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Background: The programmed cell death 1 (PD-1) pathway is used by tumors to evade immune surveillance. Pembrolizumab is a humanized anti–PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab has shown robust antitumor activity against several advanced malignancies, including triple-negative breast cancer. We assessed the safety and efficacy of pembrolizumab in patients with PD-L1–positive, ER+/HER2-negative advanced breast cancer. Methods: KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) is an ongoing multicohort, open-label phase 1b study evaluating the safety and efficacy of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Key eligibility criteria for this cohort include ER+ and HER2-negative tumor status defined by institutional standards, locally advanced or metastatic disease, ECOG performance status of 0 or 1, failure of or inability to receive standard therapy, and PD-L1 expression in stroma or in ≥1% of tumor cells as assessed at a central laboratory using a prototype immunohistochemistry assay with the 22C3 antibody (Merck). Pembrolizumab was administered at a dose of 10 mg/kg every 2 weeks for up to 24 months or until confirmed progression or intolerable toxicity. Response is based on RECIST v1.1 as assessed by investigator review every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary efficacy end point is overall response rate (ORR). Results: Of the 248 patients with ER+/HER2-negative breast cancer who had evaluable tumor samples screened for PD-L1 expression, 48 (19%) had PD-L1–positive tumors. Of these, 25 patients were enrolled. Median age was 53 years (range, 36-79), and 44% of patients had an ECOG performance status of 1. Patients were heavily pretreated, with 76% having received ≥3 prior lines of therapy for advanced disease, including 48.0% who received ≥5 prior lines. Analyses of ORR, duration of response, and adverse events are ongoing and will be completed by September 4, 2015. Conclusion: Data from this KEYNOTE-028 cohort will provide information on the antitumor activity and safety of pembrolizumab in patients with heavily pretreated, PD-L1–positive, ER+/HER2-negative advanced breast cancer. Citation Format: Rugo HS, Delord J-P, Im S-A, Ott PA, Piha-Paul SA, Bedard PL, Sachdev J, Le Tourneau C, van Brummelen E, Varga A, Saraf S, Pietrangelo D, Karantza V, Tan A. Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-07.

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PurposeAZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet.MethodsAdults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a ‘4-days-on/3-days-off’ schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and Cmax ratios of 0.75–1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2).ResultsIn evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and Cmax were 0.90 (0.77–1.06) and 1.02 (0.86–1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later tmax and lower Cmax after food versus overnight fast. Fed and fasted AUCτ and Cmax ratios were 0.89 (0.76–1.05) and 0.67 (0.55–0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states.ConclusionsPK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability.

Background Movement Disorder Society–Unified Parkinson's Rating Scale Part III (MDS‐UPDRS III) is the gold standard for assessing medication effects in patients with Parkinson's disease (PD). However, short and rater‐independent measurements would be ideal for future trials. Objectives To assess the ability of 3 different finger tapping tasks to detect levodopa/carbidopa‐induced changes over time and to determine their correlation and compare their discriminatory power with MDS‐UPDRS III. Methods This was a randomized, double‐blind, crossover study in 20 patients with PD receiving levodopa/carbidopa and placebo capsules after overnight medication withdrawal. Pre‐ and up to 3.5 hours postdose, MDS‐UPDRS III and tapping tasks were performed. Tasks included 2 touchscreen‐based alternate finger tapping tasks (index finger versus index–middle finger tapping) and a thumb–index finger task using a goniometer. Results In the alternate index finger tapping task, levodopa/carbidopa compared with placebo resulted in significantly faster (total taps: 12.5 [95% confidence interval, CI, 6.7–18.2]) and less accurate tapping (total spatial error: 240 mm [95% CI, 123–357 mm]) with improved rhythm (intertap interval standard deviation [SD], −16.3% [95% CI, −29.9% to 0.0%]). In the thumb–index finger task, tapping was significantly faster (mean opening velocity, 151 degree/s [64–237 degree/s]), with a higher mean amplitude (8.4 degrees [3.7–13.0 degrees]) and improved rhythm (intertap interval SD, −46.4% [95% CI, −63.7% to −20.9%]). The speed‐related endpoints showed a moderate‐to‐strong correlation with the MDS‐UPDRS III (r = 0.45–0.70). The effect sizes of total taps and spatial error in the alternate index finger tapping task and opening velocity in the thumb–index finger task were comparable with the MDS‐UPDRS III. In contrast, the MDS‐UPDRS III performed better than the alternate index–middle finger task. Conclusion The alternate index finger and the thumb–index finger tapping tasks provide short, rater‐independent measurements that are sensitive to levodopa/carbidopa effects with a similar effect size as the MDS‐UPDRS III.

A BS TRACT: Background: α-Synuclein (αSyn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic αSyn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar αSyn, making UB-312 a potential immunotherapeutic for synucleopathies. Objective: To investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study. Methods: Fifty eligible healthy participants were enrolled in a 44-week, randomized, placebo-controlled, doubleblind study. Participants in seven cohorts were randomized to three intramuscular UB-312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 μg). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti-αSyn antibody concentrations. Results: Twenty-three participants received all three vaccinations of UB-312. Most adverse events were mild, transient, and self-resolving. Common treatment-emergent adverse events included headache, nasopharyngitis, vaccination-site pain, lumbar puncture-site pain, and fatigue. UB-312 induced dose-and time-dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 μg UB-312 dose regimen. The average CSF/serum ratio was 0.2%. Conclusions: UB-312 was generally safe, well tolerated, and induced anti-αSyn antibodies in serum and CSF of healthy participants. The 100 and 300 μg doses are selected for further evaluation in participants with PD.

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