M.J. Boers-Sonderen

Tyrosine Kinase Inhibitor Sorafenib Decreases 111In-Girentuximab Uptake in Patients with Clear Cell Renal Cell Carcinoma

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of metastatic clear cell renal cell carcinoma (RCC). Although TKIs have demonstrated good clinical efficacy, the lack of complete responses, the chronic nature of the treatment, and the side effects are clear disadvantages. An interesting new approach in the treatment of clear cell RCC is antibody-mediated therapy with the chimeric anti–carbonic anhydrase IX (CAIX) antibody girentuximab (cG250). As the results of several girentuximab trials become available, the question arises of whether TKI treatment can be combined with girentuximab-based therapy. In this study, we assessed the effect of the widely used TKI sorafenib on the tumor-targeting potential of 111In-labeled girentuximab. Methods: 111In-girentuximab imaging was performed on 15 patients suspected of having a renal malignancy, with surgery being part of their treatment plan. Of these, 10 patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice daily). Five patients received treatment during 1 wk, and 5 patients received treatment during 4 wk. In both sorafenib-treated groups, baseline and posttreatment tumor targeting of 111In-girentuximab were compared. Surgery was performed 3 d after the last image acquisition. Five additional patients were included as a control group and had only a single 111In-girentuximab injection and scintigraphy without any treatment. Distribution of 111In-girentuximab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of CAIX and of the vascular marker CD31 was determined immunohistochemically on specimens of both tumor and normal kidney tissue. Results: Treatment with sorafenib resulted in a marked decrease of 111In-girentuximab uptake in the tumor in clear cell RCC patients, especially in the group treated for 4 wk (mean change in both sorafenib-treated groups, −38.4%; range, +9.1% to −79.4%). Immunohistochemical analysis showed markedly reduced CD31 expression and vessel density in the sorafenib-treated groups but no differences in CAIX expression between the sorafenib-treated groups and the nontreated patients. Conclusion: Treatment with sorafenib resulted in a treatment duration–dependent significantly decreased uptake of 111In-girentumab in clear cell RCC lesions. These results indicate that the efficacy of antibody-mediated treatment or diagnosis modalities is hampered by TKI treatment.

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 2 Study of Lutetium 177-Labeled Anti-Carbonic Anhydrase IX Monoclonal Antibody Girentuximab in Patients with Advanced Renal Cell Carcinoma.

UNLABELLED Despite advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC), there is still an unmet need in the treatment of this disease. A phase 2 radioimmunotherapy (RIT) trial with lutetium 177 ((177)Lu)-girentuximab was initiated to evaluate the efficacy of this approach. In this nonrandomized single-arm trial, patients with progressive metastatic ccRCC who met the inclusion criteria received 2405 MBq/m(2) of (177)Lu-girentuximab intravenously. In the absence of persistent toxicity and progressive disease, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. A total of 14 patients were included. After the first therapeutic infusion, eight patients (57%) had stable disease (SD) and one (7%) had a partial regression. The treatment was generally well tolerated but resulted in grade 3-4 myelotoxicity in most patients. After the second cycle, continued SD was observed in five of six patients, but none were eligible for retreatment due to prolonged thrombocytopenia. In conclusion, RIT with (177)Lu-girentuximab resulted in disease stabilization in 9 of 14 patients with progressive metastatic ccRCC, but myelotoxicity prevented retreatment in some patients. PATIENT SUMMARY We investigated the efficacy of lutetium 177-girentuximab radioimmunotherapy in patients with metastatic kidney cancer. The treatment resulted in disease stabilization in 9 of 14 patients. The main toxicity was prolonged low blood cell counts. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02002312 (https://clinicaltrials.gov/ct2/show/NCT02002312).

A phase II study of cediranib as palliative treatment in patients with symptomatic malignant ascites or pleural effusion

Malignant ascites and pleural effusion are challenging clinical problems, with a major impact on quality of life. We conducted a randomized phase II trial to assess the palliative value of cediranib, an oral vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). After a baseline paracentesis or thoracentesis (on day 0), patients with symptomatic malignant ascites and/or pleural effusion were randomized between immediate treatment with cediranib (Immediate Cediranib) or delayed treatment with cediranib (Delayed Cediranib) on day 29, or after a new puncture was needed. The primary objective of the study was the puncture-free survival, defined as the time from study start (day 1) to the first need for paracentesis or thoracentesis, or time to death, whichever event occurred first. Twelve patients were enrolled. The median puncture-free survival was 45 days (range 10–368) in the Immediate Cediranib patients and 7 days (range 4–13) in the Delayed Cediranib patients (P = 0.011). The change in puncture-free interval (the puncture-free survival after study start minus the puncture-free interval before study start) increased with a median of 31 days in the Immediate Cediranib patients and shortened with a median of 3 days in the Delayed Cediranib patients (P = 0.015). The most common adverse events were fatigue and anorexia. In conclusion, cediranib increased the puncture-free survival and puncture-free interval with an acceptable toxicity profile. This is the first study in which an oral VEGFR TKI showed beneficial palliative effects in patients with malignant effusions.

A prolonged complete response in a patient with BRAF-mutated melanoma stage IV treated with the MEK1/2 inhibitor selumetinib (AZD6244).

In melanoma, the RAS/RAF/MEK/ERK pathway is frequently activated by mutations in BRAF and NRAS. Selumetinib (AZD6244) is an oral, selective, non-ATP-competitive inhibitor of MEK1/2. Here, we describe a patient with metastatic melanoma (T1N2cM1a) with a BRAF V600E mutation. She is currently being treated with selumetinib 75 mg twice daily in a phase I trial and has shown complete response for the past 4 years. This case report raises questions regarding treatment schedule, treatment duration and management of adverse events.

Better survival of renal cell carcinoma in patients with inflammatory bowel disease

Background Immunosuppressive therapy may impact cancer risk in inflammatory bowel disease (IBD). Cancer specific data regarding risk and outcome are scarce and data for renal cell carcinoma (RCC) are lacking. We aimed(1) to identify risk factors for RCC development in IBD patients (2) to compare RCC characteristics, outcome and survival between IBD patients and the general population. Methods A PALGA (Dutch Pathology Registry) search was performed to establish a case group consisting of all IBD patients with incident RCC in The Netherlands (1991–2013). Cases were compared with two separate control groups: (A) with a population-based IBD cohort for identification of risk factors (B) with a RCC cohort from the general population to compare RCC characteristics and outcomes. Results 180 IBD patients with RCC were identified. Pancolitis (OR 1.8–2.5), penetrating Crohns disease (OR 2.8), IBD related surgery (OR 3.7–4.5), male gender (OR 3.2–5.0) and older age at IBD onset (OR 1.0–1.1) were identified as independent risk factors for RCC development. IBD patients had a significantly lower age at RCC diagnosis (p < 0.001), lower N-stage (p = 0.025), lower M-stage (p = 0.020) and underwent more frequently surgical treatment for RCC (p < 0.001) compared to the general population. This translated into a better survival (p = 0.026; HR 0.7) independent of immunosuppression. Conclusions IBD patients with a complex phenotype are at increased risk to develop RCC. They are diagnosed with RCC at a younger age and at an earlier disease stage compared to the general population. This translates into a better survival independent of immunosuppressive or anti-TNFα therapy.

Severe exacerbation of Crohn's disease during sunitinib treatment

Sunitinib is a multiple tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor pathway and inhibits angiogenesis, cell proliferation, and tumor cell invasion, and stimulates apoptosis. Treatment with sunitinib in first-line metastatic renal cell carcinoma improves progression-free survival and overall survival compared with interferon-α. Crohns disease is characterized by chronic immune-mediated intestinal inflammation. Although the exact pathogenesis of Crohns disease remains unknown, the involvement of angiogenesis is acknowledged. It is unknown whether sunitinib interferes with the natural course of Crohns disease. We describe a patient with metastatic renal cell carcinoma and a history of Crohns disease who was treated with sunitinib and developed a severe exacerbation of Crohns disease. After rechallenge with sunitinib, a second exacerbation occurred. We therefore conclude that angiogenesis inhibitors should be administered with care in patients with a history of Crohns disease.

Endoscopy in patients with diarrhea during treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors: Is the cause in the mucosa?

Abstract Background Diarrhea is a frequently occurring adverse event during treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and is mostly accompanied by abdominal cramps, flatulence and pyrosis. These complaints impair quality of life and lead to dose reductions and treatment interruptions. It is hypothesized that the diarrhea might be due to ischemia in bowel mucosa or inflammation, but the exact underlying pathophysiological mechanism of the diarrhea is still unknown. We aimed at exploring the mechanism for diarrhea in these patients by thorough endoscopic and histological assessment. Materials and methods Endoscopies of the upper and lower gastrointestinal (GI) tract in 10 patients with metastatic renal cell carcinoma (mRCC) who developed diarrhea during treatment with VEGFR TKIs were performed. Results Ten patients were included. The results showed endoscopically normal mucosa in the lower GI tract in seven patients without signs of ischemic colitis or inflammation. Gastroduodenoscopy revealed gastro-esophageal reflux disease, bulbitis and/or duodenitis with ulcers in eight patients. In three selected patients with bulbitis/duodenitis additional video capsule endoscopy was performed but revealed no additional intestinal abnormalities. Conclusion We observed frequent mucosal abnormalities in the upper GI tract in VEGFR TKI-treated mRCC patients with diarrhea. Although these abnormalities provide insufficient explanation for the occurrence of diarrhea, we suggest to perform routine upper GI endoscopy in VEGFR TKI-treated patients with GI complaints.

Capecitabine, irinotecan (CAPIRI) and sunitinib in metastatic colorectal cancer

Carrato et al. [1] recently published their results of a randomized phase III trial of fl uorouracil (5-FU), leucovorin (LV) and irinotecan (FOLFIRI) plus either sunitinib or placebo in patients with metastatic colorectal cancer (mCRC). Intravenous FOLFIRI was administered every two weeks as irinotecan 180 mg/m 2 , LV 200 mg/m 2 immediately followed by 5-FU 400 mg/m 2 bolus and 5-FU 2400 mg/m 2 as a 46-hour infusion. The dosage of oral sunitinib was 37.5 mg/day in a four-weeks on/two-weeks off schedule. The study failed to demonstrate superiority for FOLFIRI plus sunitinib and showed an increased incidence of grade 3 adverse events for this combination when compared to FOLFIRI plus placebo [neutropenia (68% vs. 30%), diarrhea (16% vs. 8%, thrombocytopenia (11% vs. 1%), anemia, stomatitis, fatigue, hand-foot syndrome and febrile neutropenia). Furthermore, more deaths as a result of toxicity (n 12 vs. n 4) and signifi cantly more dose delays, dose reductions and treatment discontinuations occurred in the sunitinib arm. We performed a phase I study in a standard 3 3 trial design with capecitabine, irinotecan (CAPIRI) and sunitinib in patients with mCRC as second line treatment (NCT00777478). Both capecitabine and irinotecan were administered at a reduced starting dose (capecitabine 850 mg/m 2 on day 1 – 14 and irinotecan 200 mg/m 2 on day 1, every three weeks) due to the expected additive toxicities of the combination with sunitinib. This study was approved by the medical ethical committee and was conducted in accordance with the Principles of Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent. We treated four patients at dose level 1, with sunitinib given at 25 mg/day continuously, and observed two dose limiting toxicities (DLTs): a grade 3 neutropenia lasting more than seven days and a delay of more than 14 days of the second cycle because of neutropenia and thrombocytopenia. According to protocol we subsequently treated the following patients at a lower dose level with sunitinib 12.5 mg/day continuously. Both patients at this dose level experienced neutropenia grade 3, which led to dose delays of irinotecan and dose interruptions of sunitinib and capecitabine. In one of these two patients, sunitinib was defi nitively withdrawn after cycle 4 and thereafter this patient did not experience any hematological toxicities anymore, even when the dose of irinotecan was escalated. As any clinical benefi t was not expected with lower doses of sunitinib with already reduced doses of capecitabine and irinotecan, the study was discontinued and we concluded that a combination of CAPIRI with sunitinib was not feasible. FOLFIRI, in comparison to CAPIRI, is associated with less adverse events as has been shown in a phase III trial, in which patients were randomized between treatment with FOLFIRI and CAPIRI [2]. Grade 3 to 4 nausea, vomiting, diarrhea and dehydration occurred signifi cantly more frequently in the CAPIRI arm, and neutropenia occurred more frequently in the FOLFIRI arm (43% vs. 32%). Although these data show that CAPIRI is associated with a higher incidence of toxic events, it is considered as a Acta Oncologica, 2013; 52: 1778–1790