Data from two phase 3 studies of eribulin were pooled in analyses initially requested by the European Medicines Agency to assess whether specific patient subgroups, previously treated with an ...anthracycline and a taxane, benefited from eribulin. Study 305/EMBRACE included women after two-to-five lines of chemotherapy for advanced breast cancer who were randomized to eribulin mesylate (1.4 mg/m
2
on days 1 and 8 every 21 days) or treatment of physician’s choice. In Study 301, patients who had received up to two prior chemotherapy regimens for advanced disease were randomized to eribulin (as above) or capecitabine (1.25 g/m
2
b.i.d. on days 1–14 every 21 days). In the pooled population, overall survival (OS), progression-free survival and response rates were analysed in the intent-to-treat population and selected subgroups. Overall, 1,062 patients were randomized to eribulin and 802 patients to control. Median OS was 15.2 months with eribulin versus 12.8 months with control (hazard ratio HR 0.85; 95 % CI 0.77, 0.95;
P
= 0.003). In all subgroups assessed, OS data favoured eribulin; significant improvements occurred in some subgroups, notably in women with human epidermal growth factor receptor 2 (HER2)-negative disease (HR 0.82;
P
= 0.002), although the effect in those with HER2-negative but hormone-receptor-positive disease did not reach statistical significance; benefits were also seen, among others, in those with estrogen-receptor-negative and triple-negative disease. Eribulin improves OS in various patient subgroups with advanced/metastatic breast cancer who had previously received an anthracycline and a taxane. Women with HER2-negative disease are among those who may obtain benefit from eribulin.
Scheduling of taxanes: a review Woodward, Emma J; Twelves, Chris
Current clinical pharmacology
5, Številka:
3
Journal Article
Recenzirano
The taxanes are widely used in the cytotoxic treatment of many solid tumours. Their optimal scheduling, however, remains unconfirmed. Here we review the development of both paclitaxel and docetaxel ...to identify evidence influencing the choice of schedule. Early work with paclitaxel identified that it exhibits non-linear pharmacokinetics which has important clinical implications. Paclitaxel has been administered with a wide range of infusion times, especially 3-weekly and recently weekly schedules. Clinical activity of a weekly schedule appears at least non-inferior, and, in certain circumstances superior, to the 3-weekly schedule, with improved tolerability. Similarly, docetaxel has been investigated for 3-weekly versus weekly schedule, reporting equivalent efficacy and improved side effect profile for weekly dosing with regards myelosuppression. Both paclitaxel and docetaxel are often used with the monoclonal antibodies trastuzumab and bevacizumab. It would appear that in this setting, activity may be again improved by administering the taxane weekly, especially in combination with trastuzumab. A further recent development is the use of nab-paclitaxel, nanoparticle albumin-bound paclitaxel; this Cremaphor EC-free preparation allows shorter infusion times without premedication. Benefits of a weekly schedule with this newer drug are also emerging from the limited randomised data. Whether the possibly greater efficacy of weekly paclitaxel in particular reflects a biological effect of more frequent exposure of cancer cells to the cytotoxic is less clear as this schedule also allows a higher dose intensity to be delivered. Nevertheless, that after more than 20 years, weekly administration has emerged as the optimal schedule, especially for paclitaxel. In practice, the choice of schedule is a balance between the better tolerability (and possibly efficacy) of weekly treatment balanced against the inconvenience for both the patient and clinic of more frequent visits for chemotherapy.
This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC).
Women with MBC ...who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS).
Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio HR, 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2.
In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.
Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to ...fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer.
In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0–2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952.
Between March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6–11·6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10·3 months (95% CI 5·0–13·2) in the capivasertib group versus 4·8 months (3·1–7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39–0·84) in favour of the capivasertib group (two-sided p=0·0044; one-sided log rank test p=0·0018). The most common grade 3–4 adverse events were hypertension (22 32% of 69 patients in the capivasertib group vs 17 24% of 71 in the placebo group), diarrhoea (ten 14% vs three 4%), rash (14 20% vs 0), infection (four 6% vs two 3%), and fatigue (one 1% vs three 4%). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related.
Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials.
AstraZeneca and Cancer Research UK.
The primary objective of this study was to investigate the influence of renal impairment on the pharmacokinetics of capecitabine and its metabolites in cancer patients. Capecitabine (Xeloda) is an ...orally administered precursor of 5'-deoxy-5-fluorouridine (5'-DFUR), which is preferentially activated to 5-fluorouracil (5-FU) in tumors.
A total of 27 patients were enrolled, of whom 24 were evaluable for pharmacokinetics (6 with normal renal function, 8 with mild, 6 with moderate, and 4 with severe renal impairment at baseline). Patients received capecitabine orally at the standard dosing regimen (1250 mg/m(2) capecitabine twice daily for 2 weeks followed by a 1-week rest period). On study days 1 and 14, blood samples were collected to evaluate the pharmacokinetics of capecitabine and its metabolites. The relationship between the area under the plasma concentration-time curve (AUC) and creatinine clearance (CL(CR)) was assessed by log-linear regression analysis.
The primary pharmacokinetic parameter with respect to the effect of renal dysfunction was systemic exposure to 5'-DFUR, 5-FU and FBAL determined on study day 14. Renal impairment led to an increase in the systemic exposure to 5'-DFUR and FBAL (23% and 109% increase in AUC, respectively) for a 50% reduction in CL(CR). By contrast, renal impairment may lead to decreased exposure to 5'-DFCR. There was no evidence for an effect of renal impairment on systemic exposure to 5-FU or capecitabine. Renal impairment did not have a major effect on peak concentration (C(max)) or elimination half-life (t(1/2)) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU. However, in the case of FBAL, moderate or severe renal impairment caused up to a twofold increase in C(max) and prolongation of t(1/2). All patients with severe renal impairment (four patients) had drug-related grade 3 or 4 adverse-events (AEs) and serious AEs. Patients with moderate renal impairment experienced a similar number of grade 3 or 4 AEs (six of nine patients) but had a higher incidence of serious AEs (three of nine patients) when compared with those with normal renal function (four of six patients and one of six patients, respectively). A similar effect was seen in patients with mild renal dysfunction (grade 3 or 4 AEs in four of eight patients; serious AEs in three of eight patients). The relationship between systemic exposure to capecitabine or its metabolites and safety was investigated using logistic regression. This exploratory analysis showed a strong positive relationship between AUC of 5'-DFUR and treatment-related grade 3 or 4 AEs, whereas there was no relationship with exposure to capecitabine, 5'-DFCR, 5-FU or FBAL.
Renal impairment has no effect on the pharmacokinetics of capecitabine or 5-FU, but leads to an increase in the systemic exposure to 5'-DFUR and FBAL. However, only the AUC of 5'-DFUR is correlated with safety. Based on the safety results in patients with severe renal impairment, a dose modification cannot be recommended for these patients and they should not be treated with capecitabine. Additional data from the clinical safety database and pharmacokinetic results from the present study support the recommendation that patients with moderate renal impairment should be treated with 75% of the recommended standard starting dose to achieve systemic exposure comparable to that in patients with normal renal function.
Capecitabine (Xeloda) is a rationally designed oral, tumor-selective fluoropyrimidine carbamate aimed at preferential conversion
to 5-fluorouracil (5-FU) within the tumor. Because capecitabine is ...extensively metabolized by the liver, it is important to
establish whether liver dysfunction altered the pharmacokinetics of capecitabine and its metabolites. This was investigated
in 14 cancer patients with normal liver function and in 13 with mild to moderate disturbance of liver biochemistry due to
liver metastases. They received a single oral dose of capecitabine (1255 mg capecitabine/m 2 ) with serial blood and urine samples collected up to 72 h after administration. Concentrations of capecitabine and its metabolites
were determined in plasma by high-performance liquid chromatography or liquid chromatography coupled to mass spectrometry
and in urine by 19 F-nuclear magnetic resonance spectroscopy. Although plasma concentrations of capecitabine, 5â²-deoxy-5-fluorouridine, 5-FU,
dihydro-5-FU, and α-fluoro-β-alanine were, in general, higher in patients with liver dysfunction, the opposite was found for
5â²-deoxy-5-fluorocytidine. These effects were not clinically significant. Total urinary recovery of capecitabine and its metabolites
was 71% of the administered dose in patients with normal hepatic function and 77% in patients with hepatic impairment. The
absolute bioavailability of 5â²-deoxy-5-fluorouridine was estimated as 42% in patients with normal hepatic function and 62%
in patients with impaired hepatic function. In summary, mild to moderate hepatic dysfunction had no clinically significant
influence on the pharmacokinetic parameters of capecitabine and its metabolites. Although caution should be exercised when
capecitabine is administered to patients with mildly to moderately impaired hepatic function, there is no need for, a priori , adjustment of the dose.
Interview by Sophia Maprayil and Alexandra Hemsley, Commissioning Editors
Chris Twelves is a medical oncologist and leads the Section of Oncology and Clinical Research at Cancer Research UK's ...Clinical Centre at St James's Hospital, Leeds. His particular interest lies in new drug development and clinical pharmacology; his clinical practice to date has been in the field of colorectal and breast cancer. After training in London he was Senior Lecturer, then Reader, in Medical Oncology in Glasgow at the Beatson Oncology Centre before taking up his current post as Professor of Clinical Cancer Pharmacology and Oncology at the University of Leeds and St James's Institute of Oncology. In this role, Twelves leads his team to perform hypothesis-driven studies, prioritizing therapeutics developed locally or through the Cancer Research UK New Agents Committee, of which he has been a member.
Twelves also heads the Experimental Cancer Medicine Centre in Leeds; previously he was Chair of the New Drug Development Group of the European Organisation for Research and Treatment of Cancer. He has published over 150 papers, in addition to several books, and recently presented his group's findings from a Phase III study into the breast cancer drug eribulin.
Abstract only
2046
Background: Several plant-derived cannabinoids have shown efficacy in animal models of GBM, particularly when co-administered with temozolomide, a commonly-used treatment in both ...primary and recurrent disease. Methods: We conducted a two-part study in patients with recurrent GBM following standard chemo-radiotherapy treatment as described by Stupp et al. In Part 1 of the study, 6 patients were treated to an MTD of 1:1 CBD:THC oro-mucosal spray, as an adjunct to dose-intense temozolomide (DIT), to assess the safety of the combination. Part 2 was a double blind, randomized, placebo-controlled study in a planned 20 patients receiving either their individualized dose of 1:1 CBD:THC or placebo plus DIT. The primary endpoint was tolerability of 1:1 CBD:THC plus temozolomide. Results: There were no Grade 3 or 4 toxicities in Part 1 of the study. In Part 2, 12 patients were randomized to CBD:THC and 9 to placebo. Mean age was 58 years in both treatment groups, but there were more males in the placebo group (5 of 12 and 8 of 9, respectively). Baseline median Karnofsky score was 90 in both groups and median time from diagnosis of recurrence to start of treatment (day 1) was similar (3.6 and 3.0 weeks in the CBD:THC and placebo group, respectively). The median number of days of dosing with CBD:THC or placebo was similar (155 days range: 50-356 and 134 days range: 13-359). Median survival in the placebo group was 369 days, and > 550 days in the CBD:THC treatment group (NS) and 1 year survival was 83% and 56% in the CBD:THC and placebo groups, respectively (p = 0.042). PFS6 was 42% in the CBD:THC group and 33% in the placebo group (NS). Overall, the commonest treatment related toxicities were dizziness (in 11/18 patients) and nausea (in 7/18 patients). Results of biomarker analyses are awaited. Conclusions: This randomized study provides preliminary evidence that 1:1 CBD:THC offers some efficacy in patients with recurrent GBM when used as an adjunct to dose-intense temozolomide and confirms the safety and feasibility of individualized dosing. Clinical trial information: NCT01812603.
•Pharmacokinetic resistance is a consequence of a drug not being delivered at sufficient concentration to, or with adequate distribution in, a tumour.•Drug distribution and penetration through ...tumours and normal tissues may influence selection of the optimal candidate(s) during drug development as well as affecting the preferred dose and schedule of drug administration in clinical practice.•MALDI-MSI is a technique for imaging the distribution of anti-cancer drugs and their metabolites within tumours that can be used in drug development to: characterize drug distribution within the body to identify anticipated toxicities or target organs; define drug distribution within the tumour and its relationship with the tumour microenvironment and drug targets; select the best drug candidate, dose, schedule or combinations based on tumour pharmacokinetic profile; facilitate proof-of-concept studies for new drug delivery systems.
Failure of systemic cancer treatment can be, at least in part, due to the drug not being delivered to the tumour at sufficiently high concentration and/or sufficiently homogeneous distribution; this is termed as “pharmacokinetic drug resistance”. To understand whether a drug is being adequately delivered to the tumour, “precision pharmacology” techniques are needed. Mass spectrometry imaging (MSI) is a relatively new and complex technique that allows imaging of drug distribution within tissues. In this review we address the applicability of MSI to the study of cancer drug distribution from the bench to the bedside. We address: (i) the role of MSI in pre-clinical studies to characterize anti-cancer drug distribution within the body and the tumour, (ii) the application of MSI in pre-clinical studies to define optimal drug dose or schedule, combinations or new drug delivery systems, and finally (iii) the emerging role of MSI in clinical research.
Phase I trials are a critical first step in the study of novel cancer therapeutic approaches. As this title is the only comprehensive book on this topic, it is a useful resource for oncology trainees ...or specialists interested in understanding cancer drug development. New to this edition are chapters on Phase 0 Trials and Immunotherapeutics, and updated information on the process, pitfalls, and logistics of Phase I Trials.
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