A phase II study of stereotactic radiotherapy after FOLFIRINOX for locally advanced pancreatic cancer (LAPC-1 trial): Long-term outcome.

PURPOSE: To report the long-term outcome of a multicenter phase II study with FOLFIRINOX followed by stereotactic body radiotherapy (LAPC-1 trial) in patients with locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Patients with histological confirmation of LAPC inoperable at diagnosis were enrolled. Induction therapy with 8 cycles of FOLFIRINOX was administered. If no disease progression was found after chemotherapy, patients received stereotactic body radiotherapy (SBRT) at a total dose of 40 Gy in 5 fractions. RESULTS: In LAPC-1 trial, 50 patients were included, but due to disease progression in 11 patients under chemotherapy, 39 patients received stereotactic SBRT after FOLFIRINOX treatment. In whole population, the 1- and 3-year overall survival (OS) were 62% and 10%, respectively. Median follow-up was 13 months. The SBRT group had median OS of 18 months (95% CI 13.2-21.5) versus 5 months (95% CI 4.1-6.7) in non-SBRT group (p<0.001). After chemoradiotherapy, seven patients underwent surgery achieving a radical resection. Patients who underwent surgery had a 3-years OS of 43% compared to 6.5% in the unresected group (p=0.03). Four patients developed grade ≥ 3 adverse events during SBRT. CONCLUSIONS: Long-term survival has been found in patients with LAPC underwent FOLFIRINOX followed by SBRT. This approach increased the probability of a radical surgery. The resected patients achieved a significant better survival compared to unresected group.

[As series of success stories; the pitfall of preoperative chemotherapy in unresectable carcinoma of the colon]. / Stuk voor stuk succesverhalen.

This comment is a reflection on the case studies of three patients with T4 cancer of the colon with bladder invasion. All three patients were successfully treated with preoperative chemotherapy followed by surgery. Although we want to underline this result, we must also emphasise that some patients will not benefit from this treatment. Future research should clarify the short- and long-term effects of preoperative chemotherapy followed by surgery. Until then, it is important that patients are aware of the actual intention of the treatment plan, and that there is a chance that the intended targets will not be met.

Tivozanib: a new treatment option for renal cell carcinoma.

Tivozanib is a tyrosine kinase inhibitor that targets all vascular endothelial growth factor receptors (VEGFRs), causing inhibition of angiogenesis. It has recently been approved by the European Medicines Agency (EMA) for first-line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mammalian target of rapamycin (mTOR) pathway inhibitor-naive, following disease progression after one prior treatment with cytokine therapy for advanced RCC. This review will focus on mechanisms of action, early drug development and results of published and ongoing clinical trials of tivozanib.

Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics.

Docetaxel is used for treatment of several solid malignancies. In this study, we aimed for predicting docetaxel clearance and docetaxel-induced neutropenia by developing several genetic models. Therefore, pharmacokinetic data and absolute neutrophil counts (ANCs) of 213 docetaxel-treated cancer patients were collected. Next, patients were genotyped for 1936 single nucleotide polymorphisms (SNPs) in 225 genes using the drug-metabolizing enzymes and transporters platform and thereafter split into two cohorts. The combination of SNPs that best predicted severe neutropenia or low clearance was selected in one cohort and validated in the other. Patients with severe neutropenia had lower docetaxel clearance than patients with ANCs in the normal range (P=0.01). Severe neutropenia was predicted with 70% sensitivity. True low clearance (1 s.d.

Impact of pazopanib on docetaxel exposure: results of a phase I combination study with two different docetaxel schedules.

PURPOSE: There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib with two different schedules of docetaxel. METHODS: In a 3 + 3 + 3 design, patients with advanced solid tumors received escalating doses of oral pazopanib combined with docetaxel given either every 3 weeks (D3w) or weekly at days 1, 8, and 15 every 28 days (D1w). Pharmacokinetic data of docetaxel and pazopanib were obtained through extensive sampling and WinNonlin modeling. RESULTS: Forty-six patients were enrolled to six dose levels. Both schedules of docetaxel could be combined with 400 mg/day pazopanib. The MTD of D3w docetaxel was 50 mg/m(2), while for D1w MTD, it was 20 mg/m(2). In the D3w schedule, the administration of pazopanib led to a 33% lower docetaxel clearance (mean 31.5 vs 21.1 L/h/m(2); P = 0.019) and >50% increase in AUC(0-∞) (mean 1,602 vs 2,414 ng*h/mL; P = 0.029) compared with docetaxel single-agent data. Data for the D1w schedule were comparable. CONCLUSIONS: Both treatment schedules of docetaxel combined with pazopanib are feasible but at doses for both drugs that are considerably lower than the recommended single-agent doses. This is largely due to a clinically relevant pharmacokinetic interaction with pazopanib, substantially increasing docetaxel exposure. This interaction is most likely due to CYP3A4 and OATP1B1 inhibition.

Histological and Molecular Subclassification of Pancreatic and Nonpancreatic Periampullary Cancers: Implications for (Neo) Adjuvant Systemic Treatment.

The benefit of adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC) has been confirmed in randomized controlled trials. For nonpancreatic periampullary cancers (NPPC) originating from the distal bile duct, duodenum, ampulla, or papilla of Vater, the role of adjuvant therapy remains largely unclear. This review describes methods for distinguishing PDAC from NPPC by means of readily available and recently developed molecular diagnostic methods. The difficulties of reliably determining the exact origin of these cancers pathologically also is discussed. The review also considers the possibility of unintentional inclusion of NPPC in the most important adjuvant trials on PDAC and the subsequent implications for interpretation of the results. The authors conclude that correct determination of the origin of periampullary cancers is essential for clinical management and should therefore be systematically incorporated into clinical practice and future studies.

Hepatocellular carcinoma: Dutch guideline for surveillance, diagnosis and therapy.

UNLABELLED: Hepatocellular carcinoma (HCC) is rare in the Netherlands, even though the incidence has increased quite sharply in recent years. Standard treatment options consist of surgery, orthotopic liver transplantation, radiofrequency ablation, transarterial chemoembolisation (TACE) and systemic therapy with sorafenib. The consensus-based Dutch HCC guideline, established in 2013, serves to guide surveillance, diagnosis and treatment options: Surveillance should be performed by ultrasound at six-month intervals in well-defined cirrhotic patients and in selected high-risk hepatitis B carriers; A nodule > 1 cm in cirrhotic patients with arterial hypervascularity and venous or delayed phase washout at four-phase CT or MRI scan establishes the diagnosis of HCC; In patients with HCC without underlying cirrhosis, resection should be considered regardless of tumour size; In cirrhotic HCC patients, tumour stage, severity of underlying cirrhosis, and performance status determine treatment options. The algorithm of the Barcelona Clinic Liver Cancer (BCLC) staging system should be followed; Patients with Child-Pugh A-B cirrhosis (CP < 8 points) and performance status 0-2 are candidates for any active treatment other than transplantation; In early stage HCC (BCLC stage 0 or A, compensated cirrhosis without portal hypertension) surgical resection, liver transplantation, or radiofrequency ablation should be considered; In intermediate stage HCC (BCLC stage B) TACE and÷ or radiofrequency ablation should be considered; In advanced stage HCC (BCLC stage C) sorafenib should be considered. CONCLUSION: The Dutch HCC guideline offers advice for surveillance, diagnosis and treatment of HCC.

A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours.

BACKGROUND: The vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours. METHODS: Ombrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m(-2) with 75 mg m(-2) docetaxel, then from 30 to 35 mg m(-2) with 100 mg m(-2) docetaxel. Recommended phase II dose cohorts were expanded. RESULTS: Fifty-eight patients were treated. Recommended phase II doses were 35 mg m(-2) ombrabulin with 75 mg m(-2) docetaxel (35/75 mg m(-2); 13 patients) and 30 mg m(-2) ombrabulin with 100 mg m(-2) docetaxel (30/100 mg m(-2); 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m(-2) docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m(-2) ombrabulin), eight lasting >3 months. CONCLUSIONS: Sequential administration of ombrabulin with 75 or 100 mg m(-2) docetaxel every 3 weeks is feasible.

Pazopanib exposure decreases as a result of an ifosfamide-dependent drug-drug interaction: results of a phase I study.

BACKGROUND: The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1-3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide. METHODS: In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m(-2) per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers. RESULTS: Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide. CONCLUSION: Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m(-2) per cycle, every 3 weeks) is 800 mg daily.

Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours.

BACKGROUND: JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327. METHODS: Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood. RESULTS: JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27(kip1), phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%). CONCLUSION: JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.

A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours.

BACKGROUND: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel. METHODS: A total of 22 patients received paclitaxel (135-175 mg m(-2)) intravenously, administered once every three weeks for up to six cycles, with oral tosedostat (90-240 mg) daily. RESULTS: One DLT (grade 3 dyspnoea) was observed in one patient with tosedostat 180 mg combined with paclitaxel 175 mg m(-2). A high number of paclitaxel infusion reactions was noted during the second administration (59%) and this prompted interruption of tosedostat dosing for 5 days around every second and subsequent paclitaxel infusion. No formal MTD was determined because of the high frequency of paclitaxel infusion reactions that may have been influenced by tosedostat. Most frequently observed drug-related adverse events were alopecia, fatigue (95% each), peripheral sensory neuropathy (59%), paclitaxel hypersensitivity (59%) and rash (55%). One patient died because of eosinophilic myocarditis, possibly related to study medication. There was no PK interaction between tosedostat and paclitaxel. In all, 3 patients had a partial response and 12 patients had stable disease lasting >3 months. CONCLUSION: The combination of tosedostat with paclitaxel was well tolerated except for the high incidence of paclitaxel-related infusion reactions.

Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours.

Resistance of cancer cells to cytotoxic therapy can be caused by the activation of strong anti-apoptotic effectors, for example NF-kappaB. Therefore, compounds that inhibit NF-kappaB stimulation might overcome chemotherapy resistance. F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and activates apoptosis in human tumour cells. We performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumours. Twenty patients were enrolled, and a total of 35 cycles were administered. The most frequent haematological side-effect was mild grade 1-2 anaemia. Non-haematological toxicities included fatigue, nausea, vomiting, diarrhoea and constipation, all grade 1-2. Two lethal events were observed in which an increase in caspase-3 activity and overt apoptosis in monocytes and neutrophils could be seen. Pharmacokinetic studies showed high inter-individual variability and rendered F60008 a far from optimal derivate of triptolide.

Systemic treatment in hepatocellular carcinoma; 'A small step for man...'.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide. In localised disease, orthotopic liver transplantation, surgical resection or local ablations are the mainstay of treatment. In unresectable or metastatic HCC, systemic therapy has unfortunately yielded disappointing results and therefore until recently was generally considered to be ineffective. Most patients with HCC have an underlying liver disease and many drugs may exacerbate the underlying liver disease. Recently, two randomised phase II trials with sorafenib in patients with advanced or metastatic HCC have shown a significant increase in progression free and overall survival of approximately two months, which is an absolute novum for this disease. Sorafenib is therefore now considered a viable treatment option in patients with unresectable or metastatic HCC, a good performance status and Child-Pugh A liver cirrhosis. Despite this very promising result, of major concern is the treatment-related toxicity as observed in these and other trials by sorafenib treatment. However, the important first significant survival benefit by systemic treatment has generated hope for the development of new treatment strategies which will be more efficacious, have favourable toxicity profiles and will further extend survival of this still highly lethal disease.

The spliceosome as target for anticancer treatment.

The spliceosome is a ribonucleoprotein complex involved in RNA splicing, that is, the removal of non-coding introns from precursor messenger RNA. (Alternative) Splicing events may play an essential role in tumourigenesis. The recent discovery that the spliceosome is a target for novel compounds with anticancer activity opens up new therapeutic avenues.

A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours.

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.

Trial design for cancer (cell)-specific anticancer therapies.

The last decade has brought a totally new class of systemic anticancer treatment options, the so-called cancer (cell)-specific (CCS) anticancer agents. Until recently, this treatment modality has been referred to as 'targeted therapy' but as all existing systemic anticancer therapies have a clearly defined target, this seems to be a misnomer. Despite impressive results of several CCS drugs, the present set up of drug development is ill suited for CCSs due to the nature of the majority of these compounds. The authors focus on specific aspects of how to design early clinical trials with this new class of anticancer agents with focus on pharmacodynamic behaviour in relation to response, optimal dose and treatment duration.

First-line treatment with oxaliplatin and capecitabine in patients with advanced or metastatic oesophageal cancer: a phase II study.

This phase II study assessed the safety and efficacy of oxaliplatin and capecitabine in patients with advanced oesophageal cancer. Fifty-one eligible patients received oxaliplatin 130 mg m(-2) intravenously on day 1 and capecitabine 1000 mg m(-2) orally twice daily on days 1 to 14 in a 21-day treatment cycle as first-line treatment for advanced oesophageal cancer. Grade 3 neutropenia was seen in one patient and anaemia in another patient. No grade 4 haematological toxicities were observed. Grade 4 non-haematological toxicity (lethargy) occurred in one patient (2%). Grade 3 non-haematological toxicity was seen in 14 (27%) patients (vomiting and polyneuropathy (8%); nausea (6%); lethargy and hand-foot syndrome (4%); and anorexia, diarrhoea, and hyperbilirubinaemia (each in one patient)). In 22% of the patients, toxicity was the reason for stopping the treatment. The overall response rate was 39%. The median overall survival was 8 months; the 1-year survival rate was 26%. In the quality of life (QoL) analysis, the emotional well-being improved during treatment, but the physical functioning scores declined. The fatigue score on the symptom scales increased. Overall, the global QoL score did not change during treatment. In conclusion, the activity of oxaliplatin and capecitabine is comparable with other chemotherapy regimens in advanced oesophageal cancer with a low frequency of grade 3/4 toxicity. Because this treatment can be given on an outpatient basis, it is probably less toxic than cisplatin-based therapy and preserves QoL during treatment, it is a viable treatment option in patients with advanced oesophageal cancer.

Vascular disrupting agents in clinical development.

Growth of human tumours depends on the supply of oxygen and nutrients via the surrounding vasculature. Therefore tumour vasculature is an attractive target for anticancer therapy. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific anticancer drugs has been developed. These so-called vascular disrupting agents (VDAs) target the established tumour vasculature and cause an acute and pronounced shutdown of blood vessels resulting in an almost complete stop of blood flow, ultimately leading to selective tumour necrosis. As a number of VDAs are now being tested in clinical studies, we will discuss their mechanism of action and the results obtained in preclinical studies. Also data from clinical studies will be reviewed and some considerations with regard to the future development are given.

A phase I study assessing the safety and pharmacokinetics of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with gemcitabine and cisplatin in patients with solid tumors.

BACKGROUND: The aim of the study was to determine the safety profile, pharmacokinetics and potential drug interactions of the angiogenesis inhibitor ABT-510 combined with gemcitabine-cisplatin chemotherapy in patients with solid tumors. PATIENTS AND METHODS: Patients with advanced solid tumors received gemcitabine 1250 mg/m2 intravenously (i.v.) on days 1 and 8 and cisplatin 80 mg/m2 on day 1 of a 3-week cycle in combination with ABT-510. ABT-510 was administered subcutaneously twice daily at doses of 50 mg or 100 mg. Plasma samples for pharmacokinetics were obtained on days 1 (gemcitabine, cisplatin as single agents), 15 (ABT-510 as single agent) and 22 (gemcitabine, cisplatin and ABT-510 as combination). RESULTS: Thirteen patients received ABT-510 as either 50 mg b.i.d. (seven patients) or 100 mg b.i.d. (six patients) in combination with gemcitabine-cisplatin. The most common reported adverse events reflected the known toxicity profile induced by gemcitabine-cisplatin without ABT-510. One episode of hemoptysis occurred in a patient with non-small-cell lung cancer (NSCLC) after 13 days of treatment. No clinically significant pharmacokinetic interactions between ABT-510, gemcitabine and platinum were observed. Three partial responses were observed in 12 evaluable patients (one head and neck cancer, one melanoma and one NSCLC). CONCLUSIONS: Combining ABT-510 at doses of 50 mg and 100 mg with gemcitabine-cisplatin is feasible. Pharmacokinetic interactions were not observed and adding ABT-510 does not appear to increase toxicity.

Phase I study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with 5-fluorouracil and leucovorin: a safe combination.

We performed a phase I study with the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 combined with 5-fluorouracil and leucovorin (5-FU/LV) to determine safety profile and assess pharmacokinetic interactions. Patients with advanced solid malignancies received LV 20 mg/m(2) followed by 5-FU 425 mg/m(2) both administered intravenously in 15 min daily for 5 days every 4 weeks. ABT-510 was administered subcutaneously twice daily continuously from day 2 onwards. Blood and urine samples for pharmacokinetic analyses were collected at days 1, 5 and 22. Twelve patients received a total of 45 cycles of 5-FU/LV combined with ABT-510. ABT-510 dose levels studied were 50 and 100 mg. The combination was well tolerated, with a toxicity profile comparable to that of 5-FU/LV alone. At the dose levels studied no significant pharmacokinetic interactions were observed. These data indicate that ABT-510 administered twice daily subcutaneously can be safely combined with 5-FU/LV administered daily for 5 days, every 4 weeks.