophage-mediated phagocytosis was observed in both Ven and daratumumab, which was synergistic when the 2 drugs were combined (Figure 1B). Conclusion: An ex vivo functional genomic screen of MM patient specimens demonstrated the usefulness of this approach to identify candidate drugs and potential predictive biomarkers for continued evaluation in clinical trials. This approach confirmed known mechanisms of drug sensitivity and identified new ones, including a novel characterized immune-mediated synergy between Ven and daratumumab, and potential combination strategy for Eftoza and proteasome inhibitors. Figure 1 Disclosures Siqueira Silva: Karyopharm: Research Funding; NIH/NCI: Research Funding; AbbVie: Research Funding. Kulkarni:M2GEN: Current Employment. Mitchell:AbbVie: Other: payment for bioinformatics analysis, Research Funding; M2GEN: Current Employment, Research Funding. Dai:Cygnal Therapeutics: Current Employment; M2GEN: Ended employment in the past 24 months. Hampton:M2GEN: Current Employment. Lu:AbbVie: Current Employment, Current equity holder in publicly-traded company. Modi:AbbVie: Current Employment, Other: may own stock or stock options. Motwani:AbbVie: Current Employment, Current equity holder in publicly-traded company. Harb:AbbVie: Current Employment, Other: may hold stock or stock options. Ross:AbbVie: Current Employment, Current equity holder in publicly-traded company. Shain:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; AbbVie: Research Funding; Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy, Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: While this is a preclinical study, venetoclax for treatment of multiple myeloma is not an approved indication

High-grade serous ovarian cancer (HGSOC) is thought to progress from a series of precursor lesions in the fallopian tube epithelium (FTE). One of the preneoplastic lesions found in the FTE is called a secretory cell outgrowth (SCOUT), which is partially defined by a loss of paired box 2 (PAX2). In the present study, we developed PAX2-deficient murine cell lines in order to model a SCOUT and to explore the role of PAX2 loss in the etiology of HGSOC. Loss of PAX2 alone in the murine oviductal epithelium (MOE) did not induce changes in proliferation, migration and survival in hypoxia or contribute to resistance to first line therapies, such as cisplatin or paclitaxel. RNA sequencing of MOE PAX2shRNA cells revealed significant alterations in the transcriptome. Silencing of PAX2 in MOE cells produced a messenger RNA expression pattern that recapitulated several aspects of the transcriptome of previously characterized human SCOUTs. RNA-seq analysis and subsequent qPCR validation of this SCOUT model revealed an enrichment of genes involved in estrogen signaling and an increase in expression of estrogen receptor α. MOE PAX2shRNA cells had higher estrogen signaling activity and higher expression of putative estrogen responsive genes both in the presence and absence of exogenous estrogen. In summary, loss of PAX2 in MOE cells is sufficient to transcriptionally recapitulate a human SCOUT, and this model revealed an enrichment of estrogen signaling as a possible route for tumor progression of precursor lesions in the fallopian tube.

7030 Background: Bromodomain and extra-terminal (BET) proteins bind to acetyllysines and upregulate oncogenic target genes. Mivebresib (ABBV-075) is a pan-BET inhibitor with antitumor activity in vitro and xenograft models of AML. This 2-part phase 1 study evaluates the safety and pharmacokinetics of mivebresib at monotherapy or combination dosing schedules in patients with solid tumors (part 1) and acute myeloid leukemia (AML; part 2) (NCT02391480). Here, we report preliminary data from part 2 in patients with relapsed/refractory (RR) AML. Methods: Mivebresib monotherapy (MIV-mono), or combined with venetoclax (MIV-VEN), were administered daily to adult patients with AML. The dose-limiting toxicity (DLT) period was 28 d. Results: As of Dec 2018, 41 patients (median age: 69 y [range, 29–84]; 19 patients had > 2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-combo) and 22 who began treatment in MIV-VEN cohorts. 23 patients had high cytogenetic risk. Median time on treatment was 28 d (range, 8–562). There were no DLTs. All patients experienced a treatment-emergent adverse event (AE), most commonly (≥40% patient incidence), fatigue (56%), dysgeusia (46%), decreased appetite (44%), diarrhoea (42%), nausea (42%), vomiting (42%). 40 patients had grade ≥3 AEs (febrile neutropenia (37%), anemia (34%) and thrombocytopenia (32%). 33 patients had serious AEs, most commonly febrile neutropenia (19%). 25 deaths were reported; 15 patients died of causes unrelated to mivebresib and 10 patients due to AML progression. The median best % bone marrow blast change for 26 evaluable patients was -20% (range, -98% to +300%). Gene expression analysis in pre- and post-treatment peripheral blood samples showed that HEXIM1, DCXR and CD93 genes were reliable PD biomarkers of ABBV-075 which were consistently modulated in a dose-dependent manner. At the cutoff date, median overall survival for all patients was 2.6 m. Conclusions: Mivebresib was well tolerated and showed antileukemic effects in patients with RR AML. Clinical trial information: NCT02391480.

Background: Apoptotic cell death can be triggered by activation of extrinsic and intrinsic signaling pathways. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, binds to its death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) to selectively activate the extrinsic apoptotic pathway in cancer cells. ABBV-621 is a second-generation TRAIL receptor agonist with antitumor activity as monotherapy (621-mono) in preclinical models of AML and DLBCL. The intrinsic apoptotic pathway is regulated by the BCL2 protein family, commonly overexpressed in hematologic malignancies. Venetoclax (VEN), a highly selective small-molecule BCL2 inhibitor, has shown antitumor activity in combination therapy in AML and DLBCL. In preclinical and xenograft models of AML and DLBCL, the ABBV-621 and VEN combination (621-VEN) had antitumor activity superior to either agent alone. This first-in-human study evaluated ABBV-621 as single agent and in combination in pts with advanced solid tumors and hematologic malignancies (NCT03082209). Safety and tolerability of ABBV-621 in advanced solid tumors have previously been presented (Ratain et al. J Clin Oncol 2019;37[suppl]: abstr 3013). Here, we report preliminary data for 621-mono in pts with RR AML and for 621-VEN in pts with RR AML and DLBCL. Methods: Adult pts with RR AML or DLBCL (ECOG 0-2) were enrolled. Pts with AML received ABBV-621 at 1.25-, 3.75-, 7.5-mg/kg doses in the 621-mono and at 3.75-mg/kg dose in the 621-VEN arms. Pts in the DLBCL 621-VEN arm received ABBV-621 at 3.75- and 7.5-mg/kg doses. ABBV-621 was administered intravenously on D1, 8, and 15 of a 21-D cycle; in 621-VEN cohorts pts received 400 mg oral VEN daily, and could be escalated to 800 mg. The primary endpoint was safety. In addition, preliminary antitumor efficacy and ABBV-621 binding to decoy receptors on neutrophils from peripheral blood were assessed. Results: As of Jun 2019, 17 pts were enrolled. Pts in AML 621-mono arm (1.25 [1], 3.75 [1], 7.5 [2] mg/kg): 1 male; median (med) age, 75 yr (range 71-82); med prior treatments, 2.5 (range 1-4); med time on treatment, 15 D (range 1-70). Pts in AML 621-VEN arm (3.75 mg/kg [7]): 5 male; med age, 71 yr (60-79); med prior treatments, 2 (1-2); med time on treatment, 26 D (1-77). Pts in DLBCL 621-VEN arm (3.75 [3], 7.5 [3] mg/kg): 4 male; med age, 57 yr (40-75); stage 4 (3); med prior treatments, 2.5 (1 to ≥5); med time on treatment, 26 D (8-36). One pt in the AML 621-VEN 3.75-mg/kg dose cohort had increases in alanine aminotransferase, aspartate aminotransferase and bilirubin as dose-limiting toxicities. Sixteen pts experienced adverse events (AEs) irrespective of causality. A summary of AEs is shown in Table. One pt in the AML 621-mono 7.5-mg/kg dose cohort died due to AML progression, unrelated to ABBV-621. Antitumor activity was observed in 1 pt in the AML 621-VEN arm (with complex cytogenetics and TP53 mutation) who reached complete remission (CR). One pt in the DLBCL 621-VEN 3.75-mg/kg cohort had stable disease, 2 with AML had resistant disease (1 in 621-mono [7.5 mg/kg] and 1 in 621-VEN), and 7 had progressive disease (PD; 1 in AML 621-mono [1.25 mg/kg], 2 in AML 621-VEN, and 4 in DLBCL 621-VEN [2 each in 3.75- and 7.5-mg/kg] cohorts). Using flow cytometry, saturation of ABBV-621 binding to decoy receptors on neutrophils was observed at 2 h postdosing, followed by dose-dependent desaturation of receptors in pts with DLBCL at 48-168 h. In AML 621-VEN pts, ABBV-621 remained bound to decoy receptors for up to 168 h; in DLBCL 621-VEN pts, the duration of binding was higher at ABBV-621 7.5 mg/kg compared with 3.75 mg/kg. In AML, the baseline frequency of myeloblasts was higher in pts with PD than CR, while that of myelomonocytes was higher in the pt with CR. The frequency of myeloblasts and myelomonocytes expressing DR4 and DR5 at baseline was highest in the pt with CR (Figure). Conclusions: ABBV-621 was tolerated and showed antitumor activity in combination with VEN in pts with RR AML. Disclosures de Jonge: Faron Pharmaceuticals Ltd.: Consultancy. Carneiro:Actuate Therapeutics: Research Funding; Bayer: Research Funding; Pfizer: Research Funding; AstraZeneca: Research Funding; Medimmune: Research Funding; Astellas: Research Funding; AbbVie: Research Funding. Devriese:MSD: Consultancy. Penugonda:AbbVie: Employment, Other: Stock/stock options. Petrich:Abbvie: Employment, Equity Ownership. Nuthalapati:AbbVie: Employment, Other: Stock/stock options. Motwani:AbbVie: Employment, Other: Stock/stock options. Modi:AbbVie: Employment, Other: Stock/stock options. Chang:AbbVie: Employment, Other: Stock/stock options. Calvo:Celgene: Consultancy; Roche/Genentech: Consultancy, Other: travel/accommodations/expenses; Seattle Genetics: Consultancy; AstraZeneca: Consultancy, Research Funding; PsiOxus: Consultancy; Amcure: Consultancy; START: Other: stock/ownership interests, Research Funding; Janssen-Cilag: Consultancy; EUSA Pharma: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Oncoart Associated: Other: stock/ownership interests; Guidepoint Global: Consultancy; Nanobiotix: Consultancy; HM Hospitales Group: Honoraria; AbbVie: Consultancy; BeiGene: Research Funding; Servier: Consultancy; International Cancer Consultants: Other: stock/ownership interests; Foundation INTHEOS: Other: president and founder; Gerson Lehrman Group: Consultancy; Pfizer: Consultancy. Moreno:Puma Biotechnology: Consultancy; Sanofi/Regeneron: Other: travel/accommodations/expenses.

Background: The bromodomain and extra terminal (BET) family of proteins bind acetylated histone tails, leading to the regulation of oncogenic target genes. Mivebresib (ABBV-075; MIV) is a pan-BET inhibitor that has demonstrated antitumor activity in vitro and in xenograft models of acute myeloid leukemia (AML). This phase 1, first-in-human, 2-part study (NCT02391480) assessed the safety and pharmacokinetics (PK) of MIV at various monotherapy (MIV-mono) or combination dosing schedules with venetoclax (MIV-VEN). Here we report PK and pharmacodynamic (PD) data in correlation to biological activity in patients with relapsed/refractory AML. Methods: Gene expression analysis was performed on RNA extracted from whole blood samples collected at multiple time points (pre-and post-MIV-mono treatment). mRNA expression was analyzed from total RNA and sequenced on HiSeq 3000 (Illumina, San Diego, CA). Soluble cytokine modulation was evaluated in serum samples (pre- and post-MIV-mono treatment) on Myriad Rules-Based Medicine's ExplorerMAP® Panel (145 analytes; Myriad RBM, Austin, TX). Cytogenetic analysis was performed at each site using institutional guidelines. Molecular profiling was performed at the site and by AbbVie using targeted next-generation sequencing (myeloid-specific panel). PK sampling was done on cycle 1 day 1 (C1D1), C1D8 and C2D1. PK analyses were completed using non-compartmental analysis methods. A linear regression analysis was performed to determine association between drug exposure and percentage change in gene modulation from baseline at 6 hours on C1D1. Biologic activity was defined as measurable reduction in bone marrow (BM) blasts from baseline. Results: As of Jan 2019, 44 patients (median age: 68 y [range, 29-84]; 35 patients >2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-VEN) and 25 who began treatment in MIV-VEN cohorts. MIV (1-2.5 mg) exposures were dose proportional and MIV was rapidly absorbed with a Tmax of 2-6 hours and terminal half-life of ~15-20 hours. Concomitant administration of VEN did not show any clinically significant effect on MIV plasma PK at steady state. At 6 hours post-MIV-mono treatment, a significant correlation was observed between drug exposure and PD biomarker modulation, with a dose-dependent gene expression increase in DCXR and HEXIM1 and decrease in CD93 (p<0.05). MIV-mono treatment also inhibited BCL-2,Myc, and VEGF gene expression and induced the expression of the pro-apoptotic genes BIM and PUMA following 6 hours of MIV-mono dosing. In patients treated with MIV-mono, measurable reduction in BM blast counts was observed in 7/19 (37%) patients (Figure): complete remission (CR) with incomplete blood count recovery (n=1), ≥50% blast reduction (n=4), modest blast reduction of <50% (n=3). In patients treated with MIV-VEN (n=30, including 5 patients who switched treatment), measurable reduction in BM blasts was observed in 15/30 (50%) patients (Figure): ≥50% blast reduction (n=10), including CR (n=2), partial remission (n=2), morphologic leukemia-free state (MLFS; n=1), and modest blast reduction of <50% (n=5). Median duration of response for all treated patients was 29 days (range, 11-581). Median duration (range) of response for MIV-mono, MIV-VEN, and switched treatment was 28.5 (11, 230), 29.0 (17, 145), and 31 (28, 581) days, respectively. The majority of patients (30/44; 68%) were classified as adverse risk per ELN 2017 criteria. At baseline, 6/19 (32%) MIV-mono and 17/30 (57%) MIV-VEN patients had mutations in signaling genes; FLT3-ITD/TKD were the most commonly mutated in MIV-VEN population (10/17, 59%). In the MIV-VEN group, 4/10 (40%) patients with FLT3-ITD/TKD mutations and 4/6 (67%) patients with PTPN11 mutations had reduction in BM blasts following treatment. At baseline, 12/30 (40%) patients had mutations in either SF3B1/U2AF1 or PTPN11; 8 (67%) of these patients had reduction in BM blasts, including 1 CR and 1 MLFS. Conclusions: MIV exposure was dose proportional and a significant correlation was identified between multiple biomarkers (HEXIM1, DCXR, CD93 gene modulation) and drug exposure at 6 hours post-MIV treatment. MIV treatment inhibited BCL-2, VEGF and Myc gene expression, while inducing expression of pro-apoptotic genes. Biologic activity was observed particularly in patients treated with MIV-VEN who had SF3B1/U2AF1 or PTPN11 mutations. Disclosures Borthakur: Arvinas: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cantargia AB: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Merck: Research Funding; Janssen: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; PTC Therapeutics: Consultancy; Incyte: Research Funding; GSK: Research Funding. Odenike:Agios: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Oncotherapy: Research Funding; Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Research Funding. Aldoss:Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria; AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Rizzieri:AbbVie: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy; TEVA: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Amgen: Consultancy; Jazz Pharmaceuticals: Speakers Bureau; Millennium: Speakers Bureau. Prebet:Boehringer Ingelheim: Research Funding; pfizer: Honoraria; Tetraphase: Consultancy; Genentech: Consultancy; novartis: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria; novartis: Honoraria; novartis: Honoraria; Agios: Consultancy, Research Funding; pfizer: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria. Modi:AbbVie: Employment, Other: Stock/stock options. Joshi:AbbVie: Employment, Other: Stock/stock options. Hu:AbbVie: Employment, Other: Stock/stock options. Sun:AbbVie: Employment, Other: Stock/stock options. Wolff:AbbVie Inc: Employment, Other: Stock/stock options. Jonas:AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding.

AbstractPurpose:Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors.Patients and Methods:A 3 + 3 dose escalation for different mivebresib dosing schedules [daily, Monday/Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity.Results:Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2–3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8–1.9).Conclusions:On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.

The signaling events involved in the onset of ovarian cancer from the fallopian tube epithelium (FTE) are crucial for early detection and treatment of the disease, but they remain poorly defined. Conditional homozygous knockout of PTEN mediated by PAX8-cre recombinase was sufficient to drive endometrioid and serous borderline ovarian carcinoma, providing the first model of FTE-derived borderline tumors. In addition, heterozygous PTEN deletion in the FTE resulted in hyperplasia, providing a model to study early events of human ovarian pathogenesis. To uncover the mechanism underlying the invasion of cancerous oviductal cells to the ovary, PTEN-deficient murine oviductal cells were developed and tagged with green fluorescent protein. Loss of PTEN increased cell migration, invasion, and upregulated WNT4, a key regulator of Müllerian duct development during embryogenesis. Further investigation revealed that WNT4 was required for increased migration and colonization of the ovary by PTEN-deficient oviductal cells in a β-catenin independent manner. Human tumor microarrays and ovarian cancer cells lines confirmed WNT4 expression in cancer and its role in migration. Together, these findings provide a novel model to study the mechanism of fallopian tube tumor initiation and invasion to the ovary mediated by loss of PTEN, which may help to define early events of human ovarian carcinogenesis.

2570 Background: ABBV-075 is an oral small molecule inhibitor of the BET family of bromodomain-containing proteins that function as regulators controlling many transcriptional programs required for cancer pathogenesis. ABBV-075 is currently being evaluated in a FIH study in advanced solid tumors (M14-546). Using a 3+3 dose escalation design, a total of 72 solid tumor patients were treated across 3 dosing schedules. Dose-limiting toxicities were thrombocytopenia, fatigue, aspartate aminotransferase elevation, gastrointestinal bleed, and hypertension in the dose escalation phase. Methods: In this report, pharmacokinetic (PK) and pharmacodynamic (PD) data are presented for 40 subjects. PD effect was measured in surrogate tissue (whole blood and serum), which was collected prior to therapy and at various time points post-dosing. Gene expression was evaluated by branched DNA assay. Soluble cytokines were analyzed by immunoassay (Myriad RBM’s InflammationMAP®). Results: The observed Tmax occurred at 2-4 hours post dosing, Cmax and AUCinf increased dose-proportionally within the dose-range studies, mean t1/2 : 13 - 32 hours. Exposure (Cmax) at day 8 correlated with decrease in platelet count on day 15 compared to baseline counts (Pearson correlation: -0.46, p = 0.032). HEXIM1 and DCXR gene expression increased, CD93 gene expression decreased at 6 hours post treatment. CD93 and DCXR demonstrated dose-dependent modulation. Statistically significant correlation was observed between gene modulation at 6 hours and drug exposure at day 8 (Pearson correlation: HEXIM1 = 0.435, CD93 = 0.375, DCXR = 0.541). Soluble BDNF expression demonstrated a dose and time-dependent decrease at cycle 2 and 3 compared to baseline (p < 0.0001). Conclusions: We demonstrated target engagement in surrogate tissue via modulation of gene and soluble cytokine expression, both of which were dose dependent. Strong correlation was observed between drug exposure and gene expression modulation as well as thrombocytopenia, after ABBV-075 treatment. Correlation of these PD effects with adverse events and clinical response, are currently under investigation. Clinical trial information: NCT02391480.

Ovarian cancer is the fifth leading cause of cancer death among US women. Evidence supports the hypothesis that high‐grade serous ovarian cancers (HGSC) may originate in the distal end of the fallopian tube. Although a heterogeneous disease, 96% of HGSC contain mutations in p53. In addition, the “p53 signature,” or overexpression of p53 protein (usually associated with mutation), is a potential precursor lesion of fallopian tube derived HGSC suggesting an essential role for p53 mutation in early serous tumorigenesis. To further clarify p53‐mutation dependent effects on cells, murine oviductal epithelial cells (MOE) were stably transfected with a construct encoding for the R273H DNA binding domain mutation in p53, the most common mutation in HGSC. Mutation in p53 was not sufficient to transform MOE cells but did significantly increase cell migration. A similar p53 mutation in murine ovarian surface epithelium (MOSE), another potential progenitor cell for serous cancer, was not sufficient to transform the cells nor change migration suggesting tissue specific effects of p53 mutation. Microarray data confirmed expression changes of pro‐migratory genes in p53R273H MOE compared to parental cells, which could be reversed by suppressing Slug expression. Combining p53R273H with KRASG12V activation caused transformation of MOE into high‐grade sarcomatoid carcinoma when xenografted into nude mice. Elucidating the specific role of p53R273H in the fallopian tube will improve understanding of changes at the earliest stage of transformation. This information can help develop chemopreventative strategies to prevent the accumulation of additional mutations and reverse progression of the “p53 signature” thereby, improving survival rates.

Ovarian cancer is the most lethal gynecological malignancy. Current treatment modalities include a combination of surgery and chemotherapy, which often lead to loss of fertility in premenopausal women and a myriad of systemic side effects. To address these issues, we have designed poly(amidoamine) (PAMAM) dendrimers to selectively target the follicle stimulating hormone receptor (FSHR), which is overexpressed by tumorigenic ovarian cancer cells but not by immature primordial follicles and other non-tumorigenic cells. Fluorescein-labeled generation 5 (G5) PAMAM dendrimers were conjugated with the binding peptide domain of FSH (FSH33) that has a high affinity to FSHR. The targeted dendrimers exhibited high receptor selectivity to FSHR-expressing OVCAR-3 cells, resulting in significant uptake and downregulation of an anti-apoptotic protein survivin, while showing minimal interactions with SKOV-3 cells that do not express FSHR. The selectivity of the FSH33-targeted dendrimers was further validated in 3D organ cultures of normal mouse ovaries. Immunostaining of the conjugates revealed their selective binding and uptake by ovarian surface epithelium (OSE) cells that express FSHR, while sparing the immature primordial follicles. In addition, an in vivo study monitoring tissue accumulation following a single intraperitoneal (i.p.) injection of the conjugates showed significantly higher accumulation of FSH33-targeted dendrimers in the ovary and oviduct compared to the non-targeted conjugates. These proof-of-concept findings highlight the potential of these FSH33-targeted dendrimers to serve as a delivery platform for anti-ovarian cancer drugs, while reducing their systemic side effects by preventing nonspecific uptake by the primordial follicles.