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This phase 1b, open-label, dose-escalation study assessed the safety, efficacy, and pharmacokinetics of anti-CD38 monoclonal antibody isatuximab given in 2 schedules (3, 5, or 10 mg/kg every other week [Q2W] or 10 or 20 mg/kg weekly [QW] for 4 weeks and then Q2W thereafter [QW/Q2W]), in combination with lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (QW), in patients with relapsed/refractory multiple myeloma (RRMM). Patients received 28-day treatment cycles; the primary objective was to determine the maximum tolerated dose (MTD) of isatuximab with lenalidomide and dexamethasone. Fifty-seven patients (median 5 [range 1-12] prior regimens; 83% refractory to previous lenalidomide therapy) were treated. Median duration of dosing was 36.4 weeks; 15 patients remained on treatment at data cutoff. Isatuximab-lenalidomide-dexamethasone was generally well tolerated with only 1 dose-limiting toxicity reported (grade 3 pneumonia at 20 mg/kg QW/Q2W); the MTD was not reached. The most common isatuximab-related adverse events were infusion-associated reactions (IARs) (56%), which were grade 1/2 in 84% of patients who had an IAR and predominantly occurred during the first infusion. In the efficacy-evaluable population, the overall response rate (ORR) was 56% (29/52) and was similar between the 10 mg/kg Q2W and 10 and 20 mg/kg QW/Q2W cohorts. The ORR was 52% in 42 evaluable lenalidomide-refractory patients. Overall median progression-free survival was 8.5 months. Isatuximab exposure increased in a greater than dose-proportional manner; isatuximab and lenalidomide pharmacokinetic parameters appeared independent. These data suggest that isatuximab combined with lenalidomide and dexamethasone is active and tolerated in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT01749969.

A Phase 2 dose-finding study evaluated isatuximab, an anti-CD38 monoclonal antibody, in relapsed/refractory multiple myeloma (RRMM; NCT01084252). Patients with ≥3 prior lines or refractory to both immunomodulatory drugs and proteasome inhibitors (dual refractory) were randomized to isatuximab 3 mg/kg every 2 weeks (Q2W), 10 mg/kg Q2W(2 cycles)/Q4W, or 10 mg/kg Q2W. A fourth arm evaluated 20 mg/kg QW(1 cycle)/Q2W. Patients (N = 97) had a median (range) age of 62 years (38–85), 5 (2–14) prior therapy lines, and 85% were double refractory. The overall response rate (ORR) was 4.3, 20.0, 29.2, and 24.0% with isatuximab 3 mg/kg Q2W, 10 mg/kg Q2W/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW/Q2W, respectively. At doses ≥10 mg/kg, median progression-free survival and overall survival were 4.6 and 18.7 months, respectively, and the ORR was 40.9% (9/22) in patients with high-risk cytogenetics. CD38 receptor density was similar in responders and non-responders. The most common non-hematologic adverse events (typically grade ≤2) were nausea (34.0%), fatigue (32.0%), and upper respiratory tract infections (28.9%). Infusion reactions (typically with first infusion and grade ≤2) occurred in 51.5% of patients. In conclusion, isatuximab is active and generally well tolerated in heavily pretreated RRMM, with greatest efficacy at doses ≥10 mg/kg.

Background: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.

This phase I dose-escalation/expansion study evaluated isatuximab (anti-CD38 monoclonal antibody) monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). Patients progressing on or after standard therapy received intravenous isatuximab (weekly [QW] or every 2 weeks [Q2W]). The primary objective was to determine the maximum tolerated dose (MTD) of isatuximab. Overall, 84 patients received ≥ 1 dose of isatuximab. The MTD was not reached; no cumulative adverse reactions were noted. The most frequent adverse events were infusion reactions (IRs), occurring in 37/73 patients (51%) following introduction of mandatory prophylaxis. IRs were mostly grade 1/2, occurred predominantly during Cycle 1, and led to treatment discontinuation in two patients. CD38 receptor occupancy reached a plateau of 80% with isatuximab 20 mg/kg (highest dose tested) and was associated with clinical response. In patients receiving isatuximab ≥ 10 mg/kg, overall response rate (ORR) was 23.8% (15/63), including one complete response. In high-risk patients treated with isatuximab 10 mg/kg (QW or Q2W), ORR was 16.7% (3/18). Median (range) duration of response at doses ≥ 10 mg/kg was 25 (8–30) weeks among high-risk patients versus 36 (6–85) weeks for other patients. In conclusion, isatuximab demonstrated a manageable safety profile and clinical activity in patients with RRMM.

Metastatic triple-negative breast cancer (TNBC) is a phenotypic breast cancer subgroup with a very poor prognosis, despite standard treatments. Combined twice-weekly iniparib and gemcitabine/carboplatin (GC+tw-iniparib) showed benefit over gemcitabine/carboplatin in a randomized phase II trial, and a phase III was initiated comparing these regimens. The present phase II study was initiated to compare GC+tw-iniparib with a more practical once-weekly schedule (GC+w-iniparib) in TNBC. Metastatic TNBC patients were randomized to receive iniparib weekly (11.2 mg/kg on days 1 and 8) or twice-weekly (5.6 mg/kg on days 1, 4, 8, and 11) with gemcitabine (1000 mg/m2) and carboplatin (area under the curve 2 on days 1 and 8), every 3 weeks. The primary endpoint was the overall response rate (ORR). Pharmacokinetics of iniparib and its two metabolites were analyzed. A total of 163 patients were randomized, 82 GC+w-iniparib and 81 GC+tw-iniparib. Demographic and baseline characteristics were well balanced. ORR was 34.1% (95% CI 23.9–44.4%) vs. 29.6% (95% CI 19.7–39.6%) and median progression-free survival was 5.5 months (95% CI 4.2–5.7) vs. 4.3 months (95% CI 3.0–5.8) for GC+w-iniparib and GC+tw-iniparib, respectively. Safety was similar across treatment arms in terms of event severity and type. Iniparib plasma concentrations and exposure were two-fold higher with w-iniparib compared to tw-iniparib. Iniparib and its metabolites were cleared rapidly with a terminal half-life of

WOS: 000491229800404, [No abstract available]

Introduction In the heart, several transcription factors (TF) are powerful regulators of cardiac cell fate and organogenesis. Less well studied are the roles of TF in physiological functions. Several studies on animal models have shown that the Iroquois homeobox (Irx) TFs are key patterning and differentiation regulators that confer cell type-specific properties to specialized cardiac lineages. Importantly, studies in mice have shown that IRX5 is expressed very early during cardiogenesis and maintained in adult heart where it regulates ventricular electrophysiological properties, the repolarizing gradient. It has also been shown that IRX5 target-genes regulation occurs through recruitment of histone modifiers. Objective/Method In order to study IRX5 in human, we used cardiomyocytes differentiated from induced pluripotent stem cells (hiPS-CMs) generated from patients carrying loss of function mutations in IRX5 (IRX5Mut) and control individuals. As we detected IRX5 protein as early as in the pluripotent state, we also analyzed cells at hiPS stage in our experiments. High-throughput transcriptomic and epigenetic analyses were performed to obtain a global understanding of IRX5 function. Results The transcriptomic experiments allowed us to determine the entire set of differentially expressed genes in hiPS and hiPS-CMs IRX5Mut cells as compared to control cells. The epigenetic experiments, performed by ChIPseq, suggested that IRX5 binds to already open chromatin, and preferentially, to enhancer rich regions rather than proximal promoters. Combining these high-throughput experiments, we found direct target genes of IRX5 at hiPS-CM stage, and some of them are relevant to cardiac function. Notably, we showed that this TF regulates the expression of several actors of electrical conduction, such as SCN5A, at hiPS-CM stage. Conclusion IRX5 seems to be an important factor for the regulation of human cardiac function, and more specifically of its electrical function.

Objective The aim of the study was to evaluate the activity and tolerability of iniparib monotherapy in women with BRCA1 or BRCA2-associated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. Methods and Materials Eligible patients had advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer, germline BRCA1 or BRCA2 mutation, measurable disease, and at least 1 previous treatment regimen of platinum/taxane chemotherapy. Patients received iniparib 8 mg/kg intravenously on days 1 and 4 weekly, with imaging every 8 weeks. Treatment continued until disease progression or adverse events (AEs) prohibited further therapy. Common Terminology Criteria for AEs v3.0 was used to grade AEs. The primary endpoint was tumor response. The study was conducted with a Simon 2-stage design with 12 and 23 patients planned in the first and second stage, respectively. The study was designed to distinguish between 10% and 30% responding with types 1 and 2 error of 0.10. Results Twelve patients were treated on study, with median exposure to iniparib of 7.5 weeks. The median number of previous chemotherapeutic regimens was 7. Treatment-related AEs (≥10%) included asthenia (83.3%), constipation (25%), diarrhea (25%), nausea (25%), abdominal pain (16.7%), and decreased hemoglobin (16.7%). All treatment-related AEs were grades 1 or 2 with the following 2 exceptions: 1 grade 3 diarrhea and 1 grade 3 hypertension. One patient had stable disease lasting 2 cycles; the remaining 11 patients had progressive disease. The study did not proceed to second stage enrollment. Conclusions Iniparib did not show significant activity in this heavily pretreated ovarian cancer population, all of whom had BRCA1 or BRCA2 mutations.

Background Progressive cardiac conduction disease (PCCD) is one of the most common cardiac conduction disturbances. It has been causally related to rare mutations in several genes including SCN5A , SCN1B , TRPM4 , LMNA and GJA5 . Methods and results In this study, by applying targeted next-generation sequencing (NGS) in 95 unrelated patients with PCCD, we have identified 13 rare variants in the TRPM4 gene, two of which are currently absent from public databases. This gene encodes a cardiac calcium-activated cationic channel which precise role and importance in cardiac conduction and disease is still debated. One novel variant, TRPM4 -p.I376T, is carried by the proband of a large French 4-generation pedigree. Systematic familial screening showed that a total of 13 family members carry the mutation, including 10 out of the 11 tested affected individuals versus only 1 out of the 21 unaffected ones. Functional and biochemical analyses were performed using HEK293 cells, in whole-cell patch-clamp configuration and Western blotting. TRPM4 -p.I376T results in an increased current density concomitant to an augmented TRPM4 channel expression at the cell surface. Conclusions This study is the first extensive NGS-based screening of TRPM4 coding variants in patients with PCCD. It reports the third largest pedigree diagnosed with isolated Progressive Familial Heart Block type I and confirms that this subtype of PCCD is caused by mutation-induced gain-of-expression and function of the TRPM4 ion channel.

Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II-IIIA TNBC were randomly assigned to receive PTX (80 mg/m(2), d1; n = 47) alone or in combination with iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of iniparib at these doses plus paclitaxel in early TNBC.

Purpose There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial. Patients and Methods Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m2 and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5.6 mg/kg (days 1, 4, 8, and 11) every 3 weeks. Random assignment was stratified by the number of prior chemotherapies. The coprimary end points were OS and PFS. Patients receiving GC could cross over to iniparib on progression. Results Five hundred nineteen patients were randomly assigned (261 GCI; 258 GC). In the primary analysis, no statistically significant difference was observed for OS (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12; P = .28) nor PFS (HR = 0.79; 95% CI, 0.65 to 0.98; P = .027). An exploratory analysis showed that patients in the second-/third-line had improved OS (HR = 0.65; 95% CI, 0.46 to 0.91) and PFS (HR = 0.68; 95% CI, 0.50 to 0.92) with GCI. The safety profile for GCI was similar to GC. Conclusion The trial did not meet the prespecified criteria for the coprimary end points of PFS and OS in the ITT population. The potential benefit with iniparib observed in second-/third-line subgroup warrants further evaluation.

Background: Hematopoietic acute radiation syndrome (H-ARS) occurs in individuals that are exposed to high levels of radiation over a short period of time. The destruction of bone marrow leads to pancytopenia, which increases the incidence of infections and accounts for the majority of morbidity and mortality. Sargramostim (yeast-derived rhGM-CSF) is a leukocyte growth factor that promotes differentiation, maturation and activation of granulocytes, monocytes and macrophages. Methods: We evaluated the efficacy of repeat administrations of sargramostim (7 μg/kg/day) in a blinded, GLP study in total body irradiated non-human primates (NHPs) when administered 48 h post-irradiation with minimal supportive care (e.g., no blood products or individualized antibiotics). The primary objective was to assess the efficacy of sargramostim versus vehicle on mortality rate at Day 60 in irradiated male and female NHPs at LD50-60/60 (n=36/group). Secondary objectives included the efficacy of sargramostim on overall survival and its effect on hematology parameters. The study included an exploratory arm of male and female NHPs that were irradiated at a LD70-80/60(n= 18/group) and received the same treatments. Results: Sargramostim decreased the mortality rate at Day 60 by 36% in the LD50-60/60 group (p=0.0018) and by 44% in the LD70-80/60 group (p=0.0076). Additionally, neutrophil, platelet, lymphocyte, and white blood cell levels in survivors demonstrated accelerated recovery in the sargramostim-treated NHPs in the LD50-60/60 and LD70-80/60 groups. Conclusion: Treatment with sargramostim (7 μg/kg/day) beginning at 48 h, in the absence of blood products and individualized antibiotics, suggests that the use of sargramostim is a viable therapeutic strategy for H-ARS in a mass casualty event. Funding: This project has been funded in whole or in part with Federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under Contract No. HHSO100201300005I. Disclosures Clayton: Sanofi Genzyme: Employment. Charpentier:Sanofi: Employment. LaCasse:Sanofi Genzyme: Employment. Khan-Malek:Sanofi: Employment. Keutzer:Sanofi Genzyme: Employment.

8009Background: Isatuximab (ISA), a humanized anti-CD38 monoclonal antibody, has demonstrated activity in patients (pts) with RRMM in combination with Len/Dex in an ongoing Phase 1b study (NCT01749...

8005Background: Isatuximab (ISA) is a humanized anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement. Here, ...

Background: Isatuximab (SAR650984) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor. In the dose escalation part of the Phase I portion of the trial (NCT01749969), isatuximab ≥10 mg/kg IV given every other week (q2w) or 10 mg/kg weekly (qw) induced responses in 6/19 recipients (ORR 32%). Responses were noted at doses as low as 1 mg/kg q2w. The maximum tolerated dose (up to 20 mg/kg IV qw) was not reached. The most common treatment-emergent adverse events (TEAEs) were fatigue and nausea; few serious grade 3/4 TEAEs were reported (pneumonia 6%). The most common category of drug-related TEAE involved infusion-associated reactions (IARs) occurring in half of the patients, with grade 3/4 IARs in Methods: In Phase II, eligible patients were originally randomly assigned (1:1:1) to one of 3 treatment groups: 3 mg/kg q2w, 10 mg/kg q2w, and 10 mg/kg q2w x 4 doses then q4w. A 4th treatment group was enrolled at a higher isatuximab dose with an optimized schedule of 20 mg/kg qw x 4 doses then q2w. Patient assignment was stratified by prior anti-myeloma therapy (Stratum 1: prior treatment with pomalidomide (POM) and/or carfilzomib (CAR); Stratum 2: no prior POM or CAR). Patients continued therapy until disease progression, unacceptable AEs or physician/patient decision. Eligible patients had measurable disease (serum M-protein >1 g/dL or urine M-protein ≥200 mg/24 h, or serum free light chain ≥10 mg/dL), prior exposure to ≥3 lines of anti-myeloma therapy or were double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), prior treatment with an alkylating agent, and adequate baseline bone marrow reserve and organ function. Enrollment of 24 patients was planned for each treatment group. An interim efficacy analysis is planned when all patients have completed ≥2 disease assessments, with central review of these data currently ongoing. Enrollment has now been completed and all patients who completed at least 1 cycle of isatuximab at the cutoff date (5/29/15) are included in this preliminary analysis. Results: Patient characteristics (n=96): median age 62.5 yrs (range 38-85); median time from initial diagnosis to study treatment 5.85 yrs (1.2-24.1); 76% had IgA/G MM; 24% had light-chain only disease; and 22%, 22%, and 44% had Stage I, II, and III disease, respectively. The median number of prior lines of therapy was 5 (2-14) with 100%, 99%, and 98% having prior exposure to PIs, IMiDs, and alkylator-containing therapy, respectively. Overall, 78% of patients had previously received POM and/or CAR; 55% had been exposed to both of these agents. At data cut-off, 36.5% of patients remained on therapy and 53.1%, 6.3%, and 4.2% had discontinued therapy due to disease progression, AEs, or other reason, respectively. The median number of cycles received was 3 (1-9), with a median duration of treatment of 11.7 wks. Approximately 17% of patients required at least 1 dose delay and 7.3% of isatuximab infusions were interrupted. TEAEs occurred in 93% of patients, with 51% being grade ≥3. Drug-related TEAEs occurred in 61% of patients (grade ≥3, 10%). The most common drug-related TEAEs (>5% of patients) were nausea (14.6%), chills (14.6%), dyspnea (13.5%), chest discomfort (10.4%), flushing (7.3%), headache (7.3%), cough (6.3%), and vomiting (5.2%). The majority of the symptoms occurred within 24 h of isatuximab infusion and were attributed to an IAR. IARs occurred in 50% of patients, were predominantly grade 1/2 (grade ≥3, 3.1%), and were mostly limited to Cycle 1 (2 patients had IARs in Cycle 2). Pneumonia (6.3%) and sepsis (5.2%) were the most common serious TEAEs. Six deaths have occurred within 30 days of last dose, 4 due to disease progression, and 2 due to serious AEs unrelated to study therapy (cardiopulmonary arrest and cerebral hemorrhage). Conclusion: Isatuximab administered to heavily pre-treated patients with RRMM appears well tolerated. IARs are common in Cycle 1, but typically do not recur. Results by treatment arm, including interim analysis response data, will be presented. Disclosures Martin: Sanofi: Research Funding. Richter:Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Vij:Millennium: Honoraria, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS, Amgen, Prothena, Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Kaufman:Spectrum: Consultancy; Merck: Research Funding; Onyx: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Millenium: Consultancy. Bensinger:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acetylon: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millenium: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria. San Miguel:Millennium, Celgene, Novartis, Janssen, Onyx, BMS, MSD: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Onyx: Honoraria; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Hari:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding. Hsu:Sanofi: Employment. Charpentier:Sanofi: Employment. Strickland:Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation. Mikhael:Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; AbbVie: Research Funding.

8532 Background: SAR650984 (SAR) is a naked humanized IgG1 monoclonal antibody that binds to the CD38 receptor. SAR kills tumor cells via ADCC, CDC, direct apoptosis without secondary crosslinking ...

Background: SAR650984 (SAR) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor and may induce anti-tumor effects via antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptosis induction without secondary crosslinking and/or allosteric inhibition on CD38 enzymatic activity. Preclinical and xenograft data supported the clinical use of SAR in combination with lenalidomide (LEN). Safety, response and progression free survival (PFS) data after a median follow-up of 6 months are reported (cutoff date: June 7, 2014). (NCT01749969) Methods: Patients with relapsed or refractory myeloma (RRMM) were treated with SAR at one of three dose levels (DL) 3, 5 and 10 mg/kg, every 2 weeks, in combination with LEN and dexamethasone (Dex). SAR was given IV on day 1 and 15 with dose escalation following the classic 3+3 design. Standard doses of LEN (25 mg days 1 – 21 adjusted to 10 mg if baseline creatinine clearance ≤ 60mL/min) and Dex (40 mg days 1, 8, 15 and 22) were given in 28- day cycles. An expansion cohort of 18 patients was to be treated at the maximum tolerated dose (MTD) or the highest dose to be tested (10 mg/kg). Results: A total of 31 patients have been treated, including 24 patients (6 + 18) at the 10 mg/kg DL since the MTD was not reached. The median time from initial MM diagnosis to first dose of SAR was 4.5 years (1.1 – 11.7) and the median number of prior treatment regimens was 6 (range 2 - 12). Over 95% of patients received prior IMiD® therapy (LEN=29, pomalidomide (POM) =9) and more than 85% of these patients (27/31) were relapsed or refractory to at least one prior IMiD®-based therapy. More than 90% of patients received bortezomib (BOR) and 48% received prior carfilzomib (CAR). No dose limiting toxicities were reported. The most common treatment emergent adverse events (TEAEs- all grades) regardless of relationship included fatigue (41.9%), nausea (38.7%), upper respiratory tract infection (38.7%) and diarrhea (35.5%). Infusion associated reactions (IAR - all grades) occurred in 38.7% (n = 12) of patients, which predominantly occurred at cycle 1. Grade 3 IAR’s occurred in 2 patients resulting in treatment discontinuation. No other TEAEs led to discontinuation and there were no related TEAE with a fatal outcome. The safety profile appears uniform across the DLs. The pharmacokinetic analysis did not reveal any drug-drug interaction between SAR and Len. With a median follow-up of 6 months, the ORR (all treated patients) was 64.5% (sCR = 2, VGPR = 8, PR = 10) and clinical benefit response (CBR) was 71%. Of note, among the 24 patients who were relapsed and refractory to their last regimen containing LEN, the ORR was 62.5 % and CBR was 70.8% (VGPR = 8, PR = 7, MR = 2). In addition, patients relapsed and refractory to both IMiD® and proteasome inhibitors (n = 21) had an ORR of 52.4 % and CBR of 61.9% (VGPR = 4, PR = 7, MR =2). The median time to first response among all treated patients was 4.2 weeks (4 – 10.1) with median time to best response of 8.5 weeks (4 – 32.6). Nine patients had improvement of response after a median of 16.1 weeks (8.1– 32.6) of therapy: PR → sCR n = 1, VGPR → sCR n = 1, PR → VGPR n = 5, MR → PR n = 2. Median time on treatment was 26.4 weeks (2 - 61). 14 patients remained on treatment at the cutoff date. Median duration of response was 23.1 weeks (0.1 – 54.7). Overall 15 (48.4%) patients had PFS events (deaths n =1 [unrelated] or progression n = 14) and median PFS was 6.2 months. For patients previously treated with LEN, BOR and at least one of the newer agents (CAR and/or POM and/or elotuzumab) (n=17), median PFS was 4.8 months. Conclusion: With a median follow-up of 6 months SAR/LEN/Dex administered to heavily pre-treated patients with RRMM appears effective with an ORR of 64.5%, CBR of 71% and PFS of 6.2 months. Responses were seen following the first cycle of therapy and deepen with continued treatment. The ORR was 62.5% in patients relapsed or refractory to their last regimen containing LEN. SAR in combination with LEN/Dex was well tolerated with impressive durable responses and warrants further evaluation. Disclosures Martin: Sanofi: Research Funding; Novartis: Speakers Bureau. Baz:Sanofi: Research Funding; Karyopharm: Research Funding; Bristol Myers Squibb: Research Funding; Millennium: Research Funding; Celgene: Research Funding. Benson:Sanofi: Research Funding. Vij:Millennium: Honoraria; Novartis: Honoraria; Jannsen: Honoraria; Sanofi: Honoraria; Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

An array antenna with an integrated radome, consisting of microstrip elements with a flat radome cover layer is introduced. The effects of a flat radome layer on the microstrip array antenna at X-band frequencies are examined. The presence of a dielectric radome layer above the radiating elements influences the antenna properties such as the gain, radiation pattern, input impedance and resonant frequency. Using CAD software, simulation results have demonstrated that the integrated radome is similar to an RF lens and can enhance the directivity in the broadside direction. Detailed characteristics of the 2×2 array antenna have been analyzed for two different radome thickness. Antenna simulation and experimental results are discussed.

Background: Iniparib (I) is a novel anticancer agent initially thought to be a poly (ADP-ribose) polymerase (PARP) inhibitor. Recent preclinical data suggest that iniparib does not inhibit PARP at pharmacologically-relevant concentrations. The initial Phase 1 did not identify any dose limiting toxicity (DLT) and the dose of 5.6 mg/kg used in further development was based on a PK/PD model for PARP inhibition. This new Phase 1 study was designed to determine a maximum tolerated dose (MTD) based on DLT occurrence for single agent iniparib and in combination with gemcitabine and carboplatin (GC). Patients and Methods: Patients with advanced cancer and ECOG performance status (PS) 0-2 with no standard therapeutic option or for whom GC could be considered an adequate treatment were enrolled in this trial. In the Phase 1 portion, patients received escalating doses of single agent iniparib starting at 15 mg/kg in a 3+3 design. In the Phase 1b, two different regimens of GC and iniparib were evaluated (GC2+I: carboplatin AUC2, gemcitabine 1,000 mg/m2 and iniparib on Days 1 and 8 every 21 days; and GC5+I: carboplatin AUC5 on Day 1, gemcitabine at 1,000 mg/m2 and iniparib both on Days 1 and 8 in a 21-day cycle). At the MTD, the cohort was expanded by 12 patients. Safety, pharmacokinetics, pharmacodynamics, and antitumor effects were also evaluated. Results: Of the 59 patients (M/F= 18/41; ECOG 0/1-2=21/38) enrolled in this study, 29 received single agent iniparib (15 mg/kg=3; 20 mg/kg=16; 26 mg/kg=10); 23 received GC2+I (15 mg/kg=3; 20 mg/kg=20) and 7 were treated in the GC5+I arm at 15 mg/kg. DLT in the phase 1 was G3 transient increase in blood pressure during the iniparib infusion in 4 patients treated at 26 mg/kg. Nine patients at 20 mg/kg (5 in Phase 1 and 4 in Phase 1b) experienced also transient non-DLT hypertension. In most cases HTN was managed by interrupting the infusion; infusions were completed after blood pressure normalization. No patient was discontinued due to it. DLT for GC2+I was G4 thrombocytopenia in 3 patients. GC5+I at 15 mg/kg was considered non-tolerable due to G4 hematological toxicity in 2/5 patients. One ovarian cancer patient treated with iniparib single agent at 26 mg/kg for longer than 18 months had a durable (9 months) partial response (PR). Ten PRs were recorded in combination with GC. Conclusions: The MTD of iniparib single agent and in combination with GC2 is 20 mg/kg weekly. Hypertension during the infusion has been identified as a characteristic DLT. The MTD of GC5+I is below 15mg/kg of iniparib weekly due to hematological toxicity. The GC2+I regimen demonstrated manageable tolerability. ClinicalTrials.gov identifier: NCT01455532 Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C242. Citation Format: Monica Mita, Raffaele Baffa, Eric Charpentier, Craig A. Lockhart, John C. Morris, Olivier Rixe, John Sarantopoulos, Ramesh Ramanathan. A phase 1/1b dose escalation study of iniparib as a single agent and in combination with gemcitabine/carboplatin in patients with advanced 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 C242.

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...

1011 Background: Iniparib is an anticancer agent with a mechanism of action still under investigation. A phase 2 randomized neoadjuvant study in patients (pts) with TNBC was designed to explore the activity and tolerability of two schedules of iniparib with weekly paclitaxel (PTX). Here we report the efficacy and safety results from a planned interim analysis (IA). Methods: The trial accrued a total of 141 pts in October 2011, of whom, 74 are included in this IA. All were chemo-naive, histologicallyconfirmed Stage II-IIIA TNBC (IIA 47%; IIB 35%; IIIA 16%) with a median age of 50 yr. Triple negative status was centrally confirmed [ER/PR 2, IV, d 1; N=25) alone or in combination with iniparib, either on a once weekly (QW) (11.2 mg/kg, IV, d 1; N=25) or twice weekly (BIW) (5.6 mg/kg, IV, d 1, 4; N=24) schedule. The total planned treatment duration was 12 wks. The IA endpoint is pathological complete response in the breast (pCR) as assessed by independent pathologists. Results: Two/2/3 pts in the PTX/QW/BIW arms, respectively, discontinued due to progressive disease per RECIST. Another 3/2/2 pts, respectively, discontinued due to investigator decision or an adverse event (AE). Thirteen pts presented with Grade 3/4 Treatment Emergent AE: 3 pts in PTX arm (1 neutropenia, 1 presyncope, 1 ALT elevation), 3 in QW arm (1 lymphopenia, 1 hyperkalemia, 1 pulmonary embolism), and 8 in the BIW arm (1 febrile neutropenia, 3 neutropenia, 1 aphonia, 1 syncope, 1 radius fracture and 1 vertigo). Laboratory Grade 3/4 neutropenia occurred in 4% of pts in PTX, 0% in QW and 21% of BIW arms, with 1/2/3 pts, respectively, requiring G-CSF usage. There were 4/7/6 pts in the PTX/QW/BIW arms with PTX dose modifications. Four pts (16%) in PTX arm, 4 pts (16%) in the QW arm and 6 pts (25%) in the BIW arm had confirmed pCR in the breast. Conclusions: In this IA population, the addition of iniparib regardless of the schedule to weekly PTX did not seem to add clinically significant toxicity. pCR rate in the breast is similar across treatment arms at this IA. NCT01204125.