Trial Of Combination Therapy Research Articles

Monoclonal Antibody: A New Treatment Strategy against Multiple Myeloma

2015 was a groundbreaking year for the multiple myeloma community partly due to the breakthrough approval of the first two monoclonal antibodies in the treatment for patients with relapsed and refractory disease. Despite early disappointments, monoclonal antibodies targeting CD38 (daratumumab) and signaling lymphocytic activation molecule F7 (SLAMF7) (elotuzumab) have become available for patients with multiple myeloma in the same year. Specifically, phase 3 clinical trials of combination therapies incorporating daratumumab or elotuzumab indicate both efficacy and a very favorable toxicity profile. These therapeutic monoclonal antibodies for multiple myeloma can kill target cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent phagocytosis, as well as by direct blockade of signaling cascades. In addition, their immunomodulatory effects may simultaneously inhibit the immunosuppressive bone marrow microenvironment and restore the key function of immune effector cells. In this review, we focus on monoclonal antibodies that have shown clinical efficacy or promising preclinical anti-multiple myeloma activities that warrant further clinical development. We summarize mechanisms that account for the in vitro and in vivo anti-myeloma effects of these monoclonal antibodies, as well as relevant preclinical and clinical results. Monoclonal antibody-based immunotherapies have already and will continue to transform the treatment landscape in multiple myeloma.

Trial of Music, Sucrose, and Combination Therapy for Pain Relief during Heel Prick Procedures in Neonates

To compare the effectiveness of music, oral sucrose, and combination therapy for pain relief in neonates undergoing a heel prick procedure. This randomized, controlled, blinded crossover clinical trial included stable neonates >32 weeks of postmenstrual age. Each neonate crossed over to all 3 interventions in random order during consecutive heel pricks. A video camera on mute mode recorded facial expressions, starting 2 minutes before until 7 minutes after the heel prick. The videos were later analyzed using the Premature Infant Pain Profile-Revised (PIPP-R) scale once per minute by 2 independent assessors, blinded to the intervention. The PIPP-R scores were compared between treatment groups using Friedman test. For the 35 participants, the postmenstrual age was 35 weeks (SD, 2.3) with an average weight of 2210 g (SD, 710). The overall median PIPP-R scores following heel prick over 6 minutes were 4 (IQR 0-6), 3 (IQR 0-6), and 1 (IQR 0-3) for the music, sucrose, and combination therapy interventions, respectively. The PIPP-R scores were significantly lower at all time points after combination therapy compared with the groups given music or sucrose alone. There was no difference in PIPP-R scores between the music and sucrose groups. In relatively stable and mature neonates, the combination of music therapy with sucrose provided better pain relief during heel prick than when sucrose or music was used alone. Recorded music in isolation had a similar effect to the current gold standard of oral sucrose. www.anzctr.org.au ACTRN12615000271505.

Persistent hypothyroid symptoms in a patient with a normal thyroid stimulating hormone level.

A subset of patients being treated for hypothyroidism do not feel well while taking levothyroxine (LT4) replacement therapy, despite having a normal serum thyroid stimulating hormone level. Pursuing a relative triiodothyronine deficiency as a potential explanation for patient dissatisfaction, has led to trials of combination therapy with liothyronine (LT3), with largely negative outcomes. This review attempts to reconcile these diverse findings, consider potential explanations, and identify areas for future research. Patients being treated with LT4 often have lower triiodothyronine levels than patients with endogenous thyroid function. Linking patient dissatisfaction with low triiodothyronine levels has fueled multiple combination therapy trials that have generally not shown improvement in patient quality of life, mood, or cognitive performance. Some trials, however, suggest patient preference for combination therapy. There continues, moreover, to be anecdotal evidence that patients have fewer unresolved symptoms while taking combination therapy. The 14 trials completed to date have suffered from employing doses of LT3 that do not result in steady triiodothyronine levels, and having insufficient power to analyze results based on baseline dissatisfaction with therapy and patient genotype. Future trials that are able to incorporate such features may provide insight into what thyroid hormone preparations will most improve patient satisfaction with therapy.

Abstract 3661: Breaking down the barrier restricting infiltration and differentiation of APC in the tumor microenvironment with a first-in-class antibody targeting Semaphorin4D, and rational combination therapies

Abstract Purpose: We expand mechanistic findings in preclinical studies to demonstrate that antibody blockade of Semaphorin 4D (SEMA4D, CD100) reduces expansion of MDSC and shifts the balance of myeloid cells within the TME to facilitate tumor rejection. Efficacy is further enhanced when combined with various immunotherapies. Design of Phase 1b/2 combination trials of VX15/2503, a humanized IgG4 antibody targeting SEMA4D, with immune checkpoint inhibition will be presented. Methods: Anti-SEMA4D antibodies were evaluated alone and in combination with other immunotherapies in various preclinical models. Anti-tumor activity and immune response was characterized by immunohistochemistry, flow cytometry, functional assays, and cytokine, chemokine and gene expression analysis. A Phase I trial for single agent VX15/2503 was completed, and several 1b/2 combination immunotherapy trials are planned. Results: SEMA4D restricts migration of monocytes and promotes expansion of suppressive myeloid cells in vitro. Strong expression of SEMA4D at the invasive margins of actively growing tumors in vivo restricts the infiltration and modulates polarization of leukocytes in the TME. Antibody blockade of SEMA4D facilitated recruitment of activated DCs and T lymphocytes in preclinical models. M-MDSCs were significantly reduced in tumor and blood following treatment. A significant shift towards increased Th1 cytokines (IFNγ, TNFα) and CTL-recruiting chemokine CXCL9, with concurrent reduction in Treg-, MDSC- and M2-macrophage promoting chemokines (CCL2, CXCL1, CXCL5) was observed. Accordingly, Teff:Treg ratio (3x, p<0.005) and CTL activity (4x, p<0.0001) were increased. These coordinated changes in the tumoral immune context are associated with durable tumor rejection and immunologic memory in murine colon, breast, and melanoma models. Importantly, anti-SEMA4D treatment can further enhance activity of co-administered immunotherapies and chemotherapy. For example, the combination with immune checkpoint inhibitor anti-CTLA-4 causes complete tumor regression in 100% of mice, as compared to 22% with monotherapy (p<0.01). Additional studies of combinations with other immunomodulators, including treatment of established tumors with HDAC inhibitor Entinostat, will be presented. Conclusions: SEMA4D blockade represents a novel mechanism to promote functional immune infiltration into the tumor and enhance immunotherapy. VX15/2503 treatment was well tolerated in a Phase I multiple ascending dose trial in patients with advanced refractory solid tumors. Phase 1b/2 trials of combination therapy with avelumab in NSCLC patients who are immunotherapy naïve, and combinations with anti- anti-PD-1 and/or anti-CTLA-4 in melanoma and HNSCC patients who are refractory to PD1 inhibitors are planned in 2017. Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Stephen R. Comeau, Leslie Balch, Alyssa Knapp, John E. Leonard, Terrence L. Fisher, Siwen Hu-Lieskovan, Antoni Ribas, Ernest S. Smith, Maurice Zauderer. Breaking down the barrier restricting infiltration and differentiation of APC in the tumor microenvironment with a first-in-class antibody targeting Semaphorin4D, and rational combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3661. doi:10.1158/1538-7445.AM2017-3661

Abstract 2666: Using “omics” to select immunotherapy and conventional therapy combinations

Abstract Background: As only a subset of patients respond to immunotherapies, therapeutic biomarkers are needed to predict which patients will benefit and which should be spared from potentially toxic treatment. Proteins expressed by tumor cells and by the immune microenvironment may predict response to immune checkpoint inhibitors. In non-inflamed tumors, chemotherapy and targeted therapy may stimulate an immune response thereby affecting the relationship between tumor and immune system. Combinations of immunotherapies and conventional therapies are the subject of ongoing clinical trials. We hypothesized that genomic and proteomic evaluation of multiple immune biomarkers in tumor tissue and in lymphocytes would identify a signature that could (a) differentiate between responders and non-responders to checkpoint inhibitors and (b) identify candidates for combination therapy. Methods: A pathologist marked areas of tumor and tumor-associated lymphocytes on archived tissue sections (N=2) of non-small cell lung cancer (NSCLC) and melanoma. The marked areas were microdissected and solubilized to tryptic peptides. In each liquefied tumor sample, 110 protein biomarkers, including 60 immunomarkers were quantified with a mass spectrometry-based proteomic assay. The genomic material was analyzed by whole genome sequencing (WGS) and RNA-seq. Results: Tumor and lymphocytes expressed several immunomarker proteins (eg, PDL1, IDO1, B7H3, B7-2, STAT1, GBP1). The melanoma patient’s tumor and lymphocytes expressed protein markers for response to immunotherapy (PDL1 and IDO1), and the tumor had high mutational burden as identified by WGS. Furthermore, biomarker analysis suggested sensitivity to BRAF inhibitors and resistance to platinum and taxane. The NSCLC patient’s tumor and lymphocytes expressed IDO1 protein, but genomic analysis suggested a non-inflamed tumor. Based on expression levels of ERCC1 and hENT1, one possible regimen for this patient is platinum plus gemcitabine followed by immunotherapy. In one patient, comparison of protein expression in tumor-associated lymphocytes versus distal lymphocytes (>1 mm from marked tumor areas) showed variation < 10% for 11 proteins and < 30% for 14 proteins. Conclusions: Both lymphocytes and tumor expressed immunoproteins that may be used to select patients for approved immunotherapies or clinical trials. Proteomic and genomic profiling also characterized biomarkers that inform selection of targeted therapies and chemotherapies. Ongoing clinical trials of immunotherapy and combination therapies could benefit from precise, quantitative molecular stratification of patients. Protein level cutoffs that correlate with response to immunotherapy are in development. Citation Format: Sarit Schwartz, Robert Heaton, Yuan Tian, Zack Sanborn, Shankar Sellappan, Kerry Scott, Fabiola Cecchi, Steve Benz, Todd Hembrough. Using “omics” to select immunotherapy and conventional therapy combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2666. doi:10.1158/1538-7445.AM2017-2666

Abstract 5037: New concepts for quantifying the benefits of mono and combination therapy in an era of big data

Abstract I will describe new (unpublished) approaches to quantifying drug response at two points in the drug development pipeline: pre-clinical studies in cell lines and clinical trials of combination therapies in patient populations. Drug sensitivity and resistance in cell lines is conventionally quantified by IC50 or Emax values, but these measures suffer from a fundamental flaw when applied to growing cells: they are highly sensitive to cell division number, which varies with cell line, experimental condition, seeding density etc. The dependency of IC50 and Emax on division rate creates artefactual correlations between genotype and drug sensitivity while obscuring important biological insights and interfering with biomarker discovery. I will describe alternative growth rate inhibition (GR) metrics that are insensitive to division number and can directly measure both endpoint sensitivity and adaptive drug resistance. Theory and experiments show that GR50 and GRmax are superior to IC50 and Emax for assessing the effects of drugs in dividing cells. GR metrics promise to improve our ability to score drug sensitivity in specific-derived tumor cells, improves data reproducibility, and increase the translational potential of pharmacogenomics data. In patients, combination therapy improves tumor control compared to monotherapy and the development of combinations is motivated in most cases by pre-clinical data on synergism in cell lines. However I will describe a different way in which combinations can provide clinical benefit. Based on analysis of between-patient variability in existing trial data and a large set patient derived tumor xenograft (PDX) mice published by Gao H, Korn JM, Ferretti S, et al. (Nature medicine 2015;21:1318-25), I will argue for a simple principle: in nearly two-thirds of cases analyzed, efficacious combinations work simply by improving the likelihood that a tumor will experience an outlier response to a single drug. Thus, even in the absence of additive or synergistic tumor inhibition, combinations are generally superior to monotherapies. Superiority by “independent action” provides a principle on which to design new combinations and a scientific rationale for the use of combination therapies in poorly understood cancers whenever toxicity is acceptable. These studies, at two different points of the drug discovery pipeline, illustrate the value of combining new first-principles theories about drug mechanism of action with “big data” that is increasingly available on pre-clinical and clinical drug response. Conversely, in the absence of conceptual innovation, we miss important mechanistic insights hidden in existing data. The purpose of such insights, when obtained, is drive new laboratory and real-world experiments. I will discuss how the process of coupling computation and experimentation works in practice. Citation Format: Peter K. Sorger, Marc Hafner, Mario Niepel, Caitlin Mills, Adam Palmer, Mohammed Fallahi Sichani. New concepts for quantifying the benefits of mono and combination therapy in an era of big data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5037. doi:10.1158/1538-7445.AM2017-5037

Overcoming resistance to targeted therapy with immunotherapy and combination therapy for metastatic melanoma.

Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease. Will immunotherapy and combination therapy trials overcome resistance in metastatic melanoma? In an effort to treat resistant disease, new clinical trials evaluating the combination of immunotherapy with other therapies, such as kinase inhibitors, adoptive cell therapy, chimeric CD40 ligand to boost costimulation, or a tumor-specific oncolytic virus enhancing granulocyte macrophage colony-stimulating factor (GM-CSF) expression, are currently underway. Updated studies on the mechanisms of resistance, immune escape and options to reinvigorate immune cells support the continued discovery of new and improved forms of therapy.

TRTH-05. PREDICTORS OF SUCCESS OF PHASE 2 PAEDIATRIC ONCOLOGY CLINICAL TRIALS

AbstractThe rarity of childhood cancer, and high cure rates, mean only a limited number of novel therapies can be tested in patients with relapsed or refractory disease. Despite this, most novel therapeutic strategies fail in early phase trials. Of those that successfully pass through the different stages of clinical development, there is little evidence to identify the factors that influenced success. To better improve clinical success rates, we examined the impact of 23 preclinical and trial design variables for their influence on the success of 135 Phase 2 paediatric oncology clinical trials. Trial success was determined by an objective assessment of patient response, with data analysed using Fisher’s Exact or Pearson’s Chi-Square tests, and multivariate analysis using logistic regression models. For 61% of trials (83/135), no relevant preclinical experiments were performed. For those trials where preclinical studies were carried out (52/135 [39%]), there was no evidence the conduct of any preclinical experiments made the trial more likely to succeed. The only factors that positively influenced success related to trial design. Trials that evaluated patients with a single histological cancer type were significantly more likely to succeed than those that assessed multiple cancer types (67% versus 47%, 27%, and 17% for 1, 2–3, 4–7 and 8+; P<0·005). Liquid or solid tumour trials were more successful than central nervous system trials, or combined trials (67%, 61%, 37%, and 23%; P=0·005). Trials of combination therapies were more successful than single agents (70% versus 28%; P<0·005). Trials initiated based on adult studies were less likely to be successful, whereas trials initiated based on prior paediatric studies were more successful. Overall, the results of this study have the potential to change the way not only preclinical research is conducted and assessed prior to trial initiation but how clinical research is designed and performed moving forward.

Prophylaxis of migraine headaches with riboflavin: A systematic review.

Migraine headache is a relatively common, debilitating condition that costs our healthcare system over 78 billion dollars per year. Riboflavin has been advocated as a safe, effective prophylactic therapy for the prevention of migraines. The purpose of this study was to provide a systematic review of the current role of riboflavin in the prophylaxis of migraine headache. A MEDLINE literature search inclusive of the dates 1966-2016 was performed using the search terms: riboflavin and migraine disorders. Excerpta Medica was searched from 1980 to 2016 using the search terms: riboflavin and migraine. Additionally, Web of Science was searched using the terms riboflavin and migraine inclusive of 1945-2016. Bibliographies of all relevant papers were reviewed for additional citations. We utilized the PRISMA guidelines to select English language, human, clinical trials of riboflavin as a single entity or in combination, review articles, and supporting pharmacokinetic and pharmacogenomic data assessing the efficacy and mechanism of riboflavin therapy in the prophylactic treatment of migraine headache. A total of 11 clinical trials reveal a mixed effect of riboflavin in the prophylaxis of migraine headache. Five clinical trials show a consistent positive therapeutic effect in adults; four clinical trials show a mixed effect in paediatric and adolescent patients, and two clinical trials of combination therapy have not shown benefit. Adverse reactions with riboflavin have generally been mild. Riboflavin is well tolerated, inexpensive and has demonstrated efficacy in the reduction of adult patient's migraine headache frequency. Additional data are needed, however, to resolve questions involving pharmacokinetic issues and pharmacogenomic implications of therapy.

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide, yet ASCVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure- and cholesterol-lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of ASCVD. To determine the effect of fixed-dose combination therapy on all-cause mortality, fatal and non-fatal ASCVD events, and adverse events. We also sought to determine the effect of fixed-dose combination therapy on blood pressure, lipids, adherence, discontinuation rates, health-related quality of life, and costs. We updated our previous searches in September 2016 of CENTRAL, MEDLINE, Embase, ISI Web of Science, and DARE, HTA, and HEED. We also searched two clinical trials registers in September 2016. We used no language restrictions. We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure-lowering and one lipid-lowering component versus usual care, placebo, or an active drug comparator for any treatment duration in adults 18 years old or older, with no restrictions on presence or absence of pre-existing ASCVD. Three review authors independently selected studies for inclusion and extracted the data for this update. We evaluated risk of bias using the Cochrane 'Risk of bias' assessment tool. We calculated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I2 < 50%) and random-effects models when heterogeneity was high (I2 ≥ 50%). We used the GRADE approach to evaluate the quality of evidence. In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed-dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow-up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow-up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed-dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89, I2 = 0%, 5 studies, N = 5300) and fatal and non-fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low-quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed-dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed-dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate-quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was -6.34 mmHg (95% CI -9.03 to -3.64, 13 trials, 7638 participants, moderate-quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.61 mmol/L (95% CI -0.88 to -0.35, 11 trials, 6565 participants, low-quality evidence) and -0.70 mmol/L (95% CI -0.98 to -0.41, 12 trials, 7153 participants, moderate-quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate-quality evidence). The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes.

208 - KEYNOTE-365: Phase 1b/2 trial of pembrolizumab combination therapy for metastatic castration-resistant prostate cancer (mCRPC)

208 - KEYNOTE-365: Phase 1b/2 trial of pembrolizumab combination therapy for metastatic castration-resistant prostate cancer (mCRPC)

New pharmacological opportunities for the treatment of invasive mould diseases.

Recently, several randomized studies have been published that will shape treatment decisions in the prevention and management of invasive mould infections. Liposomal amphotericin B is an option for empirical or targeted treatment of invasive aspergillosis or mucormycosis, but for prophylaxis therapy, the triazole class now predominates. The triazole voriconazole is currently regarded as a drug of choice for the treatment of proven or probable invasive aspergillosis, and has shown significantly higher response rates than amphotericin B deoxycholate in this setting, with fewer severe drug-related adverse events. Isavuconazole, the newest triazole agent, offers the advantages of once-daily dosing, a wider spectrum of antifungal activity than voriconazole, predictable pharmacokinetics and fewer CYP enzyme-mediated drug interactions. A recent large randomized clinical trial showed mortality to be similar under isavuconazole or voriconazole in patients with invasive mould disease, with fewer drug-related adverse events in isavuconazole-treated patients. Another study has indicated that isavuconazole is also effective in mucormycosis infections but patient numbers were small and confirmation is awaited. Experimental studies combining different drug classes with antimould activity have been promising, but the clinical database is limited. A large randomized trial of combination therapy compared voriconazole plus the echinocandin anidulafungin versus voriconazole monotherapy in patients with invasive aspergillosis. Results showed the overall response rate to be similar, but combination therapy improved survival for the subpopulation of patients in whom the diagnosis was confirmed by serum and/or bronchoalveolar lavage fluid galactomannan positivity. This active field of research is likely to continue evolving rapidly in the coming years.

Initial results of CALGB 80803 (Alliance): A randomized phase II trial of PET scan-directed combined modality therapy for esophageal cancer.

1 Background: To determine whether changing chemotherapy (CT) during pre-op chemoradiation (CRT) based on response to induction CT by 18F-fluoro-deoxyglucose PET imaging can lead to improved pathologic complete response (pCR) in patients (pts) with resectable esophageal and gastroesophageal junction (GEJ) adenocarcinomas. Methods: 257 eligible pts were enrolled, underwent baseline PET scan, and were randomized to one of 2 induction CT arms: Modified FOLFOX-6 (oxaliplatin, leucovorin, 5-FU), days 1, 15, 29 or Carboplatin/Paclitaxel (CP), days 1, 8, 22, 29. Repeat PET was performed days 36-42; change in max standardized uptake value (SUV) from baseline was assessed. PET non-responders (≤35% decrease in SUV – PET-NR) crossed over to alternative CT regimen during CRT (50.4Gy/28 fractions). PET responders (&gt;35% decrease in SUV – PET-R) continued on same CT during CRT. Pts underwent surgery 6 wks post-CRT. Pts evaluable if had surgery, disease progression (PD), death due to disease, were unresectable or had adverse event (AE). Primary endpoint was pCR in PET-NR who crossed over to alternative CT (expected 5% under H0 to 20% under Ha). Results: Pre-audit PET response data after induction CT and pCR rates after CRT and surgery are shown in the table. For PET-NR who crossed over to alternative CT during CRT, pCR was 15.6%; 95% CI (0.08, 0.26). Conclusions: Efficacy criteria were met for an improvement in pCR rates among pts who were PET-NR after induction CT and received alternative CT during CRT for esophageal and GEJ adenoca. Pts receiving induction and concurrent CP had an unexpectedly low pCR. Support: U10CA180821, U10CA180882 Clinical trial information: NCT01333033. [Table: see text]

Abstract B023: Antibody blockade of Semaphorin 4D enhances infiltration of APC and CD8 T cells and reduces immune suppression to facilitate immune-mediated tumor rejection

Abstract Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer and expression correlates with invasive disease in several human tumors. We have reported a novel role for SEMA4D in modulating the tumor microenvironment (TME) to exclude activated antigen presenting cells and cytotoxic T lymphocytes so as to promote tumor growth; this effect can be reversed by antibody blockade. Purpose: Characterize immune-related anti-tumor activity mediated by antibody neutralization of SEMA4D, as a single agent and in combination with other immunomodulatory therapies, including immune checkpoint inhibition. Methods: Blockade of SEMA4D with monoclonal murine antibody was evaluated in murine melanoma and colon cancer models. Immune response in pre-clinical models was characterized by immunohistochemistry, flow cytometry, functional assays, as well as cytokine, chemokine and gene expression analysis. Therapeutic activity was evaluated in various preclinical models. A Phase I trial in patients with advanced solid tumors was completed. Results: SEMA4D restricts migration of macrophage cell lines and promotes expansion of suppressive tumor associated macrophage (TAM) and myeloid derived suppressor cells (MDSC) in vitro. Strong expression of SEMA4D at the invasive margins of actively growing tumors in vivo modulates the infiltration and polarization of leukocytes in the TME. In preclinical models, antibody neutralization disrupted the SEMA4D gradient at the invasive margin, which correlated with recruitment of activated APCs and T lymphocytes into the TME. This was accompanied by a significant shift towards increased Th1 cytokines (IFNΓ, TNFA) and CTL-recruiting CXCL9 chemokine, with concurrent reduction in Treg-, MDSC- and M2-macrophage promoting chemokines (CCL2, CXCL1, CXCL5). Accordingly, an increase in Teff:Treg ratio (3x, p&amp;lt;0.005) and CTL activity (4x, p&amp;lt;0.0001) was observed. MDSCs were significantly reduced in both tumor and blood following treatment. Nanostring gene expression analysis of on-treatment tumors confirms an increase in the gamma-inflammatory immune gene signature that was predictive of ORR and PFS in KEYNOTE 001 (Ribas, ASCO 2015), including significant increases in CXCL9, Gzmb, CCR5, Stat1, Lag3, Ptprc (NK function), Ciita (MHC presentation), Pdcd1 (PD-1), Itga1 (adhesion, leukocyte function). The coordinated anti-SEMA4D induced changes in the tumoral immune context are associated with durable tumor rejection and immunologic memory in preclinical colon, breast, and melanoma models. Importantly, the immunomodulatory activity of anti-SEMA4D antibody can be further enhanced by combination with other immunotherapies, including immune checkpoint inhibitors and chemotherapy. Strikingly, the combination of anti-SEMA4D with anti-CTLA-4 acts synergistically, with maximal increase in survival (110% tumor growth delay, p&amp;lt;0.01) and complete tumor regression in 100% of mice, as compared to 22% with monotherapy (p&amp;lt;0.01). SEMA4D antibody treatment was well tolerated in nonclinical and clinical studies; including a Phase I multiple ascending dose trial in patients with advanced refractory solid tumors. Patients with the longest duration of treatment, 48-55 weeks, included colorectal, breast, and a papillary thyroid patient, who had a partial response by RECIST. Progression free survival strongly correlated with elevated baseline lymphocyte counts (r = 0.6133), consistent with an immune mediated mechanism of action for VX15/2503, a humanized IgG4 anti-SEMA4D antibody. Conclusion: Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. Phase 1b/2a trials of combination therapy with immune checkpoint inhibition are planned. Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Ekaterina Klimatcheva, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark J. Paris, Terrence L. Fisher, Siwen Hu-Lieskovan, Antoni Ribas, Ernest S. Smith, Maurice Zauderer. Antibody blockade of Semaphorin 4D enhances infiltration of APC and CD8 T cells and reduces immune suppression to facilitate immune-mediated tumor rejection [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B023.

Design of clinical trials involving multiple hypothesis tests with a common control.

Randomized clinical trials comparing several treatments to a common control are often reported in the medical literature. For example, multiple experimental treatments may be compared with placebo, or in combination therapy trials, a combination therapy may be compared with each of its constituent monotherapies. Such trials are typically designed using a balanced approach in which equal numbers of individuals are randomized to each arm, however, this can result in an inefficient use of resources. We provide a unified framework and new theoretical results for optimal design of such single-control multiple-comparator studies. We consider variance optimal designs based on D-, A-, and E-optimality criteria, using a general model that allows for heteroscedasticity and a range of effect measures that include both continuous and binary outcomes. We demonstrate the sensitivity of these designs to the type of optimality criterion by showing that the optimal allocation ratios are systematically ordered according to the optimality criterion. Given this sensitivity to the optimality criterion, we argue that power optimality is a more suitable approach when designing clinical trials where testing is the objective. Weighted variance optimal designs are also discussed, which, like power optimal designs, allow the treatment difference to play a major role in determining allocation ratios. We illustrate our methods using two real clinical trial examples taken from the medical literature. Some recommendations on the use of optimal designs in single-control multiple-comparator trials are also provided.

Smoking Cessation and Changes in Body Mass Index: Findings From the First Randomized Cessation Trial in a Low-Income Country Setting

In high-income countries, quitting cigarette smoking is associated with weight gain, which can reduce motivation to abstain. Whether smoking cessation is associated with weight gain in a low-income country context has never been investigated. We aimed to determine the post-cessation changes in body mass index (BMI) and its predictors among smokers who received a smoking cessation intervention in a low-income country setting. We performed post hoc analyses of data from 269 smokers who participated in a two-group, parallel-arm, double-blind, placebo-controlled randomized trial of combined nicotine replacement therapy (NRT) and behavioral counseling in primary care clinics in Aleppo, Syria. We used generalized estimating equation modeling to identify predictors of changes in BMI at 6 weeks and 6- and 12-month follow-ups after quit date. The mean pre-cessation BMI of the sample was 27.9kg/m2 (SD = 5.2). Over 12 months of follow-up, BMI of smoking abstainers averaged 1.8 BMI units (approximately 4.8kg) greater than non-abstainers (p = .012). Throughout the study, greater BMI was associated with being female (p = .048), reporting smoking to control weight (p < .001) and having previously failed to quit due to weight gain (p = .036). Similar to findings from high-income countries, smoking cessation in Syria is associated with weight gain, particularly among women and those who have weight concerns prior to quitting. This group of smokers may benefit from tailored cessation interventions with integrated body weight management elements that take into consideration the prevailing local and cultural influences on diet and levels of physical activity. This study provides the first evidence regarding post-cessation changes in BMI among smokers who attempt to quit in a low-income country setting. Our findings advance knowledge regarding post-cessation weight gain and offers insight for researchers and clinicians to identify smokers at higher risk of post-cessation weight gain. This information will help in delivering interventions that take into account the prevailing cultural influence on diet and physical activity and will ultimately help in designing future tailored cessation programs in Syria and other low-income countries with similar cultural background and level of development.

Health system barriers and facilitators to medication adherence for the secondary prevention of cardiovascular disease: a systematic review.

BackgroundSecondary prevention is cost-effective for cardiovascular disease (CVD), but uptake is suboptimal. Understanding barriers and facilitators to adherence to secondary prevention for CVD at multiple health system levels may inform policy.ObjectivesTo conduct a systematic review of barriers and facilitators to adherence/persistence to secondary CVD prevention medications at health system level.MethodsIncluded studies reported effects of health system level factors on adherence/persistence to secondary prevention medications for CVD (coronary artery or cerebrovascular disease). Studies considered at least one of β blockers, statins, angiotensin–renin system blockers and aspirin. Relevant databases were searched from 1 January 1966 until 1 October 2015. Full texts were screened for inclusion by 2 independent reviewers.ResultsOf 2246 screened articles, 25 studies were included (12 trials, 11 cohort studies, 1 cross-sectional study and 1 case–control study) with 132 140 individuals overall (smallest n=30, largest n=63 301). 3 studies included upper middle-income countries, 1 included a low middle-income country and 21 (84%) included high-income countries (9 in the USA). Studies concerned established CVD (n=4), cerebrovascular disease (n=7) and coronary heart disease (n=14). Three studies considered persistence and adherence. Quantity and quality of evidence was limited for adherence, persistence and across drug classes. Studies were concerned with governance and delivery (n=19, including 4 trials of fixed-dose combination therapy, FDC), intellectual resources (n=1), human resources (n=1) and health system financing (n=4). Full prescription coverage, reduced copayments, FDC and counselling were facilitators associated with higher adherence.ConclusionsHigh-quality evidence on health system barriers and facilitators to adherence to secondary prevention medications for CVD is lacking, especially for low-income settings. Full prescription coverage, reduced copayments, FDC and counselling may be effective in improving adherence and are priorities for further research.

Abstract IA21: Opportunities for integration of PDX models into clinical trials

Abstract Patient-derived xenograft models (PDX) provide opportunities to evaluate efficacy, pharmacodynamics, response durability, and resistance mechanisms in greater details than traditionally possible with sampling of patient tumors. When PDX models are integrated with patients enrolled in clinical trials, or treated with novel agents, there are opportunities to interrogate aspects of cancer biology not traditionally evaluable, while maintaining clinical relevance. This presentation will explore the strengths and limitations of the models, with examples on how these models are being integrated into clinical trials, validation efforts, and novel insights derived from this approach. The concept of a co-clinical trial has been variously defined, including a definition proposed by the NCI as parallel or sequential trials of combination therapy in patients and in mouse and human-in-mouse models of appropriate genotypes to represent the patients. This concept is being extended for PDX models to incorporate tumor models derived from the same patients participating in the clinical trial, both with a goal of improving translational interrogation of the novel agent efficacy as well as emerging efforts to use the PDX models to guide patient therapy. Validation of the PDX models for treatment response/regression will be demonstrated, including recently completed clinical trials utilizing inhibitors of BRAF and MEK with a comparison of the response of the matched PDX models to radiographic measurements from the treated patients. Cohort based validation will be demonstrated through examples with EGFR targeted therapy and comparison to randomized clinical trial results. Limitations of these approaches will be described. PDX models from clinical trials have been demonstrated to model and replicate mechanisms of resistance in some settings, and examples from colorectal and lung cancer will be used to demonstrate this. Resistance of lung cancer to EGFR tyrosine kinase inhibitors is being explored on PDXs obtained from post-progression biopsies. Tumor heterogeneity as a mechanism of resistance has been successfully modeled in BRAF-mutant colorectal cancer, and has been integrated into prospective clinical trials. Finally, efforts to integrate PDX models as predictors of treatment response are described. These include efforts to use matched PDX models to guide treatment decisions in patients as part of prospective clinical trials. Regulatory, logistic, and biologic limitations of such efforts will be discussed. Citation Format: Scott Kopetz. Opportunities for integration of PDX models into clinical trials. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA21.

Reliability Analysis of a Newly Developed Questionnaire for Quality Control of Follow-up Visits in PolyIran Study.

The PolyIran study is a large-scale pragmatic cluster randomized controlled trial of fixed-dose combination therapy (Polypill) for prevention of cardiovascular diseases (CVD) in Iran. The PolyIran Quality Control Program (PIQCP) including a new questionnaire was developed to assess the quality of data collection during follow-up visits. The aim of this study was to assess the inter-rater reliability of PIQCP questionnaire. The study was conducted in 26 (11%) randomly selected clusters (from a total of 236 PolyIran clusters). All participants within these 26 clusters were enrolled. The quality scores were measured according to the PIQCP guidelines by two independent raters. The intraclass correlation coefficients (ICC) were measured. In addition, the quality scores were categorized into good (70%) and poor (<70%). The kappa coefficient was used to assess inter-rater agreement for this categorical quality scores. A total number of 945 PolyIran participants were enrolled of which, 501 (53%) were from intervention arm. In 934 participants (98.8%), the quality score could be successfully identified by both raters. The ICC (95%CI) of the overall quality scores was 0.985 (0.983-0.987). It was 0.976 (0.972-0.980) and 0.988 (0.986-0.990) in intervention and control arms, respectively. We found excellent agreement between the two raters in identifying participants with good and poor quality scores (kappa = 0.988, P < 0.001). The kappa values were 0.972 (P < 0.001) and 1.000 (P < 0.001) in intervention and control arms, respectively. Our results suggested that the PIQCP questionnaire is a reliable tool for assessing quality of data collection in PolyIran follow-up visits. Using this measure will help us in efficient monitoring of the PolyIran follow-ups and may ensure high quality data.

Abstract 4888: Antibody blockade of semaphorin 4D breaks down stromal barriers to enhance tumoricidal immune infiltration, supporting rational immunotherapy combinations

Abstract Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer; increased expression correlates with poor prognosis. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the tumor microenvironment (TME), SEMA4D is expressed strongly at the invasive margin and modulates the infiltration and spatial distribution of leukocytes, suppressing anti-tumor activity. Neutralization of SEMA4D was evaluated for effects on immune activity and tumor growth in preclinical models, incorporating single agent and combination treatments with other immunotherapies, including immune checkpoint blockade inhibitors. The safety and tolerability of humanized anti-SEMA4D antibody VX15/2503 was assessed in a Phase I clinical trial. RESULTS: SEMA4D restricts migration of myeloid cells expressing cognate PLXNB1/2 receptors, determined using trans-well migration assays and IHC of in vivo tumors. Antibody neutralization disrupted the SEMA4D gradient at the invasive margin, which correlated with recruitment of activated APCs and T lymphocytes into the TME, and significant shift toward increased Th1 cytokines (IFNg, TNFa) and CTL-recruiting CXCL9 chemokine, with concurrent reduction in Treg- and M2-macrophage promoting chemokines (CCL2, CXCL1, CCL17). Accordingly, an increase in Teff:Treg ratio (3x, p&amp;lt;0.005) and CTL activity (4x, p&amp;lt;0.0001) was observed. This orchestrated change in the tumoral immune context was associated with durable tumor rejection and immunologic memory in preclinical colon, breast, and melanoma models. Importantly, the immunomodulatory activity of anti-SEMA4D antibody can be further enhanced by combination with other immunotherapies, including immune checkpoint inhibitors and chemotherapy. Strikingly, the combination with antibody to CTLA-4 acts synergistically, with maximal increase in survival (110% tumor growth delay, p&amp;lt;0.01) and complete tumor regression in 100% of mice, as compared to 22% with monotherapy (p&amp;lt;0.01). SEMA4D antibody treatment was well tolerated in nonclinical and clinical studies; including a Phase I multiple ascending dose trial in patients with advanced refractory solid tumors. Patients with the longest duration of treatment, 48-55 weeks, included colorectal, breast, and a papillary thyroid patient, who had a partial response by RECIST. Progression free survival strongly correlated with elevated baseline lymphocyte counts (r = 0.6133), supporting an immune mediated mechanism of action for VX15/2503. CONCLUSION: Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. A phase 1b/2 trial of combination therapy with an immune checkpoint inhibitor is planned. Citation Format: Elizabeth E. Evans, Holm Bussler, Sebold Torno, Crystal Mallow, Christine Reilly, Maria Scrivens, Ekaterina Klimatcheva, Laurie A. Winter, Renee Kirk, Alan Howell, Leslie Balch, John E. Leonard, Mark Paris, Terrence L. Fisher, Siwen Hu-Lieskovan, Antoni Ribas, Ernest S. Smith, Maurice Zauderer. Antibody blockade of semaphorin 4D breaks down stromal barriers to enhance tumoricidal immune infiltration, supporting rational immunotherapy combinations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4888.