Clinical Study

Clinical Trial - VU Medical Center, Amsterdam, Netherlands

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Background

Diagnostic tools to predict whether a patient will develop toxicity to targeted agents are not yet available. Our general hypothesis is that immunophenotyping studies combined with (phospho)proteomic and kinase activity profiling in normal tissue before and during treatment with targeted agents may provide more insight in underlying causative mechanisms of toxicity and provide potential biomarkers for clinical use to predict for toxicity.

 

The TKIs sunitinib and sorafenib target multiple receptors, including VEGFR and platelet-derived growth factor receptor (PDGFR), and have shown clinical efficacy in diverse cancer types. Both drugs have shown benefit in patients with metastatic renal cell cancer. Furthermore, sunitinib has been approved for the treatment of gastro-intestinal stromal tumors (GIST) and pancreatic neuroendocrine tumors and sorafenib for the treatment of hepatocellular cancer.

 

The major problems that emerged during the clinical development of antiangiogenic TKIs include low response rates, intrinsic resistance and development of acquired resistance (initial response followed by disease progression). In addition and despite the initial expectation of low rate of adverse effects, since antiangiogenic TKIs primarily target proliferating endothelial cells (only 1% of endothelial cells under normal conditions- except in menstrual cycle and wound healing), significant clinical toxicities are being observed. These include, but are not limited to, skin toxicity, diarrhea, severe bleeding, hypertension, disturbed wound healing, fatigue and hypothyroidism, and nephrotoxicity. Although most side effects are usually mild at presentation, grade III-IV toxicities as defined by NCI-CTC grading system are not uncommon. In addition, multiple grade I/II toxicities at the same time do have impact on daily life of patients. Taking into consideration that these agents are usually administered over long periods of time, they interfere with quality of life, such as stomatitis, interfering with adequate food intake, hand-foot syndrome limiting walking and the urgent pattern of diarrhea. Therefore, dose modification is often required and in more severe cases, therapy is discontinued, compromising the substantial clinical benefit.

These toxicities appear to be even higher in the real-world setting; two global expanded access programs and single center reports indicated higher levels of toxicity compared to those reported in clinical trials. Pathogenesis of antiangiogenic TKIs associated diarrhea is still unclear. It has been suggested that antiangiogenic TKIs could interfere with gastrointestinal functions and these alterations could play a role in the development of diarrhea. Lacouture et al [PMID:18550575] examined clinicopathological findings of hand foot skin reaction in patients treated with sorafenib and sunitinib, in an attempt to explain the localization in palmoplantar areas. They postulated that inhibition of VEGFR, PDGFR, and c-KIT leads to inability of affected vessels and fibroblasts to repair damages in areas of trauma or friction, due to daily use (palms, soles, elbows). Robert et al [PMID:15992698] reported that acral erythema that develops in patients receiving sorafenib and sunitinib seems to be more localized and hyperkeratotic, which is distinct from classic HFSR. It was also speculated that the observed dose dependency suggests a direct toxic effect of the causative agent. Furthermore, there is accumulating evidence in the literature that sorafenib is associated with an increased occurrence of epithelial skin cancers and cases of patients who developed basal cell cancer (BCC) while on sorafenib treatment have been reported. Additionally, kinase inhibitors are known to modulate the immune system

 

We hypothesize that sunitinib/ sorafenib- induced toxicity is caused by interference with normal physiological homeostasis at the tissue level.

 

Clinical Study Design:

To further investigate this hypothesis, we (VU Medical Center, Amsterdam, Netherlands) designed an interventional, single-center, non-randomized clinical trial where patients with malignant solid tumors who will receive standard palliative treatment with sunitinib or sorafenib may participate. After study inclusion, blind biopsies of the oral mucosa, skin and colon mucosa by sigmoidoscopy for pre-treatment (phospho) proteomic profiling and kinase activity profiling will be taken as baseline normal tissue. After 4 weeks of treatment, a re-biopsy of the 3 aforementioned areas will be performed to determine possible incipient histopathological changes and to compare pre- and post-treatment (phospho) proteomic, kinase activity profiles and possible immunomodulatory changes. Furthermore, if in the meantime the patient develops mucositis, colitis or skin toxicity, biopsy specimens of the affected area will be harvested if clinically feasible and following patients' re-consent. Patients will undergo standard venipunctures before treatment and after 4 weeks to measure other possible parameters of toxicity, such as thyroid hormones and to define circulating downstream biomarkers of toxicity. In case of toxicity development, an additional blood sample will be acquired. After enrollment of the first twenty patients we will assess feasibility of the method to detect histopathological changes or changes in the (phospho)-proteomic profile in the normal tissues taken before and after treatment. If indeed changes are detected, we will proceed to enroll twenty more patients in each cohort, depending on the outcome of statistical analysis.

 

Patients will be asked for informed consent according to standard ethical procedures. Eligibility of participants in the study will be based on the results of a screening medical history, WHO performance status, physical examination and laboratory analysis. Disease history, concomitant medications and protocol procedure-related adverse events will be documented. Any major modifications that may affect the safety of the patient will be detailed in a protocol amendment and submitted to the ethics committee for approval.

 

This clinical trial has already been approved by the local ethics committee (Dutch: METC, CCMO) and is currently enrolling patients.