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Background IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses. Methods We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930). Results Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets. Conclusion Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis.

SummaryBackground Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We conducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally active, allosteric mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, in pancreas cancer patients with somatic KRASG12R mutations. Methods In this two-stage, phase II study (NCT03040986) patients with advanced pancreas cancer harboring somatic KRASG12R variants who had received at least one standard-of-care systemic therapy regimen received 75 mg selumetinib orally twice a day until disease progression or unacceptable toxicity occurred. The primary outcome of the study was best objective response (BOR). Results From August 2017 to February 2018 a total of 8 patients with confirmed somatic KRASG12R mutations and a median age of 61.5 years were treated with selumetinib. Seven out of eight (87.5%) had received two or more lines of prior systemic chemotherapy. After a median follow-up period of 8.5 months (range 2 to 20), three patients had stable disease for more than 6 months while receiving selumetinib. No patients achieved an objective partial response. Median progression-free survival (PFS) was 3.0 months (95% CI, 0.8–8.2) and median overall survival (OS) 9 months (95% CI, 2.5–20.9). Conclusion This study in heavily pre-treated pancreatic adenocarcinoma patients suggests alternative strategies beyond single agent MEK inhibition are required for this unique, molecular subset of pancreatic cancer patients. The trial was registered on February 2nd, 2017 under identifier NCT03040986 with ClinicalTrials.gov.

To define the maximum tolerated dose (MTD), recommended phase II dose (RPTD), and assess safety and tolerability for the combination of pazopanib plus TH-302, an investigational hypoxia-activated prodrug (HAP), in adult patients with advanced solid tumors. This was an open-label, non-randomized, single-center, phase I trial consisting 2 stages. Stage 1 was a standard “3 + 3” dose escalation design to determine safety and the RPTD for TH-302 plus pazopanib combination. Stage 2 was an expanded cohort to better describe the tolerability and toxicity profile at the MTD. Pazopanib was orally dosed at 800 mg daily on days 1–28 for all cohorts. TH-302 was administered intravenously on days 1, 8 and 15 of a 28-day cycle at doses of 340 mg/m2 (cohort 1) or 480 mg/m2 (cohort 2). Dose limiting toxicity (DLT) was assessed in the first 28-day cycle. Efficacy was assessed every 2 cycles. Thirty patients were enrolled between December 2011 and September 2013. In the dose escalation stage, 7 patients were enrolled in the 340 mg/m2 TH-302 cohort and 6 patients in the 480 mg/m2 TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m2 TH-302 cohort, and grade 3 vaginal inflammation (n = 1) and grade 3 neutropenia with grade 3 thrombocytopenia (n = 1, same patient) in the 480 mg/m2 TH-302 cohort. The 340 mg/m2 TH-302 cohort was determined to be MTD and RPTD. The most common treatment-related adverse events were hematologic (anemia, neutropenia, and thrombocytopenia), nausea/vomiting, palmar-plantar erythrodysesthesia syndrome, constipation, fatigue, mucositis, anorexia, pain, and hypertension. Partial response (PR) was observed in 10% (n = 3) of patients, stable disease (SD) in 57% (n = 17), and progressive disease (PD) in 23% (n = 7). Due to toxicity, 3 patients were discontinued from study drug prior to first radiographic assessment but were included in these calculations. Disease control ≥6 months was observed in 37% of patients (n = 11). The RPTD for this novel combination is pazopanib 800 mg daily on days 1–28 plus TH-302 340 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Preliminary activity was seen in treatment-refractory cancers and supports potential value of co-targeting tumor angiogenesis and tumor hypoxia.

Purpose To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design This was a standard “3 + 3” dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort −1 and −1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m2 BID days 1–14; oxaliplatin 100 mg/m2 and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.

e22095Background: Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) are painful, debilitating, and often dose-limiting complications of anticancer agents. These cutaneous reactions are en...

TPS873 Background: Initial treatment of metastatic colorectal cancer (mCRC) involves a 5-fluorouracil based chemotherapy regimen, often in combination with anti-VEGF therapy. Upon disease progression, multiple studies have suggested a benefit for continued anti-VEGF therapy. There is increasing evidence that VEGF plays a role in cancer immune evasion. Targeting of inflammatory and immune checkpoints are attractive approaches to enhance the benefits of anti-VEGF therapy. The safety and activity of the anti-PD-L1 antibody atezolizumab with bevacizumab and with 5-FU, oxaliplatin, and bevacizumab have been recently reported; the combinations were well-tolerated and suggested clinical activity. Therefore, bevacizumab may increase the immunogenicity of colorectal cancers, and the combination of atezolizumab plus bevacizumab may be associated with clinically meaningful response rates and disease control. Furthermore, there may be candidate biomarkers that may identify those patients most likely to benefit from this combination. Methods: In this randomized, double-blind, multicenter, placebo-controlled phase II study, 135 patients with mCRC will be randomized 2:1 to receive capecitabine/bevacizumab/atezolizumab or capecitabine/bevacizumab/placebo. Patients with prior PD-L1/PD-1 therapy are ineligible. Primary and secondary efficacy will be conducted using ITT analysis. Safety analyses will include all randomized patients who receive at least one dose of study treatment. The primary objective is PFS. The secondary objectives are ORR, OS, safety, and tolerability. The primary comparison will be superiority of the active treatment for the PFS endpoint, atezolizumab versus placebo testing at 1-sided α = 0.1 (log rank test). A PFS hazard ratio of 0.618 (active treatment versus placebo) is detectable with 86% power (1 sided α = 0.1). No interim analyses for futility or efficacy will be conducted. A subset analysis will be performed in the microsatellite-high patients looking at potential differences in PFS and OS. Trial is active and currently recruiting patients. Clinical trial information: NCT02873195.

Purpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a “3 + 3” design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m2 twice daily, days 1–14), oxaliplatin (130 mg/m2 on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high srcact expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.

Background. Esophageal and gastric cancers often present at an advanced stage. Systemic chemotherapy is the mainstay of treatment, but survival with current regimens remains poor. We evaluated the safety, tolerability, and efficacy of the combination capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas. Methods. Thirty-seven patients with metastatic or unresectable gastric/gastroesophageal junction tumors were enrolled and treated with capecitabine 850 mg/m2 BID on days 1–14, and oxaliplatin 130 mg/m2 with bevacizumab 15 mg/kg on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Neuropilin-1 (NRP1) and -2 (NRP2) mRNA expression was evaluated in archived tumor. Results. Thirty-five patients were evaluable for efficacy. Median PFS was 7.2 months; median OS was 10.8 months. RR was estimated at 51.4%. The regimen was tolerable with expected drug class-related toxicities. NRP2 mRNA levels significantly correlated with PFS (p = 0.042) and showed a trend toward significance with OS (p = 0.051). Nonsignificant trends for NRP1 were noted for higher expression levels and worse outcome. Conclusions. Bevacizumab can be given safely with chemotherapy in patients with metastatic esophagogastric adenocarcinomas. The combination of capecitabine, oxaliplatin, plus bevacizumab has activity comparable to other bevacizumab-containing regimens in metastatic gastroesophageal cancer.

687 Background: Patients (pts) with chemotherapy refractory mCRC have a poor prognosis, with a median survival of approximately 6 months (mos). Ziv-aflibercept is FDA-approved in combination with FOLFIRI for the 2nd line treatment of mCRC, but its tolerability and activity in pts with chemotherapy refractory disease is unknown. We designed a phase I/II study of X+TRAP to define the recommended phase II dose (RPTD), and assess the safety, tolerability, and clinical activity for the combination. Methods: Eligible pts with refractory, advanced solid tumors were enrolled in a 3+3 dose escalation cohort (ESC) to identify the RPTD. Cycle length was 21 days. Radiographic assessment occurred every 3 cycles. X was administered po bid on days 1-14. The dose of X was 850 mg/m2 bid in ESC cohort 1 and 1,000 mg/m2 bid in ESC cohort 2. TRAP was administered on day 1 of each cycle (6 mg/kg IV). Pts with mCRC that had progressed on all standard therapies were then enrolled in a single-arm, phase II expansion cohort (EXP) and treated at the RPTD. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Results: As of 6/19/2015, 55 pts were evaluable for toxicity (13 ESC; 42 EXP) and 47 pts were evaluable efficacy (12 ESC; 35 EXP). In the phase I ESC cohorts, 3 DLTs occurred (1/6 cohort 1; 2/6 cohort 2): GI perforation (1), oral mucositis (1), and fatigue (1). The RPTD was X (850 mg/m2 po bid, days 1-14) and TRAP (6 mg/kg IV, day 1). In the ESC and EXP cohorts, there were no treatment related grade 4/5 adverse events (AEs). The most frequently reported treatment related AEs (grades 2+3; grade 3) were palmar-plantar erythrodysesthesia (36%; 5%), hypertension (29%; 20%), and oral mucositis (18%; 4%). Median follow up in the phase II EXP cohort was 9.3 mos (95% C.I., 6.5–11.1). Median PFS was 4.1 mos (95% C.I., 2.3-4.8). Response assessment in 35 pts (n; %): partial response (PR) (2; 6%); stable disease (SD) (12; 34%); SD > 6 mos (2; 6%). Median OS was 9.3 mos (95% C.I., 6.2–n/a). Conclusions: The combination of X+TRAP demonstrated an acceptable safety profile, with encouraging clinical activity at the RPTD. Recruitment for the phase II EXP cohort is now complete. Clinical trial information: NCT01661972.

Background: Several molecular alterations drive acquired resistance to anti-EGFR therapies in pts with KRAS WT mCRC. We designed a clinical trial to identify and treat MET amplification (amp), a well described driver of acquired EGFR resistance. Methods: Pts with KRAS WT mCRC were enrolled in 3 cohorts: 1) C+P Dose Finding (Dose Find): 3+3 design to determine the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) of C+P; 2) C+P Expansion (Exp): to define the safety, tolerability and activity of C+P; and 3) MET amplified monotherapy (MET Mono): to determine the response rate of C alone in pts with prospectively identified MET amp/ EGFR refractory mCRC. Response assessment occurred every 2 months with computed tomography (CT) using RECIST criteria, version 1.1. cfDNA was collected at baseline and each restaging until progression. In the C+P Dose Find and Exp cohorts, peripheral blood was retrospectively sequenced for 54 gene mutations (mut) and focal amplifications, including MET (Guardant Health, Inc.). MET expressing circulating tumor cells (CTCs) were captured utilizing nanomagnetic particles conjugated to an antibody targeting extracellular MET (Janssen R&D, LLC). Genomic amp was tested in tumor tissue using next generation sequencing (NGS) or FISH. These data allowed subgroup and individual pt profiling. Results: There were no dose limiting toxicity (DLT) events at the RPTD (C 60mg PO daily and P 6 mg/kg IV Q2 weeks) in the Dose Find cohort (n = 6). Assessment of treatment response in C+P cohorts: As of 7/21/2015, 13 pts were treated at the RPTD. 3 pts had not yet received response assessment; 10 pts (6 Dose Find; 4 Exp) were evaluable for response. 8/10 evaluable pts had failed prior anti-EGFR therapy. 6/10 had reduction in RECIST lesions (2/2 EGFR naïve; 4/8 EGFR refractory). Median change was -10% (range -40% to +18%). 2/2 evaluable pts with MET amp cfDNA had a reduction in target lesions (both EGFR refractory). 7/10 had a decrease in tumor marker (CEA). Median CEA change was -39% (range -86% to +103%). Baseline cfDNA profiling in C+P and MET Mono cohorts: 13 pts with EGFR refractory mCRC (6 Dose Find; 3 Exp; 4 MET mono) had baseline cfDNA profiling. 4/13 BRAF mut (2/4 subclonal), 3/13 KRAS mut (2/3 subclonal), 1/13 NRAS mut (0/1 subclonal), 3/13 HER2 amp (3/3 confirmed in tissue), 4/13 MET amp (0/2 in tissue; 2 not tested). Pt examples: One subject (EGFR refractory) had a lymph node biopsy 3 months prior to C+P that revealed no MET amp by NGS (Foundation Medicine). Pre-treatment cfDNA revealed MET amp. Treatment with C+P resulted in a partial response (-40% in RECIST lesions). MET amp was no longer detected in cfDNA at first restaging. A second subject had MET amp in pre-treatment cfDNA. MET-expressing CTCs were captured from peripheral blood. Single cell FISH on CTCs-but not archival tissue-confirmed MET amp. Conclusions: This ongoing phase I/II study demonstrates the feasibility of: 1) using cfDNA to detect MET amp in pts with EGFR refractory mCRC, even when archival tissue is negative; and 2) capturing MET-expressing CTCs to confirm MET amp. Preliminary clinical results support prospective cfDNA screening to identify and treat pts with EGFR refractory/ MET amp mCRC. Citation Format: John H. Strickler, Tian Zhang, Andrew J. Armstrong, Donna Niedzwiecki, Hope E. Uronis, Michael A. Morse, S. Yousuf Zafar, Shiao-Wen D. Hsu, Christy C. Arrowood, Rebecca Nagy, AmirAli Talasaz, Richard Lanman, Sherri Haley, Herbert I. Hurwitz. Cell free DNA (cfDNA) to monitor clonal evolution in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (mCRC): Preliminary results of a phase I/II clinical trial of the anti-MET multi-kinase inhibitor cabozantinib (C) plus the anti-EGFR monoclonal antibody panitumumab (P). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A52.

11036 Background: Src inhibition may augment sensitivity to chemotherapy, but in unselected patients (pts) with advanced solid tumors, src inhibitors have shown limited clinical activity. Biomarkers to predict benefit from src inhibitors in advanced solid tumors are not yet known. Methods: 22 pts (dose escalation cohort= 12 pts; colorectal cancer [CRC] expansion cohort= 10 pts) were enrolled in a phase I study to determine the safety and tolerability of the src inhibitor dasatinib with capecitabine, oxaliplatin, and bevacizumab (J Clin Oncol 29: 2011 [suppl; abstr 3586]). Src activation (src-a) was assessed in tumors from 16 evaluable pts. Src-a was measured by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tumor samples using an antibody that selectively recognizes the active conformation of src (clone 28). A GI pathologist who was blinded to pt outcomes graded membranous src-a using a standard semi-quantitative method. The endpoint of this exploratory analysis was objective response rate ([ORR]= PR+CR). 2-sided Fisher’s Exact test was used to evaluate the association between ORR and src-a. Results: Across all tumor types, 8 tumors had no/faint src-a (IHC=0/1); 8 tumors had moderate/strong src-a (IHC≥2). Benign colonic epithelium had no src-a (IHC=0). The ORR was 75% (6/8) for pts with moderate/strong src-a versus (vs) 0% (0/8) for pts with no/faint src-a (p =0.007). In the CRC expansion cohort, the ORR was 83% (5/6) for patients with moderate/strong src-a vs 0% (0/2) for pts with no/faint src-a (p=0.107); progression free survival range was 7.9-24.4 months for pts with moderate/strong src-a. Conclusions: In this small phase I study, src-a is associated with benefit from the combination of dasatinib and oxaliplatin-based chemotherapy. Further evaluation of dasatinib in patients whose tumors demonstrate high levels of src-a may be warranted. Clinical trial information: NCT00920868.

490 Background: Everolimus (E), an oral rapamycin analogue, is a potent mTOR inhibitor. Combined inhibition of VEGF and mTOR pathways may increase anti-angiogenic and anti-tumor activity. We evaluated E in combination with capecitabine (C), oxaliplatin (O), and bevacizumab (B) in a phase I dose escalation study. Methods: Eligible patients (pts) had advanced solid tumors, adequate organ function and no increased risk for class-related toxicities. B and O were given intravenously; C and E were orally administered. Cycle length was 21 days. Doses for level 1: C 850 mg/m2 on days 1-14; O 130 mg/m2 on day one; B 7.5 mg/kg on day one; and E 5 mg three times a week. Doses for level -1: C 680 mg/m2, O100mg/m2. An intermediate dose level (-1b) of E escalated to 5 mg five times weekly was added to maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1. Concomitant administration of CYP3A4 substrates, inhibitors or inducers was prohibited. Results: Dose escalation is complete with 27 pts evaluable for toxicity and 24 evaluable for efficacy. Two DLTs (grade 2 intolerable fatigue, anorexia, vomiting and grade 3 diarrhea) were observed in 6 pts in cohort 1. No DLTs were observed in cohort -1; one DLT (rectovaginal fistula) was observed in the -1b cohort. Possible grade ≥3 treatment-related adverse events any time on study (n=1 except as indicated) included diarrhea (n=2), intestinal perforation/fistula, rectovaginal fistula, hypertriglyceridemia (n=3), hyperglycemia, hypoalbuminemia, hyponatremia, peripheral neuropathy, neutropenia (n=2), lymphopenia, thrombocytopenia, hypertension (n=3), deep vein thrombosis, and arterial thrombosis. Adverse events were consistent with known class-related toxicities. For efficacy, 10 pts had a partial response (PR); 10 had stable disease as best response. Of 13 pts with chemorefractory metastatic colorectal cancer (mCRC), 5 had a PR. Of 8 pts with chemonaive mCRC, 5 had a PR. Conclusions: E in combination with full dose C, O and B was associated with unacceptable toxicity, primarily GI toxicity. E at 5mg five times weekly, C at 680 mg/m2 on days 1-14, O at 100 mg/m2 and B at 7.5 mg/kg on day one appears well tolerated. Activity was noted in chemorefractory and chemonaive mCRC patients.

Background: Preclinical data suggests the combination of IGF-1R inhibitor Ganitumab and mTOR inhibitor everolimus may increase anti-tumor activity compared to each agent alone. Therefore we evaluated the maximum tolerated doses/recommended phase II dose for the doublet combination, Ganitumab (G) plus Everolimus (E) followed by an expanded cohort to better understand the safety and tolerability profile. Methods: For dose escalation, eligible patients had advanced solid tumors with adequate organ function and no increased risk for class-related toxicities. G was given intravenously, and E was orally administered; cycle length was 28 days. G was dosed at 12 mg/kg every 14 days; E was dosed at 5 mg daily in cohort one and 5 mg three times weekly in cohort −1. An intermediate dose of E at 5 mg five times weekly was added to better maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: Dose escalation is complete with 17 subjects evaluable for DLT toxicity and 16 evaluable for efficacy. Two out of 5 subjects experienced DLTs in cohort one due to dose holdings related to grade 3 hematologic toxicities: thrombocytopenia and neutropenia plus thrombocytopenia. No DLTs were observed out of 6 subjects in cohort −1; one DLT was observed out of 6 subjects in the intermediate cohort due to dose holding related to grade 2 intolerable skin rash and oral mucositis. Possible grade 3 treatment-related adverse events included neutropenia, thrombocytopenia, elevated AST/ALT, hypertriglyceridemia, vomiting and erythema multiforme minor. There were no grade ≥4 treatment-related toxicities. One non treatment- related death was due to disease progression. Two subjects had clinically significant skin rashes which resulted in protocol discontinuation. Twelve subjects have available efficacy data; 4 subjects have not yet been restaged. Two subjects with refractory NSCLC achieved a complete response. Six additional subjects had stable disease as best response. Conclusion: The recommended phase II dose for this doublet combination is G at 12 mg/kg every two weeks and E at 5 mg five times weekly. At this dose, this novel regimen is well-tolerated with potential activity in NSCLC. Enrollment in the expanded cohort has started. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B58.

3586 Background: SRC is a non-receptor tyrosine kinase involved in normal and tumor cell signaling functions including cell proliferation, angiogenesis and survival. Dasatinib (D) is a potent inhib...

3548 Background: BV inhibits vascular endothelial growth factor (VEGF). EV is an mTOR (mammalian target of rapamycin) inhibitor. E inhibits epidermal growth factor receptor (EGFR) tyrosine kinase. VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination targeted therapy, we evaluated BV + EV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: Cycle length was 28 days. Doses: BV 10mg/kg IV q14d. EV 5mg PO QD, escalating to 10mg QD. Once the recommended phase II dose (RPTD) of BV + EV was reached, E was added, starting at 75 mg PO QD. DLT was defined as any treatment-related grade 4 heme or grade 3/4 non-heme event in Cycle 1. Results: 34 pts have been enrolled (18 F, 16 M), 28 evaluable for DLT, 24 for efficacy. Median age is 58y (range 29–73). Dose level 1 (BV 10mg/EV 5mg) had no DLT’s. Dose level 2 (BV 10mg/EV 10mg) had no DLT’s and the cohort was expanded to 13 evaluable pts. E (75mg) was added to BV 10mg/ EV 10mg. 2/6 patients had DLT (grade 3 mucositis and grade 3 rash). The doses were adjusted to BV 5mg/EV 5mg/E 75mg. 3 patients had no DLT and this dose is the MTD and RPTD for the 3-drug combination. 20 more patients are being enrolled at the RPTD for biomarker studies. Other grade ¾ toxicity included: nephrotic syndrome, cardiac ischemia, ventricular thrombus, portacath thrombosis, and bowel perforation. 2 patients had PR: 1 renal and 1 osteosarcoma. 16/24 pts had SD (10–112+ weeks). 5/6 patients with colorectal cancer (CRC) previously progressing on BV had SD (16+ - 112 weeks). One CRC patient had 19% radiologic decrease. Conclusions: BV + EV + E preliminary clinical activity (notably in refractory CRC) and class-related side effects were seen. The MTD is BV 5mg/kg IV q14d + EV 5mg PO QD + E 75mg PO QD. Updated data will be presented. No significant financial relationships to disclose.

3097 Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity. E is an mTOR (mammalian target of rapamycin) inhibitor in development for cancer and solid organ transplant therapy. VEGF and mTOR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination anti-angiogenesis therapy, we evaluated BV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: BV was dosed at 10mg/kg IV q14d. E was dosed at 5mg PO QD, escalating to 10mg QD. Cycle length was 28 days. DLT was defined as any grade 4 heme or grade 3/4 non-heme event in Cycle 1 related to treatment. Pts had advanced solid tumors, adequate organ function, and no increased risks for class-related toxicities. Serial blood samples were collected for PK studies of E. Dermal wound angiogenesis assays were performed pre and on treatment for phospho VEGFR2, AKT, mTOR, and S6K. Results: 14 pts have been enrolled (8 F, 6 M), 12 evaluable for toxicity, 14 for efficacy. Median age is 58y (range 29–73). At dose level 1 (BV 10mg/E 5mg) there were no DLT’s in 5 pts. At dose level 2 (BV 10mg/E 10mg), no DLT’s were noted in the initial 3 pts and the cohort was expanded to 9 pts. Side effects were primarily grade 1–2: pain (10/14), mucositis (9/14), anorexia (8/14), rash (7/14), bleeding (7/14), hyperlipidemia (6/14), fatigue (6/14), and HTN (4/14). 1 pt had a myocardial infarction at day 72 and one pt developed nephrotic syndrome at day 70. 7/14 pts had stable disease as best response (70–278d). Conclusions: BV + E is generally well-tolerated. Preliminary clinical activity and class-related side effects were noted. The recommended phase II dose is BV 10mg/kg IV q14d and E 10mg PO QD. [Table: see text]