Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancers

Hellmann, Matthew D.; Sturm, Isrid; Trnková, Zuzana; Lettieri, John; Diefenbach, Konstanze; Rizvi, Naiyer A.; Gettinger, Scott

doi:10.1016/j.cllc.2015.04.003

Cited by 11 publications

(4 citation statements)

References 24 publications

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“…Such results are consistent with the clinical observations, which demonstrates that chemotherapy often failed to completely eliminate TNBC cells colonizing the bone, as evidenced by the clinical disease progression [30]. Furthermore, the results with 10 µM cisplatin in biomimetic bone models is not significantly different from the concentration of cisplatin (2000 ng/mL) in patients' steady-state serum [31], which suggests that biomimetic bone-metastasis models might access more physiological drug response data in vitro. We could thus expect the sensitivity to drugs in our biomimetic bone model to adequately reflect in vivo sensitivity.…”

Section: Modulated Chemo-resistance To Cis-platin Of Tnbc Cells In Biomimetic Bone Nichesupporting

confidence: 85%

In vitro bone metastasis dwelling in a 3D bioengineered niche

et al. 2021

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Bone is the most frequent metastasis site for breast cancer. As well as dramatically increasing disease burden, bone metastases are also an indicator of poor prognosis. One of the main challenges in investigating bone metastasis in breast cancer is engineering in vitro models that replicate the features of in vivo bone environments. Such in vitro models ideally enable the biology of the metastatic cells to mimic their in vivo behavior as closely as possible. Here, taking benefit of cutting edge technologies both in microfabrication and cancer cell biology, we have developed an in vitro breast cancer bone-metastasis model. To do so we first 3D printed a bone scaffold that reproduces the trabecular architecture and that can be conditioned with osteoblast-like cells, a collagen matrix, and mineralized calcium deposition. We thus demonstrated that this device offers an adequate soil to seed breast cancer bone metastatic cells. In particular, patient-derived xenografts being considered as better approach than cell lines to achieve clinically relevant results, we demonstrate the ability of this biomimetic bone niche model to host patientderived xenografted metastatic breast cancer cells. These patient-derived xenograft cells show a long term survival in the bone model and maintain their cycling propensity, and exhibit the same modulated drug response as in vivo. This experimental system enables access to the idiosyncratic features of the bone microenvironment and cancer bone metastasis, which has implications for drug testing.

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Section: Modulated Chemo-resistance To Cis-platin Of Tnbc Cells In Biomimetic Bone Nichesupporting

confidence: 85%

In vitro bone metastasis dwelling in a 3D bioengineered niche

et al. 2021

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“…Corroborating our results panobinostat levels were also below the detection limit in a recently published study in children using higher panobinostat doses [54]. Comparing our quantitation results to serum-levels from former studies, CSF-levels of dasatinib [55], imatinib [56], regorafenib [57], ribociclib [58] and vorinostat [59] showed significant differences (multiple orders of magnitude). The approach of evaluating CNS penetration via CSF sampling has been questioned [60] and studies directly measuring drug penetrance into tumor tissue are generally favored.…”

Section: Discussionsupporting

confidence: 83%

Cerebrospinal fluid penetration of targeted therapeutics in pediatric brain tumor patients

Guntner

Peyrl

Mayr

et al. 2020

acta neuropathol commun

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Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not effective against central nervous system (CNS) tumors. The failure of precision medicine approaches for CNS tumors is frequently attributed to the inability of these compounds to cross the blood-brain barrier (BBB), which impedes intratumoral target engagement. This is complicated by the fact that information on CNS penetration in CNS-tumor patients is still very limited. Herein, we evaluated cerebrospinal fluid (CSF) drug penetration, a well-established surrogate for CNS-penetration, in pediatric brain tumor patients. We analyzed 7 different oral anti-cancer drugs and their metabolites by high performance liquid chromatography mass spectrometry (HPLC-MS) in 42 CSF samples obtained via Ommaya reservoirs of 9 different patients. Moreover, we related the resulting data to commonly applied predictors of BBB-penetration including ABCB1 substrate-character, physicochemical properties and in silico algorithms. First, the measured CSF drug concentrations depicted good intra- and interpatient precision. Interestingly, ribociclib, vorinostat and imatinib showed high (> 10 nM), regorafenib and dasatinib moderate (1–10 nM) penetrance. In contrast, panobinostat und nintedanib were not detected. In addition, we identified active metabolites of imatinib and ribociclib. Comparison to well-established BBB-penetrance predictors confirmed low molecular weight, high proportion of free-drug and low ABCB1-mediated efflux as central factors. However, evaluation of diverse in silico algorithms showed poor correlation within our dataset. In summary, our study proves the feasibility of measuring CSF concentration via Ommaya reservoirs thus setting the ground for utilization of this method in future clinical trials. Moreover, we demonstrate CNS presence of certain small-molecule inhibitors and even active metabolites in CSF of CNS-tumor patients and provide a potential guidance for physicochemical and biological factors favoring CNS-penetration.

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“…Sampling time points were selected based on preclinical experience and were extensive enough to ensure that the absorption and elimination phases of the compound were adequately described. Plasma concentrations of regorafenib and its metabolites were determined using validated liquid chromatography–tandem mass spectrometry methods .…”

Section: Methodsmentioning

confidence: 99%

Topical administration of regorafenib eye drops: phase I dose‐escalation study in healthy volunteers

Zimmermann

Höchel

Becka

et al. 2018

Brit J Clinical Pharma

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AimRegorafenib is a multikinase inhibitor under investigation for use in neovascular age‐related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure.MethodsThis was a single‐centre, randomized, double‐masked, parallel‐group, dose‐escalation, placebo‐controlled study. Subjects received regorafenib eye drops (30 mg ml−1, 25 μl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study.ResultsThirty‐six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600–700‐fold lower than after multiple oral administration of 160 mg day−1, the dose approved in cancer indications.ConclusionThese results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml−1 tid for use in clinical studies.

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Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancers

Cited by 11 publications

References 24 publications

In vitro bone metastasis dwelling in a 3D bioengineered niche

In vitro bone metastasis dwelling in a 3D bioengineered niche

Cerebrospinal fluid penetration of targeted therapeutics in pediatric brain tumor patients

Topical administration of regorafenib eye drops: phase I dose‐escalation study in healthy volunteers

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