Search

Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient's tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via 'crosstalk'). The 'molecular individuality' of these tumors suggests that a customized strategy, using an "N-of-One" model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors.

We evaluated clinical outcomes of patients with metastatic cervical cancer referred to a Phase I Clinical Trials Program.We reviewed the electronic medical records of 54 consecutive phase I patients with metastatic cervical cancer over 6.5 years and analyzed the correlation between clinical outcome and potential predictors.All patients had received at least one systemic therapy for metastatic disease before referral. Only two patients declined phase I trial therapy. The median progression-free (PFS) and overall (OS) survivals were 3.6 and 10.6 months, respectively. Patients harboring phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations or phosphatase and tensin homolog loss, and those with more than two sites of metastasis who received more than one prior systemic chemotherapy before the referral had median PFS of 6.7 and 1.8 months, and median OS of 12.6 and 2.9 months, respectively.Patients with more than two metastatic sites who had received more than one prior system therapy had dismal outcomes. An aberrant PI3K pathway was frequently identified and associated with favorable outcome, providing a promising target.

Background c-MET is a receptor tyrosine kinase whose phosphorylation activates important proliferation pathways. MET amplification and mutation have been described in various malignancies, including breast cancer (BC), and c-MET overexpression is associated with worse survival outcomes in patients with BC. We describe MET mutation and amplification rates in a BC cohort of patients referred to a Phase I Unit. Methods We reviewed the electronic medical records of all patients with advanced BC tested for MET amplification, mutation, or both who were referred to the Department of Investigational Cancer Therapeutics at MD Anderson. Results A total of 107 patients with advanced BC were analyzed for MET mutation/variant (88 patients) or amplification (63 patients). Of these, 49 were tested for both genetic abnormalities. Three of 63 patients (4.7%) demonstrated MET gene amplification by fluorescence in situ hybridization (2 in primary tissue; 1 in metastatic site). MET mutation/variant was detected in 8 of 88 patients (9%). High-grade tumors were characteristic of all patients harboring MET amplification and were present in 7 of 8 (87.5%) of those with MET mutation. Metastatic sites were greater in MET -amplified compared with wild-type patients (median of 7 vs. 3 sites). Five of 8 patients (62.5%) with MET mutations had triple negative BC compared with 46% in controls. In addition, patients with positive test results for MET aberrations (n = 11) had inferior overall survival (OS) from Phase I consult compared with wild-type patients (n = 37), although this was not statistically significant (median OS = 9 vs. 15 months, P = .43). Conclusions In this cohort of patients with BC who were referred to our Phase I Department, MET aberrations were associated with higher metastatic burden and high-grade histology. We could not demonstrate differences in survival outcomes because of a small sample size.

Background Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics. Methods We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials. Results There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors. Conclusion There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

We conducted this retrospective study to identify reasons that patients referred to a phase I clinical trial failed to enroll or delayed enrollment onto the trial.Outcome analyses were conducted independently on data collected from electronic medical records of two sets of consecutive patients referred to a phase I clinical trial facility at MD Anderson Cancer Center. Data from the first set of 300 patients were used to determine relevant variables affecting enrollment; data from the second set of 957 patients were then analyzed for these variables.Results from the two sets of patients were similar. Approximately 55% of patients were enrolled in a phase I trial. Patients referred from within MD Anderson were more likely to be enrolled than patients seen originally outside the institution (p = .006); black patients were more likely than white patients to enroll (69% vs. 43%; p = .04). The median interval from the initial visit to initiation of treatments was 19 days. Major reasons for failure to enroll included failure to return to the clinic (36%), opting for treatment in another clinic (17%), hospice referral (11%), early death (10%), and lack of financial clearance (5%). Treatment was delayed for three weeks or more in 250 patients; in 85 patients (34%), the delay was caused by financial and insurance issues.Failure to return to the clinic, pursuit of other therapy, and rapid deterioration were the major reasons for failure to enroll; lengthy financial clearance was the most common reason for delayed enrollment onto a phase I trial.

// Gerald S. Falchook 1 , Aung Naing 1 , David S. Hong 1 , Ralph Zinner 1 , Siqing Fu 1 , Sarina A. Piha-Paul 1 , Apostolia M. Tsimberidou 1 , Sonia K. Morgan-Linnell 1 , Yunfang Jiang 1 , Christel Bastida 1 , Jennifer J. Wheler 1 , and Razelle Kurzrock 2 1 Department of Investigational Cancer Therapeutics (Phase I Program), U.T. MD Anderson Cancer Center, Houston, TX 2 Moores Cancer Center at the University of California, San Diego Correspondence: Gerald Falchook, email: // Keywords : Erlotinib, Cetuximab, Bevacizumab, EGFR, VEGF Received : December 06, 2012, Accepted : January 12, 2013, Published : January 14, 2013 Abstract BACKGROUND: Preclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models. METHODS: We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response. RESULTS: Thirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p

Summary Background TAS-106 was designed to inhibit RNA synthesis by blocking RNA polymerases I, II, and III. Methods This was a single-center, open-label, phase I study to identify the maximum tolerated dose (MTD), pharmacokinetics, and biologic effects of the combination of TAS-106 and carboplatin, following a standard 3 + 3 design. This phase I trial was comprised of a regimen of a 60-min IV infusion of carboplatin on day 1 of each 21-day cycle followed by a 24-h infusion of TAS-106, also on day 1 of each cycle. Results 39 patients were treated (21 male, 18 female, median age 62 years, range 21–80 years). Median number of prior therapies was 4. Maximum Tolerated Dose (MTD) was 3 mg/m2 TAS-106 with AU 4 carboplatin. Dose-limiting toxicities were neutropenia and thrombocytopenia, with and without growth factor support. While no patients achieved a complete or partial response, four patients had stable disease lasting ≥4 months, including one patient each with ovarian, non-small cell lung, basal cell and colorectal cancer. Conclusions In summary, the combination of TAS-106 and carboplatin was well-tolerated, and further studies in non-small cell lung and ovarian cancer are warranted to assess the efficacy of this drug combination.

3054Background: Imatinib mesylate can induce rapid tumor regression, inhibit tumor immunosuppressive mechanisms, and release large amounts of antigenic debris from tumor cell death with subsequent ...

2550Background: BPM 31510 targets the metabolic machinery of cancer cells to reverse the Warburg effect. The current study evaluates BPM 31510 as a 6-day continuous infusion as a single agent and i...

11057Background: Pazopanib is approved for treatment of advanced soft tissue sarcomas; however, all patients ultimately develop resistance to therapy. The mechanisms of resistance can include activ...

In previous work we found that bovine brain hsp70 has a single binding site for nucleotide, and that, with ATP at this site, the rates of association and dissociation of clathrin from hsp70 are fast, whereas with ADP at this site, these rates are unmeasurably slow. In the present study we show, first, that peptide C, cytochrome c peptide, and RNase S peptide bind competitively with clathrin, suggesting that they bind to the same site on hsp70, although RNase S peptide binds an order of magnitude more weakly than peptide C and cytochrome c peptide. Second, we show that, with ADP bound to hsp70, as occurs with clathrin, the rate constant for dissociation of peptide markedly decreases compared to the rate constant observed in ATP. In contrast, ADP only slightly decreases the rate of association of peptide. Based on these data we propose a model in which substrates of hsp70 bind to and dissociate from the ATP form of the enzyme, while, following ATP hydrolysis, they are locked onto the ATP form of the enzyme, unable to dissociate until ADP is released and ATP rebinds.

Background. The outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated in phase I clinical trials have not been systematically analyzed. Methods. We reviewed the records of consecutive patients with advanced/metastatic NSCLC who were treated in the Phase I Clinical Trials Program at MD Anderson from August 2004 to May 2009. Results. Eighty-five patients (51 men, 34 women) treated on various phase I protocols were identified. The median age was 62 years (range, 30–85). The median number of previous systemic therapies was two (range, 0–5). A partial response was observed in eight patients (9.5%) and stable disease lasting >4 months was observed in 16 patients (19%). The median overall survival time was 10.6 months and median progression-free survival (PFS) time was 2.8 months, which was 0.6 months shorter than the median PFS of 3.4 months following prior second-line therapy. Factors predicting longer survival in the univariate analysis were an Eastern Cooperative Oncology Group performance status (PS) score of 0–1, no prior smoking, two or fewer organ systems involved, a hemoglobin level ≥12 g/dL, liver metastases, a history of thromboembolism, and a platelets count > 440 × 109/L. In the multivariate analysis, a PS score of 0–1 and history negative for smoking predicted longer survival. Sixty-two (73%) patients had grade ≤2 toxicity, and there were no treatment-related deaths. Conclusion. Phase I clinical trials were well tolerated by selected patients with advanced NSCLC treated at M.D. Anderson. Nonsmokers and patients with a good PS survived longer. PFS in our population was shorter in smokers/ex-smokers and patients with a PS score of 2. It is reasonable to refer pretreated patients with a good PS to phase I clinical trials.

Introduction Recent phase III studies in advanced non–small-cell lung cancer (NSCLC) have demonstrated differential efficacy for pemetrexed according to NSCLC histology. The results of 2 phase II studies of pemetrexed and a platinum agent (carboplatin or oxaliplatin) were pooled to determine whether outcomes in the studies differed by tumor histology. Patients and Methods Chemotherapy-naive patients with stage IIIB/IV NSCLC received pemetrexed 500 mg/m 2 plus carboplatin area under the curve of 6 (n = 89) or pemetrexed 500 mg/m 2 plus oxaliplatin 120 mg/m 2 (n = 41); both regimens were administered every 21 days. The primary endpoint of both trials was response rate. Treatment arms were pooled, and Cox models with main effects for squamous histology were used to assess overall survival and progression-free survival. Cofactor adjustments incorporated terms for performance status, disease stage, and sex. Results More than three quarters of enrolled patients had a nonsquamous histology. Mean age was 59.9 years for patients with nonsquamous histology and 63.7 years for patients with squamous histology. Response rates were 30% for patients with nonsquamous histology and 17.2% for patients with squamous histology. Overall survival was 10.5 months for patients with nonsquamous histology and 9.8 months for patients with squamous histology (hazard ratio [HR], 0.95; 95% CI, 0.52-1.74). Progression-free survival was 5.6 months for patients with nonsquamous histology and 4.7 months for patients with squamous histology (HR, 0.72; 95% CI, 0.43-1.19). Conclusion In patients treated with pemetrexed/platinum doublets, nonsquamous histology was associated with better outcomes. The benefit of pemetrexed treatment among patients with nonsquamous histology is consistent with the results reported from previous studies.

Purpose To evaluate the efficacy and toxicity of pemetrexed combined with bevacizumab as second-line therapy for patients with advanced non–small-cell lung cancer (NSCLC) and to correlate allelic variants in pemetrexed-metabolizing genes with clinical outcome. Patients and Methods Patients with previously treated NSCLC received pemetrexed (500 mg/m2 intravenous) combined with bevacizumab (15 mg/kg intravenous) every 3 weeks. The primary end point, evaluated using a one-stage Fleming design for detecting a true success rate of at least 70%, was the proportion of patients who were progression free and on treatment at 3 months. Polymorphisms in genes responsible for pemetrexed transport (reduced folate carrier [SLC19A1]) and metabolism (folylpolyglutamate synthase [FPGS] and gamma-glutamyl hydrolase [GGH]) evaluated in germline DNA (blood) were correlated with treatment outcome. Results Forty-eight evaluable patients (14 females and 34 males) received a median of four cycles (range, one to 20 cycles). The most common grade 3 or 4 nonhematologic adverse events (AEs) were fatigue (13%), dyspnea (10%), and thrombosis (10%). Grade 3 or 4 hematologic AEs were neutropenia (19%) and lymphopenia (13%). Twenty-four (57%; 95% CI, 41% to 72%) of the first 42 patients met the success criteria. Median overall survival (OS) and progression-free survival (PFS) times were 8.6 and 4.0 months, respectively. The exon 6 (2522)C→T polymorphism in SLC19A1 correlated with 3-month progression-free status (P = .01) and with PFS (P = .05). The IVS1(1307)C→T polymorphism in GGH correlated with OS (P = .04). Conclusion The study did not meet its primary end point. However, the median PFS time of 4 months is promising. Pharmacogenetic studies in larger cohorts are needed to definitively identify polymorphisms that predict for survival and toxicity of pemetrexed.

Purpose To assess the pharmacokinetics and evaluate potential drug-drug interactions between erlotinib, paclitaxel and carboplatin. Experimental Design 1,079 previously untreated patients with advanced NSCLC were enrolled and randomized in a phase III trial (TRIBUTE) to receive either erlotinib or placebo in combination with paclitaxel 200 mg/m2 IV over 3 h and carboplatin at a calculated dose to achieve an AUC 6 mg∙min/mL. To determine possible drug-drug interaction with this combination, a subset of 24 (12 erlotinib, 12 placebo) patients were enrolled onto an intensive pharmacokinetic (IPK) substudy group at a single site. All IPK patients received either erlotinib 150 mg/day or placebo-controlled tablets. Analyses were completed using validated analytical methodologies. Non-compartmental modeling was utilized to estimate PK parameters. Results Complete blood sampling for pharmacokinetic analysis was obtained in 21 of 24 patients. Mean \( {\hbox{AU}}{{\hbox{C}}_{0 - \tau }} \) for erlotinib and the OSI-420 metabolite were 29,997 ng∙h/mL and 3,020 ng∙h/mL, respectively. Mean (SD) paclitaxel clearances (L/h/M2) were 11.7 (3.4) and 12.7 (6.7) in the placebo and erlotinib treatment groups, respectively. The resultant paclitaxel \( {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} \) (ng∙h/mL) was 18,400 (5,300) for the placebo group and 17,800 (5,500) for the erlotinib group. For carboplatin, the mean (SD) clearances (L/h) were 16.8 (3.9) and 16.1 (4.4) for the placebo and erlotinib groups, respectively. The resultant carboplatin \( {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} \) (ng/mL∙h) were 49,900 (9,700) for the placebo group and 48,400 (11,900) for the erlotinib group. No significant differences were observed in these paclitaxel or carboplatin pharmacokinetic group comparisons. Conclusions The addition of erlotinib to a standard chemotherapy regimen for NSCLC did not alter the systemic exposures (\( {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} \)) of paclitaxel (p = 0.80) and carboplatin (p = 0.756) when erlotinib-treated patients were compared to placebo-treated patients. The pharmacokinetics of erlotinib and its metabolite OSI-420 did not appear to be altered by the concomitant administration of paclitaxel and carboplatin.

The Abstract is incorrect in PubMed. The corrected Abstract is provided here.

Background: Patients with advanced carcinoma of unknown primary (CUP) have limited effective therapeutic options given the challenges of phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conduct an ongoing exploratory analysis of next-generation sequencing (NGS) of relapsed, refractory CUP. Methods: We identified CUP patients referred to our phase I clinic with adequate FFPE sections from archival tissue for a targeted CLIA-certified NGS assay (Foundation One, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Of 19 patients seen (10 male, 9 female; median age at diagnosis 49 years), 17 demonstrated genomic alterations (median 3 aberrations/tumor, range 0 - 10); two patients had no reportable genomic alterations. Of the 71 detected aberrations, 17 (24%) have been implicated in impaired cell cycle regulation and arrest; specifically in genes which encode the cyclin-dependent kinases (CDK12 Q570*, CDKN2A/B loss, CDKN2A p16INK4a loss and p14ARF exon 2-3 loss) or their associated proteins including amplification of CCND1 and CCNE1 (n = 3). Of these 8 patients with impaired cell cycle regulation, 5 (63%) demonstrated concurrent mutations associated with epigenetic deregulation and impaired DNA methylation, most commonly ARID1A Y1211fs*5 and S1929fs*25, which encodes the AT-rich interactive domain-containing protein 1A, Arid1a, a member of the SWI/SNF chromatin remodeling complex); other mutations observed are CREBBP S893L (encoding a ubiquitously expressed transcriptional coregulatory protein controlling chromatin remodeling via its histone acetyltransferase activity); MLL2 R4904* (encoding an H3K4-specific histone methyltransferase) and KDM6A S466* (encoding the histone H3 lysine 27 demethylase UTX). Overall 5 of 19 (26%) patients with advanced relapsed CUP demonstrated a profile of aberrations that concurrently impact cell cycle arrest and epigenetic regulation. Conclusion: Through NGS-based molecular profiling, we can a subset of patients with advanced carcinoma of unknown primary with coexisting mutations leading to impaired cell cycle arrest and epigenetic deregulation, highlighting a therapeutic combination with a cell cycle inhibitor (such as Cdk4/6 inhibitors currently in clinical trial) and histone deacetylase inhibitors. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Gauri Varadhachary, Apostolia M. Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Filip Janku, Sinchita Roy Chowdhuri, Ralph Zinner, David S. Hong. Impaired cell cycle arrest with concurrent epigenetic deregulation identified through next generation sequencing in patients with advanced carcinoma of unknown primary: Implications for personalized medicine. [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 604. doi:10.1158/1538-7445.AM2015-604

Background: BRAF inhibitors are effective in advanced melanoma and other cancers with BRAF V600mutations; however, patients ultimately develop therapeutic resistance through activation of alternative signaling pathways such as HGF/MET, PDGFR and CRAF. We hypothesized that combining the BRAF inhibitor vemurafenib and MET inhibitor crizotinib or PDGFR/CRAF inhibitor sorafenib can increase efficacy by overcoming intrinsic and acquired resistance. Methods: We designed a phase I study (3+3 design) to determine the safety of vemurafenib (240-960 mg PO BID q 28 days) with crizotinib (250 mg PO daily or BID q 28 days) in arm A or sorafenib (200 mg PO daily to 400mg PO BID q 28 days) in Arm B in patients with BRAF-mutant advanced cancers. Endpoints included maximum tolerated dose (MTD), dose limiting toxicities (DLT), safety, response (RECIST 1.1) and plasma cell-free DNA mutation analysis. Results: To date, 29 patients (Arm A, n = 11, vemurafenib 240-960mg PO BID with crizotinib 250mg PO daily; Arm B, n = 18, vemurafenib 240-720mg PO BID with sorafenib 200 mg PO BID to 400/200 mg PO), median age of 53 (33-76) years; median number of 3 (1-5) prior therapies including 22 (76%) patients with prior BRAF or MEK inhibitors were treated. Patients (melanoma 17/29, 59%; papillary thyroid cancer 4/29, 14%; colorectal cancer 3/29, 10%; lung adenocarcinoma 2/29, 7%; other 3/29, 10%) had BRAF V600E (n = 24), V600K (n = 3) or other BRAF mutations (n = 2). The MTDs have not been reached and no DLTs have been observed. Significant drug related toxicities included grade (G) 3 thrombocytopenia (n = 1) in arm A and G3 hypertension (n = 1), G3 headache (n = 1), G3 diarrhea (n = 1) in Arm B. In Arm A, 3 of 11 (27%) patients (melanoma refractory to BRAF monotherapy, -40% for 7.9 months; melanoma refractory to BRAF monotherapy, -36% for 6.0+ months and lung adenocarcinoma, -50% for 13.9 months) attained a partial response (PR) and 1 (9%) patient (melanoma refractory to MEK inhibitor, +3% for 12.5 months) with stable disease (SD) > 6 months. In Arm B, 3 of 18 (17%) patients (melanoma, -46% for 7.6 months; lung adenocarcinoma, -61% for 7.3 months and ovarian cancer refractory to MEK inhibitor, -50% for 18.7 months) attained a PR and 3 (17%) patients (papillary thyroid refractory to MEK inhibitor, -10% for 28.4 months; papillary thyroid cancer refractory to BRAF inhibitor, -6% for 7.3+ months and melanoma refractory to BRAF monotherapy -8% for 7.5 months) attained SD > 6 months. In patients with longitudinal assessment of plasma cfDNA changes in the amount of BRAF mutant DNA corresponded with clinical course (data will be presented). Conclusions: Preliminary data suggest that vemurafenib in combination with crizotinib or sorafenib are well tolerated with encouraging activity in patients previously treated with BRAF or MEK inhibitors. Citation Format: Shumei Kato, Aung Naing, Gerald Falchook, Veronica R. Holley, Vivianne M. Velez-Bravo, Sapna Patel, Ralph G. Zinner, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, David S. Hong, Razelle Kurzrock, Funda Meric-Bernstam, Filip Janku. Overcoming BRAF/MEK resistance using vemurafenib with crizotinib or sorafenib in patients with BRAF-mutant advanced cancers: phase I study. [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 2689. doi:10.1158/1538-7445.AM2015-2689

Background: Relapsed refractory colorectal adenocarcinoma (CRC) is evolving as a disease with distinct molecular subsets rather than a singular histology. Given the varied outcomes of CRC patients treated on clinical trials particularly with targeted therapies, we aimed to identify a molecular phenotype for future therapeutic targeting. Methods: We identified CRC patients referred to our Phase I clinic with adequate tissue for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Overall, 60 relapsed CRC patients (31 male, 29 female; median age 55 years; 56 colon primary, 4 rectum primary). 48 (80%) patients had a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 43 pts, 90%). Of these 48 patients, over half (n = 26, 54%) demonstrated a concurrent mutation affecting the PI3K cascade (PIK3CA in 12 patients [4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K, 1 R38C]). Of these 26 pts with concurrent aberrant Wnt and PI3K pathways, 22 also demonstrated a concomitant MAPK pathway mutation (17 KRAS and 3 BRAF). Of the 60 CRC pts overall, 22 (37%) patients had coexisting aberrations linked to in all three (Wnt, PI3K, and MAPK) cascades. Conclusions: Concomitant mutations in three pathways (Wnt, MAPK, PI3K) implicated in cancer occur frequently in patients with advanced CRC, emphasizing the need for a combinatorial therapeutic strategy ideally targeting all three cascades. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Filip Janku, Apostolia M. Tsimberidou, Aung Naing, Vivek Subbiah, Jennifer J. Wheler, Ralph Zinner, Cathy Eng, Michael J. Overman, Scott Kopetz, David S. Hong. Concurrent aberrations in the Wnt, MAPK and PI3K pathways identified through next generation sequencing of relapsed refractory colorectal adenocarcinoma (CRC): Implications for future therapeutic trials. [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 4263. doi:10.1158/1538-7445.AM2015-4263

Background: BRAF V600 mutations are prevalent in diverse cancers and can be targeted with BRAF inhibitors. Cell-free (cf) DNA from plasma offers an easily obtainable material for BRAF mutation analysis. Methods: cfDNA from plasma samples of patients with advanced cancers or malignant histiocytosis with known BRAF V600 status from formalin-fixed paraffin-embedded (FFPE) tumor samples, who progressed on systemic therapy was purified and 50-100ng were used for BRAF V600 mutations testing using the Idylla fully integrated real-time PCR-based platform (Biocartis, Mechelen, Belgium) with a quick turnaround time (< 60 minutes). Results were compared to mutation analysis of FFPE primary or metastatic tumor tissue obtained at different points of clinical care from a CLIA-certified laboratory. Results: cfDNA was extracted from plasma samples of 160 patients with advanced cancers (colorectal, n = 62; melanoma, n = 36; non-small cell lung, n = 13; breast, n = 10; thyroid, n = 10; appendiceal, n = 5; ovarian, n = 4; endometrial, n = 4; other cancers, n = 16). BRAF mutations were detected in 29% (47/160) of plasma samples and in 39% (62/160) of FFPE tumor samples, resulting in concordance in 141 cases (88%, kappa = 0.74, 95% confidence interval [CI] 0.63- 0.85) with sensitivity 73%, specificity 98%, positive and negative predictive value 96% and 85%, respectively. In addition, 35 (22%) patients had sequential plasma samples collection while on therapy including 9 of 17 patients, who had BRAF V600 mutation in FFPE but not in plasma at baseline. Of interest, in 3 of these 9 patients BRAF V600 mutation emerged in plasma later in the course of disease. If these 3 patients are included in the concordance analysis the overall agreement between testing modalities is 144 cases (90%, kappa 0.78, SE 0.05, 95% CI 0.68-0.88) with sensitivity 77%, specificity 98%, positive and predictive value 96% and 87%, respectively. In 15 of 19 discrepant cases identical plasma cfDNA samples were tested using an alternative cfDNA BRAF mutation PCR-based method (BEAMing, Sysmex Inostics, Baltimore, MD), which yielded 100% agreement with the Idylla. Longitudinally collected plasma samples were available in 16 patients with plasma and FFPE BRAF V600 mutations treated with predominantly BRAF targeting combinations. Changes in the amount of BRAF-mutant cfDNA corresponded with changes in serum tumor markers and disease burden visualized via imaging. Conclusions: Detecting BRAF V600 mutations in plasma cfDNA using the Idylla platform is a fast and noninvasive alternative to mutation testing of tumor tissue with an acceptable level of concordance and should be investigated further for testing and monitoring of BRAF mutation status in patients with cancer. Citation Format: Filip Janku, Helen J. Huang, Bart Claes, Gerald S. Falchook, Siqing Fu, Apostolia M. Tsimberidou, David S. Hong, Aung Naing, Jennifer J. Wheler, Sarina A. Piha-Paul, Daniel D. Karp, Vivek Subbiah, Ralph G. Zinner, Nishma Ramzanali, Rajyalakshmi Luthra, Sapna P. Patel, E. Scott Kopetz, Erwin Sablon, Geert Maertens, Razelle Kurzrock, Funda Meric-Bernstam. Rapid, automated BRAF mutation testing of cell-free DNA from plasma of patients with advanced cancers using the novel Idylla platform. [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 2413. doi:10.1158/1538-7445.AM2015-2413

Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to create a hallmark shift from lactate dependency towards mitochondrial oxidative phosphorylation, reversing the Warburg effect. Preclinical data indicates Ubidecarenone causes this shift resulting in tumor regression and enhances the antitumor activity in combination with chemotherapy agents in a priming schedule. This is the first clinical study to evaluate the BPM 31510 at a 4-days continuous infusion in four arms; as a single agent, and in combination with Gemcitabine, 5-FU or Docetaxel. Methods: Eligible patients (pts) (aged ≥18 y) had previously treated relapsed/refractory solid tumors. Pts in the monotherapy arm received IV BPM 31510 for 4 days in continuous infusion in 28-d cycles. Patients in the combination arms were primed for 3 weeks with BPM 31510 and then started in a weekly dosing (either gemcitabine, 5-FU or docetaxel) after the BPM 31510 infusion in a 6-week cycle. Doses were escalated in a 3+3 schema. Phase I endpoints were safety, pharmacokinetics (PK) and Multi-Omics based pharmacodynamics (PD). Dose limiting toxicities (DLTs) are determined using Cycle 1 safety data. Tumor response is evaluated at week 2 and every 4 -6 weeks. Results: As of 01 Dec 2014, 56 pts with advanced solid tumors have been enrolled. Pts have been treated at 3 dose levels up to 137 mg/kg of BPM 31510. No DLTs or study treatment-related SAEs have been reported. The MTD has not yet been established. The most frequently reported related AEs in all 4 arms were grade 1-2 INR prolongation that was resolved after Vitamin K administration. Pre-load of pts with Vitamin K have resolved these events. No bleeding reported. Grade 1-2 thrombocytopenia has been seen in the Gemcitabine arm requiring dose modification. Preliminary PK data indicated linear distribution. Tmax and Cmax are associated with the end of the infusion. Twelve out of twenty five patients (48%) that are evaluable for efficacy after cycle 2 showed various responses including: tumor reductions, decrease FDG, arrested tumor progression, stable disease, decrease in tumor markers, clinical improvements reflected on QOL. Conclusions: Emerging data from this study suggest that BPM 31510 is well tolerated in monotherapy or in combination with chemotherapy agents. Early anti-tumor activity is seen. Dose-escalation on a 6-day infusion schedule is ongoing to determine the recommended phase II dose. Citation Format: Manish A. Shah, Peter Yu, Niven Narain, Rangaprasad Sarangarajan, Michael Kiebish, Vivek Vishnudas, Yezhou Sun, Leonardo Rodrigues, Viatcheslav R. Akmaev, Susan Brouwer, Janice Stevens, Ely Benaim, Ralph Zinner. Phase I study of BPM 31510 (ubidecarenone) 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 CT315. doi:10.1158/1538-7445.AM2015-CT315

11019 Background: With the paradigm shift to precision medicine, we hypothesized that matching patients to therapy based on molecular profile could significantly improve outcomes. Methods: Archival...

105 Background: Although BRAF inhibitors have demonstrated efficacy, resistance develops in most pts. We hypothesized that BRAF inhibitor vemurafenib, in combination with carboplatin and paclitaxel...

2539 Background: BPM 31510 is a small molecule that targets the metabolic machinery of the cancer microenvironment to create a hallmark shift from lactate dependency towards mitochondrial oxidative...

9624 Background: Limited data exist about sleep quality (SQ) in patients (pts) on phase 1 clinical trials. Poor SQ is often not captured as an adverse event (AE) and its association with fatigue, o...

TPS2617 Background: Cancer cells deficient in BRCA1/2 and other components of the homologous recombination repair pathway are selectively sensitive to the double stranded DNA breaks whose repairs a...

3511 Background: BRAF V600 mutations, present in 5-10% of patients (pts) with metastatic colorectal cancer (mCRC), are poor prognostic markers and are associated with a low response to the combinat...

4072 Background: CC is an aggressive disease with a dismal prognosis and no clear therapy in the refractory setting. Mek inhibition and anti-angiogenic therapies have shown modest activity in advan...

2597 Background: Although C and D both demonstrate activity resistance can develop. Preclinical studies demonstrated that activation of MET requires c-SRC. We hypothesized that a c-SRC inhibitor (D...

2584 Background: Preclinical models suggest synergistic anticancer activity of histone deacetylase (HDAC) and mTOR inhibitors by reducing activity of AKT/mTOR and HDAC. Methods: This is a phase I s...

3608 Background: We initiated a prospective, institution-wide study to determine whether genomic testing with a 409-gene panel in solid tumors can identify new actionable genomic information (beyon...

Background: Intratumoral injection of Clostridium novyi-NT (attenuated strain of Clostridium) induced a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model and in companion dogs bearing spontaneous solid tumors. Furthermore, intratumoral injection can plausibly induce an immune mediated abscopal effect in non-injected tumor sites. Methods: A standard 3 + 3 dose escalation Phase 1 study of a single intratumoral injection of C.novyi-NT was designed to determine the DLTs, MTD and preliminary activity in adult patients with advanced cancers and superficially located tumors (1-12 cm in size). The SOFA score and temperature are used to guide antibiotic usage. Results: To date, a total of 5 patients (women, n = 3; men, n = 2) with advanced sarcomas (leiomyosarcoma, n = 2; chondrosarcoma, n = 1; carcinosarcoma, n = 1; angiosarcoma, n = 1), median age 54 years, have received an intratumoral injection of 1 x104 (n = 3) and 3 x104 spores (n = 2). Evidence of germination has been noted in 3 patients and has consisted of pain in the injected tumor, fever, elevated WBC with a left shift, an elevated C-reactive protein, and necrosis and gas pockets in the injected tumor on radiographic imaging. Treatment-related grade 3 adverse events include leukocytosis, pathologic fracture, pain and respiratory insufficiency. The most significant morbidity was observed in a patient with a large volume of tumor destruction leading to a pathologic fracture of the necrotic right proximal humerus, which required an aggressive orthopedic surgical procedure. Of note histopathology demonstrated extensive tumor necrosis with small foci of residual tumor cells during surgery. Two patients had between 22-24% shrinkage in the injected tumor and an overall response of stable disease at 2 months. Because exploratory cytokine analysis suggests the potential for a systemic response and because abscopal responses were seen in the companion dog studies, the clinical protocol has been amended to include biopsies of both injected and non-injected tumors pre and post C.novyi-NT injection. Conclusions: Intratumoral injection of Clostridium novyi-NT is feasible and has lead to significant destruction of injected tumor masses in the first two doses studied.

320 Background: Pancreatic cancer is a disease that generally presents in advanced stage and is nearly fatal in all cases. In 2011, we reported our experience with pancreatic cancer patients enrolled on phase 1 clinical trials from 2004-2009. At the time, gemcitabine and erlotinib were the only US FDA approved drugs for pancreatic cancer. Median overall survival from presentation in the phase 1 clinic was 5 months. After an additional 5 years of progress, we queried the impact of novel cancer therapeutics, evolving molecular profiling, and targeted therapy on pancreatic cancer patient outcomes in the phase 1 setting. Methods: A retrospective review of advanced pancreatic adenocarcinoma patients from the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, was conducted for patients treated from 1/2009 to 1/2014. Statistical analyses utilized the Kaplan-Meier method. Results: A total of 90 patients were identified in 50 trials reviewed. Median age was 62 years (40-84), 57% were male, and 40% had stage IV disease at presentation. Median documented PS was 1 (range 0-3). The median time from diagnosis to treatment on a phase I protocol was 15 months (0.2-119). Patients were treated with an average of 4 prior regimens prior to Phase 1 referral (0-10) with 8% having undergone >5 treatments. The median overall survival from the first phase I treatment was 5.2 months, 95% CI = (4.4-6.3) and the 1 year overall survival from the first phase 1 treatment was 15% (9%- 25%). The median duration on regimen with best phase I response was 1.9 months (0.2-21.3). Of 88 evaluable, the best responses were PR in 1 patient and SD (> 6 months) in 5 patients. Although 47 patients had biomarker profiling performed and 61 patients were treated with targeted therapy alone or in combination with cytotoxic therapy, only 6 patients (5 PD, 1 SD currently on protocol) were placed on trials based on biomarker testing results. Conclusions: Pancreatic cancer remains a difficult disease to treat with poor outcome. Referral to phase 1 occurs late in the disease course. Biomarker based therapies may be more successful with more stringent patient selection and when referred earlier or used prior to cytotoxic treatment.

605 Background: Advanced relapsed colorectal adenocarcinoma (CRC) is emerging as a cancer not with a singular phenotype but rather as a multitude of ‘diseases’ subdivided based on its molecular genotype. Given the heterogeneity in outcomes of CRC patients on targeted therapy clinical trials, we sought to identify a unique molecular subset within this disease. Methods: To that end, we identified advanced CRC patients in our Phase I clinic on whom adequate tissue was available for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: We identified 51 patients with advanced relapsed CRC (26 male, 25 female; median age 54 years; 49 colonic primary lesion, 4 rectum primary). Overall, 44 (86%) harbored a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 40 pts, 78%). Of these 44 patients, half (n=22, 50%) had ≥1 concurrent mutation affecting the PI3K/AKT/MTOR pathway, most commonly PIK3CA in 11 patients (4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K). Furthermore, 20 of these 22 pts with both Wnt and PI3K pathway mutations also demonstrated a concomitant MAPK pathway abnormality, most commonly KRAS (n=16) and 3 BRAF (V600E, G466R, D594G). Overall 20 of 51 (39%) patients had coexisting mutations implicated in all three signaling pathways (Wnt, PI3K, and MAPK). Conclusions: Three prominent pathways linked to the continuum of development and progression of cancer (Wnt, MAPK, PI3K) occur frequently in concurrence in patients with advanced CRC, thereby highlighting the role for an innovative therapeutic combination targeting all three pathways.

Background The primary objective of this retrospective study was to investigate the potential role of East Asian ethnicity or origin in predicting response to gefitinib in advanced-stage non–small-cell lung cancer (NSCLC). Patients and Methods A chart review was done of all patients treated with gefitinib at M. D. Anderson Cancer Center on the Expanded Access Program. Results There were 223 patients with advanced-stage NSCLC who were enrolled. Of these, 182 received ≥ 1 dose, and 160 were evaluable for response. The partial response rate was 8.8%, and the stable disease rate was 26.3%. Median time to progression was 2.5 months, and median survival was 6.8 months. The 1- and 2-year survival rates were 35.3% and 12.4%, respectively. Partial responses were seen in 7 of 12 patients (58.3%) of East Asian origin compared with 7 of 131 patients who were white (5.3%). This difference was statistically significant when controlling for histology, smoking status, hemoglobin, and diarrhea. Never smoking and diarrhea were also independent predictors of response. Conclusion For the first time, in a multivariate analysis, we observed a positive relationship between East Asian origin and response to gefitinib. These findings might help determine which patients will likely benefit from gefitinib.

Pemetrexed is a novel multitargeting antimetabolite that has first-line and second-line activity against non-small cell lung cancer (NSCLC). Phase II studies have shown significant efficacy and a favorable toxicity profile of the combination of pemetrexed plus platinum as first-line therapy for NSCLC. Second-line activity against NSCLC was demonstrated in a phase III trial comparing single-agent pemetrexed with docetaxel; in that trial, survival was comparable between these agents but side effects were significantly less for patients who received pemetrexed. Pemetrexed is also an active agent against mesothelioma. A phase III trial comparing pemetrexed plus cisplatin with cisplatin alone showed for the first time a regimen that improves survival in this disease and led to FDA approval of pemetrexed in combination with cisplatin for mesothelioma. As a radiosensitizer, pemetrexed has been well-tolerated when given concurrent with chest radiation, and a phase I study is under way assessing its tolerability in combination with carboplatin in this setting. Pemetrexed is clearly a useful agent in the treatment of thoracic malignancies, and is worthy of further study in combination with other drugs having novel mechanisms of action.

The purpose of this study was to evaluate the feasibility, efficacy, safety, and pharmacokinetics of trastuzumab plus cisplatin and gemcitabine in patients with Her2-overexpressing stages IIIB or IV non-small cell lung cancer (NSCLC) and to study the relationship between results from the two methods for determining levels of Her2 overexpression. Chemonaive patients were eligible if they had stages IIIB or IV NSCLC with either a Her2 score of at least 1+ by immunohistochemical (IHC) analysis or a serum Her2 shed antigen level of at least 15 ng/ml by enzyme-linked immunosorbent assay (ELISA). Treatment consisted of cisplatin 75 mg/m(2) day one plus gemcitabine 1250 mg/m(2) days one and eight plus trastuzumab 4 mg/kg day one and 2 mg/kg weekly thereafter on a 21-day cycle for six cycles followed by weekly maintenance trastuzumab therapy. Of the 21 patients enrolled, 8 (38%) patients had a partial response. The 1-year survival rate was 62% (13/21). Median time to progression was 36 weeks. Pharmacokinetic studies revealed no interaction between trastuzumab and gemcitabine plus cisplatin. In patients screened for this study, Her2 expression was zero in 283/360 (79%); 1+ in 32/360 (9%); 2+ in 27/360 (8%); and 3+ in 18/360 patients (5%). Serum Her2 shed antigen was15 ng/ml in 27/ 288 (9%) patients. Of patients who had both Her2 assays, 24% (4/17) with ELISA scores15 ng/ml had IHC scores of 3+, compared with only 2% (3/145) of the patients15 ng/ml and 4% (7/162) of all patients. The addition of trastuzumab to cisplatin and gemcitabine was well tolerated, but further study will be required to determine whether this combination is superior to chemotherapy alone. This may be demonstrated if only those patients with Her2, having a score of IHC 3+ were eligible. Since IHC 3+ is rare in NSCLC, performing IHC in only those patients with serum Her2 shed antigen15 ng/ml would greatly increase the efficiency of IHC screening though at the cost of excluding nearly half the patients with Her2 scores of 3+ on IHC analysis. Thus, if sequential screening consisting of serum ELISA followed by IHC analysis is implemented, it may make a trastuzumab trial feasible but should ultimately be supplanted by another screening system if trastuzumab is shown to be beneficial to some patients with IHC Her2 scores of 3+.

The overexpression of HER2, a transmembrane glycoprotein tyrosine kinase, has been implicated in mitogenesis, cell survival, invasion and angiogenesis. Preclinical evidence suggests that HER2 overexpression contributes to tumor progression in non-small cell lung cancer (NSCLC) and retrospective clinical correlative studies show that it is probably associated with poor clinical outcome. Trastuzumab (Herceptin, Genentech Inc., South San Francisco, CA) is a recombinant humanized monoclonal antibody that targets HER2 and is currently approved for use in the treatment of patients with HER2-overexpressing metastatic breast cancer. Two primary mechanisms proposed for the activity of trastuzumab are downregulation of HER2 and induction of antibody-dependent cell-mediated cytotoxicity. Evidence from preclinical studies of trastuzumab in NSCLC and other cell lines, the presence of HER2 overexpression in NSCLC clinical specimens and the clinical benefit derived from trastuzumab in phase II and III metastatic breast cancer trials have led to the development of clinical trials of trastuzumab in NSCLC. Phase II studies of trastuzumab in patients with stage IIIB or IV NSCLC are being conducted to test the efficacy of trastuzumab as a single agent or in combination with chemotherapy. Preliminary results show combinations of chemotherapy plus trastuzumab are well tolerated, with encouraging response rates of 21-40%. A randomized phase II trial of chemotherapy with or without trastuzumab showed promise in a small subgroup of patients with 3+ HER2 overexpression by immunohistochemistry or HER2 DNA amplification by fluorescence in situ hybridization. Taken together, these data indicate that trastuzumab warrants further investigation in a clinical study in selected patients with NSCLC.

A prospective randomized study was conducted to determine whether amifostine (Ethyol) reduces the rate of severe esophagitis and hematologic and pulmonary toxicity associated with chemoradiation or improves control of non-small cell lung cancer (NSCLC). Sixty patients with inoperable stage II or III NSCLC were treated with concurrent chemoradiotherapy. Both groups received thoracic radiation therapy (TRT) with 1.2 Gy/fraction, 2 fraction per day, 5 days per week for a total dose 69.6 Gy. All patients received oral etoposide (VP-16), 50 mg Bid, 30 minutes before TRT beginning day 1 for 10 days, repeated on day 29, and cisplatin 50 mg/m(2) intravenously on days 1, 8, 29, and 36. Patients in the study group received amifostine, 500 mg intravenously, twice weekly before chemoradiation (arm 1); patients in the control group received chemoradiation without amifostine (arm 2). Patient and tumor characteristics were distributed equally in both groups. Of the 60 patients enrolled, 53 were evaluable (27 in arm 1, 26 in arm 2) with a median follow-up of 6 months. Median survival times were 26 months for arm 1 and 15 months for arm 2, not statistically significantly different. Morphine intake to reduce severe esophagitis was significantly lower in arm 1 (2 of 27, 7.4%) than arm 2 (8 of 26, 31%; P =.03). Acute pneumonitis was significantly lower in arm 1 (1 of 27, 3.7%) than in arm 2 (6 of 26, 23%; P =.037). Hypotension (20 mm Hg decrease from baseline blood pressure) was significantly more frequent in arm 1 (19 of 27, 70%) than arm 2 (1 of 26, 3.8%; P =.0001). Only 1 patient discontinued treatment because of hypotension. These preliminary results showed that amifostine significantly reduced acute severe esophagitis and pneumonitis. Further observation is required to assess long-term efficacy.

Organ-specific delivery of agents by the aerosol route offers many advantages since it targets the organ where metastases are and provides significantly less toxic effects. The purpose of this study is to evaluate safety of aerosol IL-2 in patients > 12 yrs. with lung metastases to establish the maximum tolerated dose (MTD) to use for combination therapies with infused natural killer cells and/or autophagy inhibitors in patients with Osteosarcoma (OS) lung metastases. Lung metastases constitute the main cause of death in patients with OS. Survival has remained the same in the past 15 years. Using a human OS mouse model we demonstrated therapeutic efficacy of aerosol IL-2 in OS lung metastases (p = 0.03) and there was significant increase in apoptosis measured by TUNEL (p= 0.003). In addition, aerosol IL-2 significantly increased proliferation of local infused NK cells in the lungs (p= 0.03 and p=0.007 at 24 and 72 hours respectively) with no proliferation demonstrated in other organs including bone marrow. Moreover, immunocompetent mice treated with aerosol IL-2 had significant increase in the number of local NK cells in the lung and there was no evidence of T regulatory cells, a group of cells known to abrogate immune response. Additionally, there is recent evidence to suggest that IL-2 induces autophagy, an evolutionary, conserved, intracellular self-defense mechanism, in CD4+ T cells and NK cells and contributes to growth factor withdrawal cell death. Inhibition of autophagy augments immune cell function allowing a better anti-tumor effect. We initiated a Phase I/II clinical trial of aerosol IL-2 to include patients > 12 years with lung metastases. The primary objective is to determine feasibility and safety of aerosol IL-2. The secondary objective is to determine local effects of aerosol IL-2 by analyzing pre and post-treatment surgical samples for evidence of increase NK cell number, function and autophagy induction. Patients received aerosolized IL-2 for 3 consecutive weeks (21 day cycle) for 2 cycles with 1-week rest between cycles providing no drug limiting toxicities (DLTs) occur. The first treatment is delivered in the hospital. Subsequent treatments are given at home providing patients had been educated. From dose levels 1-4 only 1 patient/dose level was enrolled. From dose level 5 on, 3 patients will be enrolled. Once MTD is reached an additional 14 patients will be treated. 34 to 56 patients may be enrolled. Clinical response will be assessed by chest CT and determined using modified Response Evaluation Criteria in Solid Tumor (RECIST) after 2nd cycle. We have reached dose level 4 and the only side effects were grade 1 fatigue (n= 1), grade 1 cough (n= 2), and grade 1 wheezing (n=1) Adverse events were not attributed to the IL-2 therapy since symptoms resolved without intervention. Serum levels of IL-2 were undetectable in the first three patients. The fourth patient has detectable but low serum levels of IL-2. All patients had progressive disease. In conclusion, feasibility and safety of aerosol IL-2 therapy will set the ground for future combination therapies with NK cells and/or autophagy inhibitors as potential therapeutic options for patients with recurrent and resistant OS lung disease. Citation Format: Nancy B. Gordon, Peter Anderson, Sergei Guma, Hsuan-Chu Chien, Lacey M. McQuinn, Joshua P. Hein, Ralph Zinner, Eugenie S. Kleinerman, Aung Naing. Feasibility and safety of aerosol IL-2 in patients with lung metastases for future combination therapies for the treatment of osteosarcoma lung metastases. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A82.