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Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non–small-cell lung cancer (NSCLC). We report updated results, including a pooled analysis of the two studies. Methods Patients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease progression during or after prior platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Minimum follow-up for survival was 24.2 months. Results Two-year overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to 30%) versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%) versus 16% (95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the risk of death with nivolumab versus docetaxel remained similar to those reported in the primary analyses. Durable responses were observed with nivolumab; 10 (37%) of 27 confirmed responders with squamous NSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing responses after 2 years’ minimum follow-up. No patient in either docetaxel group had an ongoing response. In the pooled analysis, the relative reduction in the risk of death with nivolumab versus docetaxel was 28% (hazard ratio, 0.72; 95% CI, 0.62 to 0.84), and rates of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%). Conclusion Nivolumab provides long-term clinical benefit and a favorable tolerability profile compared with docetaxel in previously treated patients with advanced NSCLC.

Background The combination of gemcitabine, platinum and inhibition of DNA repair results in synergistic chemosensitivity in triple-negative and BRCA1-deficient breast cancer cell lines. This study was designed to assess efficacy, safety and predictors of response to iniparib, a small molecule whose mechanism of action is under investigation, in combination with GC in early-stage triple-negative and BRCA1/2 mutation-associated BC. Methods: This single-arm, phase II study (NCT00813956) enrolled patients with clinical stage I-IIIA (T ≥1cm by MRI) estrogen receptor-negative (≤ 5%), progesterone receptor-negative (≤ 5%), and HER2−negative or BRCA1/2 mutation-associated BC. Neoadjuvant gemcitabine (1000 mg/m2; IV; D1, 8), carboplatin (AUC 2; IV; D1, 8), and iniparib (5.6 mg/kg; IV; D1, 4, 8, 11) were given every 21 days for 4 cycles, until the protocol was amended to increase the treatment duration to 6 cycles with enrollment of 36 patients. The protocol was further amended to increase the patient number with expansion to additional centers. Prior to expansion, reporting of interim safety and efficacy results was specified. The primary endpoint is pathologic complete response (pCR), defined as the absence of invasive carcinoma in the breast and axilla. Pathologic response was assessed using the residual cancer burden (RCB) index. Secondary endpoints included safety, radiographic response by MRI, breast conservation eligibility and correlation of baseline gene expression with response. Results: The pre-expansion cohort consisted of 13 patients assigned to 4 cycles of treatment and 36 patients assigned to 6 cycles of treatment. Among these 49 patients (50 tumors), median tumor size is 35 mm, and median age is 48 years. The overall pCR rate is 34% (95% CI = 22–48); the pCR rate at 6 cycles is 41% (95% CI = 26–57). RCB 0/I was observed in 5/13 pts (38%; 95% CI = 18–64) treated with 4 cycles; 21/37 (57%; 95% CI = 41–71) treated with 6 cycles; and 9/9 pts (100%) with known BRCA1/2 mutations. Two pts experienced disease progression, two locoregional relapse, and three distant relapse. Among 45 tumors with Affymetrix-based RNA microarray gene expression data, 39/45 (87%) are classified as basal-like, 3/45 (7%) luminal B, and 3/45 (7%) normal breast-like. Most common G3/4 adverse events include neutropenia (31%), anemia (10%), and elevated ALT/AST (10%). Alopecia and chemotherapy-induced amenorrhea were uncommon. Analyses of secondary endpoints are ongoing and will be presented. Conclusions: Preoperative GC plus iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-08.

BACKGROUND: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen. METHODS: The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. RESULTS: Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. CONCLUSIONS: The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided. Cancer 2010. © 2010 American Cancer Society.

Background Patients with sickle cell disease (SCD) have high rates of perioperative complications, including bleeding 1,2. Procedures We conducted a retrospective review of pre-operative coagulation studies in pediatric patients with SCD followed by a prospective study of 100 well children with SCD to determine the prevalence of abnormal coagulation screening tests, and to evaluate potential etiologies. Results In the retrospective study, 32/84 (38.1%) had a prolonged prothrombin time (PT), compared to 8/100 in the prospective study. Prolongations of the activated partial thromboplastin time (aPTT) were less common. Children in the prospective study with prolonged PTs had significantly lower levels of Factor V and VII compared to those with normal PTs. Factor VII levels were

BACKGROUND. Sentinel lymph node (SLN) status is an important prognostic factor for survival for patients with primary cutaneous melanoma. To address the issue of selecting patients at high and low risk for a positive SLN, prognostic factors were sought that predict SLN involvement by examining characteristics of both the primary tumor and the patient within the context of a biological model of melanoma progression. METHODS. The study included 682 patients with primary vertical growth phase (VGP) melanoma and no clinical evidence of metastatic disease who underwent SLN biopsy (1995–2003). Logistic regression and classification tree analyses were used to investigate the association between SLN positivity and Breslow thickness, Clark level, tumor infiltrating lymphocytes (TIL), ulceration, mitotic rate (MR), lesion site, gender, and age. RESULTS. In all, 88 of the 682 patients had � 1 positive SLN (12.9%). In the multivariate analysis, MR, TIL, and thickness were found to be independent prognostic factors for SLN positivity. In the classification tree, four different risk groups were defined, ranging from minimal risk (2.1%) to high risk (40.4%). In lesions � 2.0 mm, MR was important in risk-stratifying patients, and in lesions >2.0 mm TIL was important. CONCLUSION. By incorporating biologically based variables such as VGP, TIL, and MR along with thickness into a prognostic model, both patients at high risk and minimal risk for SLN positivity can be identified. If validated, this model can be used in patient management and trial design to select patients to undergo or be spared SLN biopsy. Cancer 2006;107:2436–45. � 2006 American Cancer Society.

Introduction: NIVO is a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor providing long-term survival with a favorable safety profile and QoL benefit, approved for previously treated advanced/metastatic NSCLC. Although the likelihood of benefit from NIVO appears correlated with PD-L1 expression in non-SQ NSCLC, pts without PD-L1 may also benefit; this trend is not seen in SQ NSCLC. As sHLA-G/E are immunosuppressive molecules, we hypothesized that baseline peripheral sHLA-G/E may be associated with NIVO outcomes. Methods: CheckMate 063 is a phase 2, single-arm study of NIVO in SQ NSCLC pts who progressed on/after prior platinum-based doublet chemotherapy (PT-DC). Of 117 pts treated, 50 had evaluable baseline serum and archived tumor samples. sHLA-G and -E serum levels (‘low’ defined as Results: Pts achieving PR or SD had lower baseline sHLA-G and -E (Table). Pts with longer OS had low sHLA-G and -E. Median OS was 8.6 vs 6.0 mo (HR 0.58 [0.31, 1.09]) in pts with low vs high sHLA-G, respectively; median OS was 13.6 vs 4.6 mo (HR 0.52 [95% CI 0.27, 0.97]) in pts with low vs high sHLA-E. Longest OS occurred in pts with both low sHLA-G and -E (n=14; median OS 15.1 mo [4.57, not reached]). No correlation was seen between baseline sHLA-G and -E levels (Spearman’s r=0.18; P=0.22). High peripheral sHLA-G and -E were negatively correlated with CD3/CD8+ T-cell tumor microenvironment infiltration (CD3+ r=-0.39 and -0.26; CD8+ r=-0.40 and -0.24, respectively). sHLA-G and -E were not associated with smoking and ECOG performance status. Table.Baseline sHLA-G and -E levels stratified by RECIST v1.1PR n=7SD n=3PD n=33bNE n=4PMedian sHLA-Ga4.687.5410.2921.140.41Median sHLA-Ea15.2511.3019.7330.830.39ang/mL; bn=32 for sHLA-ENE=non-evaluable; PD=progressive disease; PR=partial response; SD=stable disease Conclusion: Lower baseline sHLA-G and -E levels in NIVO pts with advanced, refractory SQ NSCLC were associated with improved OS. Further studies are warranted to determine if sHLA-G/E are prognostic or predictive biomarkers in SQ and non-SQ NSCLC. Citation Format: Vera Rebmann*, Wilfried E. Eberhardt*, Naiyer Rizvi, Scott J. Antonia, David Planchard, Federico Cappuzzo, Julien Mazières, Gérard Zalcman, Hervé Lena, Jürgen Wolf, Leora Horn, Thomas Stinchcombe, Grace Dy, Anne Blackwood-Chirchir, Chelsea Jin, William J. Geese, Suresh S. Ramalingam, *Authors contributed equally to the current work. Soluble HLA-G and -E (sHLA-G/E) as potential biomarkers of clinical outcomes in patients (pts) with advanced, refractory squamous (SQ) NSCLC treated with nivolumab (NIVO): CheckMate 063 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT126. doi:10.1158/1538-7445.AM2017-CT126

TPS8577 Background: At initial diagnosis, 20% of patients (pts) with NSCLC present with early-stage disease. The 5-year overall survival (OS) rate after surgery for stage IB–IIIA NSCLC is 25%–60%. Addition of adjuvant chemotherapy to surgery only provides a 5% absolute OS benefit at 5 years. Neoadjuvant treatment with immune checkpoint inhibitors may extend OS in early-stage NSCLC by enhancing systemic immunity and eradicating micrometastatic disease. In contrast to the adjuvant setting, the neoadjuvant setting is associated with a higher tumor burden, the presence of abundant tumor antigens, and the consequent potential for tumor-associated neoantigen presentation to the immune system. In an ongoing feasibility trial in pts with stage IB–IIIA NSCLC, nivolumab (nivo; a fully human PD-1 immune checkpoint inhibitor antibody) given alone as neoadjuvant treatment induced a major pathological response (MPR; < 10% residual viable tumor cells) rate of 39% (7/18), did not delay or interfere with surgery, and was not associated with new safety signals. In a phase 1 study in pts with stage IIIB/IV NSCLC, first-line nivo + ipilimumab (ipi; a CTLA-4 immune checkpoint inhibitor antibody) showed a greater radiologic objective response rate than nivo alone (39% vs 23%). These data provided the rationale for Checkmate 816 (NCT02998528), a phase 3 study evaluating nivo + ipi vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC. Methods: Approximately 326 pts aged ≥18 years with resectable stage IB/II/IIIA NSCLC, ECOG performance status 0–1, pulmonary function capable of tolerating lung resection, and available lung tumor tissue will be enrolled in North America, South America, Europe, and Asia. Pts are ineligible if they have autoimmune disease or had received prior treatment with immune checkpoint inhibitors. Pts will be randomized to receive nivo + ipi or platinum-doublet chemotherapy. The primary endpoint is MPR rate. Secondary endpoints include event-free survival, OS, and complete pathological response. Start date is January 2017. The estimated primary completion date is July 2019. Clinical trial information: NCT02998528.

Background: Nivo, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, is approved in the United States and European Union for the treatment of pts with advanced SQ NSCLC refractory to prior chemotherapy, based on results of phase 2 (CheckMate 063) and phase 3 (CheckMate 017) trials. In these studies, PD-1 ligand (PD-L1) expression was neither predictive nor prognostic of survival benefit. Here we present results of exploratory analyses from these studies evaluating the potential correlation of baseline serum cytokines with overall survival (OS) in pts with SQ NSCLC. Methods: Baseline serum cytokine concentrations in evaluable pts from CheckMate 063 and CheckMate 017 treated with nivo (n = 222) or doc (n = 118) were analyzed using a custom HumanMAP quantitative multiplexed immunoassay (Myriad RBM, Austin, TX). Multivariate analyses using a stepwise variable selection were performed in a Cox model using a 6:4 training:test validation in nivo-treated subjects. The performance of the association with OS of the identified cytokine set in nivo-treated subjects was tested using time-varying receiver-operating characteristic (ROC) analysis. SQ-cytoscore, generated to quantify the effect of the identified cytokine set on OS, was computed as follows: 1) calculation of the tertile bin distribution of each cytokine in the set in all pts and assignment of a point score (0, 1, or 2) for each tertile expression of each cytokine; 2) calculation of SQ-cytoscore for each pt as the sum of points; 3) categorization of pts as SQ-cytoscore “high” or “low” based on the median cutoff. OS was analyzed in pts with high vs low SQ-cytoscore treated with nivo and doc using the Kaplan-Meier method and 18-mo data cutoffs for CheckMate 063 (June 2015) and CheckMate 017 (August 2015). Results: Of 26 evaluable baseline cytokines, a set of 14 was identified to be associated with OS. Median OS was longer in pts with high vs low SQ-cytoscore in both nivo- and doc-treated cohorts (nivo [n = 102 vs 120]: 15.6 vs 5.3 months, HR:0.48, 95%CI:0.36-0.64, P Conclusion: In pts with advanced SQ NSCLC pooled from 2 clinical trials, a set of serum cytokines (details to be presented) potentially associated with OS benefit was identified. The benefit of a high SQ-cytoscore appeared more profound in pts treated with nivo vs doc. These preliminary findings require prospective validation in future studies. Citation Format: Benedetto Farsaci, William J. Geese, Kaushal D. Desai, Chelsea Jin, Scott J. Antonia, Hervé Lena, Leora Horn, David Planchard, Karen L. Reckamp, Thomas E. Stinchcombe, Scott Gettinger, Hossein Borghaei, Matthew D. Hellmann, Christopher Harbison, Dong Xu, M. Anne Blackwood-Chirchir, Naiyer Rizvi. Impact of baseline serum cytokines on survival in patients (pts) with advanced squamous (SQ) non-small cell lung cancer (NSCLC) treated with nivolumab (nivo) or docetaxel (doc): Exploratory analyses from CheckMate 063 and CheckMate 017. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-072.

9038Background: CNS mets occur in 20%–40% of pts with adv NSCLC and are associated with poor overall survival (OS; median ≈7 mo). We evaluated nivo in this subgroup by: 1) pooling nivo-treated pts ...

Silent infarcts have been reported most commonly in school-aged children with homozygous sickle cell disease (SCD-SS) and are associated with neurocognitive deficits. However, the prevalence of silent infarcts in younger children with SCD-SS is not well defined. In this retrospective study, brain magnetic resonance imaging and angiography (MRI/A) studies performed before six years of age in a cohort of children with SCD-SS were analyzed and the prevalence of abnormalities was calculated. Clinical and laboratory parameters were compared between the groups with and without silent infarcts. Sixty-eight of 96 children in the cohort had brain MRI/A performed prior to age 6 years. Of the 65 who were neurologically asymptomatic, 18 (27.7%, 95% confidence interval 17.3 – 40.2%) had silent infarcts (mean age 3.7 ± 1.1 years, range 1.3 – 5.9 years). Factors associated with silent infarcts included cerebral vessel stensosis by magnetic resonance angiography, lower rates of vaso-occlusive pain and acute chest syndrome, and lower hemoglobin levels. The prevalence of silent infarcts in young children with SCD-SS is similar to that of older children and anemia and severe vasculopathy may be risk factors.

Characterizing the key determinants of variability in the exposure of orally administered drugs may be important in understanding the implications of exposure variability on clinical responses. In particular, partitioning overall variability into interoccasion variability (IOV) and interindividual variability (IIV) allows a better assessment of the clinical importance of exposure variability. The IOV characterizes the dose-to-dose variability in exposure within a subject and is likely to be less clinically relevant than IIV for chronically administered drugs as the effect of IOV averages out over repeated dosing. The main aims of this model-based analysis were (1) to characterize the IOV and IIV of dasatinib, a novel, orally administered, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases that is indicated for the treatment of chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia and (2) to demonstrate using simulated data that it is possible to estimate IIV and IOV in relative bioavailability (F(R)) of an orally administered drug, given an adequate sampling scheme. Variability in dasatinib exposure was estimated to be mainly due to IOV in F(R) (44% coefficient of variation [CV]) and, to a lesser extent, due to IIV in F(R) and IIV in clearance (32% and 25% CV, respectively). The IIV is expected to be more clinically relevant than IOV for chronically administered oral drugs such as dasatinib, as the overall variability in cumulative exposure will be mainly due to IIV. The analysis of simulated data demonstrated that models ignoring either IIV or IOV in F(R) resulted in upwardly biased estimates of interindividual or residual variability. Thus, it may be important to account for both IIV and IOV in F(R), particularly for orally administered agents that exhibit absorption-related variability in exposure.

SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [(14)C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of

Dasatinib (BMS-354825) is a potent, oral multi-targeted kinase inhibitor. It is an effective therapy for patients with imatinib-resistant or -intolerant Ph+ leukemias,. It has demonstrated promising preclinical anti-tumor activity, and is under clinical evaluation in solid tumors. To support the clinical development of dasatinib, we identified a pharmacodynamic biomarker to assess in vivo SRC kinase inhibition, with subsequent evaluation in cancer patients. The biomarker, phosphorylated SRC (phospho-SRC), was first identified in human prostate PC-3 tumor cells and peripheral blood mononuclear cells (PBMCs) in vitro. It was further assessed in nude mice bearing PC-3 xenografts. Phospho-SRC[pY418] in tumors and PBMC were measured by western blot analysis, and were quantified by ELISA assays. Dasatinib plasma concentrations were determined using LC/MS/MS. In PC-3 cells, dasatinib showed dose-dependent anti-proliferative effect, which correlated with the inhibition of phospho-SRC[pY418] and of SRC kinase activity. With a single oral dose of 50 or 15 mg/kg, tumoral phospho-SRC[pY418] was maximally inhibited at 3 h, partially reversed between 7 and 17 h, and completely recovered after 24 h post dose. At 5 mg/kg, tumoral phospho-SRC[pY418] inhibition was less pronounced and recovered more rapidly to baseline level within 24h. Dasatinib (1 mg/kg) resulted in little inhibition. In PBMCs, a similar time course and extent of phospho-SRC[pY418] inhibition was observed. Inhibition of phospho-SRC[pY418] in vivo appeared to correlate with the preclinical in vivo efficacy and PK profiles of dasatinib in mice. Phospho-SRC[pY418] may potentially be used as a biomarker to enable assessment of target inhibition in clinical studies exploring dasatinib antitumor activity.

Background The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome–positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCRABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). Methods Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study. Dasatinib (15 to 240 mg per day) was administered orally in four-week treatment cycles, once or twice daily. Results A complete hematologic response was achieved in 37 of 40 patients with chronicphase CML, and major hematologic responses were seen in 31 of 44 patients with accelerated-phase CML, CML with blast crisis, or Ph-positive ALL. In these two phases, the rates of major cytogenetic response were 45 percent and 25 percent, respectively. Responses were maintained in 95 percent of patients with chronic-phase disease and in 82 percent of patients with accelerated-phase disease, with a median follow-up more than 12 months and 5 months, respectively. Nearly all patients with lymphoid blast crisis and Ph-positive ALL had a relapse within six months. Responses occurred among all BCR-ABL genotypes, with the exception of the T315I mutation, which confers resistance to both dasatinib and imatinib in vitro. Myelosuppression was common but not dose-limiting. Conclusions Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib. (ClinicalTrials.gov number, NCT00064233.)

Background: CC-486 is an orally bioavailable formulation of azacitidine that has demonstrated clinical activity in subjects with Myelodysplastic Syndromes (MDS) and Acute Myleoid Leukemia (AML). In these patient populations, CC-486 in extended dosing regimens, 200 mg and 300 mg given daily on a 14 or 21 out of 28-day schedule, induces sustained global genomic hypomethylation. Methods: This Phase I, multicenter, open-label study was conducted in subjects with solid tumors to evaluate: 1) the effect of carboplatin or ABI-007 on the PK of CC-486; 2) the effect of CC-486 on the PK of carboplatin or ABI-007; and 3) the PD (DNA methylation) effects of CC[[Unable to Display Character: ‑]]486 as a single agent and in combination with carboplatin or ABI-007. Safety and efficacy information of this trial are presented in a separate abstract submission. Subjects received CC-486 on Days 1-14 with carboplatin AUC 4 on Day 8 of a 21-day cycle (Arm A), CC-486 on Days 1-14 with ABI-007 100 mg/m2 given weekly starting on Day 8 of a 21-day cycle (Arm B), or CC-486 on Days 1-21 of a 21-day cycle (Arm C). Results: High inter-subject variability was observed in PK concentrations and parameters. In subjects from Arms A and B, following administration of CC-486 alone or in combination with carboplatin or ABI-007, CC-486 was rapidly absorbed and reached Tmax within approximately 1.0 hour post-dose (median); azacitidine PK parameters (AUC, Cmax, half-life elimination, apparent clearance, and volume of distribution) were comparable following administration of CC-486 alone or in combination. Similarly, carboplatin and ABI-007 PK parameters were similar following administration of carboplatin or ABI-007 alone or in combination with CC-486. In subjects from the 3 Arms, global genomic hypomethylation was observed in PBMCs, with maximum effect on Day 15. A PK/PD (AUC/hypomethylation change on Day 15) correlation was noted (r>0.5; p Conclusion: Carboplatin and ABI-007 had minimal to no effect on CC-486 PK parameters, and vice-versa. Following administration of CC-486, global genomic hypomethylation was correlated with plasma AUC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B217. Citation Format: Eric Laille*, Aaron N. Nguyen*, Gengxi Chen, Drew Rasco, Patricia LoRusso, Daniel D. Von Hoff, Johanna Bendell, Pamela Munster, William J. Edenfield, Ramesh Ramanathan, Michael B. Gonzalez, Anne Blackwood-Chirchir, Jorge DiMartino. A Phase I study of CC-486 (oral azacitidine) to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of azacitidine administered alone and in combination with carboplatin or ABI-007 (NAB-paclitaxel) in subjects with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B217.

Background: CC-486, an oral formulation of 5-azacitidine, induces global genomic hypomethylation and clinical responses in MDS patients at doses of 200 mg and 300 mg/day for 14 or 21/28 days with acceptable safety. This non-randomized, multi-center Phase Ib study was designed to determine whether CC-486 can be delivered safely as priming for carboplatin or NAB-Paclitaxel (ABI-007) in patients with solid tumors. Methods: In Part 1 of this study, patients with refractory solid tumors were assigned to Arm A: CC-486 days 1 - 14 with carboplatin AUC 4 on day 8 of a 21 day cycle (n = 13) or Arm B: CC-486 days 1 - 14 with ABI-007 100 mg/m2 given weekly starting on Day 8 of Cycle 1 (n = 24). 200 mg and 300 mg dose levels (DLs) of CC-486 were evaluated in cohorts of 6 to identify a recommended Part 2 dose (RP2D). Results: On Arm A, 200 mg and 300 mg doses of CC-486 were tolerated. There was one DLT (Grade 3 pericardial effusion) at the 300 mg DL. Other related treatment-emergent adverse events (TEAEs) included anemia (53.8%) and neutropenia (46.3%). On Arm B, there were 2 DLTs of neutropenia at the 200 mg DL. The protocol was amended to give ABI-007 on days 8 and 15/21. No DLTs were encountered on 200 mg of CC-486 with intermittent ABI-007. At 300 mg, the MTD was exceeded with 2 DLTs of neutropenia (cholangiocarcinoma, pancreatic). Other common TEAEs in Arm B included nausea/vomiting (45.8%) and peripheral neuropathy (50%). Evidence of activity seen at both DLs included hypomethylation in PBMCs, 3 PRs in Arm B and 5 subjects with stable disease (> 4 mos) in Arm A. CC-486 plasma exposure showed high interpatient variability but was higher at 300 mg than 200 mg. Incidence and severity of AEs did not differ significantly between the 2 DLs. 300 mg was selected as the RP2D in combination with carboplatin and 200 mg in combination with ABI-007. Conclusion: CC-486 dosed 14/21 days is tolerated as a priming agent with carboplatin and ABI-007. Both combinations show evidence of clinical activity. Expansion cohorts at the RP2D of Arm A (relapsed/refractory bladder or ovarian carcinoma) and Arm B (relapsed/refractory NSCLC or pancreatic carcinoma) are enrolling to further characterize safety, PK/PD and anti-tumor activity. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A120. Citation Format: Patricia LoRusso, Drew Rasco, Johanna Bendell, Jasgit Sachdev, Ramesh Ramanathan, Glenn Weiss, Pamela Munster, William J. Edenfield, Kejian Liu, Anne Blackwood-Chirchir, Jorge DiMartino, Jorge DiMartino, Daniel D. Von Hoff. A Phase Ib study of CC-486 (Oral Azacitidine) as a priming agent for carboplatin or NAB-paclitaxel in subjects with relapsed and refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A120.

1007 Background: A randomized phase II study in mTNBC suggested that iniparib (I), an anticancer agent with PARP inhibitory activity, added to GC improved overall survival (OS), without potentiating GC toxicity (O’Shaughnessy et al. NEJM 2011). This confirmatory study evaluated the safety and efficacy of GC with or without I in a similar mTNBC pt population. Methods: This randomized, open-label phase III study enrolled pts ≥18 years with mTNBC, measurable disease, and ≤2 prior cytotoxic regimens for metastatic TNBC. Pts were stratified based on having 0 vs. 1–2 prior metastatic therapies. Pts were randomized (1:1) to GC alone or GCI. G (1000 mg/m2; IV) and C (AUC 2; IV) were given on days 1 and 8, and I (5.6 mg/kg; IV) on days 1, 4, 8, and 11 every 21 days. Upon central confirmation of disease progression on GC, crossover to GCI was permitted. Primary endpoints were OS and progression-free survival (PFS); secondary endpoints were objective response rate and safety. Results: Between July 2009 and March 201...