Patricia Soetekouw

Signalling pathways in vasculogenic mimicry.

Solid tumour growth is dependent on the development of an adequate blood supply. For years, sprouting angiogenesis has been considered an exclusive mechanism of tumour vascularization. However, over the last years, several other mechanisms have been identified, including vessel-co-option, intussusception, recruitment of endothelial precursor cells (EPCs) and even mechanisms that do not involve endothelial cells, a process called vasculogenic mimicry (VM). The latter describes a mechanism by which highly aggressive tumour cells can form vessel-like structures themselves, by virtue of their high plasticity. VM has been observed in several tumour types and its occurrence is strongly associated with a poor prognosis. This review will focus on signalling molecules and cascades involved in VM. In addition, we will discuss the presence of VM in relation to ongoing cancer research. Finally, we describe the clinical significance of VM regarding anti-angiogenesis treatment modalities.

Ipilimumab in pretreated metastastic uveal melanoma patients. Results of the Dutch Working group on Immunotherapy of Oncology (WIN-O)

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Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives

The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on future perspectives in the treatment of metastasized RCC.

Long-term dietary sodium, potassium and fluid intake; exploring potential novel risk factors for renal cell cancer in the Netherlands Cohort Study on diet and cancer

Background:As sodium, potassium and fluid intake are related to hypertension, an established risk factor for renal cell cancer (RCC), they may be independent risk factors for RCC.Methods:The Netherlands Cohort Study (NLCS) with case-cohort design included 120 852 participants aged 55–69 years. At baseline, diet and lifestyle were assessed with questionnaires. After 17.3 years of follow-up, 485 RCC cases and 4438 subcohort members were available for analyses.Results:Sodium intake increased RCC risk (P-trend=0.03), whereas fluid and potassium intake did not. For high sodium and low fluid intake, the RCC risk additionally increased (P-interaction=0.02).Conclusion:Sodium intake is a potential risk factor for RCC, particularly if fluid consumption is low.

Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-Label Studies.

PURPOSE The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. METHODS Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0-t and Cmax fell within the bioequivalence range of 0.80-1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or Cmax in the presence of rifampin compared with olaparib alone). FINDINGS In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: Cmax treatment ratio, 1.42 (90% CI, 1.33-1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44-2.97). Mean CL/F and Vz/F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t½ was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: Cmax treatment ratio, 0.29 (90% CI, 0.24-0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11-0.16). CL/F and Vz/F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t½ was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile. IMPLICATIONS Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).

Abstract CT216: Phase I dose escalating study of 2B3-101, glutathione PEGylated liposomal doxorubicin, in patients with solid tumors and brain metastases or recurrent malignant glioma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Without active delivery across the blood-brain barrier (BBB) the efficacy of doxorubicin in brain tumors is limited. 2B3-101, glutathione PEGylated liposomal doxorubicin, has been developed as brain-targeted chemotherapy. In preclinical studies, 2B3-101 showed a 5-fold enhanced doxorubicin brain-delivery versus pegylated liposomal doxorubicin (Doxil®). Patients with either solid tumor brain metastases or recurrent malignant gliomas were treated with 2B3-101 by a 90 min IV infusion q21d to assess (1) safety, tolerability and MTD (2) pharmacokinetics (PK) and (3) preliminary anti-tumor activity of 2B3-101, determined by brain MRIs and body CTs, according to RANO or RECIST criteria. Doses were escalated in cohorts of 3-6 patients. 28 patients received 2B3-101 at doses of 5-70 mg/m2, without DLTs. 15 patients had brain metastases from solid tumors, and 13 patients had recurrent malignant gliomas WHO grade III (3) or IV (10). Twenty-three patients (82%) received ≥ 3 prior therapies before 2B3-101. No cardiac or CNS toxicity was observed. At doses of ≥ 40 mg/m2, adverse events ≥ grade II (CTCAE v.4.0) were: neutropenia (21%), thrombocytopenia (4%), mucositis (4%), and PPE (18%). Grade I-II infusion reactions were observed in 4/28 patients, being transient and manageable with standard treatments. Pharmacokinetic data showed non-linear exposure of 2B3-101 without signs of accumulation with repeat dosing. Due to one case of thrombocytopenia grade IV at 60 mg/m2, this cohort was expanded to 6 patients. 2B3-101 demonstrates preliminary antitumor activity in the brain. At doses of ≥ 40 mg/m2, 12 of 16 patients demonstrated stable disease as best outcome (brain metastases (n=4), glioblastoma (n=5) and grade III glioma (n=3)). 2B3-101 also showed responses in extracranial disease. 2B3-201 is safe and well tolerated up to 70 mg/m2 q21d in both brain metastases from solid tumors and recurrent malignant gliomas. A dose intensity of 15 mg/m2/week was sustainable over at least 4 cycles. Based on this information, the phase IIa dose expansion study is currently ongoing with treatment regimens of 50 mg/m2 every 3 weeks for patients with brain metastases and 60 mg/m2 every 4 weeks for patients with recurrent malignant glioma. ClinicalTrials.gov [NCT01386580][1], sponsored by to-BBB technologies BV. Citation Format: Pieter J. Gaillard, Bojana Milojkovic Kerklaan, Philippe Aftimos, Sevilay Altintas, Agnes Jager, Werner Gladdines, Fredrik Lonnqvist, Patricia Soetekouw, Henk Verheul, Ahmad Awada, Jan Schellens, Dieta Brandsma. Phase I dose escalating study of 2B3-101, glutathione PEGylated liposomal doxorubicin, in patients with solid tumors and brain metastases or recurrent malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT216. doi:10.1158/1538-7445.AM2014-CT216 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01386580&atom=%2Fcanres%2F74%2F19_Supplement%2FCT216.atom

472PPHASE 1/2A STUDY OF GLUTATHIONE PEGYLATED LIPOSOMAL DOXORUBICIN (2B3-101) IN PATIENTS WITH BRAIN METASTASES (BM) FROM SOLID TUMORS OR RECURRENT HIGH GRADE GLIOMAS (HGG)

ABSTRACT 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.

A QTc study of cabazitaxel in patients with advanced solid tumors.

257 Background: Cabazitaxel (Cbz) improves overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure, compared with mitoxantrone (HR 0.70; 95% CI 0.59-0.83; P < 0.0001). Following Cbz approval for the treatment of mCRPC, this study was undertaken to evaluate any effect of Cbz on the QTc interval. METHODS This prospective, multinational, open-label study ( NCT01087021 ) enrolled pts with advanced solid tumors (without other therapeutic options). Cbz 25 mg/m² IV was administered on Day 1 Q3W. QTc and other ECG intervals were assessed on Day 1 of Cycle 1. Triplicate ECGs were obtained from 12-lead Holter recordings and concomitant serial blood samples were collected for pharmacokinetic (PK) analysis. The primary endpoint was change from baseline in the corrected QTc interval (according to the Fridericia formula QTcF). RESULTS A total of 96 pts were enrolled; 32 pts under the original protocol (6-h Holter) and 64 pts following protocol amendment 1, which extended ECG and PK monitoring (24-h Holter). Median age was 63 yrs (69.8% male), 30.5% and 57.9% of pts were ECOG PS 0 and 1 respectively; 33 pts (34.4%) had prostate cancer. Screening ECG was abnormal but not clinically significant in 39.6% of pts. The majority (n = 65) of pts received ≥ 3 treatment cycles; safety and ECG parameters were evaluated in 95 and 94 pts, respectively. In the 24-h Holter group (n = 63), the maximum least squares (LS) mean change from baseline in QTcF was 4.8 msec (90% CI 2.1-7.5), returning to baseline by 24 h. Similar results were observed in the overall population (n = 94). At Cmax, Cbz concentration had no effect on QTcF change from baseline; the mean (CV%) Cmax (n = 91) and AUC (n = 92) were 276 ng/ml (63%) and 1245 ng.h/ml (82%). The LS mean change from baseline in heart rate increased up to 24 h but remained < 10 beats per minute. The most common Grade 3/4 AEs were neutropenia (27.4%), febrile neutropenia (12.6%), fatigue (12.6%) and dehydration (5.3%). No Grade 3/4 cardiac AEs were reported. Of the 6 deaths reported, 1 (infection) was study drug related. CONCLUSIONS Cbz had no significant effect on QTc interval in pts with advanced tumors. The Cbz safety profile is consistent with previous findings and with other taxane-based therapies.

Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth: PDFG signaling promotes vascular mimicry

Aggressive tumor cells can adopt an endothelial cell‐like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry‐positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular‐like networks. The pericyte recruitment is mediated through platelet‐derived growth factor (PDGF)‐B. Consequently, preventing PDGF‐B signaling by blocking the PDGF receptors with either the small tyrosine kinase inhibitor imatinib or blocking antibodies inhibits vascular mimicry and tumor growth. Collectively, the current study identifies an important role for pericytes in the formation of vascular‐like structures by tumor cells. Moreover, the mechanism that controls the pericyte recruitment provides therapeutic opportunities for patients with aggressive vascular mimicry‐positive cancer types.

Abstract P6-16-04: Phase 1/2a study of glutathione PEGylated liposomal doxorubicin (2B3-101) in breast cancer patients with brain metastases

Background: The incidence of brain metastases (BM) in breast cancer (BC) patients (pts) has increased over the past decade. The brain is regarded as a sanctuary site for metastatic cells which are partially protected from drugs by the blood-brain barrier (BBB). 2B3-101 is a doxorubicin (DOX) liposomal formulation that uses glutathione transporters on the BBB to penetrate the brain. Non-clinical studies have shown a 5-fold enhanced delivery of DOX to the brain after IV administration of 2B3-101 compared to liposomal DOX, without signs of cardio- or neurotoxicity. Methods: This phase 1/2a open label study assessed the safety, tolerability, MTD, PK, and anti-tumor activity of single agent 2B3-101 in pts with BM of solid tumors, or high-grade gliomas. For this analyses BCBM pts (n=25) were included. These pts received 2B3-101 at a starting dose of either 40 (n=3) or 50 (n=22) mg/m 2 IV every 3 weeks, until disease progression or unacceptable toxicity. Anti-tumor activity was assessed by RECIST 1.1. Patients with HER2-positive BCBM were treated with concurrent trastuzumab. Results: As of May 30, 2014, 88 cycles (median 2, range 1-10) of 2B3-101 alone or with trastuzumab were administered to 25 heavily pretreated BC pts, 3 pts are still on treatment. Median age was 47 (33–61) years and 18 (72%) pts had HER2+ disease. Pts had received a median of 7 (4–15) prior regimens; 18 (72%) had received prior radiation therapy to the brain. In phase 1, 2B3-101 alone or with trastuzumab was well tolerated up to a dose intensity of 15 mg/m 2 /wk. Cycle 1 MTD was not reached. Phase 2a dose of 50 mg/m 2 was selected based upon tolerability after repeated dosing. The most frequent reported treatment emergent AEs are qualitatively consistent with conventional PEGylated liposomal DOX and were (≥ grade 2): neutropenia (59%), palmar plantar erythrodysesthesia (PPE) (50%), fatigue (45%), stomatitis (22%), and infusion reaction (18%). Notable Grade 3–4 AEs were neutropenia (35%) and PPE (13%). All AEs were transient and manageable with dose delays, reductions and standard medication. 57% of pts had 2B3-101 dose delays and 39% of pts required dose reductions. 2B3-101 showed no neuro- or cardiotoxicity. PK data showed non-linear exposure of 2B3-101 without signs of accumulation upon repeat dosing, a mean half-life of 69h (range 43-120h) and independent of trastuzumab co-treatment. Best overall and intracranial tumor responses of 2B3-101 in 23 evaluable BCBM pts (92% of total) are summarized in Table 1. Conclusions: 2B3-101 alone or with trastuzumab is safe and well tolerated and shows intra- and extracranial anti-tumor activity in heavily pretreated BC pts. A 12-week PFS rate of 56% in HER2+ BCBM was observed, which warrants further clinical studies. An international, multicenter, randomized, controlled phase IIb study in HER2+ BCBM is being planned. NCT01386580, sponsored by to-BBB technologies BV. Citation Format: Philippe G Aftimos, Bojana Milojkovic-Kerklaan, Veronique Dieras, Sevilay Altintas, Carey Anders, Monica Arnedos, Hans Gelderblom, Patricia Soetekouw, Werner Gladdines, Pieter Gaillard, Carlos de Sousa, Agnes Jager, Myra van Linde, Ahmad Awada, Jan Schellens, Dieta Brandsma. Phase 1/2a study of glutathione PEGylated liposomal doxorubicin (2B3-101) in breast cancer patients with brain metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-16-04.