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Background The role of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer is unknown. This non-randomized dose-finding phase I–II study was designed to assess the safety and feasibility of HIPEC, following systemic chemotherapy, in patients with gastric cancer and limited peritoneal dissemination. The maximum tolerated dose of normothermic intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin was also explored. Methods Patients with resectable cT3–cT4a gastric adenocarcinoma with limited peritoneal metastases and/or tumour-positive peritoneal cytology were included. An open HIPEC technique was used with 460 mg/m2 hyperthermic oxaliplatin for 30 min followed by normothermic docetaxel for 90 min in escalating doses (0, 50, 75 mg/m2). Results Between 2014 and 2017, 37 patients were included. Of 25 patients who completed the full study protocol, four were treated at dose level 1 (0 mg/m2 docetaxel), six at dose level 2 (50 mg/m2) and four at dose level 3 (75 mg/m2). At dose level 3, two dose-limiting toxicities occurred, both associated with postoperative ileus. Thereafter, another 11 patients were treated at dose level 2, with no more dose-limiting toxicities. Based on this, the maximum tolerated dose was 50 mg/m2 intraperitoneal docetaxel. Serious adverse events were scored in 17 of 25 patients. The reoperation rate was 16 per cent (4 of 25) and the treatment-related mortality rate was 8 per cent (2 patients, both in dose level 3). Conclusion Gastrectomy combined with cytoreductive surgery and HIPEC was feasible using 460 mg/m2 oxaliplatin and 50 mg/m2 normothermic docetaxel.

Background: BYON3521 is a novel c-MET targeting antibody-drug conjugate (ADC) with a cleavable linker-duocarmycin (vc-seco-DUBA) payload that causes irreversible alkylation of DNA in tumor cells. BYON3521 has demonstrated potent and selective killing of c-MET expressing tumor cells in preclinical models, even at low c-MET expression levels. In addition, in vitro studies showed that the active toxin can passively permeate the cell membrane and kill neighboring, c-MET negative cells as a bystander effect. Methods: Patients with previously treated progressive locally advanced or metastatic solid tumors, c-MET positive membrane staining by immunohistochemistry and/or MET-amplified by dual in situ hybridization and/or known activating MET-mutation (excluding exon14m), ECOG performance status 0-1 and adequate organ function are eligible for the dose-escalation part of this first-in-human trial (ClinicalTrials.gov identifier: NCT05323045). An adaptive approach using the Continual Reassessment Method of Neuenschwander (N-CRM model) is used to evaluate the safety of BYON3521 and to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE). BYON3521 is administered intravenously every three weeks until tumor progression or unacceptable toxicity. Results: Up to 01 January 2023, 8 patients (1F, 7M, median age 61 yrs) were enrolled. Tumor types were: 4 colorectal cancer, 1 NSCLC, 1 renal cell carcinoma, 1 esophageal cancer and 1 pancreatic cancer. One patient received 0.8 mg/kg, three patients each 1.6 and 3.2 mg/kg and one patient received 4.8 mg/kg. So far, no grade 3 or 4 related adverse events and no dose-limiting toxicities (DLTs) occurred. Most commonly observed related AEs were decreased appetite/weight, fatigue, abdominal pain, back pain, vomiting and chills. Typical ADC associated AEs as keratitis and pneumonitis have not been observed so far. Stable disease was the best response observed in 2 patients at a dose of 3.2 mg/kg. Human PK was in line with predicted preclinical in vivo PK. Conclusions: To date, BYON3521 is well-tolerated with no DLTs at the investigated dose levels. Patient enrollment is ongoing and updated safety, efficacy and pharmacokinetic data will be presented. After the dose-escalation phase the trial will continue with expanded cohorts of patients with specific c-MET expressing cancer types. Citation Format: N. Kotecki, C.M.L. van Herpen, C. Curigliano, M. Hendriks, T C. Vermaas, L. Corrigan, C. Belli, C. Jungels, I.M.E. Desar, N.P. Koper, J.H.M. Schellens, U. Banerji. First in human dose-escalation trial with the c-MET targeting antibody-drug conjugate BYON3521 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT185.

Background KRAS oncogene mutations are causing sustained signaling through the mitogen-activated protein kinase (MAPK) pathway resulting in uncontrolled cell growth. Efforts to target KRAS directly or to inhibit downstream effectors have been unsuccessful. Preclinical research revealed that KRAS mutated (KRASm) cells are intrinsically resistant to MEK inhibitors due to upstream growth receptors that reactivate the MAPK and phosphoinositide 3-kinase (PI3K) pathway. Concurrent inhibition of MEK, EGFR and HER2 resulted in synergistic anti-tumor activity, with complete inhibition of tumor growth in vitro and in vivo. Methods This is a single-center, phase I dose-escalation study to assess the safety, tolerability and anti-tumor activity of the MEK inhibitor trametinib combined with the dual EGFR/HER2 inhibitor lapatinib in patients with advanced KRASm and PIK3CA wildtype colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and pancreatic cancer. Patients received escalating doses of continuous or intermittent, once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg, respectively. The primary objective was to determine the recommended phase 2 dose (RP2D) and schedule. Results Thirty-four patients with CRC (n = 16), NSCLC (n = 15) or pancreatic cancer (n = 3) were enrolled across five dose-levels, 2 patients are still on treatment. Dose-limiting adverse events were reported in twelve patients; grade 3 diarrhea (n = 3), rash (n = 2), nausea (n = 1), several grade 2 toxicities (n = 1) and aspartate aminotransferase elevation (n = 1) resulting in inability to receive 75% of the planned doses (n = 2) or treatment delay (n = 2). The established RP2D was 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Out of 22 patients evaluable for response, regression of target lesions was seen in six, with one confirmed partial response in NSCLC. Reductions in pERK and pS6 levels were demonstrated in paired tumor biopsies. Pharmacokinetic results were as expected. Conclusions Lapatinib and trametinib could be combined in an intermittent dosing schedule with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed with sufficient target engagement. Clinical trial identification NCT02230553. Legal entity responsible for the study The Netherlands Cancer Institute. Funding Novartis. Disclosure N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Meyers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte. K. Monkhorst: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Benecke; Advisory / Consultancy: Pfizer; Advisory / Consultancy: BMS; Advisory / Consultancy: Abbvie; Advisory / Consultancy: Diaceutics. J.H.M. Schellens: Shareholder / Stockholder / Stock options, and patent holder on oral taxanes: Modra Pharmaceuticals. All other authors have declared no conflicts of interest.

Background The clinical benefit of combined treatment with BRAF- and MEK-inhibitors (BRAFi; MEKi) in BRAFV600 mutant (BRAFm) melanoma is limited due to resistance after 6-14 months, associated with emerging secondary mutations. Withholding of treatment leads to reversible hyperactivation of the MAPK pathway, causing transient growth arrest and increase in Reactive Oxygen Species (ROS) in preclinical studies. Treatment of BRAFi/MEKi resistant melanoma cells with vorinostat leads to a further increase in ROS, effectively killing BRAFi resistant cells. In vivo, switch from BRAFi to vorinostat in BRAFi resistant BRAFm melanoma resulted in a decline in tumor volume. Six patients with resistant BRAFm melanoma were treated with vorinostat 360 mg QD continuously. These patients revealed regression of mutant clones and progression of BRAFi sensitive clones. Tumor biopsies showed newly developed secondary MAPK pathway mutations, e.g. NRASQ61H and KRASG12C amplifications at start and a complete absence of these resistant mutations after two weeks of vorinostat. Based on these findings we postulate that BRAFi resistant BRAFm melanoma cells can be eliminated by a short treatment with vorinostat due to killing of tumor cells harboring a secondary mutation in the MAPK pathway. In vitro experiments confirmed this hypothesis. Trial design This is a proof of concept study to determine the efficacy of sequential treatment with vorinostat and BRAFi/MEKi in BRAFi resistant BRAFm melanoma. Patients with age ≥ 18 years, WHO performance 0-2 and progression on BRAFi/MEKi are eligible. 26 evaluable patients with resistant BRAFm melanoma will be treated with vorinostat 360 mg continuously for 2 weeks and thereafter switch back to BRAFi/MEKi. The primary aim is to demonstrate ≥ 30% anti-tumor response of progressive lesions according to RECIST 1.1 upon sequenced treatment with vorinostat and BRAFi/MEKi. Secondary endpoints are to demonstrate that emerging resistant clones with a secondary mutation in the MAPK pathway can be detected by ctDNA analysis and purged by short term treatment with vorinostat. Blood and tumor biopsies will be taken for pharmacokinetic, pharmacodynamic and pharmacogenetic exploratory analyses. Clinical trial identification NCT02836548. Legal entity responsible for the study The Netherlands Cancer Institute. Funding Oncode. Disclosure J.H.M. Schellens: Shareholder / Stockholder / Stock options, and patent holder on oral taxenes: Modra Pharmaceutical. All other authors have declared no conflicts of interest.

Background: Phosphatidylinositol-3-kinase (PI3K) pathway activation has been associated with resistance to anti-estrogen receptor (ER) therapy and PIK3CA mutated ER+ breast cancer (BC) cells are sensitive to inhibition of PI3K under estrogen deprivation. In an in vitro study, the combination of BYL719 and fulvestrant was synergistic in PIK3CA mutated BC cell lines. In the BYL719 single agent part of this study out of 21 ER+ BC patients (pts), 3 partial responses were observed and 5 pts remained on the study with stable disease for over 26 weeks. Median PFS in pts with ER+ PIK3CA mutated BC was 5.5 months (Gonzalez-Angulo, 2013). Methods: This phase I study was amended to determine the Maximum Tolerated Dose (MTD) of BYL719 in combination with the ER antagonist fulvestrant in PIK3CA mutated ER+ breast cancer pts. Dose escalation of BYL719 in combination with fixed dose fulvestrant used an adaptive Bayesian logistic regression model with overdose control. The starting dose of BYL719 was 300 mg once daily, 25% below the MTD of single agent BYL719. All pts received the standard dose of 500 mg fulvestrant every 4 weeks. No dose escalation of fulvestrant was permitted. Following the MTD declaration, a dose expansion cohort will open. Results: At the data cut-off (27 March 2013), 4 pts were enrolled in the initial cohort of 300 mg/q.d. BYL719 plus 500 mg/qmonth (with an additional dose at week 2) fulvestrant, followed by 8 pts into the subsequent 400 mg/q.d. BYL719 plus fulvestrant dose combination. No pts experienced dose limiting toxicity (DLT) in the 300 mg cohort, and 1 pt experienced a DLT of CTCAE grade 3 diarrhea, vomiting, fatigue, anorexia and bloating in the 400 mg cohort. The MTD of BYL719 in combination with fulvestrant has been declared as 400 mg/q.d. The most frequent BYL719 related toxicities (>15% pts), regardless of grade and treatment group, are diarrhea (42%), hyperglycemia (33%), decreased appetite (25%), nausea (25%), and fatigue (17%). Systemic drug exposure of oral BYL719 when given in combination with fulvestrant was found to be similar to the single agent data. The patients were typically pre-treated with numerous chemotherapy, hormonal or targeted therapies. One pt in the 300 mg/q.d. cohort had a confirmed partial response, and 2 pts in the 400 mg/q.d. cohort had a partial response (one confirmed and one only occurring after the data cut-off). From the 12 breast cancer pts treated, 2 (17%) discontinued treatment due to progressive disease, and the median exposure of all pts at the time of data cut-off was 9 weeks. Conclusions: This combination displays a favorable safety and PK profile, both comparable to the single agent BYL719 experience. BYL719 in combination with fulvestrant shows encouraging preliminary anti-tumor activity, which supports further investigation of this combination. Recruitment within the dose expansion is continuing to obtain a sample size of 20 patients carrying the PIK3CA mutation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-14.

PURPOSE: A phase II study was performed to assess the efficacy and toxicity of oral cyclosporine (CsA) plus paclitaxel in advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive or previously treated patients (one regimen) with measurable disease and World Health Organization performance status ≤ 2 were eligible. Oral paclitaxel was given weekly in a dose of 90 mg/m2 bid. CsA (10 mg/kg) was given 30 minutes before each dose of oral paclitaxel. RESULTS: Twenty-six patients with a median age of 54 years (range, 32 to 77 years) were entered onto this study. Eighteen patients (69%) had received one prior chemotherapy regimen. The most frequently recorded toxicities were as follows: National Cancer Institute common toxicity criteria grade 3 neutropenia, eight patients (31%); grade 4, six patients (23%); grade 4 febrile neutropenia, three patients (12%); grade 2/3 neurotoxicity, three patients (12%); and grade 2 nail changes, four patients (15%). The overall response rate (ORR) of the 23 assessable patients was 26% (95% confidence interval [CI], 10% to 48%). In the intention-to-treat population, the ORR was 23% (95% CI, 9% to 44%). The median time to progression was 3.5 months (95% CI, 1.2 to 3.9 months), and median overall survival was 6.0 months (95% CI, 2.3 months to not available). Pharmacokinetics revealed that the mean area under the concentration-time curve (AUC) of oral paclitaxel was 5.0 ± 2.3 μmol/L/h in week 1 and 4.6 ± 2.0 μmol/L/h in week 2, with interpatient variabilities (coefficient of variation [%CV]) of 45% and 42%, respectively. The intrapatient variability (%CV) of the AUC was 14.5%. CONCLUSION: Oral paclitaxel plus CsA is active and safe in advanced NSCLC, including in patients previously treated with chemotherapy.

Objective. Current modalities used in the treatment of cancer often cause unacceptable damage to normal tissue. Toxins targeted toward tumor cells by antibodies or growth factors have the potential to selectively kill tumor cells while leaving normal tissue intact. The purpose of this review is to provide background information on targeted toxins and current clinical studies for this new class of anti-cancer compounds. Data sources. A MEDLINE search was conducted using the term “immunotoxins.” Relevant articles were also obtained by the systematic examination of article references. Data synthesis. The toxins Pseudomonas exotoxin, diphtheria toxin, and ricin toxin are often used as targeted toxins. Deletion or mutation of the binding domains of these toxins decreased binding of the toxins to normal tissues. Antibodies or growth factors can be used as targeting moiety, and the resulting agents are called immunotoxins or fusion proteins, respectively. DNA technology and chemical modifications of the toxin as well as the antibody moiety led to smaller and less immunogenic targeted toxins. Smaller targeted toxins are less toxic and penetrate further into the tumor. The summary of several targeted toxins elicited during clinical trials in this review makes it clear that several targeted toxins are potential agents for the treatment of various cancers, although some problems still need to be overcome. These problems include toxicity, immunogenicity, cross-reactivity of the targeted toxin with life-sustaining tissue, heterogenicity of tumor cells, and limited tumor penetration.

In order to unravel possible mechanisms of clinical resistance to topoisomerase I inhibitors, we developed a topotecan-resistant human IGROV-1 ovarian cancer cell line, denoted IGROV(T100r), by stepwise increased exposure to topotecan (TPT). The IGROV(T100r) cell line was 29-fold resistant to TPT and strongly cross-resistant to SN-38 (51-fold). However, the IGROV(T100r) showed only threefold resistance to camptothecin (CPT). Remarkably, this cell line was 32-fold resistant to mitoxantrone, whereas no significant cross-resistance against other cytostatic drugs was observed. No differences in topoisomerase I protein levels and catalytic activity as well as topoisomerase I cleavable complex stabilization by CPT in the IGROV-1 and IGROV(T100r) cell lines were observed, indicating that resistance in the IGROV(T100r) cell line was not related to topoisomerase I-related changes. However, resistance in the resistant IGROV(T100r) cell line to TPT and SN-38 was accompanied by decreased accumulation of the drugs to approximately 15% and 36% of that obtained in IGROV-1 respectively. No reduced accumulation was observed for CPT. Notably, accumulation of TPT in the IGROV-1 cell line decreased under energy-deprived conditions, whereas the accumulation in the IGROV(T100r) cell line increased under these energy-deprived conditions. The efflux of TPT at 37 degrees C was very rapid in the IGROV-1 as well as the IGROV(T100r) cell line, resulting in 90% efflux within 20 min. Importantly, the efflux rates of TPT in the IGROV-1 and IGROV(T100r) cell lines were not significantly different and were shown to be independent on P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP). These results strongly suggest that the resistance of the IGROV(T100r) cell line to TPT and SN-38 is mainly caused by reduced accumulation. The reduced accumulation appears to be mediated by a novel mechanism, probably related to impaired energy-dependent uptake of these topoisomerase I drugs. Images Figure 2 Figure 3 Figure 4 Figure 5

27 patients with recurrent high grade glioma following surgery and radiation therapy were treated with 100 mg/m2 cisplatin and 6 g/m2 ifosfamide per cycle, administered on days 1-3 in 4 week cycles, for a maximum of six cycles. Toxicity was assessed after every cycle. Response was assessed following every second cycle, and a 50% decrease of the largest cross-sectional tumour area on contrast enhanced magnetic resonance imaging or computed tomography scan was considered a partial response (PR). A total of 95 cycles was administered; 26 patients were evaluable for response. In 5 patients (19%), a PR was obtained (median time to progression (TTP): 34 weeks). Stable disease was observed in 6 patients (23%, median TTP: 22 weeks). The most frequent toxicity was haematological: 37% of cycles were complicated by a grade 3 or 4 leucopenia. 1 patients died, probably as a consequence of increased cerebral oedema induced by the cisplatin hydration schedule. Determination of the cisplatin concentration in this patient showed a 10-fold increase in the tumour concentration as compared with that in normal brain tissue, demonstrating the absence of a blood-brain barrier in the tumour. In conclusion, generally this schedule was well tolerated, but it is of moderate activity for recurrent glioma.

Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with GI147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. GI147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m(-2) to 6.0 mg m(-2); the dose for i.v. administration was fixed at 1.2 mg m(-2). Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of GI147211 averaged 1.3 +/- 5.2%. Drug appeared quickly in plasma with a median Tmax at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of GI147211. The terminal half-life after administration of oral GI147211 was 6.85 +/- 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor GI147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor.

Topoisomerase I inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase I inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase I inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase I inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and GI147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions.

PURPOSE Topotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS Patients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. RESULTS Thirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point "t" [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function. CONCLUSION The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.

As a dose-response relationship has been suggested for cisplatin, it appeared attractive to explore high-dose-intensity regimens in non-small-cell lung cancer. In a phase I study of weekly administration of cisplatin combined with oral etoposide we achieved a cisplatin dose intensity of 52.5-60 mg/m2 per week in most patients. We subsequently explored this regimen in advanced non-small-cell lung cancer. Patients were treated with cisplatin infused at 70 mg/m2 on days 1, 8, 15 and 29, 36, 43 in combination with oral etoposide given at 50 mg on days 1-15 and 29-43. Patients showing stable disease or a better response were continued on treatment with oral etoposide given at 50 mg/m2 per day on days 1-21 every 28 days for a maximum of four cycles. In all, 22 patients with stage III disease and 31 patients with stage IV disease entered the study. The median number of cisplatin administration was 6 per patient; 17 patients reached the planned cisplatin dose intensity of 60 mg/m2 per week, 11 patients achieved 52.5 mg/m2 per week, and 7 patients reached 47 mg/m2 per week. Overall, 11 of 21 stage III patients had a partial response [response rate 51%, 95% confidence interval (CI) 36-81%], as did 9 of 28 patients with stage IV disease (32%; 95% CI 15-49%). Toxicity was mainly hematologic, with leukocytopenia being the most frequent cause of treatment delay. Nephrotoxicity of grade 1 was observed in seven patients. Two patients developed clinical hearing loss. With this schedule a high median cisplatin dose intensity of 52.5-60 mg/m2 per week was reached. The 51% response rate achieved in stage III disease makes this schedule attractive for further exploration; however, it is not recommended for routine use in stage IV disease.

We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure-response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available oral formulation.

The study was designed to investigate possible relationships between tumour response and exposure to cisplatin (area under the curve of unbound cisplatin in plasma, AUC) and DNA-adduct formation in leucocytes (WBC) in patients with solid tumours. Patients were treated with six weekly courses of cisplatin at a dose of 70 or 80 mg m-2. The AUC was determined during the first course and DNA-adduct levels in WBC during all courses at baseline, 1 h (A(max)) and 15 h after a 3 h infusion of cisplatin. The area under the DNA-adduct-time curve (AUA) was calculated. The tumour response was determined after six courses. Forty-five evaluable patients received 237 courses of cisplatin. Sixteen patients with head and neck cancer received a dose of 80 mg m-2 and 29 with various other tumour types received 70 mg m-2 plus daily 50 mg oral etoposide. There were 20 responders (partial and complete) and 25 non-responders (stable and progressive disease). The AUC was highly variable (mean +/- s.d. = 2.48 +/- 0.51 micrograms h-1 ml-1; range 1.10-3.82) and was closely correlated with the AUA (r = 0.78, P < 0.0001) and A(max) (r = 0.73, P < 0.0001). The AUC, AUA and A(max) were significantly higher in responders than in non-responders in the total population (P < 0.0001) and in the two subgroups treated at 70 or 80 mg m-2. In logistic regression analysis AUC, AUA and A(max) were important predictors of response. The magnitude of exposure to cisplatin is, through DNA-adduct formation, the major determinant of the response rate in this population. Hence, individualised dosing of cisplatin using AUC or DNA-adducts should lead to increased response rates.

Topoisomerase I inhibitors are interesting anti-cancer agents with a novel mechanism of action. We performed a phase I study with intravenous GI147211, a new semisynthetic camptothecin analogue, using a daily x 5 schedule administered every 3 weeks, to evaluate the side-effects and pharmacokinetics of the agent. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard froms of therapy were eligible for the study. GI147211 was given as a 30 min intravenous infusion daily for 5 consecutive days, repeated every 3 weeks. In subsequent patient cohorts the dose was escalated from 0.3 to 1.5 mg m-2 day-1. Pharmacokinetics analysis was performed on days 1 and 4 of the first course using a validated high-performance liquid chromatographic assay and non-compartmental methods. A total of 19 patients were entered into the study, one patient was not evaluable for toxicity because only one drug administration was given. Eighteen patients received a total of 67 courses through four dose levels. The dose-limiting toxicities were neutropenia and thrombocytopenia at the dose of 1.5 mg m-2 day-1. Nadirs occurred on day 15 and day 15 respectively. Other toxicities were mild and infrequent and included nausea/vomiting, headache and alopecia. The maximal tolerated dose was 1.2 mg m-2 day-1. One partial response was observed in a patient with colorectal cancer. The total plasma clearance was 999+/-184 ml min-1 (range 640-1329). The volume of distribution was 190+/-461 m-2 and the terminal half-life was 3.7+/-1.2 h. The AUC increased linearly with the administered dose. A steep and significant sigmoid relationship was established between the AUC and the percent decrease of ANC. GI147211 is a new topoisomerase I inhibitor that induced dose-limiting neutropenia and thrombocytopenia in this phase I study. The recommended dose for phase II studies with this schedule is 1.2 mg m-2 x 5 every 3 weeks.

Summary Background Limited sampling models for the estimation of the topotecan Area Under the concentration versus time Curve (AUC) and its lactone ring opened form (AUC Tm), from one or more plasma concentration determinations, are desired for further population-kinetic studies. Patients and methods The models were developed and validated using 34 pharmacokinetic curves in 19 patients who participated in a phase I study. Results A single point model was selected as optimal: AUC (μmol/L. min) = 499(min). C2h(μmol/L) + 0.85(m2/mg. μmol/L. min). dose(mg/m2), and for topotecan-metabolite (Tm), AUC Tm(μmol/L.min) = 55.1 (min). CTm2h (μmol/L) / -0.011(m2/mg. μmol/L. min). dose (mg/m2), where C2h is the plasma concentration (μmol/L) of topotecan at 2 h after the end of a 30-min infusion, and CTm2h the concentration of the opened form at the same time point. The models are valid for dosages ranging from 0.5 to 1.5 mg/ m2/day and proved to be unbiased (MPE% = −1.8% and −9.3%, respectively) and precise (RMSE% − 17.9% and 22.7%, respectively). From the predicted AUCs, the clearance (Cl = dose (μmol)/AUC(μmol/L. min)) could also reliably be predicted, as well as the total AUC (AUC + AUC Tm) (RMSE% = 17.1% and MPE% = −0.02%). Half-life values could not be predicted with acceptable precision and accuracy. Conclusion The limited sampling models presented may be useful for future studies focused on pharmacokinetic/ pharmacodynamic relationships of topotecan in large populations.

Background: The programmed death receptor 1 (PD-1) pathway is implicated in evasion of the antitumor immune response. Pembrolizumab is a potent, highly selective humanized monoclonal antibody against PD-1 designed to block interaction with its ligands, PD-L1 and PD-L2, thus removing inhibition of T-cell activation against cancer. PD-L1 is overexpressed in malignant pleural mesothelioma (MPM) and associated with poor prognosis. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1-positive MPM. Methods: KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab for PD-L1-positive advanced solid tumors. Key eligibility criteria for the MPM cohort were measurable disease, PD-L1 expression in ≥1% of cells in tumor nests or PD-L1-positive bands in stroma as determined by a prototype immunohistochemistry assay at a central laboratory, failure of standard therapy, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, adequate organ function, and no autoimmune disease or interstitial lung disease. Pembrolizumab 10 mg/kg was given every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points are safety, tolerability, and preliminary efficacy. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. Results: Of the 84 patients with MPM who were screened, 38 (45%) had PD-L1-positive tumors. Between March 2014 and December 2014, 25 patients with MPM were treated (68% men; median age, 65 years; 64% ECOG PS 1). 36% of patients had epithelioid histology. 88% of patients received ≥1 prior therapy (28% ≥2); 80% received a platinum and pemetrexed. Fifteen patients (60%) experienced a drug-related adverse event (DRAE); only 3 (12%) had grade ≥3 DRAEs. DRAEs with incidence >25% were nausea (40%), fatigue (32%), and decreased appetite (28%). Four patients (16%) experienced immune-related AEs, but only 2 patients required dose interruption (1 because of ALT increased, 1 because of uveitis). There was no treatment-related mortality, and no patients discontinued because of DRAEs. Preliminary overall response rate (confirmed and unconfirmed) was 24% (n = 6); 13 patients (52%) had stable disease, resulting in a disease control rate of 76%. Four patients (16%) had progressive disease, and 2 patients had no assessment at the time of analysis. 16 patients (64%), including all responders, remain on treatment (duration 8+ to 24+ weeks). Conclusion: Pembrolizumab is generally well tolerated and provides robust antitumor activity in patients with advanced PD-L1+ MPM. The 76% disease control rate in this previously treated MPM population is unprecedented and warrants further study. Citation Format: Evan W. Alley, L. Rhoda Molife, Armando Santoro, Kim Beckey, Sammy Yuan, Jonathan D. Cheng, Bilal Piperdi, Johannes H.M. Schellens. Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT103. doi:10.1158/1538-7445.AM2015-CT103

Background: MET dysregulation occurs in multiple cancers, causing activation of the MET receptor tyrosine kinase. INC280 is an oral, highly selective MET inhibitor that has exhibited preclinical and preliminary clinical anti-tumor activity in various solid tumors. This dose escalation and expansion study was designed to evaluate INC280 safety and efficacy in patients (pts) with advanced MET-dependent solid tumors. Methods: The primary objectives of this Phase (Ph) I study were to determine the MTD or recommended Ph II dose (RP2D), and safety and tolerability of INC280. The secondary objectives were efficacy and PK assessment. Eligible pts (aged ≥18 years, PS ≤2) had tumors with high Met expression that were refractory to currently available therapies or for which no therapies existed. Results: As of Sep 28, 2014, 91 pts were enrolled (median age 57 years, 70% male, 56% PS 0, 47% Asian): 38 in the dose escalation part and 53 in the dose expansion part. Pts were treated in 7 dose cohorts of 100-600 mg BID capsules or 400 mg BID tablets. DLTs occurred at 200, 250, and 450 (1 pt each) mg BID capsules and were Grade 3 fatigue (2 pts) and Grade 3 blood bilirubin increase (1 pt). The most frequent drug-related AEs (any grade) were nausea (33%), fatigue (25%), and vomiting (24%). The most common Grade 3/4 drug-related AEs were fatigue (4%) and increased lipase levels (3%) and occurred at 200 (1 pt), 250 (2 pts), 450 (1pt) and 600 (3 pts) mg BID capsules. RP2D was established at 600 mg BID capsules, but film-coated 400 mg INC280 tablets were developed and tested to improve pt convenience and compliance. INC280 400 mg BID tablets had comparable tolerability, safety profile and exposure compared with 600 mg BID capsules. The mean (CV%) steady state AUClast (Tlast ∼ 8h) and Cmax after 400 mg BID tablet vs 600 mg BID capsule were 24654 (33%, N = 4) vs 21249 (60%, N = 23) h*ng/mL and 7425 (30%, N = 4) vs 5240 (67%, N = 23) ng/mL respectively. Clinical activity was observed in advanced NSCLC patients, and updated efficacy data will be presented. Conclusions: Orally administered INC280 was well tolerated with a manageable safety profile. MTD was not reached, but the RP2D was established at 600 mg BID for capsules and 400 mg BID for tablets. Clinical trial identifier: NCT01324479.

The purpose of this study was to determine the mechanism of the pharmacodynamic interaction between docetaxel/paclitaxel and cisplatin. Cisplatin- induced DNA-adducts and cisplatin accumulation were quantitated in peripheral blood leukocytes (WBC). The WBC were obtained from patients treated with docetaxel or paclitaxel in phase I/II studies and were incubated in vitro with cisplatin. In addition, blank whole-blood samples were obtained from pa- tients and healthy subjects and incubated in vitro with cisplatin or docetaxel/paclitaxel and cisplatin. The cis- platin-induced DNA-adduct levels measured in WBC after treatment with docetaxel or paclitaxel were signif- icantly lower than those determined in non-pretreated WBC. Docetaxel and paclitaxel reduced the intracellu- lar accumulation of cisplatin in WBC by 46—47%. If the pharmacodynamic interaction between docetaxel/pac- litaxel and cisplatin also occurs in other normal tissues such as bone marrow, it may well contribute to the sequence dependent toxicity that has been observed in clinical studies.

PURPOSE: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate–binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(−/−) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918. PATIENTS AND METHODS: In cohort A, eight patients received 1.0 mg/m2 oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m2 intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan. RESULTS: After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 ± 9.6 μg·h/L without GF120918 to 78.7 ± 20.6 μg·h/L when GF120918 was coadministered (P = .008). The mean maximum plasma concentration of total topotecan increased from 4.1 ± 1.5 μg/L without GF120918 to 11.5 ± 2.4 μg/L with GF120918 (P = .008). The apparent bioavailability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P = .008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecan, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan. CONCLUSION: Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.

oral CL Doseoral where CL is the total clearance of drug in the body. A review of their article revealed that their calculation of the absolute bioavailability of docetaxel in the control study without cyclosporine was correctly determined because the CL was determined after intravenous admin- istration without cyclosporine. The authors used the same CL value to determine absolute bioavailability of docetaxel when cyclosporine was coadministered in the interaction study, apparently assuming no change in the CL of docetaxel by cyclosporine. However, such a critical assumption is inconsistent with reports that cyclosporine, a cytochrome P450 3A inhibitor, may also decrease CL for other cytochrome P450 3A substrates. For example, oral administration of cyclosporine 50 mg/kg has been reported to decrease the CL of intravenous paclitaxel by approximately 70% (from 0.92 0.07 to 0.28 0.01 L/h/kg) in mice. 4 Therefore, it seems likely that docetaxel's mean absolute bioavailability of 90% reported by Malingreet al in their interaction study may be considerably overestimated. This overestimation of oral bioavailability may also have occurred with their earlier study 5 on the effect of coadministration of oral cyclosporine on the absolute bioavail- ability of paclitaxel in patients, because the new CL during the interaction study was not obtained and only the same CL obtained during the control study was used to calculate absolute bioavailability. In that study, an eight-fold higher absolute bioavailability value of paclitaxel was reported because of cyclosporine coadministration. 5 Malingree t al 1 also found significant amounts of four metabolites of docetaxel in plasma after coadministration with cyclosporine. These metabolites, interestingly, were not detected in plasma after oral administration of the drug alone. They stated that such increased metabolism after coadministration with cyclosporine may result in lower levels of the active drug and, possibly, reduced efficacy. They further stated that the achieved gain in increased uptake largely outweighs the possible loss by the increased metabolism. 1 We wish to point out that increased metabolism per se may not necessarily result in lower levels of the parent drug, even if one assumes no change in uptake. In addition to oral bioavailability, plasma levels and AUC oral are determined by CL. The above-mentioned lower CL of docetaxel with coadministration of cyclosporine is theoretically expected to increase its plasma levels and AUCoral. In addition to the above- mentioned direct inhibition of the enzymatic activity by cyclosporine, P-glycoprotein may also play an important role in affecting the CL of docetaxel. For example, compared with wild-type mice, the CL of erythromycin 6-8 and paclitaxel 9 was markedly reduced and their plasma drug levels were markedly increased in P-glycoprotein knockout mice after intravenous administration, despite their higher metabolite levels (ie, increased metabolism) and their virtually identical hepatic enzyme contents. The decrease in the metabolic clearance of erythromycin and paclitaxel has been attributed mainly to the indirect inhibition of metabolism of parent drug due to accumulation of metabolites, also assumed to be P-glycoprotein substrates, in hepatocytes and entero- cytes. 7,8,10,11 For tacrolimus, which is metabolized almost exclusively in the body, hepatic metabolic clearance and apparent hepatic intrinsic clearance have been estimated to be reduced by 65% and 90%, respectively, in the P-glycoprotein knockout mice compared with wild-type mice, apparently due to the same mechanism. 10 It is possible that cyclosporine, a potent P-glycoprotein inhibitor, may also signifi- cantly decrease the hepatic and intestinal metabolic clearance of docetaxel by the same P-glycoprotein-mediated mechanism. It is hoped that the above discussions may be of interest to your readers and may stimulate further research in this rapidly evolving area.

Materials and Methods: The use of plant extracts to alleviate inflammatory diseases is centuries old and continues to this day, therefore we screened thirty-four methanolic plant extracts for inhibition of constitutive NF-uB activity by a NF-uB-luciferase reporter gene assay. There was strong inhibition of NF-uB activity by Nuphar lutea L. SM. (Nuphar), leaf and rhizome extracts. An active fraction containing a mixture of dimeric sesquiterpene thioalkaloids was purified by solvent extraction, pH adjustment silica gel chromatography and HPLC. Oneand twodimensional NMR spectroscopy indicated the presence of nupharidine, 6-hydroxythionuphlutine as a major component. Results: Nupharidine showed a dose dependent inhibition of NF-uB activity by luciferase reporter gene assay as well as reduction of nuclear NF-uB subunits expression as tested by western blots and immunohistochemistry. Diminution of DNA binding was demonstrated by Electro Mobility Shift Assay (EMSA). Nupharidine inhibited both inducible and constitutive NF-uB activation and affected the canonical and alternative pathways. Suppression of NF-uB was not cell type specific. Conclusions: Induction of apoptosis by Nupharidine was demonstrated by time and dose dependent cleavage of procaspase-9 and PARP. Synergistic cytotoxicity of nupharidine with cisplatin and etoposide was demonstrated, therefore suggesting its possible use as a ‘sensitizer’ in anticancer treatment.

Aim: To evaluate the safety profile of RG7116 in combination with cetuximab or erlotinib. Methods: Patients (pts) with advanced or metastatic carcinomas with centrally confirmed HER3 protein expression were included. RG7116 plus cetuximab (400 mg/m2 followed by 250 mg/m2 qw IV) and RG7116 plus erlotinib (150 mg/day p.o.) combinations were evaluated in a dose escalation study with “3 + 3” design at a starting dose of 400 mg IV of RG7116 in a q2w regimen. Results: Twenty-seven pts were enrolled in 5 cohorts (400 to 2000 mg) in the cetuximab arm. One dose-limiting toxicity (DLT) of grade 3 dehydration was reported in the 800-mg cohort. Twenty-seven pts were enrolled in 4 cohorts (400 to 2000 mg) in the erlotinib arm. One DLT was reported in the 1600-mg cohort (grade 3 diarrhea and grade 3 hypokalemia) and one DLT was reported in the 2000-mg cohort (grade 3 blood bilirubin increase). No maximum tolerated dose was reached. The most frequently reported adverse events of any grade were diarrhea (78%) and rash (59%) for the cetuximab arm and diarrhea (82%) and decreased appetite (48%) for the erlotinib arm. In the erlotinib arm treatment-related grade 3 diarrhea was observed more frequently at higher doses of RG7116 (400 mg: 0%; 800 mg: 17%; 1600 mg: 43%; 2000 mg: 33%). Overall, infusion-related reactions related to RG7116 occurred in 11% of pts. Two of these were grade 3 (4%). The pharmacokinetic profile of RG7116 in combination with cetuximab and erlotinib was comparable to that in the monotherapy setting (Meulendijks et al. J Clin Oncol 31, 2013 suppl; abstr 2522). HER3 membranous protein down-regulation was observed from 400 mg onwards in on-treatment tumor and skin tissue. In the cetuximab arm, two pts with colorectal carcinoma had a confirmed partial response (PR). In the erlotinib arm, one patient with ovarian carcinoma had a confirmed PR. Metabolic PR on FDG-PET occurred in 42% of pts in the cetuximab arm and in 28% of pts in the erlotinib arm. Conclusions: RG7116 combination with cetuximab or erlotinib was well tolerated, and demonstrated preliminary signs of clinical activity. Disclosure: U.N. Lassen: discloses Research grants from Roche; A. Cervantes Ruiperez: discloses Research grants, advisory boards and lectures for Roche; C. Adessi, A. Keelara, F. Michielin, B. Bossenmaier, G. Meneses-Lorente, I. James, W. Jacob and M. Weisser: Employee of Roche. All other authors have declared no conflicts of interest.

Background: Without active delivery across the blood-brain barrier, the efficacy of doxorubicin is limited in the treatment of brain tumors. Therefore, 2B3-101 has been developed as a brain-targeted doxorubicin product. In preclinical studies, 2B3-101 showed a 5-fold increased delivery of doxorubicin to the brain and improved survival of mice with HGG, compared to Caelyx®. Methods: This study assessed the safety, tolerability, MTD, PK, and anti-tumor activity of 2B3-101 in pts with advanced solid tumors and BM or HGG. In phase 1, pts with BM or HGG received 2B3-101 (5-70 mg/m2 q21d) and breast cancer (BC) BM pts received 2B3-101 (40-50 mg/m2 q21d) with trastuzumab. In phase 2a, BCBM pts received 2B3-101 (50 mg/m2 q21d) alone or with trastuzumab, HGG pts received 2B3-101 (60 mg/m2 q28d); melanoma and SCLC pts received 2B3-101 (50 mg/m2 q21d) in exploratory arms. Results: Results up to March 2014 from pts treated with ≥40 mg/m2 are described. PK data showed non-linear exposure of 2B3-101 without signs of accumulation upon repeat dosing, a half-life of 69h (range 43-120h) independent of trastuzumab co-treatment. 203 cycles (range 1-10) of 2B3-101 alone or with trastuzumab were given to 68 pts. 2B3-101 alone or with trastuzumab was well tolerated up to a dose intensity of 15 mg/m2/wk. Cycle 1 MTD was not reached. Phase 2a doses were selected based upon tolerability after repeated dosing. Most frequent reported treatment emergent AEs ≥ grade 2 were: neutropenia (36%), PPE (34%), fatigue (32%), stomatitis (19%), and infusion reaction (18%). All were transient and manageable with standard treatment. 2B3-101 showed no CNS- or cardiotoxicity. In evaluable BCBM pts (n = 19), 11% had PR and 53% SD as overall best response, including 4 pts with intracranial (IC) response of ≥ 20% with 3-months PFS rate of 58%. In evaluable HGG pts (n = 24), 54% had SD as best response, including 3 pts with IC response of ≥ 20% and a 3-months PFS rate of 33%. Conclusions: 2B3-101 is safe and well tolerated and shows activity in advanced BCBM and HGG pts, diseases with limited treatment options. Results warrant further randomized, controlled Phase 2b studies, with initial focus on (HER2+) BCBM. ClinicalTrials.gov NCT01386580, sponsored by to-BBB technologies BV. Disclosure: B. Milojkovic Kerklaan: research grant; W. Gladdines: employee; F. Lonnqvist: employee. All other authors have declared no conflicts of interest.

Aim: Germline gene polymorphisms may impact clinical outcome in patients with gastrointestinal malignancies, but there are no data on the interaction between chemotherapy pharmacokinetics (PK) and gene polymorphisms, to assess their independent predictive value. Methods: Two studies prospectively assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, -M1, -T1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2, UGT2B7) by Sanger sequencing in 64 patients with advanced colorectal cancer (CRC) receiving capecitabine/oxaliplatin chemotherapy, and 76 patients with advanced gastroesophageal (GE) cancer receiving epirubicin/cisplatin/capecitabine (ECC) chemotherapy, respectively. Plasma concentrations of all anticancer drugs were sampled for up to 24 hours, analyzed using validated LC-MS/MS (capecitabine), HPLC (epirubicin) and flameless atomic absorption spectrometry (platinum), and results submitted to population PK analysis using non-linear mixed effects modeling. We calculated the association between gene polymorphisms, anticancer drug exposure, radiological tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. Results: Patients with a low clearance of the active metabolite 5FU had an increased risk of neutropenia in both groups (p A and A2846T were associated with diarrhea (p Conclusions: Carriers of the TYMS high-expression genotype have a markedly inferior outcome when receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. Therapeutic targeting of this molecularly-defined subgroup of patients should be explored to improve their prognosis. Disclosure: All authors have declared no conflicts of interest.