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Background: This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma. Methods: Phase I endpoints—maximum tolerated dose in previously treated patients; Phase II endpoints—best response, progression free survival and overall survival and incidence of adverse events in previously untreated patients; Phase I treatments—escalating doses of trabectedin (1.0, 1.2, 1.5 mg/m2) as continuous intravenous infusion over 24 h every 3 weeks, 1 mg/kg of ipilimumab given intravenously every 12 weeks, and 3 mg/kg of nivolumab given intravenously every 2 weeks; Phase II treatments—maximum tolerated dose of trabectedin and defined doses of ipilimumab and nivolumab. Results: Phase I (n = 9)—the maximum tolerated dose of trabectedin was 1.2 mg/m2; Phase II (n = 79)—6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median progression-free survival, 6.7 months (CI 95%: 4.4–7.9), median overall survival, 24.6 months (CI 95%: 17.0–.); Grade 3/4 therapy-related adverse events (n = 92)—increased ALT (25%), fatigue (8.7%), increased AST (8.7%), decreased neutrophil count (5.4%) and anemia (4.6%). Conclusion: SAINT is a safe and effective first-line treatment for advanced soft tissue sarcoma.

Objective: Endogenous Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion occurs most commonly from small-cell lung carcinoma. Ectopic ACTH secretion from a neuroendocrine tumor of the breast is very rare, with only 7 previously reported cases in the literature.Methods: We describe a rare case of a metastatic ACTH-producing neuroendocrine carcinoma of the breast causing Cushing syndrome that was managed with bilateral simultaneous retroperitoneoscopic adrenalectomy.Results: A 51-year-old female with a history of bilateral mastectomy for ACTH-secreting neuroendocrine carcinoma of the breast presented with medically intractable Cushing syndrome. Elevated 24-hour urine free cortisol and ACTH levels and clinical findings of diabetes, vertebral compression fractures, and venous thromboembolism were present. Computed tomography scan of the abdomen demonstrated bilateral adrenal hyperplasia. The patient underwent simultaneous retroperitoneoscopic bilateral adrenalectomy. Histopathology revealed diffuse adrenal cortical hyperplasia. By her 3-month postoperative visit, the patient had reduction in facial plethora, 30-pound weight loss, and significant improvement in quality of life.Conclusion: This rare case of metastatic ACTH-producing neuroendocrine carcinoma of the breast was successfully managed with bilateral adrenalectomy. This is a viable strategy to decrease the morbidity of hypercortisolism in patients with medically refractory Cushing syndrome due to ectopic ACTH secretion.Abbreviations: ACTH = adrenocorticotropic hormone;CT = computed tomography;HbA1c = hemoglobin A1c;PET-CT = positron emission tomography-computed tomography;SCLC = small-cell lung carcinoma

11520 Background: Sarcoma cells are most immunogenic earlier in the disease. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first-line therapy. Methods: Eligible patients include previously untreated male or female patients, ≥ 18 years of age with locally advanced unresectable or metastatic soft tissue sarcoma (STS), with measurable disease by RECIST v1.1. Immune checkpoint inhibitors I (1 mg/kg i.v. q 12 weeks) and N (3 mg/kg i.v. q 2 weeks) were given with T (1.2 mg/m2 i.v. q 3 weeks), a tumoricidal agent that depletes growth-promoting macrophages in the tumor microenvironment. Primary endpoint: Objective response rate by RECIST v1.1; Secondary endpoints: (1) Progression-free survival (PFS) at 6 months, (2) Overall survival (OS) at 6, 9, 12, 24, and 48 months, and (3) Incidence of adverse events. Results: Efficacy analysis: There were forty-one evaluable subjects. Best overall response rate was 19.5%; disease control rate 87.8%. The median OS was >12.5 months; median PFS was >6.0 months (6-month OS rate: 75%; 6-month PFS rate: 50%). Safety analysis: Grade 3 TRAEs include fatigue (n = 5), increased TSH (n = 3), decreased TSH (n = 1), adrenal insufficiency (n = 1), hyperglycemia (n = 1), dehydration (n = 1), hyponatremia (n = 2), bipedal edema (n = 2), increased AST (n = 8), increased ALT (n = 19), increased ALP (n = 2), increased CPK (n = 3), port site infection (n = 2), psoriasis exacerbation (n = 1), anemia (n = 6), thrombocytopenia (n = 2), and neutropenia (n = 2). Grade 4 TRAES include neutropenia (n = 1), thrombocytopenia (n = 2), and increased CPK (n = 2). Conclusions: These data suggest that combinatorial therapy with Ipilimumab, Nivolumab and Trabectedin (1) may have synergistic activity in achieving disease control, and (2) is safe with manageable toxicity for patients with previously untreated STS. Clinical trial information: NCT03138161 . [Table: see text]

TPS11572 Background: Talimogene laherparepvec (TVEC), an oncolytic HSV expressing huGMCSF, may be synergistic with trabectedin (T) and nivolumab (N) in treating advanced sarcoma. Objectives: (1) To evaluate the best overall response by RECIST v1.1, progression-free survival rate (PFS), and overall survival rate, (2) To determine the incidence of conversion of an unresectable tumor to a resectable one, and (3) To evaluate the incidence of adverse events related to the drug combination. Methods: This is an open label phase 2 study. A total of 40 patients will receive T (1.2 mg/m2 CIV over 24 hours q3 weeks), N (240 mg IV over 30 min q 2 weeks) and TVEC (intratumorally q 2 weeks according to tumor size). Eligible patients are those with histopathologically confirmed diagnosis of locally advanced, unresectable or metastatic sarcoma including desmoid tumor and chordoma, previously untreated or treated, with measurable disease by RECIST v1.1, and at least, one accessible tumor for intratumoral injection of TVEC. Currently, 31 of the 40 patients have been enrolled. Statistical Considerations: Continuous variables will be summarized by the sample size (n), mean, standard deviation, first and third quartiles, minimum and maximum. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. Safety (incidence and severity of adverse events and significant laboratory abnormalities) will be performed on all patients (ITT population). Patient incidence of all treatment emergent AEs will be tabulated by system organ class and preferred term. Clinical trial information: 03886311 .

11057 Background: Immune checkpoint inhibitors that promote sustained T cell activation may have synergistic activity with an mTOR inhibitor. This phase 1/2 study is aimed to investigate if ABI-009 a novel albumin-bound mTOR inhibitor is feasible and improve clinical outcomes in combination with nivolumab. Methods: Eligible patients with advanced UPS, LPS, CS, OS, or Ewing sarcoma are treated with the standard dose of nivolumab (240 mg given IV every 3 weeks, Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. Phase 1 portion is a dose-finding study using the 3+3 design. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75 and 100 mg/m2. The primary endpoint is to identify the maximum-tolerated dose (MTD) of ABI-009 + nivolumab, secondary endpoints include disease control rate, progression-free survival (PFS), and overall survival (OS). Exploratory endpoints include correlation of PFS and OS with PD-L1 and other biomarkers. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: 9 patients were treated in Phase 1 (n = 3 each dose level); 5/9 patients had OS, 3/9 CS, and 1 had Ewing sarcoma. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1: Grade 3 treatment-related adverse events (TRAEs) included hyper dyslipidemia (n = 1), and hyperglycemia (n = 1). At Dose 2: Grade 3 TRAEs included increased ALT (n = 1). At Dose 3: Grade 3 TRAEs included hypophosphatemia (n = 1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. The median PFS at dose level 3 has not yet been reached. Conclusions: The MTD was not reached and Dose 3 (100 mg/m2) has been designated as the phase 2 dose of ABI- 009, combinable with nivolumab. Enrollment to phase 2 is ongoing. Clinical trial information: NCT03190174.

18 Background: Due to their immuno-modulatory effects, anti-angiogenic drugs have been clinically investigated in combination with anti-PD-1 therapies. The addition of rivoceranib (apatinib), a highly-selective VEGFR-2 tyrosine kinase inhibitor, is being evaluated in an ongoing 2-part Phase I trial in subjects with locally advanced unresectable/metastatic solid tumors who have received at least 3 doses of nivolumab. A classic 3+3 dose escalation has been completed (Part 1) and the study is currently ongoing with an extension period (Part 2). Herein, we present the safety and preliminary efficacy. Methods: To date, 10 subjects were enrolled in Part 1 while 3 subjects have been enrolled in Part 2. Median number of prior lines of therapy were 3 and 1, respectively, for the two study segments. The major inclusion criteria specified that patients must have received at least 3 doses of nivolumab and are continuing nivolumab therapy. Escalating doses of rivoceranib at 400, 600, and 700 mg po qd was proposed in combination with nivolumab at 240 mg iv q2w to determine the MTD. Best tumor response and time of progression was assessed using RECIST v1.1 and iRECIST. Results: 300 mg rivoceranib was determined as RP2D for Part 2. 5/13 patients had G2/3 hypertension. Common treatment-related AEs were hypertension, hand and foot syndrome, and nausea and immune-related AEs were hypothyroidism and diarrhea. Notably, in 10 evaluable patients, 3 patients had PD and 4 patients showed tumor shrinkage (5-29%). A patient with Malignant Spindled/Epitheloid Sarcoma, who had PD during previous nivolumab treatment has shown tumor reduction, so far, of 9%. A patient with Gastric Cancer, who had stable disease (a 4% increase) after 2 months of nivolumab showed a reduction of 29%, 2 months after introduction of rivoceranib. 2 patients have had stable disease for more than 8 months as of Oct 26, 2018. Conclusions: Preliminary results indicate the potential clinical benefit of a 300 mg starting dose in combination with 240 mg of nivolumab in unresectable/metastatic solid tumors with a tolerable safety profile. Efficacy of ongoing and future patients in Part 2 will be further evaluated. Clinical trial information: NCT03396211.

21 Background: Objectives: (1) To investigate the MTD of ABI-009 when given with nivolumab, a PD-1 inhibitor, in previously treated advanced undifferentiated pleomorphic sarcoma, liposarcoma, chondrosarcoma, osteosarcoma and Ewing sarcoma; (2) To investigate the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of this combination therapy in the above mentioned patient group, and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: This is an IRB approved protocol with 2 parts. The Phase 1 part is a dose-finding study using the “cohort of three design”, wherein standard doses of nivolumab 240 mg is given iv every 3 weeks (Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75, and 100 mg/m2. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: The Phase 1 part of study is closed, after 9 patients were treated successfully at 3 dose levels. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1 (n=3): Grade 3 treatment-related adverse events (TRAEs) included hyperdyslipidemia (n=1), and hyperglycemia (n=1). At Dose 2 (n=3): Grade 3 TRAEs included increased ALT (n=1). At Dose 3 (n=3): Grade 3 TRAEs included hypophosphatemia (n=1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. Conclusions: The primary objective has been met with no DLTs, the MTD was not reached and Dose 3 has been designated as the phase 2 dose of ABI-009 which is on-going. Clinical trial information: NCT03190174.

IPI-504 (retaspimycin hydrochloride) is an Hsp90 inhibitor that is the subject of multiple clinical trials for the treatment of cancer. IPI-504 is an aqueous soluble (>200 mg/ml) hydroquinone hydrochloride salt of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a quinone derivative also undergoing clinical evaluation, albeit with suboptimal formulations that address its inferior aqueous solubility (∼50 µg/ml). IPI-504 interconverts with 17-AAG in vivo through oxidation-reduction reactions that result in a dynamic redox equilibrium. The development challenges associated with redox active molecules are significant due to the pH, oxygen, and temperature sensitivities associated with such chemotypes. The API and sterile drug product manufacturing processes thus warrant the monitoring and control of these key variables. Furthermore, the pharmaceutical development challenges associated with cancer agents that are often fast-tracked due to unmet medical needs mandate a rapid development cycle with associated regulatory hurdles. Drug Dev Res 71: 429–438, 2010. © 2010 Wiley-Liss, Inc.

CD44v6 is a cell surface protein involved in cell migration, cell adhesion, tumor progression and metastatic spread. We evaluated its role as a molecular marker for urothelial bladder cancer.A tissue microarray was constructed containing 410 primary urothelial bladder cancers, each in triplicate. Immunohistochemical staining was done with a commercially available antibody. The percent of tumor cells staining positive for CD44v6 was evaluated and we assessed associations with stage, grade and survival.CD44v6 expression was higher in noninvasive (Ta, Tis) vs invasive (T1-T4) tumors (p0.001). It decreased with increasing grade (p0.001). In patients who underwent transurethral bladder resection absent CD44v6 expression was associated with a 2.3-fold increased risk of recurrence (95% CI 1.28 to 4.08). Median time to recurrence for tumors with vs without CD44v6 expression was 23 vs 9 months (p = 0.003). In a multivariate Cox model absent CD44 expression was an independent adverse prognostic factor for tumor recurrence (HR 2.33, p = 0.006). In cystectomy cases median overall survival for CD44v6 nonexpression vs expression was 30 vs 75 months (p = 0.0027) and CD44v6 expression was retained as an independent prognostic factor for overall survival (HR 1.54, p = 0.042).Absent CD44v6 expression is an independent adverse predictor of urothelial bladder cancer recurrence and overall survival. Routine evaluation of CD44v6 expression may allow the identification of high risk patients who require more intensive surveillance or aggressive therapy. Targeting of CD44v6 with monoclonal antibodies may provide new avenues for urothelial bladder cancer imaging and treatment.

Purpose: Adrenocortical adenomas are common, whereas adrenocortical carcinomas are rare. Discriminating between benign and malignant adrenocortical tumors using conventional histology can be difficult. In addition, adrenocortical carcinomas generally have poor prognosis and limited treatment options. MicroRNAs are short noncoding RNAs that are involved in regulation of gene transcription. Experimental Design: To identify microRNAs involved in the pathogenesis of adrenocortical tumors, expression profiling of microRNAs was done on a cohort of 22 adrenocortical carcinomas, 27 adrenocortical adenomas, and 6 normal adrenal cortices. Results: Twenty-three microRNAs were found to be significantly differentially expressed between adrenocortical carcinomas and adrenocortical adenomas. miR-335 and miR-195 were significantly downregulated in adrenocortical carcinomas compared with adrenocortical adenomas. This result was further validated in an external cohort of six adrenocortical carcinomas and four adrenocortical adenomas. Using Kaplan-Meier analysis, downregulation of miR-195 and upregulation of miR-483-5p in adrenocortical carcinomas were significantly associated with poorer disease-specific survival. Conclusions: These findings indicate that deregulation of microRNAs is a recurring event in human adrenocortical carcinomas and that aberrant expression of miR-195 and miR-483-5p identifies a subset of poorer prognosis adrenocortical carcinomas. (Clin Cancer Res 2009;15(24):7684–92)

BACKGROUND: The objective of this study was to evaluate the role of carbonic anhydrase IX (CAIX) in urothelial carcinoma of the bladder. METHODS: A tissue microarray was constructed that contained 724 tissue samples from 340 patients. Immunohistochemical staining was performed using the antibody MN-75, the percentage of positive cells was evaluated, and their association with tumor (T) classification, grade, and survival was assessed. RESULTS: All normal urothelial tissue samples were negative for CAIX expression, whereas 71% of bladder cancers expressed CAIX. CAIX expression was higher in noninvasive (Ta) versus invasive (T1-T4) tumors (P < .001), in low-grade versus high-grade bladder cancer (P < .001), and in metastases versus the corresponding primary tumor (P = .032). For patients with nonmuscle invasive carcinoma who underwent transurethral resection (TUR), higher CAIX expression was associated with poorer recurrence-free survival (P = .001). In addition, for patients with T1 tumors who underwent TUR, higher CAIX expression conveyed a 6.5-fold higher risk of progression into muscle-invasive disease (P = .006). In patients who underwent cystectomy, higher CAIX expression was associated with worse overall survival (P = .003). Multivariate Cox models revealed that CAIX expression was the strongest, independent prognostic factor of recurrence-free survival (hazard ratio, 2.29; P = .001) and overall survival (hazard ratio, 1.9; P < .001). CONCLUSIONS: CAIX was expressed differentially in noninvasive versus invasive tumors, in low-grade versus high-grade bladder cancer, and in primary tumors versus metastases. The current results indicated that CAIX is a strong predictor of recurrence, progression, and overall survival of patients with bladder cancer; and the integration of CAIX expression into conventional prognostic models significantly improved their predictive accuracy. The data suggest a tripartite role of CAIX as a diagnostic, prognostic, and therapeutic molecular marker in bladder cancer. Cancer 2009. © 2009 American Cancer Society.

Background This phase I/II trial was conducted to determine the toxicities, recommended dose, pharmacokinetics, and response rate of erlotinib plus trastuzumab in metastatic HER2+ breast cancer. Patients and Methods In phase I, sequential groups of patients with unlimited previous treatment received erlotinib at dose levels of 50, 100, and 150 mg plus standard dose weekly trastuzumab. In phase II, only patients with no previous chemotherapy or trastuzumab in the metastatic setting were allowed. Results The combination was well tolerated among the 16 patients enrolled in phase I, and the recommended phase II dose of erlotinib was initially set at 150 mg. After an interim review of the first 8 patients in phase II revealed a higher incidence of rash and diarrhea than expected from the phase I experience, the protocol was amended to treat new phase II patients at erlotinib 100 mg, with the opportunity to escalate to 150 mg after 3 weeks, based on individual patient tolerability. As a result of advances in other therapies aimed at HER2+ breast cancer, phase II closed before meeting its accrual goal. Among the 12 evaluable chemotherapy- and trastuzumab-naive patients treated at the recommended phase II dose level, there were 4 partial responses, and the time to progression was 9.03 months (95% CI, 1.2-undetermined). No pharmacokinetic interaction between the 2 agents was observed. Conclusion The combination of erlotinib and trastuzumab was well tolerated when the dose of erlotinib was tailored to individual patient experience, and there was preliminary evidence of anticancer activity.

Amplification and resulting overexpression of the HER-2/ neu proto-oncogene is found in approximately 30% of human breast and 20% of human ovarian cancers. To better understand the molecular events associated with overexpression of this gene in human breast cancer cells, differential hybridization was used to identify genes whose expression levels are altered in cells overexpressing this receptor. Of 16 000 clones screened from an overexpression cell cDNA library, a total of 19 non-redundant clones were isolated including seven whose expression decreases (C clones) and 12 which increase (H clones) in association with HER-2/ neu overexpression. Of these, five C clones and 11 H clones have been confirmed to be differentially expressed by northern blot analysis. This group includes nine genes of known function, three previously sequenced genes of relatively uncharacterized function and four novel genes without a match in GenBank. Examination of the previously characterized genes indicates that they represent sequences known to be frequently associated with the malignant phenotype, suggesting that the subtraction cloning strategy used identified appropriate target genes. In addition, differential expression of 12 of 16 (75%) cDNAs identified in the breast cancer cell lines are also seen in HER-2/ neu -overexpressing ovarian cancer cells, indicating that they represent generic associations with HER-2/ neu overexpression. Finally, up-regulation of two of the identified cDNAs, one novel and one identified but as yet uncharacterized gene, was confirmed in human breast cancer specimens in association with HER-2/ neu overexpression. Further characterization of these genes may yield insight into the fundamental biology and pathogenetic effects of HER-2/ neu overexpression in human breast and ovarian cancer cells.

Angiogenesis contributes to the progression of urothelial carcinoma (UC). In the current study, the authors investigated the role of maintenance sunitinib in patients with advanced UC.Patients with locally recurrent/metastatic UC and adequate organ function who achieved stable disease or a partial or complete response after 4 to 6 chemotherapy cycles were randomized to sunitinib at a dose of 50 mg/day (28 days on and 14 days off) or placebo. The primary endpoint was the 6-month progression rate. Secondary endpoints were safety, survival, change in serum vascular endothelial growth factor (VEGF)/soluble VEGF receptor-2 (sVEGFR2), and the activity of sunitinib in patients who developed disease progression while receiving placebo. A total of 38 eligible patients per treatment arm were required to select better therapy with 90% probability (α = .05).A total of 54 eligible patients were randomized to either the sunitinib arm (26 patients) or the placebo arm (28 patients). The median number of cycles received was 2 cycles per treatment arm. The most common grade 3 to 4 adverse events (graded according to version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) among patients receiving sunitinib were thrombocytopenia, diarrhea, mucositis, fatigue, and hypertension. There were no grade 3 or 4 adverse events noted among5% of patients receiving placebo. The 6-month progression rate was 72% versus 64%. The median progression-free survival (PFS) was 2.9 months (range, 0.5 months-32.5 months) versus 2.7 months (range, 0.8 months -65 months) for the sunitinib versus placebo arms, respectively. Patients receiving placebo were found to have no changes in their serum VEGF/sVEGFR2 levels over time. Patients treated with sunitinib had no significant change in their VEGF level, but the sVEGFR2 level significantly decreased after cycles 1 and 2 (P .0001) and at the time of disease progression (P = .0002). A baseline VEGF level that was at or greater than the median was found to be correlated with a longer PFS. Sixteen patients who were receiving placebo received sunitinib at the time of disease progression, with the best responses being 1 partial response (6.3%), 6 cases of stable disease (37.5%), and 5 cases of progressive disease (31.3%); 4 patients were not evaluable for response. The median PFS was 3.7 months (range, 0.1 months-22 months).The current multicenter study was limited by premature closure and a small sample size. Maintenance sunitinib did not appear to improve the 6-month progression rate. Open-label sunitinib was found to have only modest activity. The sVEGFR2 level decreased among patients receiving sunitinib.

Purpose: PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies. Experimental Design: PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non–small cell lung cancer (NSCLC) patients. Results: 121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/d. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non–small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804. Conclusions: The MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients. Clin Cancer Res; 17(5); 1131–9. ©2011 AACR.

Mitogen-activated protein kinases (MAPK) play important roles in malignancy. The ability to detect and quantitate MAPKs in live animal models of cancer will facilitate an understanding of disease progression. We have developed a gene expression-based imaging system that detects and quantifies MAPK activity in prostate cancer tumors implanted into severe combined immunodeficient mice. The imaging technology uses a modified version of two-step transcriptional amplification (TSTA). The tissue specificity of gene expression is imparted by an enhanced version of the prostate-specific antigen regulatory region that expresses GAL4-ELK1. GAL4-ELK1 confers MAPK specificity by activating a firefly luciferase (FLuc) reporter gene when the Ets-like transcription factor (ELK) 1 activation domain is phosphorylated by MAPK. FLuc activity in live animals was detected using the Xenogen In vivo Imaging System. We validated the TSTA-ELK1 system by analyzing its response to epidermal growth factor treatment in transfected tissue culture cells and in adenovirus (AdTSTA-ELK1)–injected prostate cancer xenograft tumors. We measured MAPK activity in two well-characterized xenograft models, CWR22 and LAPC9. Although no significant differences in MAPK levels were detected between androgen-dependent and androgen-independent xenografts, the CWR22 models display significantly higher levels of AdTSTA-ELK1 activity versus LAPC9. Western blots of tumor extracts showed that the elevated imaging signal in CWR22 xenografts correlated with elevated levels of phosphorylated extracellular signal-regulated kinase 1/2 but not p38 or c-Jun NH2-terminal kinase. We conclude that a gene expression-based optical imaging system can accurately detect and quantify MAPK activity in live animals. (Cancer Res 2006; 66(22): 10778-85)

Background: Fibroblast growth factor receptors (FGFRs) play a role in cell proliferation and survival. Genetic alterations of FGFRs can lead to deregulated activation in various cancers, including squamous cell carcinoma (SCC) of the lung and urothelial bladder cancer. Here, we report on a phase I study of BGJ398 a potent, selective pan-FGFR inhibitor. Methods: Eligible patients (pts; ≥ 18 years of age) had tumors with any FGFR genetic alteration identified by central or local prescreening. Pts received BGJ398 once or twice daily (qd or bid) in 28-day cycles in escalating cohorts. Dose-limiting toxicities (DLTs) were predefined and included both severe events and those resulting in significant dosing delays. Upon determination of maximum tolerated dose (MTD), 3 expansion arms were treated: arm 1 included FGFR1-amplified SCC of the lung (continuous qd dosing); arms 2 and 3 included FGFR-altered solid tumors given qd continuous doses (arm 2) or qd doses on a 3-weeks-on/1-week-off schedule (arm 3). Results: As of September 24, 2013, 94 pts were enrolled (median age 57.5 years). Pts were treated in qd dose cohorts (5-150 mg; n = 90) or a bid dose cohort (50 mg; n = 4). Arms 1 and 3 are ongoing. Of the 82 pts who discontinued, the most common reasons were disease progression (n = 56), consent withdrawal (n = 12), and adverse events (AEs; n = 10). DLTs during dose escalation were grade 3 aminotransferase increases (1 each at 100 and 125 mg), hyperphosphatemia (125 mg), and grade 1 corneal toxicity (150 mg). The 125-mg qd dose was identified as the MTD. Common treatment-emergent AEs (any grade, suspected to be related) at 125 mg qd (n = 41) include hyperphosphatemia (78%), stomatitis (37%), alopecia (32%), decreased appetite (32%), and fatigue (22%) and were generally mild, with stomatitis (7%) the only grade 3/4 AE occurring ≥ 5%. Elevated serum phosphate levels, a pharmacodynamic marker of FGFR pathway inhibition, could be managed through diet, phosphate lowering therapy, and drug interruptions. Preliminary analysis of efficacy data indicates tumor regressions in pts with various FGFR genetic alterations, including 4 of 5 pts with urothelial cell carcinomas (4 of which originated in the bladder) with FGFR3-activating mutations (with tumor reductions ranging from 27% to 48%). Additionally, 1 pt with FGFR1-amplified SCC lung cancer achieved confirmed partial response (PR) while another pt achieved a PR confirmed after 27 days. Tumor reductions were also observed in cholangiocarcinoma with an FGFR2 gene fusion, and FGFR1-amplified breast cancer. Conclusions: BGJ398 had a tolerable safety profile and demonstrated single-agent activity in pts with FGFR-genetically altered solid tumors. The 3-weeks-on/1-week-off schedule has been chosen for future studies based on its improved safety profile. Clinical activity was observed in multiple tumor types, and pts with FGFR3-mutated bladder cancer may be especially sensitive to BGJ398. Citation Format: Lecia V. Sequist, Phillippe Cassier, Andrea Varga, Josep Tabernero, Jan HM Schellens, Jean-Pierre Delord, Patricia LoRusso, D. Ross Camidge, Manuel Hidalgo Medina, Martin Schuler, Mario Campone, G. Gary Tian, Steven Wong, Jesus Corral, Randi Isaacs, Suman K. Sen, Diana Graus Porta, Swarupa G. Kulkarni, Caroline Lefebvre, Jürgen Wolf. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT326. doi:10.1158/1538-7445.AM2014-CT326

490 Background: Carbonic anhydrase IX (CAIX) is an attractive target for the development of a RCC specific vaccine. We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with mRCC. This is a ph1 study of cancer vaccine against CAIX gene expressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) was produced per GMP in collaboration with the NCI RAID program. The final product is produced in an in-house GMP cell processing facility using DCs cultured ex vivo from patients’ PBMC's and engineered with AdGMCAIX prior to intradermal injection. The transduced DCs are expected to stimulate an antigen specific immune response against CAIX expressing RCC, leading to a potential anti-tumor effect. Dose escalation in 3 dose cohorts (5 X 106, 15 X 106, and 50 X 106 cells/administration) follows the std 3+3 ph1 design with an expansion cohort. DC-AdGMCAIX is given intradermally Q 2 weeks X 3 doses. The primary aim is safety of DC-AdGMCAIX injections. Secondary aims are to evaluate immune responses & the antitumor effects per RECIST 1.1. Pts with clear cell mRCC with ECOG 0-1 & measurable disease & adequate organ function were enrolled. Results: Six pts with clear cell mRCC are enrolled. Four pts received all 3 planned vaccine doses and the fifth pt only the 1st dose. No SAE’s were seen to date. One pt had chills that lasted several minutes and transient Gr1 leucopenia. One pt has worsening of pre-existing proteinuria, though unclear if related to the vaccine. One pt has PD & the other two have SD on D85 scans. Tumor bx shows intra-tumoral infiltration by T cells. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any acute SAE’s noted at the doses tested so far. The study will complete its 3rd cohort & expansion cohort enrollment. This data support the further development of Ad-GMCAIX vaccine strategies either alone or in combination with approved therapies. Funding: Supported by NCI RAID Initiative NSC 740833 and Kite Pharma.

We thank Dr. Tombol and colleagues for their interest in our article and their comments. As with our study, Dr. Tombol and colleagues also performed microRNA (miRNA) profiling of adrenocortical tumors. There were however only two miRNAs in common between the two studies. This is, of course

e16052 Background: CRPC represents a growing public health concern that has not been adequately quantified. In the absence of metastases, CRPC represents a transitional disease state defined by increases in prostate specific antigen (PSA) despite castration levels of androgens during androgen deprivation therapy (ADT). We developed a model to estimate M0 CRPC prevalence in selected countries. Methods: A patient-flow model was developed to estimate 5-year limited duration prevalence of prostate cancer (PC) and M0 PC in each country, each year (2008 to 2028) using age-specific incidence and survival data from population cancer registries from 28 countries in North (US, Canada, Mexico) and South America (Brazil), Europe (18 countries), Asia (5 countries), and Australia. The proportion of men with M0 PC treated with ADT was based on literature reports and survey research with physicians treating PC. PSA relapse rates from published literature were used to estimate CRPC among ADT treated. Results: PC prevalence is driven by size and aging of populations, with notable increases predicted within 15 years in regions other than US, Canada, and EU5 (table). The prevalence model, which utilized country-level data, indicates that M0 CRPC represents a relatively small proportion (2-8%) of the total PC population. Nonetheless, widespread screening and demographic changes dictate that the prevalence of CRPC will increase over the next 15 years, assuming current ADT rates. Conclusions: Incidence trends in PC are dependent on PSA screening, which is projected to lead to an increase in M0 PC and PC prevalence in most regions. The number of men treated with ADT and who ultimately develop CRPC will increase accordingly, as demonstrated in the model. [Table: see text]

Aberrant epidermal growth factor (EGF) signaling is associated with tumor growth in squamous cell carcinoma of the head and neck in humans (HNSCC), and is a major focus of targeted therapy. Cetuximab, a monoclonal antibody against EGFR, has been successful at prolonging survival but has only a 10% tumor shrinkage response rate in a clinical setting. The goal of this study was to compare dacomitinib (PF-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple HER family receptors (HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases), to cetuximab, the current FDA approved anti-EGFR medication for HNSCC and erlotinib, an EGFR specific small molecule tyrosine kinase inhibitor. Dacomitinib, erlotinib and cetuximab were tested in a panel of 27 HNSCC cell lines. Treatment with 100 ug/ml of cetuximab or 1 uM of erlotinib inhibited growth by at least 50% in 7/27 cell lines, while treatment with 1 uM of dacomitinib had similar growth inhibition in 17/27 lines. Cell lines representing three levels of sensitivity to dacomitinib were further examined using Western blots, cell cycle and apoptosis analysis. Treatment with 100 nM of dacomitinib reduced EGFR activity and downstream AKT and ERK pathways more effectively than treatment with 100 ug/ml of cetuximab in all ten tested lines. Although both compounds induced apoptosis at similar levels, dacomitinib caused greater G0/G1 arrest. Sensitivity to EGFR blockade was associated with levels of EGFR and ERK and was not associated with common oncogenic mutations and copy number variations. Phosphorylated and total EGFR and ERK levels correlate with sensitivity to both cetuximab and dacomitinib. Three of the four lines in the exquisitely sensitive group had the highest levels of phosphorylated and total EGFR and ERK among the ten lines selected, while the three resistant lines collectively had the lowest levels. Neither pAKT nor tAKT was associated with sensitivity.

8027 Background: PF-00299804 (PF) is an orally bioavailable, potent, irreversible small molecule inhibitor of HER1, HER2, and HER4. HER1 overexpression/aberrant function is widely observed in NSCLC and HER1 mutations are implicated in mechanisms of tumorigenesis and are associated with sensitivity to EGFR inhibitors gefitinib (G) and erlotinib (E). Results in pts with refractory NSCLC enriched for HER gene amplification, HER1/HER2 mutation, or wild type (WT) KRAS, within the phase I study are reported. Methods: NSCLC pts (n=42) received PF 16 mg (n=1), 30 mg (n=2), 45 mg, the MTD (n=33) or 60 mg (n=6) QD either continuously or for 2 weeks of a 3- week cycle. NSCLC pts were included in both the dose-escalation phase and at MTD, when additional NSCLC pts with HER1 mutant or KRAS WT tumors were recruited. Results: 44 pts with NSCLC have been enrolled to date (29 evaluable for response). Baseline characteristics were: median age 57 yrs (range 26–77), prior EGFR inhibitors 94% (E n=21, G n=6, E + G n=3; cetuxi...

3599 Background: There are scientific rationale for inhibitors which provide combined and irreversible blockade of HER family members. PF-00299804 is an orally available, potent, irreversible small molecule inhibitor of the HER tyrosine kinases. Methods: The safety, tolerability, PK, PD, and efficacy of PF-00299804 administered orally once daily in 3-week cycles were assessed in patients with advanced solid tumors using an accelerated dose-escalation design. Safety assessments included adverse event (AE), laboratory, ECG, and LVEF assessments. PK parameters were determined after a single lead-in dose and on Day 14 by non-compartmental techniques. PD measures included assessment of HER-related signaling pathways via IHC analyses of serial skin and, in some patients, tumor biopsies. Serial 18F-FDG- PET/CT has been performed on a subset of patients with scans being classified according to modified EORTC criteria by a central reader. Results: 32 pts have been treated across 8 sequential dose levels ranging from 0.5 to 60 mg. The most common AEs were diarrhea, fatigue, nausea, and rash. 3/6 patients at 60 mg experienced a DLT [hand-foot syndrome (1), dehydration related to diarrhea(1), mucositis(1)]. Cmax and AUC of PF-00299804 increased with dose in an approximately proportional manner. Accumulation ranged from 3.3 to 6.8, suggesting a terminal t1/2>24 h. At the 30 mg dose level, mean Day 14 drug concentration was above the predicted efficacious concentration for tumor growth inhibition based on A431 xenograft model. Of 7 sets of PET data evaluated thus far, partial responses (PR) have been observed in 2 patients. A PR as assessed using RECIST criteria has been reported in 1 of 2 patients with advanced refractory NSCLC treated to date. Conclusions: Daily administration of PF-00299804 across many dose levels appears safe and tolerable. Diarrhea, fatigue, nausea, and rash are the most frequent AEs. Evaluation of 45 mg/d as the potential MTD is ongoing. Systemic exposures at doses = 30 mg exceed the threshold for efficacy as predicted from preclinical studies. Clinical and biological activity of PF-00299804 was observed including a PR in 1 of 2 patients with advanced refractory NSCLC. No significant financial relationships to disclose.

The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.

Carcinoma of the breast and ovary account for one-third of all cancers occurring in women and together are responsible for approximately one-quarter of cancer-related deaths in females. The HER-2/neu proto-oncogene is amplified in 25 to 30 percent of human primary breast cancers and this alteration is associated with disease behavior. In this report, several similarities were found in the biology of HER-2/neu in breast and ovarian cancer, including a similar incidence of amplification, a direct correlation between amplification and over-expression, evidence of tumors in which overexpression occurs without amplification, and the association between gene alteration and clinical outcome. A comprehensive study of the gene and its products (RNA and protein) was simultaneously performed on a large number of both tumor types. This analysis identified several potential shortcomings of the various methods used to evaluate HER-2/neu in these diseases (Southern, Northern, and Western blots, and immunohistochemistry) and provided information regarding considerations that should be addressed when studying a gene or gene product in human tissue. The data presented further support the concept that the HER-2/neu gene may be involved in the pathogenesis of some human cancers.