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Background Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. Methods We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. Results The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. Conclusions The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. Clinical Trial Registration NCT01218555

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Purpose: Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor. Patients and Methods: We used the Bayesian Escalation with Overdose Control design to test escalating doses of everolimus (5 or 10 mg) and buparlisib (20, 40, 60, 80, and 100 mg) in eligible patients. Pharmacokinetic assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1. Results: We enrolled 43 patients, median age of 63 (range, 39–78) years; 25 (58.1%) females, 35 (81.4%) Caucasians, and 8 (18.6%) Blacks. The most frequent toxicities were hyperglycemia, diarrhea, nausea, fatigue, and aspartate aminotransferase elevation. Dose-limiting toxicities observed in 7 patients were fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1), and urinary tract infection (1). The recommended phase II dose (RP2D) for the combination was established as everolimus (5 mg) and buparlisib (60 mg). The best response in 27 evaluable patients was progressive disease and stable disease in 3 (11%) and 24 (89%), respectively. The median progression-free survival and overall survival were 2.7 (1.8–4.2) and 9 (6.4–13.2) months. Steady-state pharmacokinetic analysis showed dose-normalized maximum concentrations and AUC values for everolimus and buparlisib in combination to be comparable with single-agent pharmacokinetic. Conclusions: The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5 and 60 mg on a continuous daily schedule.

Colleen Lewis, MSN, ANP-BC, AOCNP®, and R. Donald Harvey, PharmD, BCOP, FCCP, FHOPA, presented on the new world of tumor-agnostic treatment approaches, including those aimed at managing patients with tumors that have high microsatellite instability (MSI-H) or neurotrophic receptor tyrosine kinase (NTRK) fusions. Learn about the clinical trial designs that enable development of these novel therapies, and discover how testing methodologies support precision medicine advances.

Background Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy. Methods We performed a retrospective review of 90 patients enrolled on immunotherapy‐based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil‐to‐lymphocyte ratio, monocyte‐to‐lymphocyte ratio, and platelet‐to‐lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias‐adjusted log‐rank test. A four‐level risk stratification was used to create low‐risk (PLR, The interaction between chronic inflammation and body composition is particularly important in the era of immunotherapy, considering that immune checkpoint inhibitors rely on the host immune system for their efficacy. This article reports on the combined effects of inflammation and sarcopenia on clinical outcomes in patients with solid tumors treated with immunotherapy‐based regimens.

BACKGROUND Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy. METHODS A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS. RESULTS The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m2 , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P

PURPOSE: Debate continues over whether explicit recommendations for a clinical trial should be included as an element of shared decision making within oncology. We aimed to determine if and how providers make explicit recommendations in the setting of phase I cancer clinical trials. METHODS: Twenty-three patient/provider conversations about phase I trials were analyzed to determine how recommendations are made and how the conversations align with a shared decision-making framework. In addition, 19 providers (9 of whose patient encounters were observed) were interviewed about the factors they consider when deciding whether to recommend a phase I trial. RESULTS: We found that providers are comprehensive in the factors they consider when recommending clinical trials. The two most frequently stated factors were performance status (89%) and patient preferences (84%). Providers made explicit recommendations in 19 conversations (83%), with 12 of those being for a phase I trial (12 [63%] of 19). They made these recommendations in a manner consistent with a shared decision-making model; 18 (95%) of the 19 conversations during which a recommendation was made included all steps, or all but 1 step, of shared decision making, as did 11 of the 12 conversations during which a phase I trial was recommended. In 7 (58%) of these later conversations, providers also emphasized the importance of the patient’s opinion. CONCLUSION: We suggest that providers not hesitate to make explicit recommendations for phase I clinical trials, because they are able to do so in a manner consistent with shared decision making. With further research, these results can be applied to other clinical trial settings.

BACKGROUND Optimal prognostic and predictive biomarkers for patients with advanced-stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced-stage cancer who received IO. METHODS A retrospective review was conducted of 90 patients with advanced cancer who received treatment on phase 1 clinical trials of IO-based treatment regimens. NLR, MLR, and PLR values were log-transformed and treated as continuous variables for each patient. Overall survival (OS), progression-free survival (PFS), and clinical benefit were used to measure clinical outcomes. For univariate associations and multivariable analyses, Cox proportional-hazards models or logistic regression models were used. RESULTS The median patient age was 63 years, and most were men (59%). The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). High baseline NLR, MLR, and PLR values were associated significantly with worse OS and PFS (P < .05) and a lower chance of benefit (NLR and PLR; P < .05). Increased NLR, MLR, and PLR values 6 weeks after baseline were associated with shorter OS and PFS (P ≤ .052). CONCLUSIONS Baseline and early changes in NLR, MLR, and PLR values were strongly associated with clinical outcomes in patients who received IO-based treatment regimens on phase 1 trials. Confirmation in a homogenous patient population treated on late-stage trials or outside of trial settings is warranted. These values may warrant consideration for inclusion when risk stratifying patients enrolled onto phase 1 clinical trials of IO agents.

Background: The impact of age-, gender-, and race-based differences on safety and efficacy in phase I clinical trials has not been well studied. Methods: We analyzed data from phase I clinical trials evaluating targeted biologic agents in patients with advanced solid malignancies. Race and gender distribution of enrolled patients was compared to the referral population demographics at the city, metro, and state levels. The association between age, gender, and race with type, frequency, and severity of treatment-emergent toxicities and clinical benefit was assessed using univariate and multivariable models. Results: Data from 117 eligible patients – Blacks/Caucasians/Others (27/85/5); male/female (66/51) – were obtained. Blacks were younger than Caucasian patients (median age of 56 vs. 62 years, p = 0.004). Nausea/vomiting was more frequent in female patients (43 vs. 24%, p = 0.03), while hematologic toxicity was more likely in Whites. While median time on treatment was comparable (113 vs. 91; p = 0.840), the median overall survival was significantly shorter for Blacks versus Caucasians (7.4 vs. 11.4 months; p = 0.0227). Black race (HR 2.11; 95% CI 1.24–3.60; p = 0.006) and older age (HR 1.03; 95% CI 1.00–1.06; p = 0.029) were associated with an increased risk of death. Conclusions: Age-, gender-, and race-based disparities were observed with specific toxicity and survival outcomes on phase I clinical trials of anticancer agents.

Background: Psychological stress – when an individual perceives that the environment exceeds their ability to meet the demands placed on them - is common in college students and exercise, and specifically instructional physical activity courses, is frequently cited as a one method of stress reduction. Objective: Determine any relationship between exercise empowerment and perceived life stress for those participating in instructional physical activity courses (IPAC). Methods: All undergraduate students (n = 3388) enrolled in IPAC in 15-week IPAC at a large university were surveyed on perceived life stress (PSS), empowerment in exercise (EES), and specific demographic variables. Results: 944 of 3388 enrolled students (Nov. 2015, April 2016) completed the survey. The data revealed GPA (p < 0.002), sex (p < 0.000), and EES (p < 0.001) showed differences for PSS. It was determined that EES, sex, and GPA predicted PSS differently for students according to their year in college. Conclusions: For freshman and seniors, sex and lower GPA were a stronger predictor of PSS with no mitigating effect of exercise empowerment. For sophomores and juniors the level of life stress was lower at higher levels of exercise empowerment. These findings support a complex relationship between exercise empowerment and life stress. While exercise is cited as a method for stress reduction the relationship between exercise empowerment and life stress for college-aged students is not as straightforward as it may seem.

Introduction Bortezomib plus lenalidomide and dexamethasone (VRD) is a standard induction therapy for newly diagnosed multiple myeloma (NDMM) patients. Given preclinical and clinical data suggesting the synergistic activity of the histone deacetylase inhibitor vorinostat with both bortezomib and lenalidomide for the treatment of multiple myeloma, we hypothesized that adding vorinostat to VRD (R2V2) would increase the rate and the quality of responses to induction treatment. Here we report the results of a phase 1 trial (NCT01038388) evaluating R2V2 as up-front treatment for NDMM patients. Patients and Methods R2V2 was tested as induction therapy in a dose-escalation phase 1 study in 30 NDMM patients deemed eligible for autologous stem-cell transplantation. Treatment consisted of 4 induction cycles with R2V2, followed by either autologous stem-cell transplantation or 4 additional R2V2 cycles and lenalidomide maintenance therapy. Results The maximum tolerated dose of vorinostat was 200 mg daily. The most common adverse events were gastrointestinal (87%), fatigue and peripheral neuropathy (60%), and thrombocytopenia (33%). R2V2 induced an objective response in 96% of patients, with 48% obtaining at least a complete remission. Median progression-free survival was 52 months, with 77% of patients alive at 5 years. Conclusion R2V2 as induction treatment for NDMM patients resulted in remarkable response rates at the cost of increased toxicity.

Background Immune checkpoint inhibitor (ICI) therapy is a fast-developing field within the spectrum of cancer care. ICIs are associated with distinctive immune-related adverse events (irAEs), reflecting their unique mechanisms of action. Objectives Effective management of irAEs requires early recognition and prompt reporting of their signs and symptoms; appropriate patient education is critical to maximizing this opportunity. Methods A comprehensive literature search was conducted in the public domain concerning awareness, assessment, and management of irAEs associated with ICIs. Findings Educational resources should provide timely, consistent, and personalized information, using a variety of teaching strategies that consider individual patient needs. Patient education should be developed with interprofessional team input and regularly reviewed in response to emerging guidance. Key messages include timing of therapeutic response and corresponding irAEs, early identification of irAEs, and the unique ability of ICIs to influence immune responses after treatment discontinuation.

Programmed death-1 (PD-1) immune checkpoint inhibitors are novel immuno-oncology agents. Unlike chemotherapy or targeted agents, which inhibit tumor cell proliferation or induce tumor cell death, immune checkpoint inhibitors are designed to stimulate a patient's own immune system to eliminate tumors. As a result of their mechanism of action, PD-1 pathway inhibitors are associated with adverse events (AEs) with immunologic etiologies, termed immune-mediated AEs (imAEs). These include skin and gastrointestinal AEs, and endocrine, hepatic, renal, and respiratory AEs, including pneumonitis. Most imAEs can be effectively managed with treatment interruption/discontinuation and/or steroids or other immunosuppressive agents. A specialist consult may be required in some cases, and endocrine imAEs may require permanent hormone replacement therapy.This article provides an overview of PD-1 inhibitors, including the potential mechanism of action, key clinical trial data, and strategies for managing patients who may receive PD-1 inhibitors for the treatment of non-small cell lung cancer.Information in the article comes from PubMed literature searches and the author's experience with these agents in clinical trials.Oncology clinicians must thoroughly assess baseline functioning and symptoms and be vigilant for imAEs, which require prompt diagnosis and management. A good understanding of the clinical profile of PD-1 pathway inhibitors is instrumental in helping clinicians manage patients receiving these new therapies.

e24193 Background: It is difficult for patients to distinguish non-therapeutic from therapeutic procedures in research. In phase I trials, day 1 pretreatment biological samples are used for research and care; posttreatment samples are for research purposes only. Preliminary data suggested patients did not understand this difference. Our study tested to see if a simple information chart would improve understanding of the nontherapeutic research procedure. Methods: A sequential two arm study was conducted. Controls (C) were asked whether samples taken at different times on day 1 of the trial were to be used for their care, for research only, or for both. The experimental (E) group provided patients with a study-specific information chart labeling the purpose of required samples and patients were then asked the same questions. Results: 100 patients (50 each C and E) were interviewed after consenting to a trial. Patients were mostly white (63%), male (53%), with an annual income > $60,000 (51%); 49% had a college degree. In both arms, understanding that pretreatment samples were for patient care and research was moderate (50% C; 62% E). Understanding that posttreatment samples were for research was significantly higher in the experimental arm (16% C; 44% E p = 0.002). Conclusions: Questions regarding the purpose of biological samples taken pre-administration of study drug were less susceptible to therapeutic misconception due to the “both” option being true. Since the provision of an informational chart significantly improved understanding of the purpose of the posttreatment sample, we suggest that providing such a chart may help alleviate this type of therapeutic misconception. [Table: see text]

Proteasome (PIs) and hystone deacetylase inhibitors (HDACis) have previously shown synergistic activity in the treatment of relapesed/refractory multiple myeloma (RRMM) patients. In this phase 1 study, we combined carfilzomib, a second generation PI, with panobinostat, a HDACi, to determine the maximum tolerated dose (MTD) of the combination (CarPan) and assess safety and efficacy among RRMM patients. Thirty-two patients (median of 4 prior lines of therapy) were enrolled. The MTD was carfilzomib 36 mg/m2 (on days 1, 2, 8, 9, 15, and 16) and panobinostat 20 mg (TIW, 3 weeks on/1 week off, every 28 days), administered until progression. At the MTD, the most common grade 3/4, treatment-related adverse events were thrombocytopenia (41%), fatigue (17%), and nausea/vomiting (12%). The objective response rate (ORR) and clinical benefit rate were 63% and 68%, respectively. Median progression-free survival (PFS) and overall survival (OS) for the entire population were 8 and 23 months, respectively. No differences in terms of ORR (55% vs. 57%), median PFS (months 8 vs. 7 months) and OS (24 vs. 22 months) were observed between bortezomib-sensitive and -refractory patients. CarPan proved to be a safe and effective steroid-sparing regimen in a heavily pre-treated population of MM patients. (Trial registered at ClinicalTrial.gov: NCT01549431), Key points CarPan is a highly active, steroid-sparing regimen, effective in both bortezomib-sensitive and refractory patients.The safety profile of CarPan, particularly thrombocytopenia and gastrointestinal adverse events, compares favorably with that of panobinostat and bortezomib.

Background Given the increasing number of available immunotherapeutic agents, more patients are presenting after failing immunotherapy in need of new treatment options. In this study, we investigated the clinical outcomes of patients treated with sequential immunotherapy. Methods We performed a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute from 2009 to 2017. We included 49 patients with an immune checkpoint inhibitor (ICI)-indicated histology. Patients were analyzed based on whether they had received prior ICI. Clinical outcomes were overall survival (OS), progression-free survival (PFS), and clinical benefit (best response of complete response, partial response, or stable disease). Univariate analysis (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazard or logistic regression model. Covariates included age, liver metastases, number of prior lines of therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). More than half of patients (n = 27, 55%) received at least one ICI prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination, and ten received multiple ICI. In MVA, ICI-naive patients had significantly longer OS (HR: 0.22, CI: 0.07–0.70, p = 0.010) and trended towards higher chance of CB (HR: 2.52, CI: 0.49–12.97, p = 0.268). Patients who received prior ICI had substantially shorter median OS (10.9 vs 24.3 months, p = 0.046) and PFS (2.8 vs. 5.1 months, p = 0.380) than ICI-naive patients per Kaplan-Meier estimation. Within the ICI-naive group, 78% (7 of 9) of patients who received prior interleukin (IL-2) or interferon gamma (IFNγ) experienced disease control for at least 6 months, compared to a disease control rate of 15% (2 of 13) in patients who had received chemotherapy, targeted therapy, or no prior treatment. Conclusions ICI-naive patients may experience improved clinical outcomes on immunotherapy-based phase 1 clinical trials than patients who have received prior ICI. This may be particularly true for patients who received prior IL-2 or IFNγ. Further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. These results should be validated in a larger study.

Background Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO. Methods We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient’s histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology. Results The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node (n = 58), liver (n = 40), lung (n = 37), bone (n = 24), and brain (n = 8). Most patients (80.7%) were RMH good risk. Most patients (n = 62) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17–0.84, p = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41–1.19, p = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p = 0.0048). Conclusions Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.

Rebecca D. Pentz*, Kristopher A. Hendershot, Louisa Wall, Taylor E. White, Susan K. Peterson, Cheryl B. Thomas, Jennifer McCormick, Michael J. Green, Colleen Lewis, Zachary Luke Farmer, Fay J. Hlubocky, Tehseen Dossul, Margie D. Dixon, Yuan Liu, Jeffrey M. Switchenko, Carolina Salvador, Taofeek K. Owonikoko, R. Donald Harvey and Fadlo R. Khuri Emory University School of Medicine, Atlanta, GA, USA Winship Cancer Institute, Atlanta, GA, USA The University of Texas M.D. Anderson Cancer Center, USA Mayo Clinic, Rochester, MN, USA Penn State College of Medicine, Hershey, PA, USA Emory Healthcare, Atlanta, GA, USA The University of Alabama School of Medicine, Birmingham, AL, USA The University of Chicago Medical Center, USA Interactive Research and Development, Main Shahrah-e-Faisal, Karachi, Pakistan

Background: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination. Methods: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m−2. Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria. Results: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m−2 were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m−2. Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m−2 and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients. Conclusion: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.

BACKGROUND: Ethical concerns about phase 1 trials persist. Important conceptual advances have been made in understanding concepts used to describe misunderstanding. However, a systematic, empirical evaluation of the frequency of misunderstanding incorporating recent developments is lacking. METHODS: The authors queried 95 participants in phase 1 trials to provide a more sophisticated estimate of the proportion who had therapeutic misconception (TM), defined as misunderstanding the research purpose or how research differs from individualized care, and therapeutic misestimation (TMis), defined as incorrectly estimating the chance of a research trial benefit as >20% or underestimating risk as 0%. RESULTS: Sixty-five of 95 respondents (68.4%) had TM, which was associated in a multivariate analysis with lower education and family income (P ¼ .008 and P ¼ .001, respectively), but TM was not associated with the vulnerability of having hardly any treatment options. Eighty-nine of 95 respondents (94%) had TMis, although only 18% reported this was a factual estimate. Although the risks of investigational agents and those exacerbated by research, such as uncertain outcomes, were mentioned (39% and 41% of respondents, respectively), risks novel to research, such as research biopsies, were rarely mentioned (3% of respondents). Although most of these respondents believed that their chance of benefit was greater and that their risk was lower than the population chance (optimists) (54.6%), a substantial minority of respondents (37.6%) were pessimists. CONCLUSIONS: TM continues to be prevalent. Estimates of personal benefit were not usually meant to report facts, it remains unknown whether respondents in the current study had TMis. Although they are not more vulnerable, phase 1 participants need improved understanding of key TM concepts, with attention to risks that are not present in standard of care. Cancer 2012;118:4571-8. V C 2012 American Cancer Society.

Background: There are now six approved immune checkpoint inhibitors for several different malignancies including melanoma, head and neck cancer, lung cancer, and renal cell carcinoma. Given the increased number of available immunotherapeutic agents, more patients are presenting in clinic as candidates for sequential immunotherapy. However, the efficacy of sequential immunotherapy in a trial setting is unknown. We investigated the association between prior treatment with immune checkpoint inhibitors and clinical outcomes in patients treated with subsequent immunotherapy in a phase 1 clinical trial. Methods: We conducted a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute between 2009 and 2017. We included 49 patients with an immune checkpoint-indicated histology (melanoma, lung cancer, head and neck cancer, and bladder cancer). Patients were then analyzed based on whether they had received at least one immune checkpoint inhibitor prior to enrollment. Overall survival (OS) and progression-free survival (PFS) were calculated in months from immunotherapy initiation on trial to date of death and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard or logistic regression model. Covariates included age, presence of liver metastases, number of prior lines of systemic therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results: The median age was 67 years and most patients (78%) were men. The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). The majority (81%) of patients were RMH good risk. More than half of patients (n=27, 55%) had received at least one immune checkpoint inhibitor prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination therapy, and ten received multiple immune checkpoint inhibitors. In MVA, patients who had not received a prior immune checkpoint inhibitor had significantly longer OS (HR: 0.22, CI: 0.07-0.70, p=0.010). These patients also trended towards longer PFS (HR: 0.86, CI: 0.39-1.87, p=0.699) and higher chance of CB (HR: 2.52, CI: 0.49-12.97, p=0.268). Immunotherapy-naïve patients had substantially longer OS (24.3 vs 10.9 months) and PFS (5.1 vs. 2.8 months) than patients who had prior immunotherapy per Kaplan-Meier estimation. Conclusion: Optimal treatment options for oncology patients who progress on immune checkpoint inhibitors are lacking. In this study, patients who received at least one prior immune checkpoint inhibitor had worse clinical outcomes on immunotherapy-based phase 1 clinical trials than immune checkpoint-naïve patients. This suggests that further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. The results from this study should be validated in a larger, prospective study. Citation Format: Mehmet Bilen, Dylan Martini, Yuan Liu, Colleen Lewis, Hannah Collins, Julie Shabto, Mehmet Akce, Haydn Kissick, Bradley Carthon, Walid Shaib, Olatunji Alese, Rathi Pillai, Conor Steuer, Christina Wu, David Lawson, Ragini Kudchadkar, Bassel El-Rayes, Viraj Master, Suresh Ramalingam, Taofeek Owonikoko, R. Donald Harvey. Sequential immunotherapy and association with clinical outcomes in advanced-stage cancer patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B176.

Background: Optimal biomarkers for cancer pts treated with IO are currently lacking. Markers of inflammation, such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) are readily available and associated with poor outcomes. We investigated the association between these markers and CO in pts treated with IO. Methods: We conducted a retrospective review of 90 pts with advanced cancer treated on IO-based phase I trials at the Winship Cancer Institute of Emory University between 2009-2017. Baseline NLR, MLR, and PLR were treated as continuous variables and rescaled by their own standard deviation. Overall survival (OS) was measured from the first dose of IO to date of death or hospice referral. Progression-free survival (PFS) was determined from first dose of IO to clinical or radiographic progression or death. We defined clinical benefit (CB) as complete response, partial response, or stable disease. Univariate association (UVA) and multivariable analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Baseline covariates included race, gender, ECOG PS, # of prior therapies, Royal Marsden Hospital (RMH) risk group, IO indication, and # of metastatic sites. Results: The median pt age was 63 years and most (59%) were men. The most common histologies were melanoma (33%) and GI cancers (22%). The majority (81%) were RMH good risk. 46% of pts had CB on IO. The median NLR, MLR, and PLR was 3.63, 0.48, and 182.65, respectively. Increased NLR, MLR, and PLR were all associated with worse OS, PFS, and chance of CB (Table 1). NLR, MLR and PLR are highly correlated to each other (Pearson correlation coefficients ≥ 0.8, all p < 0.0001). Conclusion: NLR, MLR, and PLR are strongly associated with CO in pts treated with IO. Prospective validation of these findings are warranted. Table 1: UVA and MVA of NLR, MRL, and PLR with CO OS PFSCBUVAMVAUVAMVAUVAMVAHR (CI)p-valueHR (CI)p-valueHR (CI)p-valueHR (CI)p-valueOR (CI)p-valueOR (CI)p-valueNLR1.37 (1.11-1.70)0.003*1.30 (1.02-1.66)0.031*1.42 (1.18-1.70) *statistically significant Citation Format: Dylan J. Martini, Yuan Liu, Colleen Lewis, Hannah Collins, Mehmet Akce, Haydn Kissick, Bradley C. Carthon, Walid L. Shaib, Olatunji B. Alese, Rathi Pillai, Conor E. Steuer, Christina Wu, David H. Lawson, Ragini Kudchadkar, Bassel El-Rayes, Viraj A. Master, Suresh Ramalingam, Taofeek K. Owonikoko, R Donald Harvey, Mehmet Asim Bilen. Blood based biomarkers and association with clinical outcome (CO) in advanced stage patients (pts) treated with immunotherapy (IO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2607.

e15022Background: Ideal biomarkers for cancer pts receiving IO are currently lacking. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR...

e14035 Background: Optimal use of molecularly targeted therapies is achieved by pairing agents with driver mutations present in tumor tissue. Enrollment on clinical trials designed to demonstrate this objective requires obtaining informed consent prior to molecular analysis, with potential delays in tissue acquisition, testing results, and treatment initiation. We reviewed our experience and patient disposition with studies where assignment to treatment required mutation data. Methods: We identified trials requiring consent prior to tissue mutational analysis. Review included time intervals between landmark events starting with trial presentation to patient, consent, tissue shipment, mutation analysis results, and if and when treatment was initiated. Demographic data, change in ECOG PS, and subsequent therapy were also collected. Patients were included in the analysis if they signed consent. Results: Experience with 68 patients consented across 4 molecular selection trials was reviewed. Median age: 60 years (32-87); 56% female; self-identified race White (72%), African-American (24%), Asian (4%). Most common cancers were lung (35%), colorectal (18%), parotid (7%) and sarcoma (7%). Nineteen patients required new biopsies; 15 patients (22%) discontinued participation prior to molecular results being available. Common reasons for discontinuation included insufficient archival tissue (5), lost to follow up, initiation of other treatment, and death (2 each). In 53 patients who continued, overall median time from consent to test results received was 41 days (12-149); with median time from consent to obtaining tissue of 22 days (0-121), and tissue sent to results received was 13 days (1-77). In those with advanced disease (n = 36), PS worsening occurred in 28%. Three patients matched to therapy; 1 received more than 1 cycle. In those not matching (n = 50), 46% received approved therapies, 22% were lost to follow-up, 18% enrolled on another trial and 14% died. Conclusions: Molecular selection of patients for clinical trials requires additional time and resources, and many patients do not have driver mutations. Long time intervals between decision points can delay therapies and impair the ability to explore alternative treatment.

Posttraumatic stress disorder (PTSD) patients with histories of cocaine and alcohol abuse (CA-PTSD) were compared with normal volunteers. Positron emission tomography (PET) scans with 15O-butanol were used to compare regional cerebral blood flow (rCBF) between the groups during rest and during an auditory continuous performance task (ACPT). CA-PTSD patients had significantly higher rCBF in right amygdala and left parahippocampal gyrus than normals during the ACPT. Normals had higher rCBF at frontal cortex during the resting scan and during the ACPT. The role of the amygdala in attention and fear conditioning suggests that increased amygdala rCBF may be related to clinical features of PTSD. Cocaine use may be associated with increased amygdala rCBF in PTSD patients. Amygdala and frontal cortex attention system components may be reciprocally related and their relative contributions to processing of neutral stimuli perturbed in CA-PTSD.

A current theory of anxiety effects in cognition claims that anxiety disrupts normal processing within the working memory system. We examined this theory in the context of a reading task, for participants who were high or low in assessed mathematics anxiety. The task was designed to measure the ability to inhibit attention to distracting information and the effects of this ability on explicit memory performance. The results suggested that math-anxious individuals have a deficient inhibition mechanism whereby working memory resources are consumed by task-irrelevant distracters. A consequence of this deficiency was that explicit memory performance was poorer for high-anxious individuals. Based on these results, the recommendation is made that Eysenck and Calvo's (1992) processing efficiency theory be integrated with Connelly, Hasher, and Zack's (1991) inhibition theory to portray more comprehensively the relation between anxiety and performance.

Background: Preclinical work showed improved anticancer efficacy with the combination of an mTOR and a PI3K inhibitor over either agent alone. We conducted a phase I study to determine the recommended phase II dose (RP2D) of the combination of everolimus (E), an mTOR inhibitor and buparlisib or BKM120 (B), a pan-PI3K inhibitor. Methods: Patients with advanced solid malignancies who have exhausted standard treatment options were enrolled. Main eligibility criteria include ECOG performance status 0-2, adequate end organ function and absence of glucose intolerance, uncontrolled hepatitis, anxiety or depression. Dose escalation was performed using a Bayesian Escalation with Overdose Control (EWOC) design to evaluate different doses of E (5mg or 10mg) and B (20, 40, 60 and 80 mg,) once daily continuously. Eligible patients were enrolled in cohorts of 3 patients. Pharmacokinetic (PK) assessment was conducted in cycle 1 on day 8 using peripheral blood samples collected at time 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours and prior to dosing on cycle 1 D day 15. Pharmacodynamic (PD) impact on mTOR/PI3K pathway modulation was evaluated in skin punch biopsies collected at baseline and at end of cycle 1. Results: We enrolled 35 patients: Median age 63yrs (range:40-79), 21 females (58%); 2 Latinos (6%), 7 Blacks (20%) and 26 Caucasians (74%); with cancers of the lung (8), colorectal (7), sarcomas (3), salivary gland (3), breast (3), thyroid (3), thymic (2), bladder (2), ovarian (2), head and neck (1) and PNET (1). The safety of 6 different dose combinations of E and B (5/20; 10/20; 5/40; 5/60; 10/60; 5/80) was assessed. The most frequent toxicities were: hyperglycemia, diarrhea, nausea, fatigue and AST elevation. The dose limiting toxicities observed in 6 patients were: fatigue (3), hyperglycemia (1), mucositis (1), acute renal failure (1) and urinary tract infection (1). The 5/60 combination was defined as the RP2D. The median number of cycles completed was 2 (range: 0-20). Of the 25 patients evaluable for efficacy, 8 (32%) had disease progression while 17 (68%) achieved stable disease (SD). Median duration of SD was 18 weeks (range: 2-83) and 7 patients had SD lasting ≥6 months. Steady-state PK data for both agents in 24 evaluable patients showed no evidence of drug-drug interaction, with dose-normalized maximum concentrations (Cmax) and area-under-the-curve (AUC0-∞) values for E and B in combination being comparable to single agent data. Preliminary signal of efficacy for the combination was observed in patients with thymic, breast and lung cancer. PD analysis is ongoing and will be presented at the meeting. Conclusion: The safety profile of the combination of everolimus plus buparlisib is well tolerated and the RP2D is 5mg/day and 60mg/day respectively on a continuous daily schedule. The efficacy data are encouraging and warrant further evaluation in phase II studies. Citation Format: Taofeek Kunle Owonikoko, R.Donald Harvey, Colleen Lewis, Zhengjia Chen, John S. Kauh, Meredith Renfroe, Rijalda Deovic, Gabriel L. Sica, Bradley C. Carthon, Wayne Bernard Harris, Bassel F. El-Rayes, Suresh S. Ramalingam, Fadlo R. Khuri. A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT303. doi:10.1158/1538-7445.AM2015-CT303

Introduction: Patients with myeloma ultimately become refractory to current therapies, requiring new approaches to treatment. Carfilzomib is a second generation proteasome inhibitor that has demonstrated significant activity in patients with relapsed and refractory disease. Panobinostat is a pan-deacetylase inhibitor that has been shown to be effective and overcome resistance in combination with bortezomib in refractory patients. In addition, patients treated with a combination of bortezomib/dexamethasone/panobinostat had a significant improvement in progression free survival (PFS) compared to bortezomib/dexamethasone alone. Based on preclinical data supporting combined HDAC and proteasome inhibition, we hypothesized that carfilzomib and panobinostat would be safe and effective in relapsed/refractory myeloma patients. Herein we report the initial findings of the MMRC multicenter phase I study of the combination. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of the combination of panobinostat and carfilzomib using a standard 3+3 alternate dose escalation design with 4 cohorts. An additional 12 patient expansion group will be treated at the MTD to further assess the activity and safety of the combination. Secondary objectives are to evaluate the extended safety of this combination and to assess response, response duration and progression free survival (PFS). Panobinostat is administered orally three times weekly for three of four weeks, ranging from 15 to 20 mg. Carfilzomib is administered IV days 1, 2, 8, 9, 15, and 16, ranging from 20/27 mg/m2 to 20/45mg/m2. Cycles are repeated every 4 weeks. Dose limiting toxicities (DLT) are determined in the first cycle, and all adverse events are assessed according to CTCAE V4. Responses are assessed using IMWG criteria (plus MRs as per the EBMT criteria). Results: To date, 20 patients in four cohorts have been enrolled and all have completed the first cycle. Median age is 64.5 years (48-75). All patients had refractory and progressive disease; with a median number of 4) prior treatment lines. Three DLTs occurred. One patient had grade 4 thrombocytopenia with grade 3 acute kidney injury, one patient developed persistent grade 4 thrombocytopenia without bleeding and one patient had grade 3 diarrhea uncontrolled by maximal medical therapy. The MTD is panobinostat 20 mg and carfilzomib 20/36 mg/m2. The most common grade 3 toxicities were hematologic. Regardless of causality, grade 3 or higher anemia, thrombocytopenia and neutropenia occurred in 35%, 35%, and 20% of patients, respectively. The most common grade 3/4 or higher nonhematologic toxicities were fatigue (15%), anorexia (10%), hyponatremia (10%) and nausea (10%). The overall response rate is 50% with 30% PRs and 20% VGPR or better. The median PFS is 14.3 months. Conclusion: The combination of carfilzomib and panobinostat is well tolerated with no unexpected toxicities. Response, durability of response, and PFS are encouraging and warrant further study. Disclosures Kaufman: Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Off Label Use: Carfilzomib treatment in amyloidosis . Zimmerman:Onyx: Honoraria. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Harvey:Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Acetylon: Research Funding; Amgen: Research Funding. Gleason:Celgene: Consultancy; Novartis: Consultancy. Lewis:Array BioPharma: Consultancy. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Background: Age, gender and ethnic-based differences in drug metabolism have been previously reported from large population-based studies. The potential impact of these factors on safety and efficacy outcomes in early phase clinical trials has not been well studied. Methods: We analyzed data from five investigator-initiated phase I clinical trials of targeted biologic agents in solid malignancies conducted at a single academic cancer center. Ethnic distribution of enrolled patients was compared to the referral population demographics at the city, metro and state level. We also analyzed all toxicity experience, dose limiting toxicity (DLT) and clinical benefit to determine any significant differences based on ethnicity i.e. African American, (AA) vs. Caucasian, age or gender. A multivariate logistic regression model was performed to identify significant predictors of DLT. Results: Data from 117 eligible patients was employed for this analysis: AA/Caucasians (27/85); male/female (66/51); median duration on study was 88 days. AA patients were younger in age than Caucasian patients (56 vs. 62 years, p=0.004), otherwise were comparable in terms of weight, Body Mass Index, frequency or grade of toxicity, DLT experience and gender distribution. GI toxicity of nausea/vomiting was more frequent in female patients (43% vs. 24%, p=0.03) but no disparity by age, gender or ethnicity with other types of toxicities or DLT experience. Using median duration of time on study as surrogate for treatment efficacy, there was no difference by gender (M/F 89 vs. 88 days, p=0.822) or ethnicity (AA/Caucasian: 113 vs. 91 days, p=0.840) but significant correlation with age (-0.194, p=0.038) and body weight (0.234, p=0.012) was observed. AA patients had worse overall survival 7.4 (95%CI: 5.3-16.1) vs. 11.4 (95%CI: 9.2-26.3) months with a higher risk of death on univariate [1.812 (95%CI: 1.079-3.045), p=0.025] and multivariate [HR: 2.037 (95%CI: 1.182-3.512), p=0.010] analyses. There was a modest increase in the risk of death in older patients [HR: 1.028, (95%CI: 1.000-1.056), p=0.046] a non-significant trend in improved survival for female patients [HR: 0.687 (0.357-1.321), p=0.260]. Conclusions: Age-, gender- and ethnic-based disparities were observed with specific toxicity and survival of phase I clinical trials of anticancer agents. An enrichment strategy for age and ethnic subgroups in phase I trials is warranted to ensure reliable generalization of study findings. Citation Format: Taofeek K. Owonikoko, Colleen Lewis, Adeniyi K. Busari, Sungjin Kim, Zhengjia Chen, David H. Lawson, Bradley C. Carthon, Bassel F. El-Rayes, Fadlo R. Khuri, John Kauh, R. Donald Harvey, Suresh S. Ramalingam. Ethnic, gender, and age disparities and outcome of phase I clinical trials of biologically targeted anticancer agents. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C26. doi:10.1158/1538-7755.DISP13-C26

11113 Background: AV-203 is an IgG1k humanized monoclonal antibody with high affinity and specificity for the anti-v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3) receptor. Based ...

Despite recent advances in understanding the biology of thrombopoiesis, autoimmune thrombocytopenia caused by inhibition of megakaryocytic precursors, remains a treatment dilemma. We report a case of a 43-year-old female who developed amegakaryocytic thrombocyto- penia refractory to intravenous immunoglobulin (IVIG), prednisone, cytoxan and vincristine. She was subsequently treated with myeloablative chemotherapy (busulfan and cyclophosphamide) followed by allogeneic bone marrow transplant from a 6/6 HLA-matched sibling. The patient is currently more than 1 year after transplant with complete donor chimerism and restoration of normal thrombopoiesis. A review of the literature shows that the clinical syndrome known as amegakaryocytic thrombocytopenia represents a heterogeneous group of disorders, and clinical experience with immunosuppression varies. Appropriate initial treatment for these patients requires immunosuppressive agents, including antithymocyte globulin (ATG) for steroid refractory disease. However, in the case of symptomatic patients who have an appropriate sibling donor, early hematopoietic progenitor cell transplant, even before administration of ATG, may be necessary. Further studies are needed to better define the pathogenesis and mechanism of this heterogeneous disorder before more definitive treatment algorithms can be established.

6083 Background: Platinum-based therapy in combination with Cet is the standard first line systemic therapy in RMSCCHN. Preclinical studies suggest that mTOR inhibitors may restore sensitivity to EGFR inhibitors in resistant cell lines, and that in combination with Cet may augment anti-tumor activity. We conducted a phase Ib trial of C, Cet and E for untreated RMSCCHN. Methods: Patients received C at AUC=2 on a 3 weeks on 1 off schedule with Cet weekly at a fixed dose and E at escalating dose levels of 2.5, 5.0, 7.5 and 10 mg daily using a 3+3 design. After 4 cycles of therapy patients without disease progression continued on maintenance Cet and E until disease progression or intolerable toxicity. Patients had previously untreated RMSCCHN not amenable to surgery or radiotherapy, age ≥ 18 years and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2. Results: After IRB approval, the study enrolled 18 patients with RMSCCHN between February 8, 2011 and Jan 25 2013. One patient was a screen failure. Four had an anaphylactic reaction to Cet and were excluded from the analysis. A total of 13 patients received E (M/F: 92%); median age 65 (44-75yrs). Two of six patients treated at dose level 1 (E-2.5 mg/day) experienced dose limiting toxicity (DLT) with grade 3 hyponatremia and nausea. Additional 7 patients were treated with de-escalated dose of E (2.5 mg QOD). No DLTs were observed at this dose level. Salient clinically relevant Grade >2 toxicities included: leukopenia (23%), neutropenia (15%) hyponatremia (18%), hyperglycemia, nausea, rash, hypokalemia, urinary infection, bacteremia, (each 8%). Dose reductions of C were necessary for a total of 18/61 delivered cycles of therapy. A response rate (RR) of 62.5% with all responders having partial responses (PR) was observed. The PFS was 7.8 months. Conclusions: The MTD of E in combination with Cet and C is estimated at 2.5 mg QOD. Though this is less than the commonly utilized dose of E, the regimen was associated with encouraging response rate and PFS Clinical trial information: NCT01283334.

Abstract 336 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate (Richardson et al, Blood 2010; Kumar et al, Blood 2012). The addition of a novel targeted agent to RVD may improve depth of response as reflected by an increase in complete remission (CR) rate. Preclinical studies have demonstrated that vorinostat (Vor), a histone deacetylase inhibitor, is synergistic with bortezomib, immunomodulatory compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study was to determine the tolerability and activity of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (pts) received the classical RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5–8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. Dose limiting toxicity (DLT) (Grade (G) 3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of neutrophils to 1,000/μL or platelets to 50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified European Group for Blood and Marrow Transplantation and Uniform Criteria. Pts with partial remission (PR) or better could proceed to autologous transplant after 4 cycles. After completion of 8 cycles, patients could continue maintenance with lenalidomide +/− bortezomib, with Vor not administered during maintenance therapy. Results: Thirty pts (median age 56 years [range 40–76], 63% men) were enrolled with 4 pts in cohort 1 (Vor 100mg), 15 pts in cohort 2 (Vor 200mg), 8 pts in cohort 3 (Vor 300 mg) and 3 pts in cohort 4 (Vor 400mg). The maximum tolerated dose was determined to be 200 mg Vor with RVD. Including maintenance, the median number of cycles completed was 4 (range Conclusion: The combination of RVD with vorinostat using the classical dose and schedule proved most tolerable at 200mg Vor dosing D1-14 every 21 days. The remarkably high VGPR/CR rate after 4 cycles and favorable progression free survival suggest that this combination is very effective. Alternative dosing and schedule of Vor may improve tolerability and so enhance clinical benefit, thus warranting further study. Disclosures: Kaufman: Onyx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Merck: Research Funding. Off Label Use: use of vorinostat in myeloma; use of lenalidomide as induction. Shah:Novartis: Honoraria, Research Funding, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harvey:Celgene: Research Funding. Heffner:Millenium: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Orlowski:Celgene: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck; all < $10,000 per year and disclosed to my institution: Consultancy.

2576 Background: Everolimus (E), an mTOR inhibitor, and Lenalidomide (L) are both potent anti cancer agents with immunomodulatory effects. Preclinical evidence of enhanced cytotoxicity of the combination of an mTOR inhibitor and lenalidomide provided the rationale for this phase I study. Methods: Patients with advanced solid malignancies, ECOG performance status (PS) 0-2 and adequate organ function were eligible. Using standard 3+3 dose escalation schema, patients were treated in cohorts of three with increasing doses of E (5mg, 10mg) and L (10, 15, 20, 25mg) on day 1-28 of a 28-day cycle. Treatment cycles were repeated until disease progression by RECIST criteria or intolerable toxicity. Pharmacodynamic (PD) effects of treatment on circulating B and T lymphocytes subsets were assessed by multiparameter flow cytometry at baseline and after 2 cycles. Results: We enrolled 21 patients (thyroid-5, salivary gland-5, colon-4, sarcoma-2, and others-5); median age-58 (29-74); male-13; ECOG PS of 0, 1, 2 (3/17/1). Salient grade 3/4 toxicities included rash (67%), anemia (19%) and vomiting (5%) without dose limiting toxicities. The median number of completed cycles was 3 (1 - ≥15) and best response in 14 of 18 evaluable patients was stable disease (range 2- ≥14 months); median PFS was 116 days (14- ≥498). The RP2D of E and L was defined as 10mg and 25mg once daily, respectively. PD endpoint analysis after 2 cycles of treatment showed a significant increase in activated cytotoxic T cell subset (CD8+ICOS1+) in patients with salivary or thyroid cancers compared to other tumor types (+2051.0 vs. +394 vs. -1687.4 respectively; p=0.0303) and a trend for an increase in patients with non-progressing tumors (+661.7 vs. -384.1; p=0.0988). Other significant correlations were: Changes in total B-cells (CD3-CD19+) with PFS; NK cells with age (p=0.0211) and activated T cells (CD3+CD69+; CD3+CD62L-; p=0.01) with gender. Conclusions: The combination of E and L is well tolerated at the recommended single agent doses and showed promising efficacy in neuroendocrine and salivary adenoidcystic carcinoma. Modulation of activated T cell subsets (CD8+ICOS1+) correlates with efficacy of these agents.

Abstract 3954 Background: A prognostic scoring system for patients enrolled in phase I trials was developed by the Royal Marsden Hospital (RMH) (Arkenau H-T et al., 2008). The risk score consisted of a score of 0–3 based on the presence of three variables - elevated LDH, low albumin, and > 2 metastatic sites. Median survival for patients with score 0–1 vs. 2–3 was 33 weeks vs. 15 weeks. The RMH prognostic system was validated in a large group of patients at the MD Anderson Cancer Center Phase I Clinic (Stephen et al., 2011) and three additional independent negative prognostic variables were identified (ECOG PS > 1; > 3 prior lines and GI tumor site). Median survival in patients with score of 0 vs. 6 was 27 months vs. 9 weeks. These scoring systems are intended for patients with solid tumor malignancies, and no equivalent scoring system exists for hematologic malignancies. We propose a disease-specific prognostic scoring system for MM patients enrolled in phase I clinical trials. Methods: In total, 21 phase I trials for relapsed/refractory MM from February 1, 2005 through August 2, 2011 were reviewed. Cutoff date for censoring was 08/02/2011. Autologous stem cell transplant was deemed as a line of therapy. In addition to the significant prognostic factors detailed, factors such as prior autologous stem cell transplant, prior radiation therapy, prior history of venous thromboembolism (VTE), monoclonal protein (IgA), BMI > 35 kg/m2, labs at enrollment (Hb10.2, ANC 2, LDH>ULN) were considered in the model. Adverse cytogenetic abnormalities were defined as t (4;14), t (14;16) or del 17p diagnosed by FISH or presence of t (4;14), t(14;16), del 17p or complex karyotype diagnosed by conventional karyotyping. Results: 151 consecutive relapsed/refractory MM patients that were enrolled in at least one trial in the Phase I clinic were identified. The median patient age at the time of diagnosis and at the time of phase I trial enrollment was 57 years (range, 28–75) and 61 years (range, 34–80), respectively. Median time from diagnosis to enrollment in a phase I trial is 50 months (range, 3–154). The median number of cycles received on phase I trialswas 3 (range, 0–30) and the prior lines of therapy was 4 (range, 0–13). The median overall survival was 18 months (95% confidence interval, 14.18–21.82). 57 (47%) patients had high risk cytogenetics; 37 (26%) had Stage III ISS; 12 (9%) had ECOG PS ≥ 2 and 113 (75%) received ≥4 lines of therapy. In the univariate analysis, the factors that influenced the OS were lines of therapy ( Conclusion: We demonstrate the first predictive model of outcomes for relapsed/refractory MM patients in phase I studies incorporating routinely used clinical measures. This information can be used to accurately inform patients of potential outcomes when enrolling to phase I trials. A larger, prospective trial is needed to validate our model. Disclosures: Kaufman: Millenium: Consultancy; Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Novartis: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy.

9108 Background: ASCO recently published guidelines recommending that physicians assess the treatment goals and preferences of patients with advanced cancer. Formal assessment is important before a...

5589 Background: Thyroid cancer is the most common endocrine cancer worldwide and the fastest growing malignancy in the US. Therapeutic options remain limited for patients with radioiodine-refracto...

2538 Background: Sunitinib (S) inhibits several receptor tyrosine kinases (RTKs) involved in tumor proliferation and angiogenesis, specifically PDGFR, VEGFR, KIT, FLT-3, and RET. Bortezomib (B), a ...

8577 Background: Adding rituximab (R) to chemotherapy improves survival for patients (pts) with follicular lymphoma (FL) and other indolent non-Hodgkin lymphomas (NHL), but not all pts respond. Bortezomib (B) + RCHOP has a high complete response (CR) rate, but higher doses of B with standard vincristine produced severe neuropathy. We developed a phase I/II trial to test if adding B to RCHOP with modified vincristine dosing can be well-tolerated and yield a high CR rate. Methods: Untreated pts with indolent NHL and indications for treatment based on GELF criteria or FLIPI ≥3 received R 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, vincristine 1.4mg/m2 (capped at 1.5mg) on day 1, B 1.0- 1.6mg/m2 days 1 and 8, and prednisone 100mg days 1–5 for 6–8 cycles. The maximum tolerated dose (MTD) was defined as the regimen at which 14 days) occurs. Dose escalation used the Escalation with Overdose Control Bayesian method with upper bound (θ=0.3). This facilitated MTD finding with fewer pts given prior data on B+RCHOP. Functional Assessment of Cancer Therapy (FACT) Neurotoxicity (11-item; 4 point scale), EMG, nerve conduction velocity and epidermal nerve fiber density measures were taken at baseline and after cycle 4. Results: 11 pts with FL (n=6) or other indolent NHL enrolled in phase I. Median age was 59 years (range 29–69). 6 pts (55%) had stage IV disease; 8 (64%) had FLIPI ≥2. Pts received RCHOP + B at 1.0 mg/m2 (n=1), 1.3 mg/m2 (n= 6) or 1.6 mg/m2 (n= 4) and together completed 67 cycles. Treatment was well tolerated. Neuropathy occurred in 4 pts (36%), with 2 grade 1, 1 grade 2 and 1 grade 3 toxicity ( Table ). Grade 4 neutropenia occurred in 4 pts (36%), but none >14 days. Overall response rate was 100% with 5/8 finished pts (63%) achieving CR. 3 continue on treatment. Mean FACT Neurotoxicity after cycle 4 remained < 1 for all items. Conclusions: Adding bortezomib to RCHOP produces limited toxicity when vincristine is capped at 1.5 mg. Phase II will explore the efficacy of this regimen. [Table: see text] [Table: see text]

3094 Background: Ganetespib is a next-generation Hsp90 inhibitor unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has superior activity to these agents in preclinical studies. Ganetespib is well tolerated with promising antitumor activity. Based on synergy between ganetespib (G) and docetaxel (D), a phase I study evaluating preclinical dosing models was performed. Methods: Patients (pts) with advanced solid tumor malignancies and ECOG performance status (PS) 0-2 were eligible. Sequential cohorts of pts were treated (3+3 design) with increasing doses of D (day 1) and G (days 1, 8) (A) Q 21 days. Following MTD determination, safety and exploratory cohorts of D day 1 with G days 1, 15 (B); or G days 1, 4, 15 (C) were completed. PK sampling was performed during schedule A. The primary endpoint was determination of optimal doses and schedule of the two agents for combination therapy. Results: Twenty-seven patients were enrolled in schedules A (n=12), B (n=8), and C (n=7). Median age-64 (44-75); 11-M, 16-F; ECOG PS: 0 (n=5), 1 (n=21), 2 (n=1). Most pts had NSCLC (n=9), others were head/neck (n=4), and SCLC (n=3). The defined MTD was level 2 (D-75 mg/m2, G-150 mg/m2), as 2 of 4 pts at level 3 (D-75 mg/m2, G-200 mg/m2) had DLTs (febrile neutropenia and one g4 neutropenia of > 7 days), requiring expansion of level 2. The median number of cycles received is 2 (1-11), with 3 pts in schedule C still on study. Among 22 pts evaluable for response, 1 had a PR (head/neck), 12 had SD following 6 weeks evaluation, 10 pts for 12 weeks and 6 pts for 18 weeks. Common AEs included neutropenia, diarrhea, anemia, fatigue, nausea, and febrile neutropenia. Prophylactic filgrastim/pegfilgrastim was not used at any time. PK data indicates similar G exposure alone compared to G administered prior to D. No accumulation was observed following once-weekly dosing, consistent with studies of G alone. Conclusions: The combination is well tolerated at the recommended doses of D 75 mg/m2 and G 150 mg/m2. Promising anti-cancer activity was noted, and a randomized phase 2b/3 study with D day 1 and G days 1, 15 regimen is ongoing in advanced NSCLC (NCT01348126).