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

Objectives: Heat shock protein 90 regulates multiple signaling proteins involved in key pathways of pancreatic cancer pathogenesis. Ganetespib binds to heat shock protein 90 and interferes with its binding to client proteins thus leading to inactivation and degradation of the signaling proteins that promote cancer progression. This phase II study was designed to evaluate the efficacy of ganetespib in patients with refractory metastatic pancreatic cancer (rMPC). Methods: Patients with rMPC received 175 mg/m2 ganetespib intravenously once weekly for 3 weeks in 4-week cycles. Primary endpoint was disease control rate at 8 weeks, with a goal of 70%. Secondary endpoints were progression-free survival, overall survival, and safety. Simon’s 2-stage design was used to assess futility and efficacy. Ganetespib was considered inactive if ≤8 patients among the first 15 treated had disease control after 8 weeks of treatment. Results: Fourteen patients were treated on study. Grade 3 treatment-related toxicities were diarrhea, abdominal pain, fatigue, nausea, vomiting, and hyponatremia. Disease control rate at 8 weeks was 28.6%, and median progression-free survival and overall survival were 1.58 months and 4.57 months, respectively. Early stopping rules for lack of clinical efficacy led to study closure. Conclusions: Single-agent ganetespib was tolerable with only modest disease control in rMPC. This disease is resistant to chemotherapy, and given the emerging data in lung and rectal cancers, as well as in pancreatic cancer cell lines, suggesting improved activity of ganetespib in combination with cytotoxic agents, studies combining this agent with chemotherapy in rMPC are more likely to yield success.

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.

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.

8038 Background: Tobacco-related non-small cell lung cancer (NSCLC) is associated with reduced survival and greater genomic instability. Veliparib (V) is a PARP inhibitor that augments platinum-induced DNA damage in preclinical studies, and a recent Ph 2 trial of advanced NSCLC trended to improved survival (HR 0.80; CI 0.54–1.18) when V was added to carboplatin (C) and paclitaxel (P). Here we report outcomes based on smoking status from a randomized Ph 2 study of CP with either V or placebo in advanced NSCLC. Methods: Patients (pts) with previously untreated advanced/metastatic NSCLC were randomized 2:1 to CP with either V at 120 mg BID or placebo (pre-specified stratification by histology and smoking history). Cotinine (COT) was measured in pt plasma samples as an index of recent tobacco use. Results: Of 158 pts, 68% were male, and 49% had squamous NSCLC. At study entry, 60% of pts were self-reported current smokers (CS), 27% former smokers, and 13% never smoked. There were no significant differences in V PK parameters between the COT-high and low pts.Most common AE in CS were neutropenia (41% VCP; 27% CP), alopecia (36%; 33%), and anemia (31%; 40%). G3/4 AEs were elevated in CS treated with VCP vs CP (66% vs. 40%, p=0.026); all-grade AEs and SAEs were similar between the two groups. In a COT sensitivity analysis of OS, HR VCP/CP for COT-high was 0.52 (0.29–0.92) and COT-low was 1.07 (0.63–1.81). Conclusions: Smoking status was a strong predictor of efficacy for veliparib-chemotherapy combination in advanced NSCLC. No differences in PK of V were seen based on plasma COT; toxicity of VCP was acceptable regardless of smoking history. A Ph 3 study has been initiated in pts with smoking history. Clinical trial information: NCT01560104. Median months (95% CI) CP CS, n=31 Former, 14 Never, 8 VCP CS, n=64 Former, 28 Never, 13 HR VCP/CP HRadj VCP/CP (Adjusted for gender and ECOG PS) PFS CS Former Never 3.3 (1.4–4.2) NA (3.3–NA) 5.6 (1.4–8.2) 5.6 (4.1–7.0) 6.0 (2.4–NA) 6.4 (1.0–NA) 0.38 (0.21–0.67) 2.10 (0.66–6.65) 1.03 (0.27–3.85) 0.37 (0.21–0.68) 0.77 (0.20–3.06) 0.96 (0.21, 4.46) OS CS Former Never 5.4 (3.8–8.8) 14.6 (9.2–NA) NA (3.6–NA) 12.5 (9.9–16.6) 8.6 (5.9–17.5) 13.2 (5.0–NA) 0.43 (0.26–0.70) 1.62 (0.73–3.6) 1.34 (0.40–4.44) 0.45 (0.27–0.76) 0.72 (0.27–1.92) 0.71 (0.18–2.74)

Abstract Background Myelodysplastic syndrome (MDS) is a common disease of the elderly characterized by ineffective maturation of hematopoietic cells manifesting as low blood counts, morphologic atypia, and predisposition to the development of acute leukemia. The only FDA-approved drugs for the treatment of all subytpes of MDS are the DNA methyltransferase inhibitors (DNMTis), azacytidine and decitabine. However, only a minority of patients achieve a hematologic response or better on these agents. We have previously identified a miRNA signature which distinguishes MDS patients from normal controls. We sought to investigate whether miRNA expression might also be predictive of how patients respond to therapy with DNA methyltransferase inhibitors (DNMTis). Design We collected paired fresh frozen bone marrow mononuclear cells (BM-MNCs) from 28 patients with MDS both pre and post treatment with DNMTis as well as from 30 normal controls. Following enrichment for miRNAs and other small RNA species using the TruSeq Small RNA sample preparation kit (Illumina, San Diego, CA), miRNAs were sequenced on an Illumina HiSeq 2500. Alignment was performed using Bowtie 2 against reference sequences from mirBASE and differential expression analysis was analyzed using a rank sum score from the following analysis programs: DESeq, edgeR and baySeq. The response to the DNMTis was characterized based upon the following scale: 1 = complete remission, 2 = marrow complete remission, 3 = partial remission, 4 = hematologic improvement, 5 = stable disease, and 6 = progressive disease. Linear regression analysis was conducted using the response score as outcome and miRNA expression value as the predictor. Results Several differences were found between the control samples and the pre-treatment MDS samples, many of which have been described previously, including hsa-miR-125b, hsa-miR-342, hsa-miR-140, and hsa-miR-150. Not unexpectedly, the expression of numerous miRNAs was significantly altered as a result of treatment with DNMTis. However, there were no significant miRNA expression differences between responders and non-responders in the post-treatment samples and no significant differences between the changes in miRNA expression (pre versus post treatment changes) in responders and non-responders. Interestingly, 5 miRNAs demonstrated significant association between their pre-treatment expression and the degree of response (FDR < 0.05): hsa-miR-125a, hsa-miR-342, hsa-miR-146b, hsa-miR-146a, hsa-miR-423, and hsa-miR-150. These miRNAs share striking overlap in their mRNA targets including key pathway regulators in the p53 pathway as well as numerous growth factors implicated in hematopoietic stem cells as well as hematopoietic stem cell markers. Conclusion These studies confirm that miRNA expression differences differentiate between MDS and normal controls. The administration of DNMTis results in widespread expression changes regardless of the response to therapy. However, the expression of a small handful of miRNA are positively correlated with the degree of response in MDS pre-treatment samples to DNMTis and therefore may be useful as markers which predict responders to DNMTi therapy in addition to suggesting biological pathways implicated in the mechanism of response. These results await further prospective studies for confirmation. Disclosures No relevant conflicts of interest to declare.

297 Background: Heat shock protein 90 (HSP90) regulates folding, stability and function of signaling proteins such as EGFR, IGF-1R, c-Met, ERBB4, PDGFRα and c-Ret, several of which are key pathways for MPC pathogenesis. G prevents Hsp90 binding to client proteins leading to inactivation and degradation, disrupting signaling that promotes cancer progression. This phase II study is designed to evaluate the efficacy of G in patients (pts) with refractory MPC. Methods: Pts with MPC in the 2nd or 3rd line setting, with PS 0-1, received G 175 mg/m2intravenously once weekly for 3 weeks out of a 4 week cycle. Primary endpoint was disease control rate (DCR) at 8 weeks, with a goal of 70% DCR. Secondary endpoints were response rate (RR), overall survival (OS), and safety. 43 pts were planned for initial accrual. Simon’s optimal two-stage design was used to assess 8 week DCR. G was considered inactive if 8 or fewer pts among the first 15 treated had disease control after 8 weeks of treatment (tx). Results: Seventeen...

Aim: Platinum-based regimens are the current standard of care for patients (pts) with metastatic non-small cell lung cancer (NSCLC). Veliparib (V) is a potent, orally bioavailable PARP inhibitor that (1) enhances the efficacy of platinum-containing DNA damaging therapies in preclinical models, and (2) has been safely combined with full dose carboplatin (C) and paclitaxel (P) in Ph 1 trials.

Polycythemia rubra vera is a chronic myeloproliferative disorder characterized by panmyelosis with the resultant potential for thrombosis, myelofibrosis, and acute leukemia. Treatment has rested on phlebotomy and hydroxyurea. In 2002, we reported two patients who were unable to tolerate hydroxyurea but responded to imatinib mesylate (Gleevec). These patients have remained in complete hematologic remission on imatinib since 1999. As a result we began a phase II, open label trial of imatinib in patients with polycythemia vera. Patients meeting the Polycythemia Vera Study group criteria for the diagnosis of polycythemia vera, either naïve or intolerant to prior treatment were allowed to enroll. Initial therapy was begun with imatinib mesylate at 400 mg a day and two dose escalations, one to 600 and second to 800 mg a day, were allowed for patients not achieving a target hematocrit of 44 or less; or a platelet count of less than 600,000/mm 3 . Twenty patients were enrolled, 15 achieved complete hematologic remission within 12 weeks and ten remain on study. Six patients remain in remission on 400 mg a day and four on 500 mg a day. Gastrointestinal or cutaneous toxicities were primarily grade I or II. All patients were negative for bcr/abl. Imatinib mesylate is capable of producing hematologic remission in the majority of patients with polycythemia vera and provides another option for patient management, particularly in those intolerant to hydroxyurea.