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11 pages, 1212 KiB

Open AccessCommunication

Framework for Implementing Individualised Dosing of Anti-Cancer Drugs in Routine Care: Overcoming the Logistical Challenges

by Jason van Leuven, Simon Evans, Ganessan Kichenadasse, Neeltje Steeghs, Billie Bonevski, Gerd Mikus and Madelé van Dyk

Cancers 2023, 15(13), 3293; https://doi.org/10.3390/cancers15133293 - 22 Jun 2023

Cited by 2 | Viewed by 2877

Abstract

Precision medicine in oncology involves identifying the ‘right drug’, at the ‘right dose’, for the right person. Currently, many orally administered anti-cancer drugs, particularly kinase inhibitors (KIs), are prescribed at a standard fixed dose. Identifying the right dose remains one of the biggest [...] Read more.

Precision medicine in oncology involves identifying the ‘right drug’, at the ‘right dose’, for the right person. Currently, many orally administered anti-cancer drugs, particularly kinase inhibitors (KIs), are prescribed at a standard fixed dose. Identifying the right dose remains one of the biggest challenges to optimal patient care. Recently the Precision Dosing Group established the Accurate Dosing of Anti-cancer Patient-centred Therapies (ADAPT) Program to address individualised dosing; thus, use existing anti-cancer drugs more safely and efficiently. In this paper, we outline our framework, based on the Medical Research Council (MRC) framework, with a simple 6-step process and strategies which have led to the successful implementation of the ADAPT program in South Australia. Implementation strategies in our 6-step process involve: (1) Evaluate the evidence and identify the cancer drugs: Literature review, shadowing other experts, establishing academic partnerships, adaptability/flexibility; (2) Establishment of analytical equipment for drug assays for clinical purposes: assessment for readiness, accreditation, feasibility, obtaining formal commitments, quality assurance to all stakeholders; (3) Clinical preparation and education: educational material, conducted educational meetings, involve opinion leaders, use of mass media, promote network weaving, conduct ongoing training; (4) Blood collection, sample preparation and analyses: goods received procedures, critical control points (transport time); (5) Interpret and release results with recommendations: facilitate the relay of clinical data to providers; (6) Clinical application: providing ongoing consultation, identify early adopters, identify, and prepare champions. These strategies were selected from the 73 implementation strategies outlined in the Expert Recommendations for Implementing Change (ERIC) study. The ADAPT program currently provides routine plasma concentrations for patients on several orally administered drugs in South Australia and is currently in its evaluation phase soon to be published. Our newly established framework could provide great potential and opportunities to advance individualised dosing of oral anti-cancer drugs in routine clinical care. Full article

(This article belongs to the Special Issue Therapeutic Monitoring of Anti-cancer Agents)

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18 pages, 17797 KiB

Open AccessArticle

Identification of Thiazolo[5,4-b]pyridine Derivatives as c-KIT Inhibitors for Overcoming Imatinib Resistance

by Yunju Nam, Chan Kim, Junghee Han, SeongShick Ryu, Hanna Cho, Chiman Song, Nam Doo Kim, Namkyoung Kim and Taebo Sim

Cancers 2023, 15(1), 143; https://doi.org/10.3390/cancers15010143 - 26 Dec 2022

Cited by 1 | Viewed by 1907

Abstract

c-KIT is a promising therapeutic target against gastrointestinal stromal tumor (GIST). In order to identify novel c-KIT inhibitors capable of overcoming imatinib resistance, we synthesized 31 novel thiazolo[5,4-b]pyridine derivatives and performed SAR studies. We observed that, among these substances, 6r is [...] Read more.

c-KIT is a promising therapeutic target against gastrointestinal stromal tumor (GIST). In order to identify novel c-KIT inhibitors capable of overcoming imatinib resistance, we synthesized 31 novel thiazolo[5,4-b]pyridine derivatives and performed SAR studies. We observed that, among these substances, 6r is capable of inhibiting significantly c-KIT and suppressing substantially proliferation of GIST-T1 cancer cells. It is of note that 6r is potent against a c-KIT V560G/D816V double mutant resistant to imatinib. Compared with sunitinib, 6r possesses higher differential cytotoxicity on c-KIT D816V Ba/F3 cells relative to parental Ba/F3 cells. In addition, kinase panel profiling reveals that 6r has reasonable kinase selectivity. It was found that 6r remarkably attenuates proliferation of cancer cells via blockade of c-KIT downstream signaling, and induction of apoptosis and cell cycle arrest. Furthermore, 6r notably suppresses migration and invasion, as well as anchorage-independent growth of GIST-T1 cells. This study provides useful SAR information for the design of novel c-KIT inhibitors overcoming imatinib-resistance. Full article

(This article belongs to the Special Issue Therapeutic Monitoring of Anti-cancer Agents)

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16 pages, 3811 KiB

Open AccessArticle

Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial

by Selinde S. Wind, Manon A. A. Jansen, Melanie Rijsbergen, Michiel J. van Esdonk, Dimitrios Ziagkos, Wing C. Cheng, Tessa Niemeyer-van der Kolk, John Korsten, Agnieszka Gruszka, Debora Schmitz-Rohmer, David Bonnel, Raphael Legouffe, Florian Barré, Marcel W. Bekkenk, Ellen R. M. de Haas, Koen D. Quint, Harald Schnidar, Melanie Rolli, Henk Johan Streefkerk, Jacobus Burggraaf, Maarten H. Vermeer and Robert Rissmann Show full author list Hide full author list

Cancers 2022, 14(6), 1510; https://doi.org/10.3390/cancers14061510 - 15 Mar 2022

Cited by 2 | Viewed by 2440 | Correction

Abstract

Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy [...] Read more.

Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm² on 400 cm², with a mean C_avg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean C_avg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs. Full article

(This article belongs to the Special Issue Therapeutic Monitoring of Anti-cancer Agents)

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14 pages, 1333 KiB

Open AccessArticle

An Easily Expandable Multi-Drug LC-MS Assay for the Simultaneous Quantification of 57 Oral Antitumor Drugs in Human Plasma

by Niklas Kehl, Katja Schlichtig, Pauline Dürr, Laura Bellut, Frank Dörje, Rainer Fietkau, Marianne Pavel, Andreas Mackensen, Bernd Wullich, Renke Maas, Martin F. Fromm, Arne Gessner and R. Verena Taudte

Cancers 2021, 13(24), 6329; https://doi.org/10.3390/cancers13246329 - 16 Dec 2021

Cited by 9 | Viewed by 2830

Abstract

Oral anticancer drugs have led to significant improvements in the treatment of multiple tumor entities. However, in patients undergoing oral antitumor therapy, plasma concentrations are highly variable, resulting in risks of reduced therapeutic effects or an increase in side effects. One important tool [...] Read more.

Oral anticancer drugs have led to significant improvements in the treatment of multiple tumor entities. However, in patients undergoing oral antitumor therapy, plasma concentrations are highly variable, resulting in risks of reduced therapeutic effects or an increase in side effects. One important tool to reduce this variability is therapeutic drug monitoring. In this work we describe a method to simultaneously quantify the plasma concentrations of 57 oral antitumor agents. Quantification of these drugs was achieved using liquid chromatography coupled to an Orbitrap mass spectrometer. The method was fully validated according to the FDA guidelines and constitutes a simple and robust way for exposure monitoring of a wide variety of oral anticancer drugs. Applicability to clinical routine was demonstrated by the analysis of 71 plasma samples taken from 39 patients. In summary, this new multi-drug method allows simultaneous quantification of 57 oral antitumor drugs, which can be applied to exposure monitoring in clinical studies, taking into account the broad variety of oral antitumor drugs prescribed in clinical routine. Full article

(This article belongs to the Special Issue Therapeutic Monitoring of Anti-cancer Agents)

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15 pages, 810 KiB

Open AccessArticle

Developing a Nationwide Infrastructure for Therapeutic Drug Monitoring of Targeted Oral Anticancer Drugs: The ON-TARGET Study Protocol

by Anna M. Mc Laughlin, Eduard Schmulenson, Olga Teplytska, Sebastian Zimmermann, Patrick Opitz, Stefanie L. Groenland, Alwin D. R. Huitema, Neeltje Steeghs, Lothar Müller, Stefan Fuxius, Gerald Illerhaus, Markus Joerger, Frank Mayer, Uwe Fuhr, Stefan Holdenrieder, Georg Hempel, Oliver Scherf-Clavel, Ulrich Jaehde, Charlotte Kloft and for the ON-TARGET Study Consortium

Cancers 2021, 13(24), 6281; https://doi.org/10.3390/cancers13246281 - 14 Dec 2021

Cited by 9 | Viewed by 2940

Abstract

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive [...] Read more.

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs. Full article

(This article belongs to the Special Issue Therapeutic Monitoring of Anti-cancer Agents)

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16 pages, 2376 KiB

Open AccessArticle

Ex Vivo Expanded Circulating Tumor Cells for Clinical Anti-Cancer Drug Prediction in Patients with Head and Neck Cancer

by Kuan-Chou Lin, Lai-Lei Ting, Chia-Lun Chang, Long-Sheng Lu, Hsin-Lun Lee, Fang-Chi Hsu, Jeng-Fong Chiou, Peng-Yuan Wang, Thierry Burnouf, Dennis Chun-Yu Ho, Kai-Chiang Yang, Chang-Yu Chen, Chu-Huang Chen, Ching-Zong Wu and Yin-Ju Chen

Cancers 2021, 13(23), 6076; https://doi.org/10.3390/cancers13236076 - 02 Dec 2021

Cited by 19 | Viewed by 3110

Abstract

The advanced-stage head and neck cancer (HNC) patients respond poorly to platinum-based treatments. Thus, a reliable pretreatment method for evaluating platinum treatment response would improve therapeutic efficiency and outcomes. This study describes a novel strategy to predict clinical drug responses in HNC patients [...] Read more.

The advanced-stage head and neck cancer (HNC) patients respond poorly to platinum-based treatments. Thus, a reliable pretreatment method for evaluating platinum treatment response would improve therapeutic efficiency and outcomes. This study describes a novel strategy to predict clinical drug responses in HNC patients by using eSelect, a lab-developed biomimetic cell culture system, which enables us to perform ex vivo expansion and drug sensitivity profiling of circulating tumor cells (CTCs). Forty liquid biopsies were collected from HNC patients, and the CTCs were expanded ex vivo using the eSelect system within four weeks. Immunofluorescence staining confirmed that the CTC-derived organoids were positive for EpCAM and negative for CD45. Two illustrative cases present the potential of this strategy for evaluating treatment response. The statistical analysis confirmed that drug sensitivity in CTC-derived organoids was associated with a clinical response. The multivariant logistic regression model predicted that the treatment accuracy of chemotherapy responses achieved 93.75%, and the area under the curves (AUCs) of prediction models was 0.8841 in the whole dataset and 0.9167 in cisplatin specific dataset. In summary, cisplatin sensitivity profiles of patient-derived CTCs expanded ex vivo correlate with a clinical response to cisplatin treatment, and this can potentially underpin predictive assays to guide HNC treatments. Full article

(This article belongs to the Special Issue Therapeutic Monitoring of Anti-cancer Agents)

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9 pages, 942 KiB

Open AccessArticle

Effect of Scalp Cooling on the Pharmacokinetics of Paclitaxel

by Leni van Doorn, Mandy M. van Rosmalen, Wendy M. van der Deure, Esther Oomen-de Hoop, Robert Porrazzo, Sophie M. Wijngaard, Ingrid A. Boere, Paola Veenstra, Eman Ibrahim, Peter de Bruijn, Lena E. Friberg, Stijn L. W. Koolen, Ron H. J. Mathijssen and Agnes Jager

Cancers 2021, 13(15), 3915; https://doi.org/10.3390/cancers13153915 - 03 Aug 2021

Cited by 2 | Viewed by 2347

Abstract

Chemotherapy-induced alopecia (CIA), a side effect with high impact, can be prevented by cooling the scalp during the administration of some cytotoxic drugs. However, the effects of this prolonged scalp cooling on the pharmacokinetics of chemotherapy have never been investigated. In this study, [...] Read more.

Chemotherapy-induced alopecia (CIA), a side effect with high impact, can be prevented by cooling the scalp during the administration of some cytotoxic drugs. However, the effects of this prolonged scalp cooling on the pharmacokinetics of chemotherapy have never been investigated. In this study, we compared the pharmacokinetics of the widely used chemotherapeutic agent paclitaxel (weekly dose of 80–100 mg/m²) in female patients with solid tumors using concomitant scalp cooling (n = 14) or not (n = 24). Blood samples were collected in all patients for pharmacokinetic analyses up to 6 h after one course of paclitaxel administration. The primary endpoint was the clearance (L/h) of paclitaxel. Paclitaxel clearance—expressed as relative difference in geometric means—was 6.8% (90% CI: −16.7% to 4.4%) lower when paclitaxel was administered with concomitant scalp cooling versus paclitaxel infusions without scalp cooling. Within the subgroup of patients using scalp cooling, paclitaxel clearance was not statistically significantly different between patients with CIA (alopecia grade 1 or 2) and those without CIA. Hence, scalp cooling did not negatively influence the clearance of paclitaxel treatment. Full article

(This article belongs to the Special Issue Therapeutic Monitoring of Anti-cancer Agents)

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13 pages, 595 KiB

Open AccessArticle

Germline Variation in PDCD1 Is Associated with Overall Survival in Patients with Metastatic Melanoma Treated with Anti-PD-1 Monotherapy

by Mirjam de With, Daan P. Hurkmans, Esther Oomen-de Hoop, Ayoub Lalouti, Sander Bins, Samira El Bouazzaoui, Mandy van Brakel, Reno Debets, Joachim G. J. V. Aerts, Ron H. N. van Schaik, Ron H. J. Mathijssen and Astrid A. M. van der Veldt

Cancers 2021, 13(6), 1370; https://doi.org/10.3390/cancers13061370 - 18 Mar 2021

Cited by 11 | Viewed by 1719

Abstract

A substantial number of melanoma patients do not benefit from therapy with anti-PD-1. Therefore, we investigated the predictive value of single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis in patients with metastatic melanoma. From 119 consecutive melanoma patients who were [...] Read more.

A substantial number of melanoma patients do not benefit from therapy with anti-PD-1. Therefore, we investigated the predictive value of single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis in patients with metastatic melanoma. From 119 consecutive melanoma patients who were treated with pembrolizumab or nivolumab monotherapy, blood samples were genotyped for 11 SNPs in nine genes. Associations between SNPs and OS were tested using Cox regression analysis and internally validated by bootstrapping. For SNPs with a statistical significance, an expression quantitative trait loci (eQTL) analysis was performed. In a subset of patients, immunophenotyping was performed. Patients with a SNP in PDCD1 (804C > T; rs2227981) had a significantly poorer OS with a 3-year OS rate of 51.8%, as compared to 71% in wild type patients (hazard ratio [HR] 2.37; 95% CI: 1.11–5.04; p = 0.026). eQTL analysis showed that this SNP was associated with decreased gene expression. In addition, PDCD1 804C > T carriers had a reduced fraction of peripheral PD-1⁺CD4⁺ T cells. No other associations between SNPs and OS were found. PDCD1 804C > T is associated with poorer OS after anti-PD-1 monotherapy in patients with metastatic melanoma. This SNP may affect clinical benefit from ICIs by decreasing transcription initiation and expression of PD-1 in T cells. Full article

(This article belongs to the Special Issue Therapeutic Monitoring of Anti-cancer Agents)

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2 pages, 188 KiB

Open AccessCorrection

Correction: Wind et al. Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial. Cancers 2022, 14, 1510

by Selinde S. Wind, Manon A. A. Jansen, Melanie Rijsbergen, Michiel J. van Esdonk, Dimitrios Ziagkos, Wing C. Cheng, Tessa Niemeyer-van der Kolk, John Korsten, Agnieszka Gruszka, Debora Schmitz-Rohmer, David Bonnel, Raphael Legouffe, Florian Barré, Marcel W. Bekkenk, Ellen R. M. de Haas, Koen D. Quint, Harald Schnidar, Melanie Rolli, Henk Johan Streefkerk, Jacobus Burggraaf, Maarten H. Vermeer and Robert Rissmann Show full author list Hide full author list

Cancers 2023, 15(5), 1485; https://doi.org/10.3390/cancers15051485 - 27 Feb 2023

Viewed by 895

Abstract

The authors wish to make the following corrections to this paper [...] Full article

(This article belongs to the Special Issue Therapeutic Monitoring of Anti-cancer Agents)

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