Helen Swaisland

Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers

BACKGROUND The inhibition of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. METHODS This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. RESULTS We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). This led us to enroll another cohort, consisting only of carriers of a BRCA1 or BRCA2 mutation, to receive olaparib at a dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens. CONCLUSIONS Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation. (ClinicalTrials.gov number, NCT00516373.)

Phase I Safety, Pharmacokinetic, and Pharmacodynamic Trial of ZD1839, a Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Five Selected Solid Tumor Types

PURPOSE To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for >or= 3 months; seven of these patients remained on study drug for >or= 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.

ZD1839, a Selective Oral Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor, Is Well Tolerated and Active in Patients With Solid, Malignant Tumors: Results of a Phase I Trial

PURPOSE To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for > or = 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for > or = 6 months. CONCLUSION ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.

Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Is Generally Well-Tolerated and Has Activity in Non–Small-Cell Lung Cancer and Other Solid Tumors: Results of a Phase I Trial

PURPOSE To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR. METHODS This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity. RESULTS Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non-small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses >or= 800 mg, 45% of patients required dose reductions. No increased or cumulative toxicity was observed over 250 patient-months of exposure. Pharmacokinetic analysis showed that steady-state occurred by day 7, interpatient exposure was more variable than intrapatient exposure, and variability of exposure did not change with dose. One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients >or= 3 months, 22% >or= 6 months, and 7.2% >or= 1 year). No relationship between dose, response, or duration on study was observed. CONCLUSION Rash and diarrhea, generally mild and tolerable at doses <or= 600 mg/d, were DLTs at 800 mg/d (maximum-tolerated dose). Antitumor activity was observed at all doses. Pharmacokinetic analyses confirmed suitability of once-daily oral dosing.

Pharmacokinetic Drug Interactions of Gefitinib with Rifampicin, Itraconazole and Metoprolol

AbstractBackground and objectives: Gefitinib (IRESSA®, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, has been approved in several countries for the treatment of advanced non-small-cell lung cancer. Preclinical studies were conducted to determine the cytochrome P450 (CYP) isoenzymes involved in the metabolism of gefitinib and to evaluate the potential of gefitinib to cause drug interactions through inhibition of CYP isoenzymes. Based on these findings, three clinical studies were carried out to investigate pharmacokinetic drug interactions in vivo with gefitinib. Methods: In preclinical studies radiolabelled gefitinib was incubated with: (i) hepatic microsomal protein in the presence of selective CYP inhibitors; and (ii) expressed CYP enzymes. Human hepatic microsomal protein was incubated with selective CYP substrates in the presence of gefitinib. Clinical studies were all phase I, open-label, single-centre studies; two had a randomised, two-way crossover design and the third was nonrandomised. The first and second studies investigated the pharmacokinetics of gefitinib in the presence of a potent CYP3A4 inducer (rifampicin [rifampin]) or inhibitor (itraconazole) in healthy male volunteers. The third study investigated the effects that gefitinib had on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in patients with solid tumours. Results: The results of preclinical studies demonstrated that CYP3A4 is involved in the metabolism of gefitinib and that gefitinib is a weak inhibitor of CYP2D6 activity. In clinical studies when gefitinib was administered in the presence of rifampicin, geometric mean (gmean) maximum concentration and area under the plasma concentration-time curve (AUC) were reduced by 65% and 83%, respectively; these changes were statistically significant. When gefitinib was administered in the presence of itraconazole, gmean AUC increased by 78% and 61% at gefitinib doses of 250 and 500mg, respectively; these changes also being statistically significant. Coadministration of metoprolol with gefitinib resulted in a 35% increase in the metoprolol area under plasma concentration-time curve from time zero to the time of the last quantifiable concentration; this change was not statistically significant. There was no apparent change in the safety profile of gefitinib as a result of coadministration with other agents. Conclusions: Although CYP3A4 inducers may reduce exposure to gefitinib, further work is required to define any resultant effect on the efficacy of gefitinib. Exposure to gefitinib is increased by coadministration with CYP3A4 inhibitors, but since gefitinib is known to have a good tolerability profile, a dosage reduction is not recommended. Gefitinib is unlikely to exert a clinically relevant effect on the pharmacokinetics of drugs that are dependent on CYP2D6-mediated metabolism for their clearance, but the potential to increase plasma concentrations should be considered if gefitinib is coadministered with CYP2D6 substrates that have a narrow therapeutic index or are individually dose titrated.

Pharmacokinetics and Tolerability of the Orally Active Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 in Healthy Volunteers

AbstractObjective: To investigate the pharmacokinetics and tolerability of ZD1839 (Iressa™), an orally active selective epidermal growth factor receptor-tyrosine kinase inhibitor, in healthy volunteers. Design: Two randomised, double-blind, placebo-controlled, parallel-group studies of pharmacokinetics and tolerability, followed by a nonblind, randomised, 2-period crossover study to assess the effect of food on bioavailability. Setting: Two centres in the UK. Study participants: Healthy male volunteers aged between 18 and 62 years. Interventions: The first study investigated the pharmacokinetics and tolerability of ascending single oral doses of ZD1839 (1 to 75mg). The second study investigated the pharmacokinetics and tolerability of multiple doses of ZD1839 (100mg once daily for 3 days). The third study investigated the effect of food on the bioavailability of a single 50mg dose of ZD1839. Outcome measures and results: Peak plasma drug concentrations (Cmax) of ZD1839 occurred between 3 and 7 hours after administration. Cmax and area under the concentration-time curve (AUC) were dose-proportional from 10 to 100mg. The terminal elimination half-life (t1/2β) was 28 hours (range 12 to 51 hours). Cmax was reduced by 34% and AUC by 14% by ingestion of food; t1/2β was not affected. Urinary recovery of ZD1839 was <0.5%, indicating that this was not a major route of elimination. The pharmacokinetics of ZD1839 during administration of multiple doses could be predicted from day 1 values. There were no serious adverse events or withdrawals, and the frequency of adverse events was similar that with placebo. Conclusions: These data support the further clinical investigation of ZD1839. The elimination half-life suggests that once daily oral administration is appropriate.

Single-Dose Clinical Pharmacokinetic Studies of Gefitinib

BackgroundThe objective of the five clinical studies presented in this article was to investigate the single-dose pharmacokinetics of gefitinib (IRESSA®, ZD1839), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in healthy volunteers and patients with advanced cancer.MethodsStudies 1 and 3–5 recruited healthy male volunteers aged 18–65 years; study 2 recruited male or female patients aged ≥18 years with any solid malignant tumour expressing EGFR and refractory to standard therapy. Gefitinib administration was as follows: study 1 (bioavailability in healthy volunteers; n = 12) — intravenous infusion of 50 or 100mg followed by a single oral dose of 250mg; study 2 (bioavailability in cancer patients; n = 19) — intravenous infusion of 50mg followed by a single oral dose of 250mg; study 3 (intrasubject variability; n = 24) — two single oral doses of 250mg; study 4 (dose-proportionality; n = 15) — three single oral doses of 50–500mg; study 5 (effect of food; n = 26) — two single doses of 250mg under either fed or fasted conditions. In all studies, venous blood samples for determination of gefitinib plasma concentrations were collected at predetermined intervals. Plasma concentrations of gefitinib were measured using liquid-liquid extraction after basification followed by high-performance liquid chromatography with tandem mass spectrometric detection. Appropriate pharmacokinetic parameters were determined by noncompartmental methods.ResultsStudy 1: Oral bioavailability of a gefitinib 250mg dose was 57% in healthy volunteers. Absorption was moderately slow, with geometric mean (gmean) peak plasma concentration (Cmax) of 85 ng/mL (range 43.5–110 ng/mL) reached 5 hours following an oral dose of 250mg. Study 2: Oral bioavailability of a gefitinib 250mg dose was 59% in patients. Absorption was again moderately slow, with gmean Cmax of 159 ng/mL (range 48.7–324 ng/mL) typically reached 3 hours (range 1–8 hours) following an oral dose of 250mg. Study 3: Area under the plasma concentration-time curve from time zero to infinity (AUC∞) and Cmax were variable — up to 15-fold between subjects and 2-fold within an individual. Study 4: AUC∞ and Cmax increased with dose across the range of 50–500mg, and increased dose-proportionally up to 250mg. Study 5: Small, clinically insignificant increases in AUC∞ and Cmax were seen in the presence of food (32% and 37%, respectively).ConclusionsThe gefitinib 250mg tablet is orally bioavailable in both healthy volunteers and cancer patients; bioavailability is independent of dose and unaffected by food to any clinically significant extent. Gefitinib undergoes rapid plasma clearance and has an extensive volume of distribution, resulting in a pharmacokinetic profile supportive of a once-daily dosage regimen.

Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man

1. Following oral administration of [14C]-gefitinib to albino and pigmented rats, radioactivity was widely and rapidly distributed, with the highest levels being found in liver, kidney, lung and gastrointestinal tract, but with only low levels penetrating the brain. Levels of radioactivity persisted in melanin-containing tissues (pigmented eye and skin). 2. Binding to plasma proteins was high (86–94%) across the range of species examined and was 91% in human plasma. Substantial binding occurred to both human serum albumin and α-1 acid glycoprotein. 3. Following oral and intravenous administration of [14C]-gefitinib, excretion of radioactivity by rat, dog and human occurred predominantly via the bile into faeces, with <7% of the dose being eliminated in urine. 4. In all three species, gefitinib was cleared primarily by metabolism. In rat, morpholine ring oxidation was the major route of metabolism, leading to the formation of M537194 and M608236 as the main biliary metabolites. Morpholine ring oxidation, together with production of M523595 by O-demethylation of the quinazoline moiety, were the predominant pathways in dog, with oxidative defluorination also occurring to a lesser degree. 5. Pathways in healthy human volunteers were similar to dog, with O-demethylation and morpholine ring oxidation representing the major routes of metabolism.

Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours

Background:Olaparib (AZD2281) is a potent oral poly(ADP-ribose) polymerase inhibitor with anti-tumour activity and acceptable toxicity as monotherapy in patients with BRCA-deficient cancers. The vascular endothelial growth factor receptor inhibitor bevacizumab has been incorporated into standard of care with chemotherapy in various tumours. This phase I study established the safety, tolerability and clinical pharmacokinetics of olaparib alone and in combination with bevacizumab.Methods:Patients with advanced solid tumours received increasing doses of continuous oral olaparib (100, 200 and 400 mg b.i.d. capsule formulation) in combination with bevacizumab (10 mg kg−1 intravenous q2w).Results:In all, 12 patients enrolled and received treatment. The most common adverse events (AEs) related to olaparib were grade 1/2 nausea and fatigue. No haematological parameters were reported as AEs. No serious AEs related to olaparib or dose-limiting toxicities (DLTs) were reported. Three patients discontinued due to AEs, two patients discontinued both olaparib and bevacizumab and one patient discontinued olaparib. Five patients received combination treatment for over 6 months. There was no evidence that bevacizumab affected olaparib.Conclusion:The combination of olaparib 400 mg b.i.d. with bevacizumab 10 mg kg−1 q2w was generally well tolerated with no DLTs. This combination could be considered for future clinical investigation.

Development of the Novel Biologically Targeted Anticancer Agent Gefitinib: Determining the Optimum Dose for Clinical Efficacy

The emergence of novel, biologically targeted anticancer agents such as gefitinib (‘Iressa’, ZD1839) has raised the question of how the dose for later-stage clinical development and clinical use is best determined. For cytotoxic drugs, because toxic effects and antitumor activity often fall within the same dose range and are dose dependent, the clinically used dose will depend on the therapeutic window. Therefore, the maximum tolerated dose identified in Phase I trials is typically used to determine the dose level for Phase II and III trials. However, because biologically targeted agents are expected to provide clinical benefits that are not predicted by surrogate end points of toxicity to normal replicating tissue, new Phase I trials have been designed to determine the optimum biological dose for use in further studies. A large, multifaceted Phase I program was designed to evaluate the pharmacokinetics, safety, efficacy, and targeted biological activity of a once-daily oral dose of gefitinib. The maximum tolerated dose was ≥700 mg/day, although doses as low as 150 mg/day provided (a) plasma concentrations sufficient for pharmacological activity, (b) evidence of targeted biological effect, and (c) antitumor activity. From these observations, two large Phase II trials (‘Iressa’ Dose Evuluation in Advanced Lung Cancer 1 and 2) evaluated 250- and 500-mg/day doses of gefitinib in patients with advanced non-small cell lung cancer (NSCLC). As predicted from the Phase I trials, doses >250 mg/day provided no additional efficacy benefit, whereas adverse effects increased in a dose-dependent manner. Consequently, the recommended dose of gefitinib in NSCLC is 250 mg/day. The early clinical trial development of gefitinib provides a model for the development of novel, noncytotoxic anticancer agents.