In recent years new targeted small molecule kinase inhibitors have become available for pediatric patients with cancer. Relationships between drug exposure and treatment response have been ...established for several of these drugs in adults. Following these exposure–response relationships, pharmacokinetic (PK) target minimum plasma rug concentration at the end of a dosing interval (Cmin) values to guide therapeutic drug monitoring (TDM) in adults have been proposed. Despite the fact that variability in PK may be even larger in pediatric patients, TDM is only sparsely applied in pediatric oncology. Based on knowledge of the PK, mechanism of action, molecular driver, and pathophysiology of the disease, we bridge available data on the exposure–efficacy relationship from adults to children and propose target Cmin values to guide TDM for the pediatric population. Dose adjustments in individual pediatric patients can be based on these targets. Nevertheless, further research should be performed to validate these targets.
In the registration trial, cabozantinib exposure ≥ 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell ...cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure-response relationship in patients with mRCC treated in routine care.
Cabozantinib trough concentrations (C
) were collected and average exposure was calculated per individual. Exposure-response analyses were performed using the earlier identified target of C
> 750 ng/mL and median C
. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response.
In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0-5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median C
was 572 ng/mL (IQR: 496-701). Only 17% of patients had an average C
≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40-64). No improved PFS was observed for patients with C
≥ 750 ng/mL or ≥ 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. ≥ 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14-0.70, p = .004).
In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy.
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.
Hypertension is a commonly reported side effect in antiangiogenic therapy. We investigated the hypothesis that telatinib, a small molecule angiogenesis inhibitor, impairs vascular function, induces ...rarefaction, and causes hypertension.
A side-study was done in a phase I trial of telatinib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors 2 and 3, platelet-derived growth factor receptor, and c-KIT in patients with advanced solid tumors. Measurements of blood pressure, flow-mediated dilation, nitroglycerin-mediated dilation, aortic pulse wave velocity, skin blood flux with laser Doppler flow, and capillary density with sidestream dark field imaging were done at baseline and after 5 weeks of treatment. Blood pressure and proteinuria were measured weekly.
Mean systolic and diastolic blood pressure values increased significantly at +6.6 mm Hg (P = 0.009) and +4.7 mm Hg (P = 0.016), respectively. Mean flow-mediated dilation and mean nitroglycerin-mediated dilation values significantly decreased by -2.1% (P = 0.003) and -5.1% (P = 0.001), respectively. After 5 weeks of treatment, mean pulse wave velocity significantly increased by 1.2 m/s (P = 0.001). A statistically significant reduction of mean skin blood flux of 532.8% arbitrary units was seen (P = 0.015). Capillary density statistically significantly decreased from 20.8 to 16.7 capillary loops (P = 0.015). Proteinuria developed or increased in six patients during telatinib treatment.
The increase in blood pressure observed in the treatment with telatinib, an angiogenesis inhibitor, may be caused by functional or structural rarefaction.
Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib ...in cancer patients.
Pharmacokinetic data were available from 96 patients from three clinical studies. A multi-compartment model including (i) a complex absorption profile, (ii) the potential non-linear dose-concentration relationship and (iii) the potential long-term decrease in exposure was developed.
A two-compartment model best described pazopanib pharmacokinetics. The absorption phase was modelled by two first-order processes: 36 % (relative standard error RSE 34 %) of the administered dose was absorbed with a relatively fast rate (0.4 h
RSE 31 %); after a lag time of 1.0 h (RSE 6 %), the remaining dose was absorbed at a slower rate (0.1 h
RSE 28 %). The relative bioavailability (rF) at a dose of 200 mg was fixed to 1. With an increasing dose, the rF was strongly reduced, which was modelled with an E
(maximum effect) model (E
was fixed to 1, the dose at half of maximum effect was estimated as 480 mg RSE 23 %). Interestingly, the plasma exposure to pazopanib also decreased over time, modelled on rF with a maximum magnitude of 50 % (RSE 27 %) and a first-order decay constant of 0.15 day
(RSE 43 %). The inter-patient and intra-patient variability on rF were estimated as 36 % (RSE 16 %) and 75 % (RSE 22 %), respectively.
A popPK model for pazopanib was developed that illustrated the complex absorption process, the non-linear dose-concentration relationship, the high inter-patient and intra-patient variability, and the first-order decay of pazopanib concentration over time. The developed popPK model can be used in clinical practice to screen covariates and guide therapeutic drug monitoring.
Context
Taste, smell, and mouthfeel disturbances are underrated and underreported, but important side effects of anti-cancer medication. These symptoms are associated with a lower quality of life ...(QoL). The prevalence and the impact of taste, smell, and mouthfeel disturbances on daily life in patients with a gastrointestinal stromal tumor (GIST) are largely unknown.
Objectives
This exploratory study assessed the prevalence and type of taste, smell, and mouthfeel disturbances and their impact on daily life and QoL in patients with a GIST treated with a tyrosine-kinase inhibitor (TKI).
Methods
Patients currently treated with TKIs for GIST completed a standardized questionnaire. The questionnaire addressed changes in taste, smell, and mouthfeel and, if changes occurred, impact on daily life and QoL. Statistics are descriptive.
Results
A total of 65 GIST patients on TKI treatment completed the questionnaire. Of these patients, 79%, 12%, and 9% currently used imatinib, sunitinib, and regorafenib respectively. Taste, smell, and mouthfeel disturbances were reported by 25 (38%), 15 (23%), and 36 (55%) patients respectively. Salty and sweet tastes were mostly affected, respectively in 14 and 13 patients. A dry mouth was experienced by 29 (45%) patients. Taste disturbances were more often reported to have impact on daily life and QoL (80% and 60%) than smell (47% and 31%) and mouthfeel disturbances (47% and 30%).
Conclusion
Taste, smell, and mouthfeel disturbances are frequent side effects of TKIs in GIST patients. Daily life and QoL are affected in a considerable number of those patients.
Trial registration
ClinicalTrials.gov Identifier: NL7827 (2019–06-25).
Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback ...activation of epidermal growth factor receptors (HER).
In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336).
Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC.
Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.
Background and Objective
As pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib ...affect systemic pazopanib concentrations.
Methods
The decreased function alleles
CYP3A4 15389 C
>
T (*22)
,
ABCB1 3435 C
>
T
,
ABCG2 421 C
>
A
, and
ABCG2 34G
>
A
were analyzed within a recently developed population-pharmacokinetic model.
Results
Incorporation of
CYP3A4*22
in the model resulted in a 35% lower clearance for variant carriers (0.18 vs. 0.27 L/h; difference in objective function value: − 9.7;
p
< 0.005). Simulated median trough concentrations of cancer patients with
CYP3A4*22
with 600 mg once daily or 800 mg once daily were 31 and 35 mg/L, respectively. The simulated trough concentrations for the population excluding the
CYP3A4*22
carriers after 600 mg once daily or 800 mg once daily were 18 and 20 mg/L, respectively.
Conclusion
This analysis shows that
CYP3A4*22
heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on
CYP3A4*22
status could be considered.
Purpose
The aim of this study was to ascertain whether the absolute bioavailability of oral imatinib (Glivec®) during steady state plasma pharmacokinetics in cancer patients could be determined ...through a concomitant intravenous administration of a single 100 μg microdose of deuterium labeled imatinib (imatinib-d8). Secondly, the usefulness of liquid chromatography–tandem mass spectrometry (LC-MS/MS) was investigated for simultaneous analysis of orally and intravenously administered imatinib.
Methods
Included patients were on a stable daily dose of 400 mg oral imatinib prior to study participation. On day 1, patients received a 100 μg intravenous imatinib-d8 microdose 2.5 h after intake of the oral dose. Plasma samples were collected for 48 h. Imatinib and imatinib-d8 concentrations were simultaneously quantified using a validated LC-MS/MS assay. The absolute bioavailability was calculated by comparing the dose-normalized exposure with unlabeled and stable isotopically labeled imatinib in plasma.
Results
A total of six patients were enrolled. All patients had a history of gastrointestinal stromal tumors (GIST). The median absolute bioavailability of oral imatinib at steady state was 76% (range 44–106%). Imatinib and imatinib-d8 plasma concentrations were quantified in all collected plasma samples, with no samples below the limit of quantification for imatinib-d8.
Conclusion
The absolute bioavailability of imatinib was successfully estimated at steady state plasma pharmacokinetics using the stable isotopically labeled microdose trial design. This study exhibits the use of a stable isotopically labeled intravenous microdose to determine the absolute bioavailability of an oral anticancer agent in patients with LC-MS/MS as the analytical tool.
Purpose
KRAS
oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in
KRAS
-mutant (
KRAS
...m) and
PIK3CA
wild-type tumors, in vitro and in vivo
.
In this phase I study, patients with advanced
KRAS
m and
PIK3CA
wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R).
Methods
Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively.
Results
Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (
n
= 2), rash (
n
= 2), nausea (
n
= 1), multiple grade 2 toxicities (
n
= 1), and aspartate aminotransferase elevation (
n
= 1), resulting in the inability to receive 75% of planned doses (
n
= 2) or treatment delay (
n
= 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected.
Conclusion
Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.
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