Supplemental Table 1. Demographics and baseline characteristics by histology: squamous cell Supplemental Table 2. Demographics and baseline characteristics by histology: non-squamous cell Supplemental Table 3. Mean {plus minus} SD pharmacokinetic parameters of veliparib on cycle 1 day 3 Supplemental Table 4. Mean {plus minus} SD (median) plasma concentrations of paclitaxel and carboplatin at 5 min before ending paclitaxel and carboplatin infusions, respectively Supplemental Figure 1: Progression-free survival (A) and overall survival (B) in responders and non-responders

Supplementary Table 1 from Chemokine Expression in Melanoma Metastases Associated with CD8⁺ T-Cell Recruitment

Supplementary Figure Legend from Chemokine Expression in Melanoma Metastases Associated with CD8+ T-Cell Recruitment

T cell receptor (TCR)-based therapy has the potential to induce durable clinical responses in patients with cancer by targeting intracellular tumor antigens with high sensitivity and by promoting T cell survival. However, the need for TCRs specific for shared oncogenic antigens and the need for manufacturing protocols able to redirect T cell specificity while preserving T cell fitness remain limiting factors. By longitudinal monitoring of T cell functionality and dynamics in 15 healthy donors, we isolated 19 TCRs specific for Wilms' tumor antigen 1 (WT1), which is overexpressed by several tumor types. TCRs recognized several peptides restricted by common human leukocyte antigen (HLA) alleles and displayed a wide range of functional avidities. We selected five high-avidity HLA-A*02:01-restricted TCRs, three that were specific to the less explored immunodominant WT137-45 and two that were specific to the noncanonical WT1-78-64 epitopes, both naturally processed by primary acute myeloid leukemia (AML) blasts. With CRISPR-Cas9 genome editing tools, we combined TCR-targeted integration into the TCR α constant (TRAC) locus with TCR β constant (TRBC) knockout, thus avoiding TCRαβ mispairing and maximizing TCR expression and function. The engineered lymphocytes were enriched in memory stem T cells. A unique WT137-45-specific TCR showed antigen-specific responses and efficiently killed AML blasts, acute lymphoblastic leukemia blasts, and glioblastoma cells in vitro and in vivo in the absence of off-tumor toxicity. T cells engineered to express this receptor are being advanced into clinical development for AML immunotherapy and represent a candidate therapy for other WT1-expressing tumors.

ImportanceNeoadjuvant systemic therapy (NST) is often administered to enable breast-conserving therapy (BCT) in stages II to III breast cancer.ObjectivesTo prospectively evaluate the role of NST in conversion from BCT ineligibility to BCT eligibility and to assess the association of response to NST, germline BRCA (gBRCA) status, and region of treatment with surgical choice in women with triple-negative breast cancer (TNBC).Design, Setting, and ParticipantsThis prespecified secondary analysis of a multicentered, phase 3, double-blind, randomized clinical trial (BrighTNess) enrolled 634 eligible women across 145 centers in 15 countries in North America, Europe, and Asia. Women with operable, clinical stages II to III TNBC who underwent gBRCA mutation testing before initiating NST were eligible to participate. Data were collected from April 1, 2014, to December 8, 2016. This preplanned analysis was performed from January 5, 2018, to October 28, 2019.InterventionsStudy participants were randomized to receive 12 weeks of weekly paclitaxel alone or with the addition of carboplatin and/or veliparib, followed by 4 cycles of doxorubicin hydrochloride and cyclophosphamide.Main Outcomes and MeasuresSurgeons assessed BCT candidacy by clinical and radiographic criteria before and after NST. Surgical choices and whether BCT eligibility was associated with the likelihood of pathologic complete response were then analyzed.ResultsAmong the 634 randomized patients (median age, 51 [range, 22-78] years), pre- and post-NST assessments were available for 604 patients. Of 141 patients deemed BCT ineligible at baseline, 75 (53.2%) converted to BCT eligible. Overall, 342 (68.1%) of 502 patients deemed BCT eligible after NST underwent BCT, including 42 (56.0%) of the 75 who converted to BCT eligible. Patients treated in Europe and Asia were more likely to undergo BCT (odds ratio, 2.66; 95% CI, 1.84-3.84) compared with those treated in North America. Among patients without gBRCA mutation undergoing mastectomy, those treated in North America were more likely to undergo contralateral prophylactic mastectomy (57 of 81 [70.4%] vs 6 of 30 [20.0%]; P < .001). Rates of pathologic complete response were similar between patients deemed BCT eligible at baseline and those who were BCT ineligible but converted to BCT eligibility after NST (55.3 [235 of 425] vs 49.3% [37 of 75]; P = .38).Conclusions and RelevanceThis prospective analysis of NST and BCT eligibility in TNBC demonstrates a conversion from BCT ineligibility to BCT eligibility of 53.2%. Lower BCT rates among eligible patients and higher bilateral mastectomy rates among patients without gBRCA mutation in North America merit investigation.Trial RegistrationClinicalTrials.gov identifier: NCT02032277.

Adoptive cell therapy using T cells expressing transgenic (tg) tumor antigen-targeting T cell receptors (TCRs) has become an attractive modality to treat hematological and solid cancers due to a broader array of accessible targets relative to CAR-T cell therapies. However, high-avidity TCRs specific for shared oncogenic antigens are difficult to identify. In addition, manufacturing of TCR-redirected T cells with single TCR specificity is desired to avoid mispairings and competition with endogenous chains, which can negatively impact T cell specificity and TCR expression levels. This can be achieved with CRISPR/Cas9-mediated replacement of the endogenous TCR α and β chains, by knocking out the TRAC and TRBC genes and inserting the tgTCR into the TRAC locus. While CRISPR/Cas9 genome editing has been demonstrated to be highly efficient, simultaneous edits in different loci could result in increased translocations, potentially impairing the quality and safety of the cell product. Moreover, existing cell engineering technology negatively impacts T cell quality and yield. Here, we focused on engineering T cells with specificity for Wilms' Tumor 1 (WT1), a transcription factor overexpressed by a wide range of hematological and solid tumors, that has both, restricted expression on healthy tissues and a strong correlation with oncogenesis. By applying rapid isolation technologies of WT1-specific T cells from healthy donors, we identified a lead TCR to the WT137-45 epitope, restricted to the common human leukocyte antigen, HLA-A*02:01. T cells expressing this tgTCR showed nM avidity and killed leukemia cell lines and primary acute myeloid leukemia (AML) blasts at low effector-to-target cell ratios. Epitope specificity evaluation by alanine scanning suggested that the minimal peptide recognition sequence for this TCR is restricted to WT1. Further, the lead TCR was able to activate CD8+ and CD4+ T cells, which may be beneficial for T cell persistence. By developing an improved T cell engineering process, we have achieved multiple sequential gene edits in primary human T cells, leading to knockout of the endogenous TCR with up to 99% efficiency and insertion of tgTCRs into 55-80% of the cells. This cell engineering process is scalable, adaptable to a closed system, and results in marked improvements in T cell expansion, yield, stem cell memory phenotype and T cell polyfunctionality, such as cytotoxicity, cytokine release and proliferation in response to WT1+ target cells. Additionally, the high viability profile of the process readily allows for sequential CRISPR/Cas9 gene knockout in T cells, leading to near-complete endogenous TCR removal while limiting TRAC/TRBC translocation to levels close to those found in untreated cells. T cells engineered to express the lead TCR using this process resulted in potent anti-tumor activity in vivo. Disseminated primary AML patient derived xenograft and acute lymphoblastic leukemia (ALL) cell line models were established by intravenous injection of the tumor cells in NSG or NOG mice. Animals were treated subsequently with WT1-specific or control T cells. Almost complete tumor growth inhibition in the blood and bone marrow was noted in the primary AML model. In the fast growing ALL model, WT1-T cells significantly reduced tumor burden and increased survival compared to control groups, which could be further boosted in human IL-15-expressing NOG mice vs. standard NOG mice. No signs of graph-versus-host disease (GvHD) were observed during the course of the study, which is consistent with removal of the endogenous TCR. NTLA-5001 is being advanced into clinical development for AML immunotherapy. Given the expression of WT1 in many solid tumors, engineered WT1 TCR-T cells are being further explored in those indications. Disclosures Liu: Intellia Therapeutics: Current Employment. Prodeus:Intellia Therapeutics: Current Employment. Becker:Intellia Therapeutics: Current Employment. Foisey:Intellia Therapeutics: Current Employment. Balwani:Intellia Therapeutics: Current Employment. Dutta:Intellia Therapeutics: Current Employment. Zhang:Intellia Therapeutics: Current Employment. Arredouani:Intellia Therapeutics: Current Employment. McKee:Intellia Therapeutics: Current Employment. Ciceri:Intellia Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sepp-Lorenzino:Intellia Therapeutics: Current Employment. Bonini:Kiadis: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Molmed: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Intellia Therapeutics: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Schultes:Intellia Therapeutics: Current Employment, Current equity holder in publicly-traded company.

e14585Background: Uveal melanoma represents 3–5% of all melanomas, and approximately half of these pts will develop metastatic disease. Progression-free survival (PFS) with systemic therapy is 2.6–...

Background Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer. Methods We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II-III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m(2) intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277. Findings Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p<0.0001), but not compared with patients receiving paclitaxel plus carboplatin (92 [58%] of 160 patients, p=0.36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 [56%] of 628 patients), anaemia (180 [29%]), and thrombocytopenia (75 [12%]) through complete treatment, and febrile neutropenia (88 [15%] of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 [13%] of 628 patients) and anaemia (20 [3%]). Interpretation Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer.

Abstract Acute myeloid leukemia (AML) co-clinical modeling has been optimized with peripheral blood mononuclear cells (PBMCs) collected from low volume (14 mL) patient samples to establish an algorithm for efficiently co-clinically modeling AML patients. Methods: PBMCs were ficoll gradient purified and viably cryopreserved. Intrahepatic (i.h.) inoculation of AML PBMCs in neonate NOD/Shi-scid-IL2rγnull (NOG) mice and intravenous (i.v.) inoculation in both juvenile NOG mice and juvenile human transgenic IL-3/GMCSF NOD/Shi-scid-IL2rγnull mice (NOG-EXL) were evaluated. Bone marrow (BM) aspirates, splenocytes and PBMCs from mice were evaluated by fluorescence-activated cell sorting (FACS) at 12 weeks post AML inoculation for engraftment as determined by % ratio of human CD33+ cells to total CD45+ cells (human + murine cells). Humerus bones from inoculated animals were also evaluated by human CD33 immunohistochemistry (IHC). Results: Cells from 2/6 AML patient samples (CTG-2224 and CTG-2357) successfully engrafted into neonate mice. Animals were dosed with vehicle, cytarabine, ABBV-075 (clinical trial-staged BET family bromodomain (BD) inhibitor), or ABBV-744 (a preclinical BDII selective inhibitor) and evaluated for tumor burden six weeks post drug treatment initiation. ABBV-075 and ABBV-744 treated animals had lower tumor burden in the CTG-2224 model, 17% (p<0.05) and 4% (p<0.01); respectively. Similar trends, albeit at lower engraftment (10%), were observed for both models in spleen and blood compartments. In an effort to improve engraftment efficiency NOG-EXL mice were evaluated as hosts for engraftment with a patient PBMC sample (CTG-2357) and compared with juvenile NOG mice. Efficiency in the number of mice engrafted (8/8 vs. 3/7) and the extent of BM engraftment (51% vs. 14%) following a 0.5 X 106 PBMC inoculation was improved with the NOG-EXL mice. Furthermore, a patient inoculum (CTG-2241) that had previously shown no engraftment in juvenile NOG mice exhibited a 92% take rate with 93% BM tumor burden in NOG-EXL mice. Discussion: Prior advances in AML modeling show engraftment in IL2rγnul mouse models including i.h. and i.v. inoculation of BM clinical isolates in neonate NSG mice, i.v. inoculation of leukapheresis clinical isolates in juvenile NSG and NSG-SGM3 mice, and i.v. inoculation of BM aspirates in MISTRG mice. Each approach has limitations in terms of tedious neonate mice husbandry, ease of clinical sample collection with respect to clinical patient compliance, and mouse strain availability. Here we examined the feasibility of efficiently engrafting AML regardless of mutation or clinical stage from 14 ml PBMC samples. Results showed that i.v. inoculation of AML clinical samples in juvenile NOG-EXL mice was advantageous. This research is prerequisite for conducting translational co-clinical in vivo pharmacology studies for ABBV-075. Citation Format: Neal C. Goodwin, Daniel H. Albert, Angela M. Davies, Jenny Rowe, Gerold Feuer, Michael Boyiadzis, Kathleen A. Dorritie, Maria Mancini, Regina Gandour-Edwards, Warren M. Kati, Mark D. McKee, Keith F. McDaniel, David J. Frost. Acute myeloid leukemia human/mouse co-clinical trial feasibility study optimized in human transgenic IL-3/GMCSF NOD/Shi-scid-IL2rγnull mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1150.

519 Background: HRD status is significantly associated with a higher rate of response to neoadjuvant platinum-based therapy and improved PFS following adjuvant doxorubicin and cyclophosphamide (AC) in TNBC. We assessed the prognostic and predictive role of the HRD assay for platinum and PARP inhibitor response in BrighTNess. Methods: 634 stage II-III TNBC pts were randomized 2:1:1 to: Arm A: Paclitaxel (T) q wk x 12 + carboplatin (P) (AUC 6) q3 wk x 4 + veliparib (TPV) - > AC q2-3 wk x 4; Arm B: T + P + placebo (TP) - > AC; or Arm C: T + dual placebo (T) - > AC. HRD status was defined as HRD+ (HRD score ≥ 42 or a tumor BRCA1/2 mutation) or HRD- (HRD score < 42 and no tumor BRCA1/2 mutation). An exploratory HRD threshold of ≥ 33 vs < 33 was also assessed. Results: HRD status was available for 438 pts. HRD data by arm for pCR for the 42 and 33 cut-offs are shown. Within each arm using the 42 and 33 cut-offs, respectively, ORs for pCR by HRD status (HRD+/HRD-) were 2.85 (p = 0.0005) and 3.10 (p = 0.004) for Arm A, 1.55 (p = 0.30) and 2.28 (p = 0.10) for Arm B and 2.13 (p = 0.13) and 1.52 (0.48) for Arm C. Comparing between arms using the 42 threshold, ORs for pCR (Arm A/Arm B, Arm A/Arm C, Arm B/Arm C) in the HRD+ group were 1.04, 3.02 and 2.90 and were not statistically significantly different than in the HRD- group (0.57 [p = 0.23], 2.26 [p = 0.60] and 4.0 [p = 0.61]). Similar results were observed with the 33 cut-off. Conclusions: In BrighTNess, higher rates of pCR were observed in HRD+ pts across all treatment arms. However, pts treated with P had higher rates of pCR in both HRD+ and HRD- subsets. The exploratory HRD threshold of 33 appeared to provide greater sensitivity to identify responders with the addition of P + V. Receipt of AC in all pts may have contributed to the lack of interaction observed between HRD status and P +/- V treatment. Clinical trial information: NCT02032277.Arm pCR HRD+ ≥ 42 pCR HRD- < 42 pCR HRD+ ≥ 33 pCR HRD- < 33 TPV-AC (A) n = 213 87/141 (61.7%) 26/72 (36.1%) 93/153 (60.8%) 20/60 (33.3%) TP-AC (B) n = 116 51/84 (60.7%); p = 0.88# 16/32 (50%); p = 0.18# 57/92 (62%); p = 0.89# 10/24 (41.4%); p = 0.61# T-AC (C) n = 109 24/69 (34.8%); p = 0.0003‡ 8/40 (20%); p = 0.08‡ 25/79 (31.6%); p = < 0.0001‡ 7/30 (23.3%); p = 0.46‡ # = for TPV-AC vs TP-AC; ‡ = for TPV-AC vs T-AC

Background Ilorasertib (ABT-348) inhibits Aurora and VEGF receptor (VEGFR) kinases. Patients with advanced solid tumours participated in a phase 1 dose-escalation trial to profile the safety, tolerability, and pharmacokinetics of ilorasertib. Methods Ilorasertib monotherapy was administered at 10–180 mg orally once daily (Arm I, n = 23), 40–340 mg orally twice daily (Arm II, n = 28), or 8–32 mg intravenously once daily (Arm III, n = 7), on days 1, 8, and 15 of each 28-day cycle. Results Dose-limiting toxicities were predominantly related to VEGFR inhibition. The most frequent treatment-emergent adverse events ( > 30%) were: fatigue (48%), anorexia (34%), and hypertension (34%). Pharmacodynamic markers suggested that ilorasertib engaged VEGFR2 and Aurora B kinase, with the VEGFR2 effects reached at lower doses and exposures than Aurora inhibition effects. In Arm II, one basal cell carcinoma patient (40 mg twice daily (BID)) and one patient with adenocarcinoma of unknown primary site (230 mg BID) had partial responses. Conclusions In patients with advanced solid tumours, ilorasertib treatment resulted in evidence of engagement of the intended targets and antitumour activity, but with maximum inhibition of VEGFR family kinases occurring at lower exposures than typically required for inhibition of Aurora B in tissue. Clinical Trial Registration: NCT01110486

The poly( ADP ‐ribose) polymerase‐1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended‐release ( ER ) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib‐ ER up to 800 mg once daily or 600 mg twice daily. Dose‐limiting toxicities ( DLT s), recommended phase II dose ( RP 2D), and maximum tolerated dose ( MTD ) were assessed in cycle 1 and safety/tolerability during continuous administration (28‐day cycles). Seventy‐one patients ( n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility ( BRCA ) gene mutations. Single‐dose veliparib‐ ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration‐time curve compared with veliparib immediate‐release ( IR ). Three patients experienced DLT s (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP 2D and MTD for veliparib‐ ER were 400 mg BID . The most frequent adverse events ( AE s) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment‐related AE s were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib‐ ER , versus veliparib‐ IR , exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA ‐mutated breast cancers.

2510 Background: BDs are protein domains that bind to acetylated histone tails, leading to upregulation of target genes driving oncogenesis. Inhibition of the BET family prevents assembly of the macromolecular complex and its transcriptional response. ABBV-075 is a pan-BET inhibitor that induces death in cell lines and tumor growth inhibition in xenograft models. This first-in-human, phase 1, two-part study (NCT02391480) assessed the safety and pharmacokinetics of ABBV-075 in pts with advanced tumors. Results from the dose escalation part in pts with solid tumors are reported. Methods: The dose escalation part of this open-label study enrolled adult pts with R/R solid tumors in a 3+3 fashion. Endpoints included maximum tolerated dose, recommended phase 2 dose (RP2D) at different ABBV-075 dosing schedules (daily, Monday/Wednesday/Friday [MWF], or 4 days on/3 off [4/7]), safety and preliminary efficacy. Results: As of Dec 2017, 72 pts with solid tumors enrolled in the dose escalation cohort. Most common tumors were: uveal/choroidal melanoma (n = 10); breast (n = 8); pancreatic (n = 6); head and neck (n = 5); and prostate (n = 3). Median age was 61.5 years (range 23–83); median treatment duration was 7.6 weeks (range 0.9–39.6). In total, 23, 27, and 22 pts entered the daily, MWF and 4/7 schedules. Overall, 71 pts (98.6%) reported ≥1 treatment-emergent adverse events (TEAEs); thrombocytopenia (56.9%), dysgeusia (48.6%), fatigue (43.1%) and nausea (34.7%) were most common. Grade 3/4 TEAEs were reported in 52 pts (72.2%); thrombocytopenia (30.6%) and anemia (15.3%) were most common; 11 pts died (none considered study drug related). Dose-limiting toxicities included thrombocytopenia, fatigue, aspartate aminotransferase elevation, gastrointestinal bleed and hypertension. The RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7 and 3 mg for MWF. Of 65 evaluable pts, 25 pts (38.5%) had stable disease and 40 pts (61.5%) had progressive disease. Median progression-free survival was 1.8 months (95% CI: 1.8, 1.9). Conclusions: ABBV-075 has a tolerable safety profile and led to stable disease in some pts with malignant solid tumors. Clinical trial information: NCT02391480.

Objective. Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies. Methods. In this phase I study, patients with metastatic or unresectable solid tumors and prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800 mg/m(2) on days 1 and 8 of a 21-day cycle for maximum 10 cycles, followed by optional veliparib maintenance therapy. Veliparib dosing commenced twice-daily (BID) continuously on day 1 of cycle 2; granulocyte colony-stimulating factor was permitted. Dose escalation used a Bayesian continual reassessment method. Safety, tolerability, and efficacy were evaluated. Results. Seventy-five patients were enrolled (ovarian cancer, n = 54; breast cancer, n = 12). Thirty-six patients with ovarian cancer (67%) had known germline BRCA mutations. Most common treatment-related adverse events (TRAEs: >= 60%) were thrombocytopenia, neutropenia, nausea, and anemia. Most common grade 3/4 TRAEs (>= 40%) were neutropenia and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia and neutropenia. The MTD/RP2D was established at veliparib 250 mg with carboplatin AUC 4 plus gemcitabine 800 mg/m(2). Responses were observed in 69% of patients with BRCA-deficient ovarian cancer (45% partial, 24% complete responses). Five patients remained on veliparib (80-310 mg BID) for >34 cycles. Conclusions. Veliparib plus carboplatin/gemcitabine is tolerated, with a safety profile similar to carboplatin and gemcitabine alone. Combination therapy demonstrated promising preliminary antitumor activity in platinum-sensitive ovarian cancer patients with germline BRCA mutations. (C) 2018 Elsevier Inc. All rights reserved.

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.

Abstract Purpose: PARP plays an important role in DNA repair. Veliparib, a PARP inhibitor, enhances the efficacy of platinum compounds and has been safely combined with carboplatin and paclitaxel. The primary endpoint of this phase II trial determined whether addition of veliparib to carboplatin and paclitaxel improved progression-free survival (PFS) in previously untreated patients with advanced/metastatic non–small cell lung cancer. Experimental Design: Patients were randomized 2:1 to carboplatin and paclitaxel with either veliparib or placebo. Veliparib (120 mg) or placebo was given on days 1 to 7 of each 3-week cycle, with carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m2) administered on day 3, for a maximum of 6 cycles. Results: Overall, 158 were included (median age, 63 years; male 68%, squamous histology 48%). Median PFS was 5.8 months in the veliparib group versus 4.2 months in the placebo group [HR, 0.72; 95% confidence interval (CI), 0.45–1.15; P = 0.17)]. Median overall survival (OS) was 11.7 and 9.1 months in the veliparib and placebo groups, respectively (HR, 0.80; 95% CI, 0.54–1.18; P = 0.27). In patients with squamous histology, median PFS (HR, 0.54; 95% CI, 0.26–1.12; P = 0.098) and OS (HR, 0.73; 95% CI, 0.43–1.24; P = 0.24) favored veliparib treatment. Objective response rate was similar between groups (veliparib: 32.4%; placebo: 32.1%), but duration of response favored veliparib treatment (HR, 0.47; 95% CI, 0.16–1.42; P = 0.18). Grade III/IV neutropenia, thrombocytopenia, and anemia were comparable between groups. Conclusions: Veliparib combination with carboplatin and paclitaxel was well-tolerated and demonstrated a favorable trend in PFS and OS versus chemotherapy alone. Patients with squamous histology had the best outcomes with veliparib combination. Clin Cancer Res; 23(8); 1937–44. ©2016 AACR.