Olaparib (AZD2281) is an orally active Poly(ADP‐ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose‐finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single‐dose on day 1, followed by twice‐daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400‐mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose‐limiting toxicities were not observed up to and including the 400‐mg b.i.d. dose level. Following twice‐daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single‐dose pharmacokinetics. PARP‐1 inhibition was observed from the 100‐mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post‐dose on day 1 during the multiple‐dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400‐mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400‐mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed. (Cancer Sci 2012; 103: 504–509)

PurposeInvestigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies.MethodsAZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80–400, 360–480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients.ResultsForty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade ≥3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years.ConclusionsIntermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.

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Purpose This was the first Phase I study to assess the safety and tolerability of the tablet formulation of olaparib (Lynparza™), an oral poly(ADP-ribose) polymerase inhibitor, in Japanese patients with advanced solid tumours. The pharmacokinetic profile and antitumour activity of olaparib tablets were also assessed. Methods In this open-label, multicentre study (D081BC00001; NCT01813474), a single dose of olaparib (200 or 300 mg, tablets) was administered on day 1, followed 48 h afterwards by multiple dosing (200 or 300 mg twice daily [bid]) for 28-day cycles. Doses were escalated in successive cohorts, with an expansion cohort enrolled at the highest dose that was confirmed to be tolerable during dose escalation. Results Twenty-eight patients were enrolled and 23 were treated ( n = 4, 7 and 12 at 200, 300 and 300 [expansion] mg bid, respectively). No patients experienced a dose-limiting toxicity, so the maximum tolerated dose was not defined. The most frequent adverse events were nausea (43.5 %), decreased appetite (30.4 %), anaemia (26.1 %) and constipation (26.1 %). No patient had dose reductions, two had dose interruptions, and two discontinued treatment because of adverse events. Absorption of olaparib was rapid following single and multiple dosing, and plasma concentrations declined biphasically after single dosing. No patients had a confirmed antitumour response. Conclusions Olaparib tablet doses of 200 and 300 mg bid were considered tolerable in Japanese patients with advanced solid tumours. Consistent with the global olaparib programme, 300 mg bid was selected as the recommended tablet dose for future studies. Clinical trial registration number NCT01813474.

Ischemic stroke is a leading cause of death and long-lasting disability. However, therapeutic options for acute ischemic stroke remain very limited.1) Ischemic stroke triggers a cascade of pathophysiological events including excitotoxicity, ionic imbalance, oxidative stress, and apoptosis-like cell death ending in destructive neurodegeneration.2-4) The cumulative evidence suggests involvement of reactive oxygen species (ROS) in the pathogenesis of ischemic injury.5) Several components of ROS including superoxides ( · O 2 Ϫ ), hydroxyl radicals ( · OH), and hydrogen peroxide (H 2 O 2 ) are generated by post-ischemia/reperfusion injury. They are known to induce DNA damage, lipid peroxidation, disruption of blood brain-barrier (BBB), and microglial activation in the ischemic tissue. The rat middle cerebral artery occlusion (MCAO) model mimics the pathophysiological consequences induced by ischemic stroke in humans and thus has been frequently employed.Cyanine photosensitizing dyes have been shown to have various biological activities, such as antimicrobial, antioxidant, macrophage activation, and oxidative phosphorylation uncoupling activities.6-9) Some of those dyes have been used as immunomodulators to treat allergy and rheumatoid arthritis, and to promote wound-healing. [10][11][12][13] It was reported that platonin, a kind of cyanine dye, suppressed acute endotoxemia in rats by inhibiting inflammatory cytokine release from lipopolysaccharide (LPS)-stimulated lymphocytes.14,15) Recent studies suggested that neutrophil infiltration and release of inflammatory cytokines (i.e., interleukin (IL)-1b, IL-6, IL-17, IL-23, and tumor necrosis factor-a) participate in a secondary mechanism of brain injury following ischemia and reperfusion. [16][17][18] Because there is substantial evidence showing that immune responses play crucial roles in mediating neuronal damage in the animal model of stroke, 16) it is reasonable to expect that cyanine dyes with anti-inflammatory properties could protect against neuroinflammatory events. To our knowledge, little is not known whether these dyes are pharmacologically active against ischemia-induced brain injury or neurodegenerative disorders. To explore this potential of cyanine dyes, it would be of interest to examine their effects in the MCAO model, an animal model of ischemic stroke. Prior to the in vivo evaluation, we screened more than 250 cyanine dyes for their neurotrophin-like activity (such as potentiation of neurite outgrowth in neural cells) and found that NK-4 (Fig. 1A), NK-150 (Fig. 1B), and some other related compounds showed remarkable neurite outgrowth-promoting activity in PC12 neural cells. NK-4 and NK-150 are thought to be safe compounds since they showed no acute toxicity when orally-administrated to mice at a dose of 2000 mg/kg (our unpublished observation). In the present report, we further examined NK-4 and NK-150 for their ability to promote nerve growth factor (NGF)-primed neurite outgrowth and for free radical scavenging activity in vitro. We also examined the...