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Background: We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide., Methods: We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours., Results: Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10-300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1-2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3-18) weeks. Four of 18 evaluable patients (22%) had stable disease., Conclusions: Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers., (© 2022. The Author(s).)

1. In vitro studies were conducted to evaluate potential inhibitory and inductive effects of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, on cytochrome P450 (CYP) enzymes. Inhibitory effects were determined in human liver microsomes (HLM); inductive effects were evaluated in cultured human hepatocytes. 2. Olaparib did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2D6 or CYP2E1 and caused slight inhibition of CYP2C9, CYP2C19 and CYP3A4/5 in HLM up to a concentration of 100 μM. However, olaparib (17-500 μM) inhibited CYP3A4/5 with an IC 50 of 119 μM. In time-dependent CYP inhibition assays, olaparib (10 μM) had no effect against CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 and a minor effect against CYP3A4/5. In a further study, olaparib (2-200 μM) functioned as a time-dependent inhibitor of CYP3A4/5 (K I , 72.2 μM and K inact , 0.0675 min -1 ). Assessment of the CYP induction potential of olaparib (0.061-44 μM) showed minor concentration-related increases in CYP1A2 and more marked increases in CYP2B6 and CYP3A4 mRNA, compared with positive control activity; however, no significant change in CYP3A4/5 enzyme activity was observed. 3. Clinically significant drug-drug interactions due to olaparib inhibition or induction of hepatic or intestinal CYP3A4/5 cannot be excluded. It is recommended that olaparib is given with caution with narrow therapeutic range or sensitive CYP3A substrates, and that prescribers are aware that olaparib may reduce exposure to substrates of CYP2B6.

1. In vitro assessments were conducted to examine interactions between olaparib (a potent oral inhibitor of poly[ADP-ribose] polymerase) and drug transporters. 2. Olaparib showed inhibition of the hepatic drug uptake transporters OATP1B1 (IC 50 values of 20.3 μM and 27.1 μM) and OCT1 (IC 50 37.9 μM), but limited inhibition of OATP1B3 (25% at 100 μM); inhibition of the renal uptake transporters OCT2 (IC 50 19.9 μM) and OAT3 (IC 50 18.4 μM), but limited inhibition of OAT1 (13.5% at 100 μM); inhibition of the renal efflux transporters MATE1 and MATE2K (IC 50 s 5.50 μM and 47.1 μM, respectively); inhibition of the efflux transporter MDR1 (IC 50 76.0 μM), but limited inhibition of BCRP (47% at 100 μM) and no inhibition of MRP2. At clinically relevant exposures, olaparib has the potential to cause pharmacokinetic interactions via inhibition of OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K in the liver and kidney, as well as MDR1 in the liver and GI tract. Olaparib was found to be a substrate of MDR1 but not of several other transporters. 3. Our assessments indicate that olaparib is a substrate of MDR1 and may cause clinically meaningful inhibition of MDR1, OCT1, OCT2, OATP1B1, OAT3, MATE1 and MATE2K.

Background: Some therapeutic agents in oncology can be causally associated with specific cardiovascular events including QT/QTc interval prolongation. We investigated the effect of multiple dosing of the oral poly (ADP-ribose)-polymerase (PARP) inhibitor, olaparib (tablet formulation) on QT/QTc interval., Methods: Two phase I, open-label, three-part studies (NCT01921140 [study 4] and NCT01900028 [study 7]) were conducted in adults with refractory/resistant advanced solid tumours. In both studies, parts A and B assessed the QT/QTc interval effects of single-dose oral olaparib 100 (study 4) or 300 (study 7) mg and multiple-dose olaparib 300 mg bid for 5 days, respectively, while part C evaluated continued access to olaparib for additional safety analyses. An ANCOVA model tested the primary objective of multiple-dose effects of olaparib on QT interval corrected using Fridericia's formula (QTcF)., Results: Data from 119 and 109 patients were pooled from parts A and B, respectively, for QT/QTc analysis. At pre-dose and up to 12 h post-dose, the upper limits of the 90 % confidence intervals (CIs) for the difference in QTcF least squares means after olaparib multiple dosing versus control (day -1) were <10 ms, suggesting a lack of clinically relevant effect on cardiac repolarization. A slight shortening of QTcF was observed at most time points versus control. QTcF results for the individual studies and single-dose olaparib paralleled the primary multiple-dose pooled analysis, with upper limits of the 90 % CIs < 10 ms., Conclusion: Olaparib tablets administered as multiple or single doses had no clinically significant effect on QT/QTc interval.

Purpose: The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses., Methods: Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC 0-t and C max fell within the bioequivalence range of 0.80-1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or C max in the presence of rifampin compared with olaparib alone)., Findings: In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: C max treatment ratio, 1.42 (90% CI, 1.33-1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44-2.97). Mean CL/F and V z /F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t ½ was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: C max treatment ratio, 0.29 (90% CI, 0.24-0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11-0.16). CL/F and V z /F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t ½ was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile., Implications: Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8)., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Background: Olaparib is poorly soluble, requiring advanced drug delivery technologies for adequate bioavailability. Sixteen capsules/day are required for the approved 400 mg twice-daily dose; a tablet formulation was developed to reduce pill burden. This clinical trial evaluated the optimal dose and administration schedule of the tablet formulation., Patients and Methods: Two stages of sequentially enrolled cohorts: stage 1, pharmacokinetic properties of tablet and capsule formulations were compared in patients with advanced solid tumours; stage 2, tablet dose escalation with expansion cohorts at doses/schedules of interest in patients with solid tumours and BRCAm breast/ovarian cancers., Results: Olaparib 200 mg tablets displayed similar Cmax,ss, but lower AUCss and Cmin,ss than 400 mg capsules. Following multiple dosing, steady-state exposure with tablets ≥300 mg matched or exceeded that of 400 mg capsules. After dose escalation, while 400 mg twice daily was the tablet maximum tolerated dose based on haematological toxicity, 65 % of patients in the randomized expansion phase eventually required dose reduction to 300 mg. Intermittent tablet administration did not significantly improve tolerability. Tumour shrinkage was similar for 300 and 400 mg tablet and 400 mg capsule cohorts., Conclusions: The recommended monotherapy dose of olaparib tablet for Phase III trials was 300 mg twice daily, simplifying drug administration from 16 capsules to four tablets per day., Clinical Trial Number: NCT00777582 (ClinicalTrials.gov).

Background: The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation., Methods: PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B., Results: A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food (t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure (C max) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC0-∞) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC0-∞ treatment ratio were within pre-defined bioequivalence limits (0.80-1.25). Adverse event data were consistent with the known safety profile of olaparib., Conclusions: Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption.

Background: The oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is well tolerated at doses of ≤400 mg twice daily (BID) (administered as capsules), and has shown efficacy in patients with advanced BRCA-mutated ovarian and breast cancer., Methods: This Phase I, open-label, randomized trial investigates the effect of food on the pharmacokinetics of olaparib in patients with refractory/resistant advanced solid tumors. In Part A, a three-period crossover study, patients received a single oral dose of olaparib 400 mg (8 × 50 mg capsules) in three prandial states: fasted, a high-fat meal or a standard meal (with a 5-14 day washout). Blood samples for pharmacokinetic (PK) assessments were taken pre-dose and up to 72 h post-dose. After completing Part A, patients could enter Part B, where they would receive olaparib 400 mg BID., Results: 32 patients were randomized; 31 contributed to the PK statistical analysis and entered Part B. The presence of food slowed the rate of absorption (time to maximal plasma concentration [t max] was delayed by ~2 h). Maximum plasma concentration (C max) was increased by 10% following a standard meal and was unchanged with a high-fat meal (ratio of geometric means [90% confidence interval (CI)]: 1.10 [1.02-1.20] for standard and 1.00 [0.92-1.09] for high-fat meal). The extent of olaparib absorption (AUC) was increased by ~20% in the fed state (ratio of geometric means: 1.21 [1.10-1.33] for standard and 1.19 [1.08-1.31] for high-fat meal)., Conclusions: The presence of food decreased the rate and increased the extent of absorption of olaparib following oral dosing of the capsule formulation. However, the effects of food on olaparib PK were not deemed clinically important, according to predefined criteria. Safety data were consistent with the known safety profile of olaparib., Funding: AstraZeneca.

Olaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies.

Zibotentan (ZD4054) is a specific endothelin A (ET(A)) receptor antagonist that is in clinical development for the treatment of castration-resistant prostate cancer (CRPC) and has shown a promising signal for improvement in overall survival compared with placebo in a Phase II study of patients with metastatic CRPC. In this study, the pharmacokinetics, disposition and metabolism of zibotentan were evaluated following administration of a single oral dose of [(14)C]-zibotentan 15 mg to six healthy subjects. Zibotentan was rapidly absorbed, with the maximum zibotentan plasma concentration being observed 1 hour after administration. Excretion was rapid with the majority of the dose being excreted in the urine (71-94%). Total recovery of radioactivity over the 5 days of the study was high (mean 93%), with 78% of the dose being recovered within 24 hours. Concentrations of radioactivity in the plasma were similar up to 12 hours post dose, and diverged thereafter, indicating the presence of circulating metabolites. The main circulating component was zibotentan with a number of metabolites being identified in excreta. Zibotentan was well absorbed and was cleared via metabolism and urinary excretion with zibotentan-related material predominantly excreted via the urine.

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.

Purpose: We investigated whether the pharmacokinetics and tolerability of gefitinib were altered in patients with hepatic impairment due to cirrhosis or hepatic metastases in two open, parallel-group, multicenter studies., Methods: In Study 1, subjects with normal hepatic function or mild, moderate, or severe hepatic impairment (Child-Pugh criteria) due to cirrhosis received single-dose gefitinib 250 mg (n = 10 per group). In Study 2, patients with solid malignant tumors with normal liver biochemistry (n = 18), moderate (n = 16), or severe (n = 7) hepatic impairment (liver biochemistry tests) due to metastases received gefitinib 250 mg daily for 28 days., Results: In Study 1, the geometric mean area under the plasma concentration-time curve (AUC) for gefitinib was significantly higher in patients with hepatic impairment compared with healthy subjects; hepatic impairment was associated with reduced gefitinib plasma clearance, longer half-life, and reduced plasma metabolite levels. In Study 2, the geometric mean gefitinib steady-state AUC during the 24-h dosing interval was slightly, but not significantly, higher in patients with moderate hepatic impairment; there were, however, no significant differences between groups in gefitinib and metabolite pharmacokinetic parameters. In both studies, gefitinib was well tolerated across all cohorts., Conclusions: We conclude that the effect of hepatic impairment on gefitinib pharmacokinetics depends on the underlying etiology of that impairment and its classification.

Background: Zibotentan (ZD4054) is a specific endothelin A (ETA) receptor antagonist being investigated for the treatment of prostate cancer. As zibotentan is eliminated by renal and metabolic routes, clearance may be reduced in patients with hepatic or renal impairment, leading to greater drug exposure., Methods: Open-label studies investigated the PK and tolerability of zibotentan in subjects with hepatic or renal impairment, compared with those with normal organ function. In the hepatic and renal studies, respectively, subjects were divided into categories using Child-Pugh classification or 24-hour urine creatinine clearance (mild, moderate, or severe impairment and normal function). Each subject received a single oral dose of zibotentan 10 mg and PK sampling was undertaken. Within the hepatic study, AUC and Cmax were expressed as the ratio of geometric means and 90% CI for each impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure was considered if the upper 90% CI for the ratio exceeded 2. In the renal study, AUC, Cmax and t1/2 were analyzed using linear regression fitting effects for creatinine clearance and age., Results: In the hepatic and renal studies respectively, 32 subjects (eight per group) and 48 subjects received treatment (n = 18 normal, n = 12 mild, n = 9 moderate, n = 9 severe). Zibotentan Cmax was not significantly affected by hepatic or renal impairment. Compared with the normal function group, zibotentan AUC was 40% (1.40; 90% CI 0.91-2.17), 45% (1.45; 90% CI 0.94-2.24) and 190% (2.90; 90% CI 1.88-4.49) higher in subjects with mild, moderate and severe hepatic impairment, respectively, and 66% (1.66; 90% CI 1.38-1.99), 89% (1.89; 90% CI 1.50-2.39) and 117% (2.17; 90% CI 1.64-2.86) higher in subjects with mild, moderate and severe renal impairment, respectively. In both studies mean t1/2 increased and zibotentan clearance decreased with the degree of impairment. Headache was the most common AE in all groups., Conclusions: Zibotentan absorption was unchanged, however, exposure was higher in subjects with hepatic or renal impairment due to slower clearance. This increased exposure did not result in differences in the range or severity of AEs observed., Trial Registration: ClinicalTrials.gov: NCT00672581 and AstraZeneca study number D4320C00016 (renal trial; conducted in Germany).

Objective: To investigate potential differences in zibotentan pharmacokinetics between Japanese and Caucasian patients with hormone-resistant prostate cancer (HRPC) following single and multiple dosing., Methods: In the Japanese study, 18 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 26 days' once-daily dosing. In the Caucasian study, 21 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 12 days' once-daily dosing., Results: Pharmacokinetic parameters were similar between populations. Absorption of zibotentan was rapid with maximum plasma concentrations typically achieved within 3 h of dosing. Mean clearance, 17.9 and 18.7 ml/min in Japanese and Caucasian patients, respectively (range 7.0 - 36.3 ml/min in Japanese patients and 7.8 - 29.5 ml/min in Caucasian patients) and volume of distribution, 14.0 and 15.6 l for Japanese and Caucasian patients, respectively (range 7.9 - 29.1 l in Japanese patients and 9.6 - 23.8 l in Caucasian patients) were relatively low, and t1/2 was approximately 12 h (range 5.7 - 18.8 h in Japanese patients and 5.0 - 22.9 h in Caucasian patients) following single dosing. Little accumulation was observed following daily dosing and multiple-dose pharmacokinetics were predictable. Exposure levels achieved in some Japanese patients receiving zibotentan 15 mg were higher than those observed in Caucasian patients, however, this may be due to differences in body weight, as exposure levels were similar when data were normalized for body weight. Zibotentan was well tolerated in both populations., Conclusions: There are no clinically relevant differences in the disposition and pharmacokinetics of zibotentan between Japanese and Caucasian patients with HRPC.

Background: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules., Patients and Methods: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects., Results: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends., Conclusions: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies.

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.), (2009 Massachusetts Medical Society)

Purpose: AZD5438 is a novel, orally bioavailable, cyclin-dependent kinase (CDK) inhibitor demonstrating preclinical pharmacodynamic (PD) effects on CDK substrates and active growth inhibition of human tumour xenografts. Clinical pharmacokinetic (PK) data shows its plasma t1/2 to be 1-3 h. The main purpose of the current study was to evaluate PD activity of single oral doses of AZD5438 in healthy volunteers. Twelve healthy male subjects received 10, 40 or 60 mg AZD5438 or placebo in a rotating placebo crossover study design. Rapidly proliferating normal tissues [buccal mucosa, peripheral blood mononucleocytes (PBMCs) and plucked scalp hair] were sampled pre-dosing, 1.5 h (tmax), +/-6 h post-dosing. The primary PD endpoint, phospho-retinoblastoma protein (pRb) levels in buccal biopsies (unit length labelling index) assessed by immunohistochemistry, was used as a biomarker of CDK activity., Results: Phospho-pRb levels were demonstrated to decrease in an epitope, dose- and time-dependent manner. Statistically significant reductions in the ratio phospho-pRb/total pRb were detected at 1.5 h post-dose compared to placebo for both 40 mg [S807-S811 epitope geometric least-squares mean (glsmean) ratio = 0.75, P = 0.014] and 60 mg AZD5438 (S807-S811 epitope glsmean ratio = 0.74, P = 0.011; T821 epitope glsmean ratio = 0.72, P = 0.031). No statistically significant differences were noted at 6 h post-dosing, indicating a close PK-PD relationship between AZD5438 and target inhibition. No effects attributable to AZD5438 were detectable on phospho-p27, p27, Ki67 in the buccal mucosa; or on phospho-pRb (S249-T252 epitope), phospho-p27 or Ki67 in the sheath cells of plucked scalp hair, raising issues about the appropriateness of different detection methods/tissues for use as PD biomarkers. In ex vivo stimulated PBMCs, statistically and near-statistically significant anti-proliferative effects, with the suggestion of a dose-response effect, were noted on the incorporation of [3H]-thymidine (stimulated/non-stimulated) at 10, 40 and 60 mg, compared to placebo, at 1.5 h post-dosing (glsmean ratio = 0.65, P = 0.019; 0.70, P = 0.056; 0.51, P = 0.001, respectively)., Conclusions: The modest PD effect, short plasma t1/2 and close PK-PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers.

Purpose: To investigate whether differences in plasma pharmacokinetic profiles of gefitinib between healthy subjects having normal (N; t(1/2)>20h) and altered (A; t(1/2)<20h) pharmacokinetic (PK) profiles might be explained by inter-individual variability in gastric emptying and/or precipitation/dissolution of gefitinib in the proximal small intestine., Methods: One hundred healthy male subjects were screened to enable identification of subjects with the two PK profiles. Twenty five subjects from the screening were subsequently enrolled in an intubation study where a 250mg gefitinib dispersion preparation (IRESSA AstraZeneca) was administered directly into the stomach. Intestinal fluid samples were withdrawn continuously for 180min post-dose using the Loc-I-Gut catheter positioned in the jejunum. The crystalline form of gefitinib was determined using Raman microscopy., Results: There were no differences between normal and altered subjects with regard to gastric emptying or the precipitation/dissolution of gefitinib in jejunal fluid. Due to difficulties in crystalline identification in the jejunal fluid samples, only the same crystalline form as the dosed form was identified., Conclusions: There was no pronounced difference in gastric emptying, precipitation and re-dissolution of gefitinib in proximal human jejunum between normal and altered subjects. Other mechanism(s) are also likely to be important in explaining the inter-individual differences in plasma exposure to gefitinib, such as polymorphism in various metabolic enzymes and/or transport proteins. However, the difference between altered and normal subjects cannot be easily explained and it is likely a multifactorial explanation including low jejunal pH, increased expression of enzymatic and transporter activity and rapid small intestine transit.

AZD5438 is a novel cyclin-dependent kinase inhibitor with preclinical pharmacodynamic (PD) activity against a range of human tumour xenografts. A first-in-man tolerability and pharmacokinetic (PK) study involving single ascending doses of AZD5438 was conducted in healthy male volunteers. Single oral doses ranging from 5 to 160 mg were studied in 23 subjects. Dose-limiting nausea and vomiting occurred at 160 mg in the absence of prophylactic anti-emetics. The maximum tolerated dose (the dose at which no dose limiting toxicities occurred) was 80 mg, and the maximum well-tolerated dose was deemed to be 60 mg, which was associated with grade1 nausea but no vomiting. Tmax occurred between 0.5-3.0 hours with a relatively short plasma half-life of 1-3 h. The coefficient of variation of exposures within a dose level ranged from 22-71% (AUC) to 16-63% (C max), and exposure increased with increasing dose across the doses studied. <1% of the parent compound was excreted in the urine, suggesting metabolism as the major clearance mechanism. The maximum well-tolerated dose and a number of doses below this level will be taken forward into a PD study using normal tissue biomarkers in humans to determine proof of AZD5438's action on the cell cycle. The pharmacokinetic profile of AZD5438 determined within this study will be used to guide the time-points for PD analysis within the planned PD study.

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 >or=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 Evaluation 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.

Background: This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included., Patients and Methods: Patients initially received a single oral dose of gefitinib followed by 10-14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT)., Results: Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. C(max) was reached within 3-7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8-79.7 h). A partial response (duration 35-361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225-700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40-127 days)., Conclusions: In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.

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.

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

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.

Objective: 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 ZD 1839 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 (t1/2beta) was 28 hours (range 12 to 51 hours). Cmax was reduced by 34% and AUC by 14% by ingestion of food; t1/2beta 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 ZD 1839. The elimination half-life suggests that once daily oral administration is appropriate.