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5038 Background: Taxane efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients is limited due to resistance development. In preclinical models it has been shown that addition of the androgen receptor signalling inhibitor (ARSI) enzalutamide improves cabazitaxel efficacy. However, we have previously shown that the clinical utility of this combination is hampered by a strong CYP3A4 drug-drug interaction with enzalutamide, resulting in a 22% reduced cabazitaxel systemic exposure. Darolutamide has much weaker CYP3A4 inducing effects and therefore may affect cabazitaxel systemic exposure to a lesser extent. Methods: We investigated the influence of darolutamide on cabazitaxel plasma exposure. mCRPC patients were enrolled on cabazitaxel monotherapy (20 mg/m2 Q3W) on day 1 and received concomitant darolutamide (600 mg b.i.d.) from day 2 onwards for maximal 12 weeks. During cabazitaxel infusion on day 1, and after 6 and 12 weeks of darolutamide treatment, we measured cabazitaxel systemic exposure via Area Under the Curve from 0 to 24 hours (AUC0-24h). Results: Cabazitaxel systemic exposure in 18 patients after 6 weeks of darolutamide was not significantly different compared to prior to darolutamide treatment (AUC0-24h: -4%; 95%CI -19 – +13%; p = 0.58). Also, after 12 weeks of darolutamide treatment, cabazitaxel systemic exposure was unaltered (AUC0-24h: +4%; 95%CI -10 – +20%; p = 0.54). Darolutamide plasma concentrations were constant throughout the study (Table). Conclusions: From a pharmacokinetic perspective cabazitaxel and darolutamide can be safely combined in mCRPC patients. Our findings pave the way for testing the efficacy of this promising combination in an era of combination regimens for prostate cancer. Clinical trial information: NL8611. [Table: see text]

TPS5590 Background: Prostate-specific membrane antigen (PSMA) is a clinically validated therapeutic target for the imaging and treatment of mCRPC. AMG 160 is an HLE BiTE immune therapy designed to redirect T cells to cancer cells by binding to PSMA on cancer cells and CD3 on T cells. BiTE immune therapy leads to direct tumor cell killing, T-cell activation and expansion, and the creation of a pro-inflammatory tumor microenvironment. Combining AMG 160 with a PD-1 inhibitor may enhance antitumor activity by enabling sustained T-cell-dependent killing of tumor cells in the inflamed tumor microenvironment. Methods: NCT03792841 is a phase I study of AMG 160 as monotherapy (part 1) and in combination with pembrolizumab (part 2) in men with histologically/cytologically confirmed mCRPC who are refractory to a novel hormonal therapy (abiraterone, enzalutamide, and/or apalutamide) and have failed 1–2 taxane regimens (or are medically unsuitable or have refused taxanes), who have ongoing castration with total serum testosterone ≤ 50 ng/dL, and have evidence of progressive disease. Patients who received prior PSMA radionuclide therapy may be eligible. Patients with CNS metastases, leptomeningeal disease, spinal cord compression, or active autoimmune disease will be excluded. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of AMG 160 given as monotherapy or in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and preliminary antitumor activity. Exploratory objectives include evaluation of potential pharmacodynamic and patient selection biomarkers, immunogenicity, and patient-reported pain and functional outcomes. The part 1 dose exploration will determine the MTD/RP2D of AMG 160. The part 1 dose expansion will confirm the safety and tolerability of the MTD/RP2D. The part 2 dose exploration will estimate the MTD/RP2D of AMG 160 in combination with pembrolizumab. Evaluation of preliminary antitumor activity will be based on RECIST 1.1 with Prostate Cancer Working Group 3 modifications, PSA response, CTC response, progression-free survival (radiographic and PSA), and overall survival. PSMA PET/CT and FDG PET/CT imaging will be used for evaluation of exploratory objectives. The study opened in February 2019 and is currently recruiting patients into both part 1 and part 2. Clinical trial information: NCT03792841 .

TPS261 Background: AMG 160 is a novel HLE BiTE immune therapy that redirects T cells to kill tumor cells by binding to PSMA on tumor cells and CD3 on T cells. Methods: Primary objectives of this open-label, ascending, multiple-dose, phase 1 study (NCT03792841) are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 160 in men with mCRPC; secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary efficacy. The dose exploration will estimate the MTD or RP2D by Bayesian logistic regression modeling. The dose expansion will assess safety, efficacy, PK, and pharmacodynamics (PD) of the selected dose and provide further safety and efficacy data. PD biomarkers and potential patient selection biomarkers will be explored. Preliminary antitumor activity will be assessed by objective response per RECIST 1.1 with PCWG3 modifications, PSA response, duration of response, time to progression, PFS (radiographic and PSA)/OS, and circulating tumor cell (CTC) response (CTC0 and CTC conversion). Imaging will include CT/MRI, bone scan, 68Ga-PSMA-11 PET/CT, and 18F-FDG PET/CT. In cycle 1, patients will be pretreated with dexamethasone before short-term IV infusion of AMG 160 and will be hospitalized for 72 h after each AMG 160 dose. Key inclusion criteria: age ≥18 y; histologically/cytologically confirmed mCRPC that progressed after novel hormone therapy; failure of 1–2 taxane-based regimens or have refused a taxane regimen; bilateral orchiectomy or continuous androgen-deprivation therapy; evidence of progressive disease; total serum testosterone ≤50 ng/dL. Key exclusion criteria: active autoimmune disease or diseases requiring immunosuppressive therapy (low-dose prednisone permitted); CNS metastases, leptomeningeal disease, or spinal cord compression; prior PSMA-targeted therapy (177Lu-PSMA-617 may be allowed). The study will enroll 30–50 patients in the dose exploration and 50 patients in the dose expansion globally. The study opened in January 2019; dose exploration is ongoing. Clinical trial information: NCT03792841.

3062 Background: MET kinase is a therapeutic target in a range of cancer indications; it is a primary oncogenic driver and a mechanism of therapy resistance. OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2). Methods: This study assesses the safety, tolerability, pharmacokinetics (PK) and preliminary activity of OMO-1 in patients (pts) with advanced malignancies (NCT03138083). Module 1 data, evaluating ascending doses of OMO-1 monotherapy, are reported here. Results: As of January 16, 2019, 34 pts were enrolled at 5 twice-daily (BD) dose levels of OMO-1: 100, 200, 250, 350, and 400 mg, including 10 with MET gene amplified or mutated tumours. OMO-1 was generally well tolerated between 100 - 250 mg BD; pts were in the study for an average of 94 days (range: 15-291 days) and 20/34 pts discontinued due to disease progression. Most frequently-reported AEs were nausea (17/34), vomiting (14/34) and fatigue (14/34), mainly G1-2. Notably, no peripheral oedema, cardiovascular events or non-malignancy related LFT abnormalities were observed. A total of 36 SAEs were reported: 17 in 11 subjects were considered related to OMO-1, and included nausea (3/17), vomiting (4/17), chills, diarrhoea, influenza-like illness (2/17), increased blood bilirubin, blood creatinine (3/17) and neutrophil count, and sepsis. A dose of 250 mg BD was determined as the recommended Phase 2 dose (RP2D); doses ≥350mg BD were not in keeping with optimum long-term dosing: at 400 mg BD, 2/3 subjects experienced influenza-like illness (G2 and G3) and at 350 mg BD 2/5 subjects had G2 fatigue and nausea/vomiting. OMO-1 has a half-life of 2.5-3 hrs and plasma exposure is dose-proportional without accumulation. Elevated creatinine was observed across all dose levels, consistent with OCT2 inhibition. IHC analysis on paired tumour biopsies from a MET-mutated NSCLC pt dosed at 200 mg BD showed near-complete inhibition of phosphorylated MET, without affecting total MET. Conclusions: OMO-1 has a favourable safety profile at a RP2D of 250mg BD. Expansion cohorts for MET mutated/amplified tumour types are enrolling. Clinical trial information: NCT03138083.

e14674 Background: The MET kinase is an established therapeutic target in a range of cancer indications, being a primary oncogenic and therapy resistance driver. Methods: OMO-1 is a highly potent, selective oral inhibitor of MET kinase and Organic Cation Transporter 2 (OCT2) that is currently being explored in a Phase I/II study (NCT03138083). Results: Pre-clinical data for OMO-1 indicates that anti-tumor efficacy against MET driven tumor models does not require 24/7 exposure in the plasma. PK/PD assessments indicate that OMO-1 efficacy is AUC driven. Exposures above a trough concentration of ~600ng/ml for a period of 6-8hr and an AUC of 3000ng.h/ml result in complete target inhibition sufficient to induce regression or stasis of MET driven in-vivo models. Dosing of OMO-1 at 12.5mg/kg BD 4hr apart, or split over 4 doses 2hr apart, with a dosing-free period of 18-20hr was sufficient to obtain the effects preclinically. The ongoing Phase I/II study in patients with solid tumours utilised learnings from the pre-clinical and FIH study (NCT01964872) where ascending single doses and multiple doses were evaluated. The selected starting dose for the patient study (100mg BD, 4 hr apart) achieved exposures above the predicted MBAD. Paired tumor biopsies were obtained from a higher dose level (200mg BD). A MET exon 14 skipping mutation NSCLC patient at this dosed demonstrated near-complete inhibition of phospho MET accompanied by signs of clinical benefit and lesion shrinkage, thereby matching the preclinical data. Certain ‘class effect’ adverse events, such as edema, were not observed. Conclusions: OMO-1 is an oral, potent MET TKI with a novel dosing regime, identified during preclinical optimization (BD 4hr apart), that demonstrates encouraging signs of clinical activity without certain ‘class-specific’ adverse events. Further evaluation of this differentiated and efficacious agent is warranted and ongoing.

190 Background: Data from the KEYNOTE-028 study (NCT02054806) suggested that pembrolizumab (pembro) has clinical activity in a subset of patients (pts) with heavily pretreated neuroendocrine tumors (NET). The KEYNOTE-158 study (NCT02628067) is a phase II basket study investigating the antitumor activity of pembro in 10 specific cancer types. An analysis of the 107 pts included in the NET cohort is presented. Methods: Key eligibility criteria for this cohort included well- and moderately-differentiated NET of the lung, appendix, small intestine, colon, rectum, or pancreas; progression on or intolerance to ≥ 1 line of standard therapy; ECOG PS 0 or 1; and provision of a tumor sample for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until progression, intolerable toxicity, or physician or patient decision. Tumor imaging was performed every 9 wks for the first 12 mo, and every 12 wks thereafter. PD-L1 positivity, defined as a combined positive score (CPS) ≥ 1, was evaluated retrospectively by IHC. Primary endpoint was ORR assessed per RECIST v1.1 by independent central radiology review. Secondary endpoints included DOR, PFS, OS, and safety. Results: 107 pts were treated. Median age was 59 (range, 29-80) y, 44.9% had ECOG PS 1, and 67.3% received ≥ 2 prior therapies for advanced disease. 15.9% of enrolled pts had PD-L1+ tumors. As of the January 15, 2018 data cutoff, the median follow-up duration was 18.6 (range, 0.2-22.7) mo. ORR was 3.7% (95% CI, 1.0-9.3), with 0 CR and 4 PR (3 pancreatic and 1 gastrointestinal [unknown primary]). 61 pts had SD as best response. The 4 responses were observed in pts with PD-L1 negative tumors. Median DOR had not been reached (range, 4.1-15.9+), with 3 of 4 responses ongoing after ≥ 9 mo follow-up. Median (95% CI) PFS was 4.1 (3.5-5.4) mo, and the 6-mo PFS rate was 38.2%. Median OS (95% CI) had not been reached (18.8-not reached), and the 6-mo OS rate was 84.6%. Treatment-related AEs occurred in 75.7% of pts, and the most common was fatigue (21.5%). 20.6% of pts had treatment-related grade 3-4 AEs. Conclusions: Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in pts with previously treated advanced NET. Clinical trial information: NCT02628067.

TPS2614Background: OMO-1, a highly selective, oral, small molecule MET kinase/OCT2 inhibitor, demonstrated single agent cellular and in vivo anti-tumour activity, including regression in MET driven...

e15155Background: High-dose (HD) IL-2 is approved for patients with melanoma and renal cell carcinoma but is associated with significant toxicity, given only in an inpatient setting. RO6874281 is a...

2537Background: Here we present a study combining BAY1217389 (BAY), a potent MPS-1 kinase inhibitor with a backbone chemotherapy paclitaxel. Since we expected overlapping toxicities we sought to im...

5014Background: Recent genome analysis efforts have shown that genomic alterations obtained from primary and metastatic prostate cancer (mPCa) vary widely, stressing the need to obtain comprehensiv...

299 Background: The need for validated circulating biomarkers is well recognised in advanced prostate cancer (PCa). Circulating biomarkers evaluating plasma cell-free nucleic acids and circulating tumour cells are being investigated for their clinical utility. There has been a lack of consensus with regards to analyses, reporting and clinical effectiveness of these biomarkers. A consensus meeting was held to address these issues. Methods: A multi-disciplinary panel comprising 18 international prostate cancer experts (including surgeons, medical and radiation oncologists) were consulted prior to the consensus meeting. Four key areas relating to the field of circulating biomarkers were deemed important for discussion: 1) The current utility of circulating biomarkers in 2017; 2) The clinical needs for circulating biomarkers in PCa; 3) The most pressing blood-based molecular assays required; and 4) The steps necessary for developing circulating biomarkers. Using a modified Delphi process, 50 consensus questions were pre-defined for the panel to answer by voting anonymously but publicly at the consensus meeting. Results: A consensus was declared (i.e. ≥ 75% of panellists who did not vote ‘unqualified’ or ‘abstain’ chose the same opinion) in 12/50 (24%) questions. A further 8/50 (16%) of replies were close to reaching consensus (≥ 60% of panellists choosing the same answer). The panel agreed that there is a very high and urgent unmet need for predictive biomarkers, with consensus that DNA repair biomarkers in particular are needed urgently. Metastatic PCa was identified as having the highest clinical need for development of biomarkers to measure response and as surrogate endpoints. Panellists unanimously voted that reproducibility validation studies are of paramount importance. The consensus panel also predicted that cfDNA will impact practice by 2020. Conclusions: This expert consensus identified the need for clinical trials of validated circulating biomarkers to develop predictive, response and surrogacy assays. These could have major clinical and healthcare economic implications, minimizing over-treatment and allowing the delivery of more precise patient care.

8530 Background: The majority of SCLC cases are diagnosed as ED, for which there is a poor prognosis and no curative treatment (Tx). V, a potent PARP inhibitor, has been shown in preclinical studies to enhance the antitumor activity of platinum-based agents and E against SCLC. The presented phase 1 dose-escalation (NCT02289690) evaluated V combined with Cb/E. Methods: Pts (≥18 years) with ED SCLC or other advanced/metastatic solid tumors with ≤1 line of prior cytotoxic therapy and ECOG performance score 0/1 were included. This study followed a 3+3 design. V starting dose and schedule were 80 mg BID PO administered on days (D) –2 to 5 in combination with Cb AUC 5 mg/mL•min administered on D 1 and E 100 mg/m2 administered on D 1 to 3 via intravenous infusion in 21-D cycles. V schedules of D –2 to 12 and continuous dosing were also explored. Primary objectives were to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for V combined with Cb/E, and to evaluate the pharmacokinetic (PK) interaction between V and E. Results: Thirty-nine pts (n = 24 ED SCLC; n = 15 other solid tumors) with median age of 62 years (range 43–79) received study Tx. Most common adverse events (AEs; ≥40%) were nausea (54%), fatigue (51%), alopecia (46%), and anemia (44%); grade 3/4 AEs (≥30%) were decreased neutrophil count, neutropenia (31% each), and anemia (26%). Dose-limiting toxicity occurred in 1 pt (n = 1 grade 3 fatigue) at V 240 mg BID D –2 to 5. The MTD was not reached; RP2D for V was set at 240 mg BID on D –2 to 12 based on long-term tolerability. Continuous dosing of V 240 mg BID with Cb/E resulted in unacceptable Cb/E dose delays due to hematologic toxicity. Coadministration of V (80 to 240 mg BID) with Cb/E exhibited dose-proportional kinetics with no impact on the E PK. Confirmed responses: ED SCLC 63% (15/24 pts) across all dose levels and in 83% (5/6) at RP2D; other tumor types: 13% (2/15) across all dose levels. Conclusions: V + Cb/E had an acceptable safety profile in pts with ED SCLC, with an RP2D of 240 mg BID D –2 to 12. Coadministration of V with Cb/E had no effect on E PK. Responses were seen across all dose levels. A phase 2 study of V with Cb/E in ED SCLC is ongoing. Clinical trial information: NCT02289690.

188 Background: Cabazitaxel and enzalutamide are effective single agent treatment options for metastatic castration resistant prostate cancer (mCRPC). Preclinical studies suggest enhanced efficacy of the combination of a taxane with enzalutamide. Recently, Morris et al. (CCR 2016) reported on an interaction study between docetaxel and enzalutamide: docetaxel mean exposure decreased by 12% during a short period of co-treatment with enzalutamide, probably due to enzyme (CYP3A4) induction. Since cabazitaxel is a CYP3A4 substrate, we investigated the influence of enzalutamide on cabazitaxel pharmacokinetics (PK) and toxicity during 3 chemotherapy cycles. Methods: We performed a cross-over study in 14 evaluable mCRPC patients who were treated with i.v. cabazitaxel Q3W (25 mg/m2). PK-sampling (over 24h) was conducted on day 1 of each cycle during 3 consecutive cabazitaxel cycles. From day 8 (±1) of the first cycle until day 8 (±1) of the third cycle, enzalutamide (160 mg/day) was administered concomitantly. Primary endpoint was the difference in geometric mean area under the curve (AUC0-24h) between the first and third cycle. Secondary endpoints included safety parameters and PSA response. Results: The AUC was 22% (95%CI 9-34%) lower during the third cycle (181 ng*h/mL, 95%CI 150-219 ng*h/mL) than during the first cycle (234 ng*h/mL, 95%CI 209-261 ng*h/mL; p = 0.005). No relevant adverse events occurred due to the drug combination. Nine patients (64%) received the full dose of cabazitaxel during the 3 study cycles. No enzalutamide dose reductions took place, and the combination was well tolerated. PSA response ( ≥ 50% decrease of baseline PSA ) was observed in 10 patients (71%). Conclusions: Cabazitaxel exposure is both statistically and clinically significantly reduced by concomitant enzalutamide use. Since the PROSELICA study (De Bono et al, ASCO 2016) may lead to an adapted standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be extensive, since it is likely to result in suboptimal exposures. We stimulate clinical studies with this combination, but these should include monitoring of the PK of cabazitaxel, and appropriate dose adaptations. Clinical trial information: NTR5164.

4550Background: Targeted agents have improved survival in ccRCC patients but resistance always develops. Since accumulating evidence suggests that resistance is partially reversible after drug with...

9551 Background: Phase I trials are essential for progress in cancer treatment but the reasons for patients to participate in these trials remain relatively ill-explored (Van der Biessen et al, 201...

3514 Background: In contrast to BRAFV600 mutated (BRAFm) advanced melanoma, BRAFm colorectal carcinoma (CRC) does not respond to BRAF inhibitors due to strong feedback activation of the epidermal g...

9009 Background: NRAS-mutant melanoma has poor prognosis with no approved targeted therapies. Enhanced MAPK pathway signaling and cell cycle checkpoint dysregulation are frequent in NRAS-mutant mel...

2536 Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-foot-syndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC0-∞ increased 1.58-fold (90%CI: 1.09–1.29) and Cmax increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n=7). Pazopanib AUC0-24 and Cmax ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC0-∞) and 1.78-fold (Cmax). Clinical trial information: NCT00732420.

2522 Background: The Human Epidermal Growth Factor Receptor 3 (HER3) is a key heterodimerization partner for other HER family members thereby acting as a downstream signal amplifier. This is a first in human study evaluating the safety of RG7116, a humanized anti-HER3 monoclonal antibody with potent HER3 signal inhibition. Due to a glycoengineered Fc-part this antibody displays enhanced antibody-dependent cellular cytotoxicity as compared to conventional antibodies. Methods: Patients (pts) with advanced or metastatic carcinomas with centrally confirmed HER3 protein expression were included. A “3+3” dose escalation design was performed starting at 100 mg flat dosing in a q2w regimen. In addition to single agent RG7116 (Part A), RG7116 plus cetuximab (Part B) and RG7116 plus erlotinib (Part C) combinations are evaluated. The results of Part A are presented. Results: Twenty-five pts have been enrolled in 6 cohorts (100 to 2000 mg). No DLTs were observed. Pts had a median (range) of 3 (2 to 6) prior chemotherapy lines. Nine infusion-related reactions (IRRs) Gr 1 to 3 occurred in 7 pts. Three drug-related AEs Gr 3 were reported, 1 IRR, 1 GGT increase, and 1 neutropenia. Only 1 patient was tested positive for human anti human antibodies (HAHA). The PK of RG7116 was non-linear from 100 mg up to 400 mg, possibly as a result of target-mediated drug disposition. Both Cmax and AUC showed a greater than doseEproportional increase over the same dose range, accompanied by a decline in total clearance. Dose proportionality was observed from 800 mg onwards. PD effects were observed from the first dose level onwards with HER3 membranous protein down-regulation in skin and from 200 mg onwards in ontreatment tumor samples. Five pts (1 NSCLC, 2 CRC, 1 SCCHN, 1 BC) had a best response of SD. Confirmed SD (>16 weeks) was observed in 2 pts. One BC patient achieved a PR in 18 FDG-PET and significant shrinkage of non-target tumor lesions on CT scan. Conclusions: RG7116 is the first glycoengineered monoclonal anti-HER3 antibody in clinical development. RG7116 monotherapy was well tolerated, and demonstrated preliminary signs of clinical activity. Clinical trial information: NCT01482377.

2596 Background: Sunitinib treatment shows a clear dose-efficacy relationship. However, due to large inter-individual variations in plasma exposure, target total trough levels (> 50 ng/mL) are frequently not reached with the current dosing schedule. Therefore, a prospective Phase I study was performed to determine the safety and feasibility of PK-guided dosing of sunitinib. Methods: Thirty patients with solid tumors with a potential benefit from sunitinib treatment were included. Patients were treated continuously with sunitinib 37.5 mg once daily. At day 15 and 29 of sunitinib treatment, plasma trough levels of sunitinib and its active metabolite (N-desethyl sunitinib) were measured. If the total trough level (TTL) was < 50 ng/mL and the patient did not show any ≥ grade 3 toxicity (CTCAE 4.02), the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from ≥ grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg. After 8 weeks a final TTL evaluation was performed. Results: All 30 patients started treatment and in 18 patients all 3 TTLs were measured at the time of this analysis. Given TTL < 50 ng/mL and < grade 3 toxicity, a first sunitinib dose increase could be applied in 10 patients and a second dose increase in 2 patients at day 15 and 29, respectively. At day 15, day 29 and 8 weeks of treatment, mean TTLs were 49.7 ng/mL (coefficient of variation (CV) 27.7%), 62.4 ng/mL (CV 35.5%) and 56.7 ng/mL (CV 47.8%), respectively. At day 15, using the sunitinib standard dose of 37.5 mg, target TTLs were reached in 8 patients (44%). At 8 weeks, the mean sunitinib daily dose intensity was increased to 40.3 mg (standard deviation (SD) ± 11.0). At the end of the 8 week study period, 5 out of 18 patients (28%) were still at an increased sunitinib dose level without additional side effects. In these patients the mean daily sunitinib dose was 55.0 mg (SD ± 6.8) and their final TTLs were all > 50 ng/mL (mean: 70.8 ng/mL (CV 29.8%)). Using PK-guided sunitinib dosing, target TTLs were reached in 10 out of 18 patients (56%) at the final TTL evaluation, compared to 44% at day 15 before any dose adjustment. Conclusions: Individual PK guided dosing is feasible and enables a significant increase in sunitinib dose intensity without causing additional toxicity.

4056 Background: Recent advances in pancreatic cancer research implicate the involvement of several heparin-binding growth factors (such as HGF, HB-EGF, PDGF, hedgehogs, and TGFs) that control tumor-stroma interactions. We have rationally designed a heparan sulfate mimetic, M402, which has been previously shown to affect tumor progression and metastasis through disruption of multiple pathways. We hypothesized that M402 could modulate tumor-stroma interactions and enhance the efficacy of gemcitabine, and evaluated its efficacy in two preclinical models. Methods: A genetically engineered mouse model (GEMM; KrasLSLG12D p53LSLR172H) featuring spontaneous pancreatic tumor formation and metastasis assessed M402’s effect on tumorigenesis and metastasis. The orthotopic Capan-2 model in nude mice evaluated the effect of M402 on desmoplasia, a fibrotic response that hinders effective delivery of chemotherapeutics, via inhibition of sonic hedgehog (SHH) signaling in fibroblasts and stellate cells. In both models, M402 was studied as monotherapy and with gemcitabine. Results: In the GEMM, M402 significantly prolonged survival in combination with gemcitabine while each monotherapy showed modest efficacy. M402, alone and in combination, also reduced metastases and local invasion and inhibited epithelial-to-mesenchymal transition. In the Capan-2 model, gemcitabine was increasingly less effective as desmoplasia progressed over time. The addition of M402 to gemcitabine increased its efficacy with respect to primary tumor burden. Metastasis, invasion, and surrounding fibrotic lesions appeared particularly impacted by the combination treatment. M402 was also effective as monotherapy with dose-dependency, which correlated with reduced SHH signaling. Conclusions: M402 can modulate tumor-stroma interactions involved in the metastatic and desmoplastic pathways in two pancreatic cancer models supporting the translation of these findings into a clinical study. A first-in-human study is planned that will evaluate the safety, pharmacokinetics, efficacy, and biomarker profiles of escalating M402 doses in combination with gemcitabine in patients with metastatic pancreatic cancer.

3018 Background: Phosphatidylinositol 3-kinase (PI3K) is critical to cancer cell growth, survival, and metabolism. GSK458 is an oral, potent inhibitor of PI3K (α, β, γ, δ), mTORC1, and mTORC2. Preclinically, GSK458 has demonstrated broad anti-tumor activity against solid tumors and hematologic malignancies in vitro and in vivo. Cell lines with common activating mutations of PIK3CA are particularly sensitive to GSK458. Methods: Adult patients (pts) with relapsed or refractory advanced solid tumors received GSK458 by mouth daily until disease progression or toxicity. Dose escalation used a modified accelerated titration scheme. Expansion cohorts further evaluated pharmacodynamics (PD), pharmacokinetics and clinical activity in specific target populations. Results: Preliminary data reveal that 78 pts (51% female) with mean age of 57 (25-85) yrs received ≥1 dose of GSK458. Doses ranged from 0.1 to 3 mg. Maximum tolerated dose was 2.5 mg daily. AUC and Cmax increased with dose. Across doses: median Tmax was 2 ...

3045 Background: Telatinib (BAY 57-9352) is an oral tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR-2). Bevacizumab is a monoclonal anti-VEGF-A antibody. ...

11002 Background: Recently we have shown that in preclinical models and in cancer patients certain types of chemotherapy can induce an acute release of progenitor cells (Shaked et al, Cancer Cell 2008). In the preclinical models these cells diminished the efficacy of chemotherapy. Little is known of the kinetics of circulating endothelial (progenitor) cells (CE(P)C) release after chemotherapy in humans and their respective temporal functionality. Here we investigated the temporal changes in CE(P)C release after chemotherapy. Methods: Patients with mainly advanced cancer treated with various types of MTD chemotherapy were included. Blood sampling was performed at base line, 4 hours, 7 and 21 days after start chemotherapy. The mononuclear cell fraction was analyzed for CE(P)C as previously described (Duda et al, Nature Protocols 2007) Response to chemotherapy was assessed after 3 cycles of chemotherapy following the RECIST criteria. Progression free survival (PFS) was monitored. Wilcoxon matched pairs test, Spearman correlation and the Kaplan-Meyer method were used. Results: 69 patients were included, 49 were evaluable for the complete data set. In all patients treated with paclitaxel there was an immediate increase in EPC 4 hours after start of treatment (median 246% (p No significant financial relationships to disclose.