4 Supplementary Figures from Small Interfering RNA–Mediated Polo-Like Kinase 1 Depletion Preferentially Reduces the Survival of p53-Defective, Oncogenic Transformed Cells and Inhibits Tumor Growth in Animals

Table S1: Schedule of pharmacokinetic analysis; Table S2: Overview of study dose levels (N=50); Table S3. Adverse events reported at any time during study therapy: grade 3-4 adverse events; Table S4: Veliparib pharmacokinetic (PK) parameters by cohort; Table S5: Total and ultrafilterable platinum pharmacokinetic parameters by cohort; Table S6: Immunohistochemistry results for 28 pre-therapy samples; Figure S1: Veliparib Cmax (ng/mL, panel A) and veliparib AUC0-6 (hr*ng/mL, panel B) by dose Cohort; Figure S2: Veliparib pharmacokinetic parameters (A) Cmax and (B) AUC0-6 at cycles 1 and 4 by cohort; Figure S3: Ultrafilterable platinum pharmacokinetic parameters Cmax and AUC0-24 at cycles 1 and 4 by cohort; Figure S4: Consort 2010 flow diagram for exploratory efficacy analysis comparing germline BRCA mutation positive to wild type; Figure S5: PAR assay results (pg/mL) for 14 patients in dose cohorts 6-8 (120-200 mg)

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 Data from Acquired Resistance to Combination Treatment with Temozolomide and ABT-888 Is Mediated by Both Base Excision Repair and Homologous Recombination DNA Repair Pathways

BackgroundVeliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC).MethodsPatients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m(2)) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1.ResultsThirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%.ConclusionVeliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.

2,3-Dichloropropene (2,3-DCP), a component of 0commercial fumigants and nematocides, was mixed with [14C]2,3-DCP and given to rats by peroral (p.o.) or intraperitoneal (i.p.) administration. Urine, feces, and expired air were collected over 72 h. Excretion of radioactivity in urine predominated over other routes, with 66% to 75% of the dose excreted in 72 h. Feces contained from 13% to 21 % of dose. 8% of the dose was exhaled as 14CO2. At the end of 72 h, only 2% to 3% of the dose remained in the carcass with the highest concentrations of 14C in liver, kidney, testes, and lung. Approx. 91 % of the p.o. dose was absorbed from the gastrointestinal (GI) tract.

BACKGROUNDA Pediatric Brain Tumor Consortium (PBTC) phase 1/2 trial of veliparib and radiation, followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: 1) estimate the recommended phase 2 dose (RP2D) of veliparib with concurrent radiation; 2) evaluate the pharmacokinetic (PK) parameters of veliparib during radiation; 3) evaluate feasibility of intra-patient TMZ dose escalation; 4) describe toxicities of protocol therapy; and 5) estimate the overall survival distribution compared to historical series.METHODSVeliparib was given Monday through Friday BID during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 BID and TMZ 135 mg/m2 daily for 5 days every 28 days. Intra-patient dose escalation of TMZ was investigated for patients experiencing minimal toxicity.RESULTS66 patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 BID with radiation. Dose-limiting toxicities (DLT) during radiation with veliparib therapy included: grade-2 intra-tumoral hemorrhage (n=1), grade-3 maculopapular rash (n=2), and grade-3 nervous system disorder (generalized neurologic deterioration) (n=1). Intra-patient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared to PBTC historical controls and accrual was stopped for futility. The 1- and 2-year OS rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively.CONCLUSIONAddition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG.

Veliparib is an orally active potent poly(ADP-ribose) polymerase (PARP) inhibitor currently in phase III clinical trials in solid tumors. This phase I study evaluated the pharmacokinetics and mass balance of veliparib administered alone and in combination with temozolomide, and assessed any potential pharmacokinetic drug–drug interaction between veliparib and temozolomide.

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.

Abstract Background: Poly(ADP-ribose) polymerase (PARP) inhibitors block DNA damage repair and may thereby enhance the clinical activity of DNA-damaging chemotherapy. Homologous recombination is defective in BRCA1/2-mutated tumors, leading to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V is a potent PARP inhibitor that enhances the antitumor activity of platinum agents in preclinical models. This phase 2 trial (NCT01506609) investigated the safety and efficacy of V+C/P or V+ temozolomide (TMZ) vs Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results of the V+C/P and Plc+C/P arms are presented; V+TMZ results will be presented separately. Methods: Pts ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7+TMZ, 28-D cycle; 2) V 120 mg BID D1–7+C AUC 6, D3 and P 175 mg/m2, D3, 21-D cycle; or 3) Plc BID D1–7+C/P. Key eligibility criteria included deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status, prior cytotoxic therapy, and ECOG PS. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 of each V arm vs Plc+C/P by independent review. Primary analysis occurred at the 112th PFS event in the V+C/P and Plc+C/P arms. Overall survival (OS), objective response rate (ORR), tolerability, and quality of life were also evaluated. Results: A total of 196 pts (193 BRCA+ per central lab) were randomized to receive double-blinded V+C/P (n=97) or Plc+C/P (n=99). Baseline demographics and disease characteristics were balanced across all treatment arms. Median study drug exposure was 10 cycles for Plc+C/P and 12 cycles for V+C/P. The V+C/P arm demonstrated numeric improvements for both PFS and OS compared to the Plc+C/P arm; improvement in ORR was statistically significant (Table 1). There was no meaningful increase of toxicity with addition of V. The most common treatment-emergent adverse events (AEs) with Plc+C/P or V+C/P were neutropenia (74%/74%), thrombocytopenia (70%/71%), and nausea (58%/71%). Grade ≥3 AEs in ≥30% of pts were neutropenia (55%/56%) and thrombocytopenia (26%/31%), respectively. There was no difference in the use of G-CSF with addition of V. Significant improvements in fatigue, pain, and insomnia (all P<0.05) were observed with V+C/P vs Plc+C/P. Conclusions: This is the first randomized phase 2 trial of a PARP inhibitor in combination with platinum-based therapy for treatment of BRCA1/2-mutated advanced breast cancer. V+C/P demonstrated significantly higher ORR and symptom improvement compared to Plc+C/P, with nonsignificant trends for improved OS and PFS. Phase 3 trials are ongoing. Table 1Efficacy (ITT population – BRCA mutation)Plc+C/P, n=98V+C/P, n=95HR (95% CI); P valuePFS(mo, 95% CI)12.3 (9.3–14.5)14.1 (11.5–16.2)0.789 (0.536–1.162); 0.231OS (mo, 95% CI)25.0 (18.1–34.8)28.5 (22.4–NR)0.725 (0.468–1.121); 0.148ORR, % (95% CI)61.3 (49.7–71.9)77.8 (66.4–86.7)P=0.027 Citation Format: Han HS, Diéras V, Robson ME, Palácová M, Marcom PK, Jager A, Bondarenko I, Citrin D, Campone M, Telli ML, Domchek SM, Friedlander M, Kaufman B, Ratajczak C, Coates A, Bonnet P, Qin Q, Qian J, Giranda VL, Shepherd SP, Isakoff SJ, Puhalla S. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-05.

Abstract Background: V is a potent, poly(ADP-ribose) polymerase (PARP) inhibitor that obstructs DNA damage repair. BRCA1/2 tumors are defective in homologous recombination, which leads to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V enhances the antitumor activity of alkylating agents such as TMZ in preclinical models. In addition, V+TMZ showed promising activity in a single-arm phase 2 study in pts with BRCA1/2 mutations. This phase 2 trial (NCT01506609) investigated the efficacy and tolerability of V+TMZ (or V+C/P) compared to Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results from the primary analysis for the V+TMZ arm vs Plc+C/P are presented, and the V+C/P vs Plc+C/P results will be presented separately. Methods: Male and female pts aged ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7 + TMZ 150–200 mg/m2 QD D1–5, 28-D cycle; 2) V 120 mg BID D1–7 + C AUC 6, D3 and P 175 mg/m2, D3, 21-D cycle; 3) placebo BID D1–7 + C/P. Key eligibility criteria included known deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status, prior cytotoxic therapy (yes vs no), and ECOG PS (0–1 vs 2). The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by independent review. Overall survival (OS), objective response rate (ORR), and safety/tolerability were also evaluated. Results: A total of 290 pts (284 BRCA+ per central lab) were randomized (V+TMZ, n=94 [91 BRCA+]). Baseline demographics and disease characteristics were comparable among treatment arms; 41.3% of pts had triple-negative breast cancer (TNBC) and 31.7% had received >2 prior regimens. Median study drug exposure was 6 cycles for the V+TMZ arm and 10 cycles for the Plc+C/P arm. Median PFS, median OS (interim), and ORR for V+TMZ were inferior to Plc+C/P (PFS 7.4 vs 12.3 mo, OS 19.1 vs 25.0 mo, and ORR 28.6% vs 61.3%). In pts with TNBC, median PFS was 5.5 (3.1–8.5) mo; 8.4 (6.8–10.6) mo for pts with non-TNBC. Treatment-emergent adverse events (AEs) of interest occurring differentially with V+TMZ are shown in Table 1. Grade ≥3 AEs in ≥30% of pts in the V+TMZ arm were thrombocytopenia (48%) and neutropenia (37%). Conclusions: V+TMZ provided durable responses, with less neutropenia, alopecia, and neuropathy than Plc+C/P; however, PFS, OS, and ORR were inferior in the TMZ arm compared to C/P. Table 1Treatment-Emergent AEs, n (%)V+TMZ, n=93Plc+C/P, n=96Neutropenia46 (50)71 (74)Alopecia10 (11)55 (57)Peripheral neuropathy11 (12)56 (58)Thrombocytopenia73 (79)67 (70)Nausea70 (75)56 (58) Citation Format: Diéras V, Han HS, Robson ME, Palácová M, Marcom PK, Jager A, Bondarenko I, Citrin D, Campone M, Telli ML, Domchek SM, Friedlander M, Kaufman B, Ratajczak C, Coates A, Bonnet P, Qin Q, Qian J, Giranda VL, Shepherd SP, Puhalla S, Isakoff SJ. Evaluation of veliparib (V) and temozolomide (TMZ) in a phase 2 randomized study of the efficacy and tolerability of V+TMZ or carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-02.

Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I–III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609).

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors block DNA damage repair and may thereby enhance the clinical activity of DNA-damaging chemotherapy. Homologous recombination is defective in BRCA1/2 -mutated tumors, leading to more error-prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. V is a potent PARP inhibitor that enhances the antitumor activity of platinum agents in preclinical models. This phase 2 trial (NCT01506609) investigated the safety and efficacy of V+C/P or V+ temozolomide (TMZ) vs Plc+C/P in pts with locally recurrent or metastatic breast cancer harboring a BRCA1 or BRCA2 mutation. Results of the V+C/P and Plc+C/P arms are presented; V+TMZ results will be presented separately. Methods: Pts ≥18 years with histologically confirmed locally recurrent or metastatic breast cancer were randomized 1:1:1 to: 1) V 40 mg BID D1–7+TMZ, 28-D cycle; 2) V 120 mg BID D1–7+C AUC 6, D3 and P 175 mg/m 2 , D3, 21-D cycle; or 3) Plc BID D1–7+C/P. Key eligibility criteria included deleterious BRCA1/2 mutation, ≤2 prior chemotherapies for metastatic disease, no prior platinum agent, and no CNS metastases. Randomization was stratified by hormone receptor status, prior cytotoxic therapy, and ECOG PS. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 of each V arm vs Plc+C/P by independent review. Primary analysis occurred at the 112th PFS event in the V+C/P and Plc+C/P arms. Overall survival (OS), objective response rate (ORR), tolerability, and quality of life were also evaluated. Results: A total of 196 pts (193 BRCA + per central lab) were randomized to receive double-blinded V+C/P (n=97) or Plc+C/P (n=99). Baseline demographics and disease characteristics were balanced across all treatment arms. Median study drug exposure was 10 cycles for Plc+C/P and 12 cycles for V+C/P. The V+C/P arm demonstrated numeric improvements for both PFS and OS compared to the Plc+C/P arm; improvement in ORR was statistically significant (Table 1). There was no meaningful increase of toxicity with addition of V. The most common treatment-emergent adverse events (AEs) with Plc+C/P or V+C/P were neutropenia (74%/74%), thrombocytopenia (70%/71%), and nausea (58%/71%). Grade ≥3 AEs in ≥30% of pts were neutropenia (55%/56%) and thrombocytopenia (26%/31%), respectively. There was no difference in the use of G-CSF with addition of V. Significant improvements in fatigue, pain, and insomnia (all P Conclusions: This is the first randomized phase 2 trial of a PARP inhibitor in combination with platinum-based therapy for treatment of BRCA1/2 -mutated advanced breast cancer. V+C/P demonstrated significantly higher ORR and symptom improvement compared to Plc+C/P, with nonsignificant trends for improved OS and PFS. Phase 3 trials are ongoing. Citation Format: Han HS, Dieras V, Robson ME, Palacova M, Marcom PK, Jager A, Bondarenko I, Citrin D, Campone M, Telli ML, Domchek SM, Friedlander M, Kaufman B, Ratajczak C, Coates A, Bonnet P, Qin Q, Qian J, Giranda VL, Shepherd SP, Isakoff SJ, Puhalla S. Efficacy and tolerability of veliparib (V; ABT-888) in combination with carboplatin (C) and paclitaxel (P) vs placebo (Plc)+C/P in patients (pts) with BRCA1 or BRCA2 mutations and metastatic breast cancer: A randomized, phase 2 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-05.

520 Background: Clinical studies suggest that TNBC is sensitive to DNA-damaging agents, including Cb. V is a potent PARP inhibitor that may enhance the antitumor activity of such agents. We present primary response data from a phase 3 randomized, placebo-controlled study (NCT02032277) evaluating the addition of V + Cb or Cb to neoadjuvant paclitaxel (P) followed by doxorubicin + cyclophosphamide (AC). Methods: Pts with histologically confirmed, invasive TNBC (T2–T4 N0–2 or T1 N1–2) amenable to surgical resection were randomized 2:1:1 to (Arm A) P 80 mg/m2 weekly + Cb AUC 6 mg/mL/min q3 weeks + V 50 mg PO BID; (Arm B) P + Cb + PO placebo; or (Arm C) P + IV placebo + PO placebo, for 12 weeks followed by AC (60 mg/m2 or 600 mg/m2 q2 or 3 weeks) × 4. Primary endpoint was pathologic complete response (pCR) in breast and nodes with > 80% power at 2-sided α of 0.05 using pair-wise comparisons for A vs B and A vs C to detect significant treatment effects using Χ2 test; secondary endpoint was rate of conversion to eligibility for breast conservation surgery (BCS). Adverse events (AEs) were assessed with NCI CTCAE V4.0. Results: Six hundred thirty-four pts (median age 50 years; range 22–79) were randomized to Arms A (n = 316), B (n = 160), or C (n = 158). Baseline characteristics were well balanced. No pCR difference was observed between Arms A and B (53.2% vs 57.5% p = 0.36), but pCR in Arm A was higher than Arm C (53.2% vs 31.0% p < 0.001). In non-prespecified analysis, pCR in Arm B was also higher than Arm C (57.5% vs 31.0% p < 0.001). Among pts ineligible for BCS at screening (n = 141), 62% were eligible after NAC in Arm A vs 44% each in Arms B (p = 0.13) and C (p = 0.14). Grade 3–4 AEs (Arms A/B/C, 86%/85%/45%) and serious AEs (30%/27%/14%) neutropenia, thrombocytopenia, anemia, nausea, and vomiting were increased with the addition of Cb; V did not impact toxicity. Median cycles of NAC were not reduced with V + Cb + P or Cb + P vs P. Conclusions: Addition of V to neoadjuvant Cb + P followed by AC did not increase pCR rate in breast and nodes in stage II–III TNBC, while addition of V + Cb or Cb alone to P followed by AC did. Cb (+/– V) increased toxicity but did not impact delivery of NAC. Clinical trial information: NCT02032277.

INTRODUCTION:Tobacco-related NSCLC is associated with reduced survival and greater genomic instability. Veliparib, a potent poly(adenosine diphosphate-ribose) polymerase inhibitor, augments platinum-induced DNA damage. A phase 2 trial of untreated advanced NSCLC showed a trend for improved outcomes (hazard ratio [HR] = 0.80, 95% confidence interval: 0.54-1.18, p = 0.27 for overall survival and HR = 0.72, 95% CI: 0.45-1.15, p = 0.17 for progression-free survival) when veliparib was added to carboplatin/paclitaxel. Here we report an exploratory analysis by smoking history. METHODS:Patients were randomized 2:1 to receive carboplatin/paclitaxel with veliparib, 120 mg (n = 105), or placebo (n = 53). Patients were stratified by histologic subtype and smoking history (recent smokers [n = 95], former smokers [n = 42], and never-smokers [n = 21]). Plasma cotinine level was measured as a chemical index of smoking. Mutation status was assessed by whole exome sequencing (n = 38). RESULTS:Smoking history, histologic subtype, age, Eastern Cooperative Oncology Group performance status, sex, and geographic region predicted veliparib benefit in univariate analyses. In multivariate analysis, history of recent smoking was most predictive for veliparib benefit. Recent smokers treated with veliparib derived significantly greater progression-free survival and overall survival benefits (HR = 0.38 [p < 0.01] and HR = 0.43 [p < 0.01]) than former smokers (HR = 2.098 [p = 0 0208] and HR = 1.62 [p = 0.236]) and never-smokers (HR = 1.025 [p = 0.971] and HR = 1.33 [p = 0.638]). Sequencing data revealed that mutational burden was not associated with veliparib benefit. The rate of grade 3 or 4 adverse events was higher in recent smokers with veliparib treatment; all-grade and serious adverse events were similar in both treatment arms. CONCLUSIONS:Smoking history predicted for efficacy with a veliparib-chemotherapy combination; toxicity was acceptable regardless of smoking history. A prespecified analysis of recent smokers is planned for ongoing phase 3 studies of veliparib in NSCLC.

e20549 Background: A Phase 2 clinical trial of veliparib + carboplatin (C) and paclitaxel (P) in patients (pts) with previously untreated metastatic/advanced NSCLC showed that veliparib may improve survival compared to placebo and that smoking history was a strong predictor of efficacy for veliparib+CP. This study compares quality of life (QoL) by smoking status in pts receiving veliparib+CP vs placebo+CP. Methods: This study is a secondary analysis of a Phase 2 clinical trial (NCT01560104) where pts were randomized 2:1 to veliparib+CP (120mg BID) or placebo+CP for up to 6 treatment cycles (study period). Pts with ≥ 1 QoL measurement at baseline (pre-treatment initiation) and during ≥ 1 cycle were selected and stratified by smoking status in the year preceding the trial (smokers [S] vs non-smokers [NS]). Proportions of pts with a QoL improvement (QoL+)/deterioration (QoL-) from baseline achieving minimal important difference ( ≥ 10 points on a 100-point scale) across the study period were compared by treatment and smoking status using generalized estimating equation models adjusted for baseline QoL score, gender, and ECOG, for each of the 22 EORTC QLQ-C15-PAL/LC13 questionnaire items. Results: Among 143 pts (657 pt-cycles), mean age was 62 years, 67% were male, and 59% were S. In S, veliparib+CP pts had better or non-different QoL compared to placebo+CP pts; a higher proportion of veliparib+CP pts had QoL+ for dyspnea (odds ratio [OR] = 3.63) and a lower proportion of pts had QoL- for physical functioning (OR = 0.46), appetite loss (OR = 0.37), and dysphagia (OR = 0.12), all p < .05. In veliparib+CP pts, S had better or non-different QoL compared to NS (emotional functioning: both QoL+ and QoL- OR = 2.80 and 0.38, respectively; pain in chest: QoL+ OR = 3.86; coughing: QoL- OR = 0.48; all p < .05). The magnitude of the difference in QoL for S vs NS was larger or non-different in veliparib+CP pts compared to placebo+CP pts (dyspnea: QoL+ OR = 8.48; appetite loss: QoL+ OR = 11.54, QoL- OR = 0.27; dysphagia: QoL- OR = 0.05; all p < .05). Conclusions: Smokers receiving veliparib+CP had better or non-different QoL compared to both non-smokers receiving veliparib+CP and to smokers receiving placebo+CP. Clinical trial information: NCT01560104.

1015 Background: Veliparib (ABT-888) is an oral, potent small molecule inhibitor of poly-ADP-ribose polymerase (PARP). The combination of veliparib (V) with carboplatin (C) and paclitaxel (P) dosed every 3 weeks has been shown to be safe with early signs of efficacy in a phase I study conducted by our group. In breast cancer patients (pts), weekly P improves disease-free and overall survival vs. every three week P with comparable safety (ECOG 1199), thus supporting the exploration of weekly C and P in combination with V. This study is designed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), adverse events (AEs), anti-tumor activity, and pharmacokinetic (PK) parameters of this combination. Methods: A standard 3+3 design was used with 4 escalating V dose levels ranging from 50-200 mg bid. C (AUC 2) and P (80 mg/m2) were administered on a weekly basis over a 21-day cycle on all dose levels. Dose escalation was followed by dose expansion in pts with TNBC with mandatory tumor biopsies. Results: A total of 30 pts were enrolled (median age 52 yr [range 33-83]; 27 female; median prior treatments 3 [range 0-8]; 24 breast [22 TNBC], 2 lung, 1 cervix, 1 ovarian, 1 prostate, 1 gastric). DLTs occurred at the following dose levels: prolonged gr 2 thrombocytopenia at 150 mg bid, and gr 4 neutropenia at 200 mg bid. The RP2D of veliparib was established to be 150 mg bid. The most common all-grade and grade 3/4 AEs included: neutropenia (gr 3/4 in 18 pts [60%]), anemia (gr 3/4 in 5 pts [17%]), and thrombocytopenia (gr 3/4 in 3 pts [10%]). PK parameters of V in this trial were comparable to historical single-agent V. Of the 27 evaluable pts, 13 (48%) responded (1 CR, 12 PR), 10 (37%) had SD, and 4 (15%) had PD. Objective response rate in TNBC was 52%. Among 21 evaluable TNBC pts, response was 60% in BRCA1/2+ pts (3/5 PR), 67% in non-BRCA1/2 pts (1/9 CR; 5/9 PR) and 29% in unknown status pts (2/7 PR). The only ovarian cancer pt was BRCA2+ and had PR. Conclusions: V in combination with weekly C and P was well tolerated with acceptable safety profile. Promising anti-tumor activity was observed, particularly in TNBC. Clinical trial information: NCT01281150.