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Background Ineffective chemotherapy may partly be caused by subtherapeutic intratumoral drug levels. Nanomedicines are developed to improve the therapeutic index, by increasing intratumoral drug exposure and preserving healthy tissue. CPC634 is a new nanoparticle entrapping docetaxel. Here, we hypothesized that CPC634 increases intratumoral docetaxel level and overall duration of exposure. Methods In this randomized cross-over study we assessed both plasma and intratumoral pharmacokinetics (PK) of docetaxel after intravenous administration of 75 mg/m2 conventional docetaxel (Cd) and CPC634. We aimed to identify a 25% increase of intratumoral docetaxel exposure after CPC634 infusion compared to Cd. Adult patients were randomized to receive Cd in cycle 1 and CPC634 in cycle 2 or vice versa. Tumor biopsies were taken 24, 48, 72, 96, 168 or 336 hours after infusion during both cycles. Total docetaxel concentration (TDC) was determined for both drugs and released docetaxel for CPC634 in tumor tissue and plasma. PK data were analyzed using mixed modeling. Results In total, 21 evaluable patients were included. In plasma, the area under the curve (AUCinf) of released docetaxel was higher (+27%, 95% CI: 11-44%, P = 0.001) while peak plasma concentration (Cmax) (-91%, 95% CI: -92:-89%, P Conclusions The plasma PK profile of CPC634 is favorable compared to Cd since a lower Cmax, lower clearance and prolonged higher systemic exposure is seen. Higher intratumoral TDC levels were reached with CPC634, while released docetaxel levels were comparable to Cd. The almost 4-fold increased tumor accumulation for prolonged period of time of TDC supports the expectation that CPC634 will exhibit beneficial efficacy/safety balance. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in platinum resistant ovarian cancer patients (NCT03742713) are currently ongoing. Clinical trial identification Netherlands Trial Registry NL6299 (NTR6474). Legal entity responsible for the study Prof. Dr. A.H.J. Mathijssen as principle investigator. Funding Cristal Therapeutics. Disclosure C.J.F. Rijcken: Officer / Board of Directors: Cristal Therapeutics; Leadership role: Cristal Therapeutics; Shareholder / Stockholder / Stock options: Cristal Therapeutics; Full / Part-time employment: Cristal Therapeutics. R. Hanssen: Full / Part-time employment: Cristal Therapeutics. R.H.J. Mathijssen: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier; Honoraria (institution): Novartis; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Astellas. S.L. Koolen: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. All other authors have declared no conflicts of interest.

showed no meaningful change in median dynamic parameters but did have a significant reduction in viable fraction. Analyzable diffusion data were available for 51/61 patients; 16 patients demonstrated a greater than 30% on-treatment increase in ADC. 15 of these patients were dosed at 30mg/kg. Conclusions: Reduction in median dynamic parameters reflective of vessel permeability and perfusion was observed in 62% of patients. On the Q2W schedule, sustained decrease across all time-points was only observed at 30mg/kg. Increase in ADC was primarily observed in patients treated at 30mg/kg. The DCE-MRI and DW-MRI findings of ontreatment decrease in tumor vessel permeability, perfusion and cellular density support the proposed anti-angiogenic mechanism of action of Vanucizumab.

3043 Background: PI3K pathway is frequently altered in cancer and can have an impact on tumor survival and proliferation. BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor with...

2518 Background: N (ABT-263) is a first-in-class orally available Bcl-2 protein inhibitor that in vitro and in vivo potentiates D activity across a variety of solid tumor types. This phase I study ...

549 Background: Tivozanib (AV-951), a highly potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, has shown additive antitumor activity with fluorouracil (5-FU) in preclinical studies. An open-label phase Ib study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and antitumor activity of escalating doses of tivozanib combined with standard-dose FOLFOX6 (i.e., oxaliplatin, leucovorin, and 5-FU) in pts with advanced GI tumors. Methods: Tivozanib was administered orally once daily in 4-week cycles (3 weeks on, 1 week off), with FOLFOX6 administered on days 1 and 15 of each cycle. Pts were allowed to continue tivozanib following discontinuation of FOLFOX6. Results: 22 pts (14 male/8 female; median age of 58 years [range, 40-75]) received 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 10) tivozanib plus FOLFOX6. Pts received a median of 8.1 weeks (range, 0.1 - 43.1) of treatment. DLTs were observed in 2 pts receiving 0.5 mg tivozanib (reversible grade 3 diarrhea and grade 3 and 4 transaminase elevations, respectively) and in 2 pts receiving 1.5 mg tivozanib (reversible grade 3 seizures and grade 3 vertigo, respectively). Other grade 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n = 2 each); and pyrexia, pulmonary embolism, and thrombosis (n = 1 each). There was no indication that drug-related AEs in this study were more frequent or severe than those observed with tivozanib or FOLFOX6 alone. The MTD was 1.5 mg tivozanib with full dose FOLFOX6. The PK profiles of tivozanib, oxaliplatin, and 5-FU will be presented. Several durable partial responses were observed. Additional safety and efficacy data are being obtained in 8 pts currently being treated at the 1.5-mg dose level. Conclusions: The combination of tivozanib and FOLFOX6 is tolerable and safe, with tivozanib given at its recommended dose of 1.5 mg. Observed clinical activity merits further exploration in several GI tumors, and these studies are being planned. [Table: see text]

2552 Background: CHR-3996, a class 1 selective HDACi inhibiting HDAC 1, 2, and 3 at low nanomolar concentrations, demonstrated antitumor activity in several xenograft tumor models. Objectives of th...

3023 Background: Ob is a tubulin binding vascular disrupting agent, derivative of combretastatin A4. In preclinical studies synergistic activity between Ob and D has been observed. Methods: Study objectives were to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic (PK) profile, preliminary antitumor activity, and to assess potential predictive biomarkers of the combination of Ob (day 1) followed by D (day 2) once every 3 weeks. Results: Forty-eight pts (M/F 17/31), median age 53 (range 28-71), were treated in 2 cohorts: D 75 mg/m2 with Ob 11.5, 15.5, 20, 25, 30, 35, or 42 mg/m2 and D 100 mg/m2 with Ob 30 or 35 mg/m2. Median number of cycles per pt was 3.5 (range 1-22). The most common tumor types were breast (n=18, including 6 triple negative pts) and oesophagus (n=9). First cohort MTD was 35/75 mg/m2 with 2 DLTs (grade 3 headache and asthenia) reported at 42/75 mg/m2. Second cohort MTD was 30/100 mg/m2 with grade 3 asthenia and deep vein thrombosis reported at 35/10...

3507 Background: Aurora proteins belong to a family of serine/threonine kinases that are key regulators of different steps in mitosis. AKs were found to be implicated in tumorigenesis and overexpre...

3540 Background: Mapatumumab (TRM-1, HGS-ETR1) is a fully human agonistic monoclonal antibody that binds and activates the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Mapatumumab combined with gemcitabine (gem) and cisplatin (cis) resulted in increased cytotoxicity in human cancer cell lines and mouse xenograft models. Administration of mapatumumab as a single agent appeared to be safe in prior phase I and II studies. In this phase 1 study we evaluated the safety, tolerability and pharmacokinetics (PK) of mapatumumab in combination with gem and cis. Methods: Gem 1,250 mg/m2 IV on days 1 and 8 and cis 80 mg/m2 IV on day 1 every 21 days was administered to patients (pts) with advanced solid malignancies for a maximum of 6 cycles. Escalating doses of mapatumumab were administered IV every 21 days. Planned dose levels were 1, 3, 10, 20 and 30 mg/kg. PK analysis of plasma mapatumumab, gem, dFdU, unbound and total platinum was performed in the first two cycles. Formation of an...

3025 Background: BIBW 2992 is a highly selective, potent, irreversible tyrosine inhibitor of EGFR and HER2. A phase 1 study of orally administered BIBW 2992 was performed to determine its safety, PK and PD. Methods: Patients (pts) with advanced solid malignancies received BIBW 2992 once daily (OD) for 2 weeks, in 4 week cycles. Adverse events were evaluated according to CTCv3.0 and tumor response according to RECIST. In cycle 1 and 2, BIBW 2992 plasma PK analysis was performed. Before and after cycle 1, biomarkers involved in EGFR activation were assessed in skin biopsies. Results: 38 pts received 10 mg (n=3), 20 mg (n=3), 30 mg (n=3), 45 mg (n=3), 70 mg (n=18), 100 mg (n=2) and 85 mg (n=6) OD. At 100 mg dose-limiting toxicities (DLTs) consisted of grade 3 skin rash (n=1) and grade 3 diarrhea despite loperamide (n=1). At the dose level of 85 mg, DLTs were seen in 2 pts (diarrhea in both). An additional 12 pts were subsequently enrolled at 70 mg. A total of 3 DLTs was seen in the 18 pts treated at 70 mg (all 3 diarrhea, in one case with additional grade 3 nausea and ALT increase). In other pts, diarrhea was controllable with loperamide, whereas skin events could be ameliorated with minocycline. The dose of 70 mg BIBW 2992 OD was therefore set as the recommended phase 2 dose. Exposure (AUC0-∞ and AUCτ,ss range 82–2080 ng·h/mL) and peak plasma concentrations (Cmax and Cmax,ss range 7–150 ng/mL) increased with increasing doses. High interpatient variability in all PK parameters was found, but was within the range expected for an orally administered drug. The volume of distribution (Vz/F) ranged from 800–2900 L, indicating high tissue distribution. Median tmax values ranged between 1–4 h. The gMean terminal t1/2 ranged between 13–32 h. Accumulation ratio based on AUC was between 2–2.9. Steady state was reached around day 8. After cycle 1, a >20% reduction in Ki-67 (range 20–83%), reflecting inhibition of keratinocyte proliferation, was seen in paired skin biopsies of 31 pts. Ki-67 positive cells (mean ± SD) decreased from 14 ± 4.5% pre-treatment to 7.9 ± 4.5% on day 13 (p [Table: see text]

3040 Background: BAY 57–9352 is a potent competitive inhibitor of the VEGFR-2 (IC50: 6 nM), VEGFR-3 (IC50: 4 nM), PDGFR-β and c-KIT tyrosine kinases. BAY 57–9352 showed tumor efficacy in colon, breast, pancreatic and NSCLC models. Methods: Patients with advanced solid tumors received oral BAY 57–9352 on a continuous basis, in escalating doses. One cycle was defined as 21 days of treatment. Extensive PK and PD (dynamic contrast-enhanced MRI [DCE-MRI]) evaluations were performed. Plasma biomarkers (e.g. VEGF)were also evaluated. Results: Forty patients (median 54 yrs) were enrolled at seven dose levels from 20 mg solution once daily to1500 mg twice daily (bid; 150 mg tablets) for a total of 169 cycles (range 1–17). The most frequent drug-related adverse events were nausea, hypertension, headache, vomiting, hoarseness, rash, dry skin and anorexia. One patient treated at 600 mg bid had a dose-limiting toxicity defined by an increase from grade 2 to 3 hypertension, despite the addition of an ACE-inhibitor and Ca-antagonist on day 8 of cycle 2. Another patient at that same dose level and also on day 8 cycle 2, had grade 3 AST/ALT increase, however this was not assessed as dose-limiting. Both patients continued treatment after dose reductions. Treatment was well tolerated, even at the highest dose levels. One patient with a hemangio-endothelioma (600 mg bid) had a clinical response and one desmoid tumor patient (900 mg bid) had a 53% reduction in tumor volume. BAY 57–9352 AUC increased dose proportionally up to 900 mg bid. The target AUC, based on animal models (5 mg × h/L) was reached in all patients at 900 mg bid. Dose levels exceeding 900 mg bid had similar plasma VEGF biomarker levels. Conclusions: BAY 57–9352 was well tolerated in doses up to 1500 mg bid. Based on safety, PK, PD and biomarker assessments, the recommended dose level is 900 mg bid. A 300 mg tablet is being tested for patient convenience. Combination chemotherapy studies have been started. [Table: see text]

2034 Background: KRN951 inhibits VEGF induced phosphorylation of VEGF receptors (VEGFR)2 and 1 (IC50 of 0.16 and 0.21 nM) and phosphorylation of c-Kit and Platelet Derived Growth Factor Receptor (PDGFR), (IC50 of 1.63 and 1.72 nM). Methods: The principal objectives of this study were (1) to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of KRN951 administered once daily (OD) for 28 days followed by 14 days off treatment, (2) to characterize safety and tolerability, (3) to characterize single and multiple dose pharmacokinetics, (4) to explore inhibitory effects on tumor blood flow, and (5) to look for evidence of antitumor activity. Results: 10 male and 5 female patients, median age 57 yrs (28–72) have been enrolled at dose levels of 1 mg (n=6), 2 mg (n=8), and 1.5 mg (n=1). The total number of courses given is 63 (1–15 per patient) At 2 mg DLT consisting of grade 3 asymptomatic proteinuria, grade 3 ataxia and grade 4 intracranial hemorrhage was seen in three patients. In the next-lower dose level of 1 mg one DLT (grade 3 fatigue) was seen. An intermediate dose of 1.5 mg is currently studied. Hypertension occurred in 14/15 patients but could be medically controlled. Pharmacokinetic analysis revealed dose dependent drug exposure and peak plasma concentrations. Plasma levels of sVEGFR2 decreased following exposure to KRN951. Exploratory analysis by means of Dynamic Contrast Enhanced MRI analysis indicated a decrease in tumorperfusion in selected patients. One confirmed partial response lasting more than 80 weeks in a patient with renal cell carcinoma was seen, and stable disease lasting more than 2 courses of treatment was seen in 6 patients. Conclusion: Once daily KRN951 can be administered safely when given for 28 days followed by 14 days off treatment. The recommended phase II dosing is currently being defined. No significant financial relationships to disclose.

3035 Background: BAY 57–9352 (BAY) is a potent anti-angiogenic drug that inhibits VEGFR-2, as well as VEGFR-1, VEGFR-3, PDGFR-β, and c-Kit tyrosine kinases. Molecular biomarkers of angiogenesis (VEGF165, soluble VEGFR-2 [sVEGFR-2], basic FGF [bFGF], and interleukin-8 [IL-8]) were used to assess the pharmacodynamic effects of BAY. Methods: Patients with advanced solid tumors from two Phase I studies received oral BAY on either an intermittent 21 day cycle (14 days on drug, 7 days off drug) or continuous schedule (21 day cycle). Doses were escalated from 20 mg once daily (od) to 1500 mg twice daily (bid). Molecular biomarkers were measured at baseline, pre-dose, and 8 hours post-dose on Days 1 and 14 of each cycle. Pharmacokinetic parameters of BAY were also assessed. Results: Plasma samples from 130 patients were analyzed for angiogenic biomarkers. Increased VEGF165 and decreased sVEGFR-2 clearly correlated with the dose of BAY, respectively. All clinical responders (as shown by tumor shrinkage) were located within the upper 10% of the total response distribution for these markers. Subgroup analysis in the three more prevalent tumors showed that patients with colorectal, renal cell, and hepatocellular carcinoma all showed biomarker responses exceeding the mean overall responses. Biomarker levels reached a plateau at daily doses of approximately 900 mg bid or 1800 mg, suggesting a saturated pharmacodynamic effect. There were no consistent changes in bFGF and IL-8. Conclusions: Both VEGF and sVEGFR-2 demonstrated a dose-dependent change with BAY 57–9352. VEGF and sVEGFR-2 may be appropriate biomarkers of the therapeutic effects of BAY, and may be useful as potential predictors of early response. [Table: see text]