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Supplementary Table S1. IC50 values of ipatasertib on cell viability in cell lines with or without alterations in PTEN or PIK3CA. Supplementary Table S2. Percent tumor growth inhibition (%TGI) in xenograft models with or without alterations in PTEN or PIK3CA. Supplementary Table S3. PI3K/Akt pathway status in archival tumors. Supplementary Table S4. Reasons for discontinuation of study. Supplementary Table S5. Common adverse events for ipatasertib in {greater than or equal to} 10% of patients in any presented group. Supplementary Table S6. All Grade {greater than or equal to} 3 adverse events related to ipatasertib. Supplementary Table S7. Hemoglobin A1C (HgbA1C) values for patients who had both pre-treatment and post-treatment values in Stages 1 and 2. Supplementary Table S8. Summary data for patients with best radiographic stable disease (SD) by RECIST version 1.0 criteria. Supplementary Figure S1. Exposure plots confirm that exposures achieved in patients in the dose-escalation stage (right side) correlated with exposures in preclinical models at TGI90 (left side). Supplementary Figure S2. Relationship between exposure of ipatasertib to the most common ipatasertib-related AEs of fatigue, diarrhea, nausea, and rash. Supplementary Figure S3. Suppression of pGSK3β in platelet-rich plasma versus ipatasertib concentrations. Supplementary Figure S4. Pharmacodynamic (PD) dose-dependent elevations in glucose and insulin following treatment with ipatasertib.

Immune checkpoint inhibitors (ICIs), by reinvigorating CD8+ T cell mediated immunity, have revolutionized cancer therapy. Yet, the systemic CD8+ T cell distribution, a potential biomarker of ICI response, remains poorly characterized. We assessed safety, imaging dose and timing, pharmacokinetics and immunogenicity of zirconium-89-labeled, CD8-specific, one-armed antibody positron emission tomography tracer 89ZED88082A in patients with solid tumors before and ~30 days after starting ICI therapy (NCT04029181). No tracer-related side effects occurred. Positron emission tomography imaging with 10 mg antibody revealed 89ZED88082A uptake in normal lymphoid tissues, and tumor lesions across the body varying within and between patients two days after tracer injection (n = 38, median patient maximum standard uptake value (SUVmax) 5.2, IQI 4.0–7.4). Higher SUVmax was associated with mismatch repair deficiency and longer overall survival. Uptake was higher in lesions with stromal/inflamed than desert immunophenotype. Tissue radioactivity was localized to areas with immunohistochemically confirmed CD8 expression. Re-imaging patients on treatment showed no change in average (geometric mean) tumor tracer uptake compared to baseline, but individual lesions showed diverse changes independent of tumor response. The imaging data suggest enormous heterogeneity in CD8+ T cell distribution and pharmacodynamics within and between patients. In conclusion, 89ZED88082A can characterize the complex dynamics of CD8+ T cells in the context of ICIs, and may inform immunotherapeutic treatments.

ImportanceAlzheimer disease (AD), a neurodegenerative disease characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression.ObjectiveTo investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers, in participants with prodromal to mild (early) AD.Design, Setting, and ParticipantsTwo phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively.InterventionsParticipants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks.Main Outcomes and MeasuresThe primary outcome was change from baseline to week 105 in Clinical Dementia Rating–Sum of Boxes (CDR-SB) score.ResultsThere were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was −0.17 (95% CI, −0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point.Conclusions and RelevanceCrenezumab was well tolerated but did not reduce clinical decline in participants with early AD.Trial RegistrationClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657

Immune checkpoint inhibitors (ICIs), by reinvigorating CD8