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PurposeCombining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67>15%).MethodsThis randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30mg daily for 5 of 7days (once daily [qd]×5days/week) plus intravenous dalotuzumab 10mg/kg/week or oral exemestane 25mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10mg qd×5days/week. The primary endpoint was progression-free survival (PFS).ResultsMedian PFS was 21.4weeks for ridaforolimus 30mg qd×5days/week plus dalotuzumab 10mg/kg (n=29) and 24.3weeks for exemestane (n=33; hazard ratio=1.00; P=0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy.ConclusionsThe combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

Cancer is becoming a collection of “niche diseases” defined by the molecular subtypes. Such understanding forms the basis of the basket trial, which pools together multiple cohorts of patients with the same molecular subtype across different tumor indications and thus facilitates the development of targeted therapies. Efficient pruning is critical in basket designs as it ensures the internal consistency of the selected indications and improves the probability of success on the selected pool of indications. In this article, we consider pruning both inactive and extremely active indications and propose a group sequential enrichment design with testing procedures to both control the family-wise error rate (FWER) in the weak sense and maintain the power for basket trials with such pruning strategy. We compare the proposed design with a relevant design which prunes only unresponsive subgroups. The total misclassification rates and misclassification rates among truly unresponsive indications are smaller...

Summary Background Patients with recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options. We aimed to assess the safety, tolerability, and antitumour activity of pembrolizumab, a humanised anti-programmed death receptor 1 (PD-1) antibody, in patients with PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck. Methods This study was an open-label, multicentre, phase 1b trial of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Patients were eligible for enrolment if they were aged 18 years or older, had a confirmed diagnosis of recurrent or metastatic squamous cell carcinoma of the head and neck, and had any level of PD-L1 expression (ie, at least 1% of tumour cells or stroma that were PD-L1-positive by immunohistochemistry). Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks. Primary outcomes were safety in the per-protocol population and the proportion of patients with centrally reviewed overall response per Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1). Overall response was analysed in the full analysis set, which was defined as all patients who had received at least one dose of pembrolizumab, had measurable disease at baseline, and one post-baseline scan or patients without a post-baseline scan who discontinued therapy because of disease progression or a drug-related adverse event. The study is registered with ClinicalTrials.gov, number NCT01848834 and is ongoing, but no longer enrolling patients. Findings Of the 104 patients screened between June 7, 2013, and Oct 3, 2013, 81 (78%) were PD-L1-positive. Of these, 60 patients with PD-L1-positive squamous cell carcinoma of the head and neck were enrolled and treated: 23 (38%) were HPV-positive and 37 (62%) were HPV-negative. Pembrolizumab was well tolerated, with 10 (17%) of 60 patients having grade 3–4 drug-related adverse events, the most common of which were increases in alanine aminotransferase and in aspartate aminotransferase, and hyponatraemia, each occurring in two of 60 patients; one patient developed a grade 3 drug-related rash. 27 (45%) of 60 patients experienced a serious adverse event. There were no drug-related deaths. The proportion of patients with an overall response by central imaging review was 18% (eight of 45 patients; 95% CI 8–32) in all patients and was 25% (four of 16 patients; 7–52) in HPV-positive patients and 14% (four of 29 patients; 4–32) in HPV-negative patients. Interpretation Pembrolizumab was well tolerated and demonstrated clinically meaningful antitumour activity in recurrent or metastatic squamous cell carcinoma of the head and neck, supporting further study of pembrolizumab as anticancer therapy for advanced head and neck cancers. Funding Merck & Co.

The phase III, randomized, active-controlled, multicenter, open-label KEYNOTE-183 study (NCT02576977) evaluating pomalidomide and low dose dexamethasone (standard-of-care [SOC]) with or without pembrolizumab in patients with refractory or relapsed and refractory multiple myeloma (rrMM) was placed on full clinical hold by the US FDA on July 03, 2017 due to an imbalance in the number of deaths between arms. Clinically-led subgroup analyses are typically used to shed light on clinical findings. However, this approach is not always successful. We propose a systematic approach using the artificial intelligence tools to identifying risk factors and subgroups contributing to the overall death (prognostic) or to the excess death observed in the pembrolizumab plus SOC arm (predictive) of the KEYNOTE-183 study. In KEYNOTE-183, with a data cutoff date of June 02, 2017, we identified plasmacytoma as a prognostic factor, and ECOG performance status as a predictive factor of death. In addition, a qualitative interaction was observed between ECOG performance status and the treatment arm. The subsequent subgroup analysis based on ECOG performance status confirmed that more deaths were associated with pembrolizumab plus SOC versus SOC alone in patients with ECOG performance status 1.

Introduction: The PD-1 receptor-ligand pathway can be used by tumors to evade immune surveillance, thereby allowing neoplastic growth. Pembrolizumab is a highly selective, humanized IgG4/kappa isotype mAb designed to block PD-1 interaction with its ligands PD-L1 and PD-L2, thereby reactivating the immune system to eradicate tumors. Methods: This is a multi-center, non-randomized trial of single agent MK-3475 treatment given intravenously at 10 mg/kg every 2 weeks, in patients with recurrent/metastatic triple-negative (ER, PR, and HER2 negative) breast cancer (TNBC). PD-L1 expression in tumor or stroma was required for study entry. PD-L1 status was determined by immunohistochemical analysis of patient’s tumor tissues using the Merck proprietary 22C3 antibody. Primary objectives of this study were to determine the safety, tolerability, and anti-tumor activity of MK-3475 in patients with PD-L1 positive, advanced TNBC. Secondary objectives included assessments of progression-free survival, overall survival, and response duration. Adverse events (AEs) reported in any patient receiving at least 1 dose of study treatment were monitored and graded using NCI CTCAE v. 4.0. Radiographic imaging was obtained every 8 weeks and evaluated by both investigator and an independent radiologist to assess clinical responses as defined by RECIST 1.1. This study (Clinicaltrials.gov: NCT01848834) is being conducted in conformance with Good Clinical Practices. Results: A total of 32 female patients with a median age of 50.5 years (range 29 – 72 years) with PD-L1 positive, recurrent/metastatic TNBC were enrolled in the study. Most of these patients had received and progressed on multiple lines of therapy for advanced disease. A preliminary analysis of data collected as of 23May2014 indicates that 5 patients (15.6%) experienced at least one drug-related serious adverse event (SAE); each of 4 patients experienced one of the following: Grade 3 anemia, headache, aseptic meningitis or pyrexia, and a fifth patient experienced disseminated intravascular coagulation (DIC) with thrombocytopenia and decreased blood fibrinogen. The patient who experienced DIC died. Preliminary analysis of data collected from investigators as of 23May2014 indicates that no patient had a complete response, 16.1% of patients had a partial response, 9.7% had stable disease, and 64.5% had progressive disease. As of 23May2014, all but one of the responders, in addition to three patients with stable disease, remain on treatment. Conclusion: This is the first report of clinical activity of an immune checkpoint inhibitor in TNBC. The preliminary results from this study suggest that single agent MK-3475 is a well-tolerated and effective treatment with significant therapeutic activity in a subset of heavily pre-treated patients with recurrent/metastatic triple-negative breast cancer. Citation Format: Rita Nanda, Laura Q Chow, E Claire Dees, Raanan Berger, Shilpa Gupta, Ravit Geva, Lajos Pusztai, Marisa Dolled-Filhart, Kenneth Emancipator, Edward J Gonzalez, Jennifer Houp, Kumudu Pathiraja, Vassiliki Karantza, Robert Iannone, Christine K Gause, Johnathan D Cheng, Laurence Buisseret. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-09.

PurposeTo evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer.MethodsThis randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10mg QD 5×/week, intravenous dalotuzumab 10mg/kg/week, and oral exemestane 25mg/day (R/D/E, n=40), or ridaforolimus 30mg QD 5×/week and exemestane 25mg/day (R/E; n=40). Primary end point was progression-free survival (PFS).ResultsMedian PFS was 23.3weeks for R/D/E versus 31.9weeks for R/E (hazard ratio 1.18; 80% CI 0.81-1.72; P=0.565). Grade 3-5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P=0.021) and pneumonitis (22.5 vs. 5.1%; P=0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate.ConclusionsR/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

Background: Vintafolide (V) is a folic acid-vinca alkaloid small molecule drug conjugate that targets tumors that over-express the folate receptor (FR). 99mTc-etarfolatide (EC20) is a folate-targeted molecular imaging agent being developed to identify FR-positive tumors. Data suggest that triple negative breast cancers (TNBCs) expressing high levels of FR are likely to benefit from treatment with vintafolide. Trial design/Patient eligibility: This is a multicenter, randomized, open-label, Phase IIa trial in subjects with advanced TNBC. Patients will be evaluated for tumor specific expression of the FR using a EC20 SPECT/CT scan and classified as FR(100%) if 100% of RECIST 1.1 target lesions are FR-positive. Only FR(100%) patients are eligible for treatment and will be randomized in a 1:1:1 ratio to V alone, V + paclitaxel (P) or P alone. V will be administered at 2.5 mg IV 3x/week for 2 weeks on Days 1, 3, 5, 15, 17 and 19 of a 28-day cycle. P will be administered at 80 mg/m2 IV on Days 1, 8, 15, and 22. Specific aims: The primary endpoint for the trial is centrally assessed progression free survival (PFS). Secondary objectives include: assess the frequency of target tumors expressing FR(100%) vs FR(20-80%) vs FR(0%) in subjects with TNBC using EC20 SPECT scans; compare the clinical activity in subjects with advanced TNBC of V alone vs P and V + P vs P alone as measured by objective response rate (ORR), (complete response [CR] + partial response [PR]), clinical benefit rate (CBR; CR + PR + stable disease for ≥6 months), and overall survival; and assess the safety and tolerability of V alone vs P alone and V + P vs P alone in subjects with advanced TNBC. Statistical methods and target accrual: PFS and overall survival will be assessed in the intention to treat population using a stratified Cox model with Efron's tie handling method, and Kaplan-Meier method for PFS and OS curve estimation, respectively, in each treatment group. Inferential comparisons between the arms will be tested using the stratified log-rank test at one sided alpha level of 5%. This study will randomize 34 subjects into each treatment group with total study duration of ∼16-17 months. The study has 80% power to demonstrate that either patients treated with V or patients treated with V + P combination have a higher median time to an event of PFS than subjects treated with P at an unadjusted one-sided, 5% alpha-level, if the underlying constant hazard ratio between treatment groups is 0.5 and median survival time of 2.6 months. First patient enrollment is targeted for October. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-15.

Background: Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A phase 1 study of the mTOR inhibitor RIDA and the anti-IGFR antibody DALO demonstrated that the combination was feasible and well-tolerated at doses that were nearly those used for the two single agents. The dose limiting toxicity was stomatitis, similar to RIDA monotherapy. Preliminary signals of anti-tumor activity, including partial responses and prolonged progression free survival (PFS), were observed in ER+ advanced breast cancer (ABC), especially in high proliferation tumors (Ki67 ≥15%). Methods: The trial was a multi-center, international randomized study with PFS as the primary endpoint. Key eligibility included ABC with prior treatment with a non-steroidal aromatase inhibitor. The original phase 2 study design was a two-part, adaptive design intended to first test the combination of RIDA (30 mg by mouth daily for 5 out of every 7 days), -DALO (10 mg/kg IV weekly) against a standard agent, exemestane in Part A. Patients were stratified into high and low proliferation strata based on baseline Ki67. Following a demonstration of PFS benefit of the combination in Part A, Part B was intended to show the PFS benefit of the combination over each single agents by comparing RIDA-DALO to RIDA and DALO. Results: The study was initiated in October 2011. Accrual was suspended after the first 66 patients were randomized due to a higher than expected rate of stomatitis in the RIDA-DALO arm. Preliminary data indicated an overall incidence of any grade stomatitis was 68% (22/33 pts), and of grade 3 stomatitis was 35% (11/33 pts). In an effort to identify a more tolerable regimen, the study was amended to eliminate Part B and to evaluate two sequential reduced dose RIDA-DALO cohorts in a non-randomized design: 20mg and 10mg for 5 out of every 7 days. The dose of DALO was unchanged. Preliminary safety results of overall and grade 3 stomatitis in the 20 mg were 81.5% (22/27 pts) and 37% (10/27 pts), respectively. Although the incidence of overall stomatitis in the 10 mg cohort remained high, 88% (22/25 pts), grade 3 stomatitis was dramatically reduced to 8% (2/25 pts). Conclusion: Preliminary evaluation of safety from this phase 2 study demonstrates that the previously recommended phase 2 dose of RIDA-DALO was not tolerable. However lower doses of RIDA (10 mg) in combination with DALO appeared to be tolerable with markedly reduced rates of grade 3 stomatitis. Final results of efficacy, safety and RNA profiling analysis from the two RIDA-DALO dose cohorts as well as from the randomized portion of the study will be available at the time of the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-04.

Background: The clinical benefit of combination of mTOR inhibition and anti-hormonal therapy has been previously established and represents a new standard of care for patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Preclinical evaluation of the mTOR pathway demonstrates that dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A completed phase 1 study of the combination of the mTOR inhibitor, RIDA and the anti-IGFR antibody, DALO demonstrated preliminary signals of anti-tumor activity. This was further evaluated in a recently completed phase 2 study of RIDA-DALO compared to exemestane in ER+ ABC. Final safety and efficacy results from that phase 2 study will be reported at this meeting (see Baselga et al). Building upon the clinical synergies of mTOR and EX as well as the biologic relationship of the mTOR and IGFR pathways, a clinical study has been initiated to evaluate the triplet combination of RIDA-DALO-EX compared to RIDA-EX. Methods: This is a multicenter, international, randomized phase 2 study of the triplet combination of RIDA (10 mg by mouth daily for 5 out of every 7 days), DALO (10 mg/kg IV weekly), and EX (25 mg QD) compared to RIDA (30 mg by mouth daily for 5 out of every 7 days) and EX (25 mg QD) in high KI67 (≥15%) expressing ER+, ABC. Approximately 84 patients will be randomized 1:1 to either triplet or doublet therapy. Key eligibility criteria include: HR+ and HER-2 negative measurable ABC, prior therapy with a non-steroidal aromatase inhibitor, and KI67 labeling index ≥15%. The primary endpoint of the study is progression free survival (PFS). Key secondary endpoints include evaluation of percent (%) reduction from baseline in the sum of imaging measurements (target lesion diameters or volumes) at 16 weeks between the two arms, and overall response rates. The sample size is event driven with a target of 38 PFS events, which provides approximately 80% power, at 1-sided alpha of 0.1, to detect a HR of 0.5, corresponding to an approximate 100% improvement in median PFS, from 10.6 to 21.2 months. Safety parameters or adverse experiences of special interest include hyperglycemia, stomatitis, mucosal inflammation, pneumonitis and hearing loss. Accrual has been completed with results expected in May 2014. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-13.

INTRODUCTION: As limited data among German women exist about HPV, Chlamydia trachomatis (CT) and Neisseria gonorrhoeae, we report the prevalence of these genital infections and general baseline demographics of the young German women enrolled in the phase III trials of the quadrivalent HPV vaccine. MATERIALS AND METHODS: German females (n = 437; 9-23 years) were recruited among 3 international phase 3 studies of an HPV-6/11/16/18 vaccine. We present baseline characteristics, prevalence of HPV-6/11/16/18 and, for women aged 16-23, abnormal cervical cytology and sexually transmitted diseases. RESULTS: Chlamydia trachomatis and Neisseria gonorrhoeae prevalence was 5 and 0.3%, respectively. Approximately 17% of participants had HPV-6, 11, 16, or 18 DNA or antibodies. All subjects

Successful completion of the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, reported in this issue of Cancer Discovery, is an important advance in the effort to improve clinical trial approaches to the simultaneous development of new therapeutics with matching diagnostic tests so that patients most likely to benefit from these therapies can be identified. Cancer Discovery; 1(1); 17–20. ©2011 AACR. Commentary on Kim et al., p. 44

Human papillomavirus types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cervical cancers worldwide. A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6, 11, 16, and 18 (HPV-6/11/16/18) for the prevention of high-grade cervical lesions associated with HPV-16 and HPV-18.In this randomized, double-blind trial, we assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo, administered at day 1, month 2, and month 6. The primary analysis was performed for a per-protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose (month 7). The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18.Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo. Vaccine efficacy for the prevention of the primary composite end point was 98% (95.89% confidence interval [CI], 86 to 100) in the per-protocol susceptible population and 44% (95% CI, 26 to 58) in an intention-to-treat population of all women who had undergone randomization (those with or without previous infection). The estimated vaccine efficacy against all high-grade cervical lesions, regardless of causal HPV type, in this intention-to-treat population was 17% (95% CI, 1 to 31).In young women who had not been previously infected with HPV-16 or HPV-18, those in the vaccine group had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group. (ClinicalTrials.gov number, NCT00092534 [ClinicalTrials.gov].).

The extensive data from the Blair et al.((1)) epidemiology study of occupational acrylonitrile exposure among 25460 workers in eight plants in the United States provide an excellent opportunity to update quantitative risk assessments for this widely used commodity chemical. We employ the semiparametric Cox relative risk (RR) regression model with a cumulative exposure metric to model cause-specific mortality from lung cancer and all other causes. The separately estimated cause-specific cumulative hazards are then combined to provide an overall estimate of age-specific mortality risk. Age-specific estimates of the additional risk of lung cancer mortality associated with several plausible occupational exposure scenarios are obtained. For age 70, these estimates are all markedly lower than those generated with the cancer potency estimate provided in the USEPA acrylonitrile risk assessment.((2)) This result is consistent with the failure of recent occupational studies to confirm elevated lung cancer mortality among acrylonitrile-exposed workers as was originally reported by O'Berg,((3)) and it calls attention to the importance of using high-quality epidemiology data in the risk assessment process.

3071 Background: Mismatch repair deficient cancers harbor high levels of microsatellite instability and somatic mutations. Treatment with anti-PD-1 antibodies has resulted in durable objective responses in MSI-H cancer. As part of the ongoing, global, multicenter phase 2 studies KEYNOTE(KN)164 and KN158, we assessed the efficacy of pembrolizumab in patients (pts) with MSI-H tumors. Methods: Both studies enrolled pts with MSI-H status determined locally by IHC or PCR. KN164 enrolled pts with MSI-H CRC and ≥2 prior therapies, whereas the multicohortKN158 study included pts with MSI-H non-CRC and ≥1 prior therapy. Eligible pts in both studies received pembrolizumab 200 mg Q3W until progression, unacceptable toxicity, or pt/investigator decision. Tumor response was assessed every 9 wk by independent review per RECIST v1.1. Primary endpoint was ORR. Secondary endpoints included DOR, PFS, OS, and safety. Analyses were performed in pts from KN164 and KN158 who had ≥27 wk of follow-up as of Aug 3, 2016 and Oct 19, 2016, respectively. Results: KN164 enrolled 61 pts with MSI-H CRC (90% with ≥2 prior therapies) whereas KN158 included 21 pts with MSI-H non-CRC (42% with ≥2 prior therapies). In KN158 the most common tumor types were endometrial and small intestinal cancer (n = 4 each), cholangiocarcinoma (n = 3), and gastric and pancreatic cancer (n = 2 each). Median follow-up was 7.4 mo for MSI-H CRC and 4.5 mo for MSI-H non-CRC. ORR for MSI-H CRC was 26.2% (95% CI, 15.8%-39.1%), with 15 confirmed responses and 1 unconfirmed response, and ORR for MSI-H non-CRC was 42.9% (21.8%-66.0%), with 8 confirmed responses and 1 unconfirmed response. DCR was 50.8% (n = 31; 37.7%-63.9%) for MSI-H CRC and 66.7% (n = 14; 38.4%-83.7%) for MSI-H non-CRC. Median duration of response was not reached for either MSI-H CRC or non-CRC, and 100% of responses were ongoing. Survival and safety analyses are ongoing. Conclusions: Early results from KN164 and KN158 confirm the robust antitumor activity of pembrolizumab in heavily pretreated pts with MSI-H cancers. Clinical trial information: NCT02628067; NCT02460198.

To investigate factors related to lung cancer mortality in four Arizona copper-smelter towns, the authors identified 142 lung cancer cases and 2 matched controls per case from decedent residents during 1979-1990. The authors obtained detailed information on lifetime residential, occupational, and smoking histories via structured telephone interviews with knowledgeable informants. The authors linked estimated historical environmental exposures to smelter emissions (based on atmospheric diffusion modeling of measured sulfur dioxide concentrations) with residential histories to derive individual profiles of residential exposure. The results of this study provided little evidence of a positive association between lung cancer and residential exposure to smelter emissions. Conditional logistic regression analysis revealed a statistically significant positive association between lung cancer and reported employment in copper mines and/or smelters, although specific factors associated with the apparently increased risk among these workers could not be identified in this community-based study.

To investigate factors related to lung cancer mortality in six Arizona copper smelter towns, we identified 185 lung cancer cases and two matched controls per case from decedent residents during 1979–1990. Detailed information on lifetime residential, occupational, and smoking history was obtained by structured telephone interviews with knowledgeable informants. Interviews were completed for 82% of 183 eligible cases and 88% of the targeted number (366) of controls. Estimated historical environmental exposures to smelter emissions, based on atmospheric diffusion modeling of measured SO 2 concentrations, were linked with residential histories to derive individual profiles of residential exposure. Occupational histories were characterized by potential exposure to smelter emissions, asbestos, and ionizing radiation. Conditional logistic regression was used to compare study factors in cases and controls with adjustment for potential confounding factors: gender, Hispanic ethnicity, and smoking. In overall and gender-specific analyses, no statistically significant associations were observed between lung cancer risk and any of the measures of residential exposure to smelter emissions considered (town of residence at time of death, highest level of exposure, and duration or cumulative exposure above background levels), or any of the estimated occupational exposures (definite or potential asbestos, potential ionizing radiation, definite or potential smelter). Among male residents of some, but not all, towns, there was some evidence of a positive association between lung cancer risk and reported copper smelter-related employment (reported as definite), with the highest risk observed for Miami, Arizona. This study provided little evidence of a positive association between lung cancer mortality and residential exposure to smelter emissions. Specific factors associated with the apparent heterogeneity in lung cancer risk across study towns cannot be identified in this community-based study.

Background The present global, open-label, single-arm, multicenter, phase IIb study was designed to determine the efficacy and tolerability of oral vorinostat combined with standard doses of bortezomib in patients with multiple myeloma considered refractory to novel myeloma agents. Patients and Methods Eligible patients were age ≥ 18 years, had received ≥ 2 previous regimens, had disease refractory to ≥ 1 previous bortezomib-containing regimen, and had received ≥ 1 dose of an immunomodulatory drug (thalidomide or lenalidomide)-based regimen. The patients received 21-day cycles of bortezomib (1.3 mg/m 2 intravenously on days 1, 4, 8, and 11) plus oral vorinostat (400 mg/d on days 1-14). Oral dexamethasone, 20 mg, on the day of and the day after each dose of bortezomib could be added for patients with progressive disease after 2 cycles or no change after 4 cycles. The primary endpoint was the objective response rate. Results The objective response rate was 11.3% (95% confidence interval, 6.6%-17.7%), and the median duration of response was 211 days (range, 64-550 days). The median overall survival duration was 11.2 months (95% confidence interval, 8.5-14.4 months), with a 2-year survival rate of 32%. The frequently reported adverse events were thrombocytopenia (69.7%), nausea (57.0%), diarrhea (53.5%), anemia (52.1%), and fatigue (48.6%); the overall safety profile was consistent with that of bortezomib and vorinostat. Conclusion The combination of vorinostat and bortezomib is active in patients with multiple myeloma refractory to novel treatment modalities and offers a new therapeutic option for this difficult-to-treat patient population (ClinicalTrials.gov identifier, NCT00773838).

9568Background: T-VEC is a herpes simplex virus (HSV)-1 -based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF and stimulate antitumor immune responses in melanoma. T-VEC significantly improved durable response rate vs GM-CSF in stage IIIB-IV melanoma patients (pts) with injectable tumors. Pembro inhibits programmed cell death protein 1 and improves survival in advanced melanoma. The combination may further improve clinical benefit. Here we report phase 1b efficacy, safety and biomarker data from a phase 1b/3 study of T-VEC+pembro in unresectable stage IIIB-IV melanoma (NCT02263508) with all pts having started on T-VEC+pembro ≥ 6 mo prior. Methods: Key inclusion criteria: unresectable stage IIIB-IV melanoma, injectable lesions; no prior systemic tx; and ECOG PS 0-1. T-VEC: ≤ 4 mL in (sub)cutaneous/nodal lesions, 106 PFU/mL d1, 108PFU/mL d22 then Q2W; pembro: IV, 200 mg d36 then Q2W. Tx until first occurrence of: complete response (CR); no injectable tumors (for T-VEC); ...

TPS3094 Background: Treatment options are limited for pts with recurrent and/or metastatic HNSCC whose disease has progressed after platinum and cetuximab therapy. Pembrolizumab (MK-3475) is a huma...

3009 Background: Pembrolizumab is a potent, highly selective, humanized monoclonal antibody against PD-1 that has shown robust antitumor activity against several advanced malignancies. In phase 1 t...

TPS4571 Background: Paclitaxel, docetaxel, and vinflunine are commonly used as second-line therapy for advanced urothelial cancer, but median OS is only 7-9 months. The PD-1 pathway plays a key role in evading the tumor immune response. Pembrolizumab is a highly selective anti–PD-1 monoclonal antibody designed to block the interaction between PD-1 and its ligands PD-L1 and PD-L2. In KEYNOTE-012, pembrolizumab 10 mg/kg every 2 weeks (Q2W) provided a 24% ORR (RECIST v1.1, central review) and an acceptable safety profile in 33 pts with PD-L1–positive advanced urothelial cancer, 76% of whom received ≥ 1 prior therapy. Methods: In the international, open-label, phase 3 KEYNOTE-045 trial (ClinicalTrials.gov, NCT02256436), pts with confirmed metastatic or locally advanced/unresectable urothelial cancer (transitional cell or predominantly transitional cell histology) of the bladder, renal pelvis, ureter, or urethra that has recurred or progressed following platinum-based chemotherapy are randomized 1:1 to pembrol...

TPS9081 Background: T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF and stimulate an anti-tumor immune response. OPTiM...

TPS6084 Background: Prognosis of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, with limited treatment options and survival rates of 6-9 months fol...

Introduction: The combination of a mammalian target of rapamycin (mTOR) inhibitor and an aromatase inhibitor has been shown to significantly increase progression-free survival (PFS) in patients with estrogen receptor-positive (ER+) advanced or metastatic breast cancer. Ridaforolimus is an alternative mTOR inhibitor with high potency and specificity. We hypothesized that triplet therapy with ridaforolimus, dalotuzumab (a humanized monoclonal antibody targeting the IGF-1 receptor [IGFR]), and exemestane (R/D/E) would be more effective than doublet therapy with ridaforolimus and exemestane (R/E). Methods: This phase 2, randomized, open-label trial enrolled 80 postmenopausal patients who had high-proliferation (KI67 staining) ER+ breast cancer that had progressed following treatment with a nonsteroidal aromatase inhibitor. Patients received either triplet therapy, at the previously determined maximum tolerated dose of oral ridaforolimus 10 mg QD×5, dalotuzumab 10 mg/kg/week IV, and oral exemestane 25 mg/day (R/D/E, n=40), or doublet therapy with R 30 mg QD×5 and E 25 mg/day (R/E, n=40). Dose increases of R to 20 or 40 mg QD×5 were permitted in the R/D/E or R/E arms, respectively, in the absence of grade ≥2 stomatitis after cycle 1. The R dose could be reduced in either arm for toxicity. The primary endpoint was PFS in the ITT population by central review. Adverse events (AE) of clinical interest (Tier 1) included stomatitis, pneumonitis, hearing loss, and hyperglycemia. Results: Baseline characteristics were balanced between treatment groups. The median PFS was 23.3 (95% CI, 8.71, 38.43) weeks for R/D/E versus 31.9 (95% CI, 16.00, 39.29) weeks in the R/E arm (hazard ratio, 1.18; 80% CI, 0.81-1.72; P=0.565). All patients experienced at least one AE. 5 (12.8%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively, discontinued the study because of AE. Serious drug-related AE occurred in 2.6% of the R/D/E arm and 15% of the R/E arm. Dose modifications due to AE occurred in 10.3% and 50% in the R/D/E and R/E arms, respectively (difference -39.7%; 95% CI, -56.7, -20.4). Tier 1 AE were primarily grade 1-2 in severity. Stomatitis occurred in 76.9% (30/39 patients) in the R/D/E arm vs 95.0% (38/40 patients) in the R/E arm (P=0.021), and grade 3-4 stomatitis was similar between arms (23.1% vs 25%). Pneumonitis occurred in 5.1% vs 22.5% (P=0.027) and hearing loss occurred in 1 patient in each treatment arm (2.6% vs 2.5%), all grade 1-2. Hyperglycemia occurred at a similar rate in both treatment arms (28.2% vs 27.5%), with grade 3-4 events in 4 (10.3%) and 3 (7.5%) patients in the R/D/E and R/E arms, respectively. Conclusions: The combination of R 10 mg QD×5, D, and E did not improve PFS when compared to R 30 mg QD×5 plus E. The incidence rates of AE were lower in the R/D/E arm than the R/E arm for most categories of adverse events, likely because of the higher dose of R in the R/E arm. The efficacy reported for R/E in this study is similar to that reported in previous studies evaluating mTOR inhibitors in combination with exemestane in ABC. Overlapping toxicities and lower doses likely contributed to the lack of improved PFS with the addition of the IGFR inhibitor to this combination. Citation Format: Hope S Rugo, Olivier Tredan, Jungsil Ro, Serafin Morales, Antonino Musolino, Noemia Afonso, Marta Ferreira, Kyong Hwa Park, Javier Cortes, Antoinette R Tan, Joanne L Blum, Lamar Eaton, Christine K Gause, Adelle (Zhen) Wang, Ellie Im, David J Mauro, José Baselga. Results from the phase 2 trial of ridaforolimus, dalotuzumab, and exemestane compared to ridaforolimus and exemestane in advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-1.

296 Background: Pembro, an anti-PD-1 monoclonal antibody, has shown antitumor activity in several advanced solid tumors. The safety, tolerability, and antitumor activity of pembro in pts with recurrent or metastatic urothelial cancer was assessed in a cohort of KEYNOTE-012 (Clinicaltrials.gov: NCT01848834). Methods: PD-L1 expression was assessed in archival or newly obtained tumor samples from pts with advanced carcinoma of the renal pelvis, ureter, bladder, or urethra using a prototype immunohistochemistry assay. Only pts with PD-L1 expression in stroma or ≥1% of tumor cells were eligible. Pts received pembro 10 mg/kg every 2 wks until complete response, progression, or unacceptable toxicity. Pts deriving benefit could remain on pembro beyond initial progression. Response was assessed every 8 wks per RECIST v1.1 by the investigator and by independent central review (primary efficacy end point). Results: 33 pts enrolled (n=30 with transitional cell histology; median age, 70 y [range 44-85]; ECOG PS 1, 70%; 2 prior therapies for advanced disease, 52%; liver metastases, 21%). 22 pts (67%) received ≥3 pembro doses. Median follow-up duration was 11 mos (range 10-13), and 7 pts (21%) remain on therapy. At least 1 drug-related AE was reported by 61% of pts, most commonly fatigue (n=6), peripheral edema (n=4), and nausea (n=3). Grade 3-4 drug-related AEs were reported for 4 pts (12%), with only rash seen in >1 pt (n=2). 29 pts received ≥1 dose of pembro and had a baseline scan with measurable disease and were evaluable for response. ORR was 24% (95% CI, 10%-44%) by investigator review, with 7 partial responses. ORR by central review was also 24% (95% CI, 10%-44%), with 3 (10%) complete and 4 (14%) partial responses. Response duration is 16-40+ wk (median not reached) by both investigator and central review. ORR in key subgroups, including visceral vs. nodal metastasis, will be presented. In pts evaluable for response, median PFS is 8.8 wks by investigator review and 8.6 wks by central review. In all pts, median OS is 9.3 mos (6-mo OS rate, 58%). Conclusions: Pembro shows acceptable safety and tolerability and provides promising antitumor activity in pts with advanced urothelial cancer. Evaluation of pembro for the treatment of urothelial cancer is ongoing. Clinical trial information: NCT01848834.

Aim: Tumors use the PD-1 receptor-ligand pathway to evade immune surveillance. The anti-PD-1 monoclonal antibody pembro has demonstrated antitumor activity in advanced solid tumors. We assessed the safety, tolerability, and antitumor activity of pembro in pts with recurrent or metastatic urothelial cancer in the KEYNOTE-012 study (Clinicaltrials.gov: NCT01848834). Methods: Archival or newly obtained tumor samples from pts with advanced carcinoma of the renal pelvis, ureter, bladder, or urethra were screened for PD-L1 expression using a prototype immunohistochemistry assay. PD-L1 expression in stroma or ≥1% of tumor cells was required for study entry. Pts received pembro 10 mg/kg every 2 wk until complete response, progression, or unacceptable toxicity. Pts deriving benefit could remain on pembro beyond initial progression. Response was assessed every 8 wk per RECIST v1.1 by independent central review (primary efficacy end point). Results: 33 pts enrolled, including 30 with transitional cell histology and 3 with nontransitional cell or mixed histology. Median age was 70 y (range 44-85), 70% had ECOG PS 1, 52% received ≥2 prior therapies for advanced disease, and 21% had liver metastases. 22 pts (67%) received ≥3 pembro doses. Median follow-up duration was 11 mo (range 10-13), and 7 pts (21%) remain on therapy. 61% of pts reported ≥1 drug-related AE, most commonly fatigue (n = 6), periphereal edema (n = 4), and nausea (n = 3); 4 pts (12%) reported grade 3-4 drug-related AEs, with only rash seen in >1 pt (n = 2). 29 pts received ≥1 dose of pembro and had a baseline scan with measurable disease and were evaluable for response. ORR by central review was 24% (95% CI 10%-44%), with 3 (10%) complete responses. Response duration is 16 to 40+ wk (median not reached), with 6 of 7 responses ongoing. In the pts evaluable for response, median PFS is 8.6 wk. In all pts, median OS is 9.3 mo (6-mo OS rate, 58%). Analysis of the relationship between PD-L1 expression and pembro efficacy is ongoing. Conclusions: Pembro shows acceptable safety and tolerability and provides promising antitumor activity in pts with advanced urothelial cancer. These data support the continued development of pembro in advanced urothelial cancer. Disclosure: E.R. Plimack: has received research funding from Merck & Co., Inc., Whitehouse Station, NJ; J. Bellmunt: Has served on advisory boards, without compensation, for Merck & Co., Inc., Genentech, and Bristol-Myers Squibb; B. Montgomery: Received research funding from Janssen, Medivation, and Tokai; E.J. Gonzalez, R. Perini, J. Cheng and C. Gause: Is employee of and holds stock in Merck & Co., Inc.; J. Pulini: Former employee of Merck & Co., Inc.; M. Dolled-Filhart, K. Emancipator and K. Pathiraja: Is employee of Merck & Co., Inc. All other authors have declared no conflicts of interest.

Aim: Background: The highly selective, anti-PD-1 humanized monoclonal antibody pembro has shown antitumor activity in several solid tumors, including HNC. We present updated safety, tolerability, and antitumor activity of pembro for recurrent/metastatic HNC (Clinicaltrials.gov: NCT01848834). Methods: During screening, PD-L1 expression in archival or newly obtained tumor samples was assessed using a prototype immunohistochemistry assay; PD-L1 expression in stroma or ≥1% of tumor cells was required for study entry. Pembro 10 mg/kg was given every 2 wk until complete response, progression, unacceptable toxicity, physician decision, or consent withdrawal. Adverse events (AEs) were recorded throughout the study. Response was assessed every 8 wk. Primary end point was overall response rate (ORR) per RECIST v1.1. Results: Out of 104 HNC pts screened, 81 (78%) were PD-L1-positive, 61 enrolled, and 60 received ≥1 pembro dose: 23 HPV+, 37 HPV-. After a median follow-up of 10.2 mo, 15 pts (25%) remain on pembro. ORR (confirmed + unconfirmed) per RECIST v1.1 by investigator review was 20%, and response duration ranged from 8+ to 41+ weeks (median not reached). 9 of 11 responders had a smaller target lesion burden (ie, sum below the median) at baseline. ORR was similar in HPV+ and HPV- pts, whereas PFS and OS were longer in HPV+ pts (Table). PD-L1 expression was positively correlated with ORR (P = 0.018) and PFS (P = 0.024). ORR was 50% in the 12 pts with high PD-L1 expression. Drug-related AEs of any grade occurred in 58% of pts (grade ≥3 in 17%). The most common drug-related AEs were fatigue (18%), pruritus (10%), and nausea (8%). There were no drug-related deaths. Conclusions: Pembro is safe and tolerable and shows antitumor activity in both HPV+ and HPV- advanced HNC. These findings support further development of pembro in advanced HNC. Overall N = 61* HPV+ n = 23* HPV– n = 38* ORR, n (%) 11 (20) 4 (20) 7 (19) Median PFS (95% CI), wk 9.3 (8.0-20.1) 17.2 (8.0-41.7) 8.1 (7.9-15.6) Median OS (95% CI), mo 12.6 (8.2-12.6) NR (9.6-NR) 9.5 (3.9-12.6) *ORR and PFS were evaluated in the 56 pts (20 HPV+, 36 HPV-) who received ≥1 pembro dose and had measurable disease per RECIST v1.1 by investigator review. Disclosure: L.Q. Chow: Advisory Board Member for Bristol Myers Squibb, Novartis, Celgene; Research funding from Bristol Myers Squibb, Novartis, AstraZeneca/Medimmune, Genentech/Roche, VentiRx, Pfizer, Lily/Imclone; B. Burtness: Advisory board membership for VentiRx and Novartis; Research funding from Merck, Genentech, Boehringer Ingelheim, and Pfizer; E.J. Gonzalez, J.K. Lunceford, C. Gause and J.D. Cheng: Employee of and stock ownership in Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; J. Pulini, J. Johnson, M. Dolled-Filhart, K. Emancipator and K. Pathiraja: Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; T. Seiwert: Advisory board membership for Novartis and Onyx/Bayer; Research funding from Boehringer Ingelheim and Genentech; Honoraria from Merck. All other authors have declared no conflicts of interest.

Background: The interaction between programmed cell death protein 1 (PD-1) and its ligands PD-L1 and PD-L2 permits evasion of antitumor immune responses. PD-l inhibition has been shown to possess significant antitumor activity in patients with advanced MEL and RCC. Preclinical data suggest that adding PEG-IFN or IPI may increase the antitumor activity of PD-1 inhibitors. Clinically, IPI + the PD-1 antibody nivolumab has shown a greater response rate than nivolumab alone in pts with MEL. MK-3475 is a potent, highly selective, humanized IgG4/kappa, anti-PD-1 monoclonal antibody designed to block the interaction between PD-1 and its ligands. Trial design: This is an open-label, multicenter, phase 1/2 study of MK-3475 in combination with PEG-IFN or IPI for pts with advanced MEL or RCC. Phase 1 is a dose escalation study designed to determine the maximum tolerated/administered dose and/or recommended phase 2 dose of MK-3475 + PEG-IFN and MK-3475 + IPI. Using a modified 3 + 3 design followed by a toxicity probability interval for dose confirmation, 3-14 pts per dose level will be enrolled sequentially at escalating/de-escalating MK-3475 doses (2 mg/kg intravenously [IV] 3 times/wk [Q3W] or 10 mg/kg Q2W) in combination with PEG-IFN (subcutaneous 1, 2, or 3 µg/kg/wk) or IPI (4 IV doses of 1 mg/kg Q3W). If dose levels are open for both PEG-IFN and IPI, pts will be randomized between the combinations. Pending phase 1 results, a randomized phase 2 study designed to evaluate the efficacy of combination therapy will be initiated. Up to 150 pts with MEL will be randomized 1:1:1 to MK-3475 + PEG-IFN, MK-3475 + IPI, or MK-3475 alone. Treatment will continue until progression, intolerable toxicity, or 24 mo of MK-3475. Primary endpoint is progression-free survival. Secondary endpoints include objective response rate, overall survival, and safety. Response will be evaluated by investigator by RECIST v1.1 at wk 12, every 6 wk thereafter until wk 30, and then every 12 wk. Adverse events will be monitored and graded according to NCI CTCAE v4.0. Phase 1 pt enrollment is ongoing. Disclosure: T.K. Choueiri: Advisory board for Pfizer, GSK, Novartis, Aveo. Research funding from Pfizer (institutional) A. Ribas: Advisory board for Merck; F.S. Hodi: Nonpaid role on advisory board for Merck. Research support to institution from Merck; W. Hwu: Advisory board member, Merck. Corporate-sponsored research, Merck; A. Tosolini: Full-time employee of Merck Sharp & Dohme with stock ownership; R. Iannone: Full-time employee of Merck & Co., Inc., with stock ownership; Z. Yang: Full-time employee of Merck & Co., Inc., with stock ownership; C. Gause: Full-time employee of Merck Sharp & Dohme with stock ownership; R. Perini: Full-time employee of Merck & Co., Inc., with stock ownership; M.B. Atkins: Advisory board for BMS, Merck, Genentech. All other authors have declared no conflicts of interest.

6011 Background: The PD-1 receptor-ligand pathway can be used by tumors to evade immune surveillance, thereby allowing neoplastic growth. MK-3475 is a highly selective, humanized IgG4/kappa isotype...

TPS3117 Background: RRMM patients refractory to proteasome inhibitors and immunomodulatory drugs (IMiD) have a very poor outcome. PD-L1 expressed on most MM plasma cells is a potential mechanism of...

TPS3116 Background: Hematologic malignancies (HMs) are responsive to immunotherapy, but in some cases appear to usurp the PD-1 pathway for tumor immune escape. MK-3475 is a potent, highly selective...

TPS3119 Background: Immune surveillance is one of the primary mechanisms to prevent neoplastic growth. The PD-1 receptor-ligand pathway can be used by tumors to evade immune surveillance. MK-3475 i...

The effects of exposure misclassification on the interpretation of results of occupational epidemiological studies has been widely investigated and reported. Usually, only the direct effects of misclassification have been considered or simple estimates of misclassification rates have been assigned to various types of exposure estimation processes. Lifelong job profile data obtained from a previously published case-control study provided complete or nearly complete job histories of 511 decedents. An analysis of these work histories and the comparison of exposures related to longest-held job to estimated total lifetime exposures suggest that single job-based exposure estimates may lead to significant exposure misclassification rates. In addition, the appearance of shorter duration jobs in a study population occurring predominantly early in the work history may exacerbate problems associated with exposure misclassification. While few specific suggestions emerge from this analysis, the inclusion of extensive recording of the work history of study subjects emerges as a reasonable basis for the investigation and potential reduction of secondary misclassification of exposures in occupational epidemiological studies.

The addition of vorinostat to lenalidomide/dexamethasone represents a novel combination therapy in multiple myeloma (MM), informed by laboratory studies suggesting synergy. This was a phase I, multicenter, open-label, non-randomized, dose-escalating study in patients with relapsed or relapsed and refractory MM. Clinical evaluation, electrocardiogram, laboratory studies and adverse events were obtained and assessed. The maximum-tolerated dose was not reached owing to a non-occurrence of two dose-limiting toxicities per six patients tested at any of the dosing levels. Patients tolerated the highest dose tested (Level 5) and this was considered the maximum administered dose: at 400 mg vorinostat on days 1–7 and 15–21, 25 mg lenalidomide on days 1–21 and 40 mg dexamethasone on days 1, 8, 15 and 22, per 28-day cycle. Drug-related adverse events were reported in 90% of patients serious adverse experiences were reported in 45% of the patients and 22% of all patients had adverse experiences considered, possibly related to study drug by the investigators. A confirmed partial response or better was reported for 14/30 patients (47%) evaluable for efficacy, including 31% of patients previously treated with lenalidomide. Vorinostat in combination with lenalidomide and dexamethasone proved tolerable with appropriate supportive care, with encouraging activity observed.

Abstract 1951 Background: Although novel treatment combinations for multiple myeloma (MM) have improved outcomes, the disease remains incurable and new drug combinations are urgently needed. Vorinostat is an oral histone deacetylase inhibitor approved in the United States for treatment of patients (pts) with advanced cutaneous T-cell lymphoma who failed prior therapies. Vorinostat alters gene expression and protein activity, promoting MM cell death through multiple pathways, and has been shown in preclinical studies to synergistically enhance the anti-MM activity of bortezomib and immunomodulatory drugs, including lenalidomide, with or without dexamethasone. Aims: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of vorinostat plus lenalidomide and dexamethasone in pts with relapsed or relapsed and refractory MM. Secondary objectives included overall safety, tolerability, response rate, duration of response, and time to progression (TTP). Methods: Pts in this Phase I multicenter open-label study were sequentially enrolled into 1 of 5 escalating doses of the combination regimen using a standard 3 + 3 design for ≤8 cycles. Pts who tolerated treatment and experienced clinical benefit were eligible for enrollment in an extension phase. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria (version 3.0). Response was assessed using the modified European Group for Blood and Marrow Transplantation criteria and International Myeloma Working Group Uniform Criteria. Safety and efficacy data were analyzed using summary statistics, except for TTP, which was estimated by the Kaplan-Meier method. Results: As of July 15, 2010, 31 pts were treated and evaluable for toxicity; 4 pts remain on study. Most pts had received prior thalidomide (n=22; 71%), bortezomib (n=20; 65%), or lenalidomide (n=14; 45%), with a median of 4 prior therapies (range, 1–10). The patient population contained both high-risk and low-risk pts, based on cytogenetic and/or fluorescence in situ hybridization analyses. Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 treatment-related AEs, experienced by 19 (61%) pts, were neutropenia (26%), thrombocytopenia (16%), diarrhea (13%), anemia (10%), and fatigue (10%); 8 pts discontinued due to toxicity. One dose-limiting toxicity (grade 3 diarrhea lasting >48 h) was observed at the maximum assessed dose (level 5), but MTD was not reached (Table) and there were no treatment-related deaths. Among 30 pts evaluable for response, the median TTP was 32 weeks (5 mo), and 4 pts remain on study as of the data cutoff date; 26 of 30 pts (87%) have achieved at least stable disease (SD). Best single responses included 2 complete responses, 3 very good partial responses (VGPR), 11 partial responses (PR), and 5 minimal responses (MR), with 5 pts achieving SD and 4 developing progressive disease, resulting in an overall response rate (ORR; PR or better) of 53%. Of 13 evaluable pts who had previously received lenalidomide, a best single response of SD or better was observed in 9 (69%; 2 VGPR, 3 PR, 1 MR, 3 SD), resulting in a 38% ORR. Notably, SD or better (2 PR, 1 MR, 3 SD) was observed in 60% of 10 evaluable pts who were relapsed, refractory, or intolerant to previous lenalidomide-containing regimens. Conclusions: Preliminary data from this Phase I study suggest that vorinostat plus lenalidomide and dexamethasone is a convenient and generally well-tolerated regimen with promising activity for relapsed or relapsed and refractory MM. The MTD for this combination was not reached. Importantly, responses were observed in pts who had received prior lenalidomide, bortezomib, and thalidomide. Further evaluation of this regimen is planned in future trials. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat, Lenalidomide, and Dexamethasone for treatment in Multiple Myeloma. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck & Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding. Dimopoulos:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Harousseau:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Houp:Merck Research Laboratories: Employment. Graef:Merck Research Laboratories: Employment. Gause:Merck Research Laboratories: Employment. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board.

Objective The purpose of this study was to inform policy regarding human papillomavirus (HPV) vaccination in North America. We measured the clinical impact of HPV-6/-11/-16/-18 vaccination in North American women. Study Design The study enrolled 21,954 women, the majority aged 16-25, across 5 studies of a quadrivalent HPV vaccine or its HPV-16 vaccine prototype. The North American subjects (n = 5996) were pooled from these trials, and the prevalence of HPV-6/-11/-16/-18 exposure was measured. The impact of vaccination on the burden of anogenital HPV lesions in an intention-to-treat population (regardless of enrollment HPV status) was calculated. Results At enrollment, the median age was 20 years; 13% of the women had had a Papanicolaou test abnormality, and 76% of the women had negative tests results for all 4 vaccine HPV types. With approximately 3 years of follow-up evaluations in the intention-to-treat population (regardless of enrollment HPV status), vaccination reduced the rate of HPV-16– and -18–related precancers and HPV-6/-11/-16/-18–related genital lesions by 66.4% (95% CI, 42.7%-81.1%) and 57.7% (95% CI, 27.3%-76.3%), respectively. Conclusion The administration of HPV vaccine to sexually active North American women reduced the burden of HPV-6/-11/-16/-18–related disease. Catch-up vaccination programs in this population are warranted.