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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

Introduction The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo‐controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60‐year‐old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non‐carriers who receive placebo. Methods Of the 252 enrolled, we present data on a total of 242 mutation carriers and non‐carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. Results We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non‐carriers, 30 to 53 years of age. Carriers were significantly younger than non‐carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. Discussion Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non‐carriers. Their demographic characteristics are representative of the local population.

Random coefficient regression (also known as random effects, mixed effects, growth curve, variance component, multilevel, or hierarchical linear modeling) can be a natural and useful approach for characterizing and testing hypotheses in data that are correlated within experimental units. Existing power and sample size software for such data are based on two variance component models or those using a two-stage formulation. These approaches may be markedly inaccurate in settings where more variance components (i.e., intercept, rate of change, and residual error) are warranted. We present variance, power, sample size formulae, and software (R Shiny app) for use with random coefficient regression models with possible missing data and variable follow-up. We illustrate sample size and study design planning using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We additionally examine the drivers of variability to better inform study design.

Introduction Autosomal-dominant Alzheimer's disease (ADAD) represents a crucial population for identifying prevention strategies that might modify disease course for cognitively unimpaired individuals at high imminent risk for developing symptoms due to Alzheimer's disease (AD), that is, who have “preclinical” AD. Crenezumab is an antiamyloid monoclonal antibody that binds monomeric and aggregated forms of amyloid β, with highest affinity for oligomers; it is in development for early stages of sporadic AD and for ADAD. Methods This is a prospective, randomized, double-blind, placebo-controlled phase 2 study of the efficacy of crenezumab versus placebo in asymptomatic PSEN1 E280A mutation carriers from family kindreds with ADAD in Colombia. Participants were randomized to receive either crenezumab or placebo for 260 weeks. The study was designed to enroll a planned total of 300 participants, including 200 preclinical mutation carriers (approximately 100 treatment, 100 placebo) and an additional control group of mutation noncarriers from the same family kindreds included to mask mutation carrier status (100 placebo only). The primary outcome is change in the Alzheimer's Prevention Initiative ADAD Composite Cognitive Test Score from baseline to week 260. Secondary outcomes include time to progression to mild cognitive impairment due to AD or dementia due to AD; changes in dementia severity, memory, and overall neurocognitive functioning; and changes in amyloid–positron emission tomography, fluorodeoxyglucose–positron emission tomography, magnetic resonance imaging volumes, and cerebrospinal fluid levels of β amyloid, tau, and p-tau. Safety and tolerability are assessed. Results Two hundred fifty-two participants were enrolled between December 2013 and February 2017. Discussion We describe the first large-scale, potentially label-enabling clinical trial of a preclinical treatment for ADAD. Results from this trial will inform on the efficacy of crenezumab for delaying onset of, slowing decline in, or preventing cognitive impairment in individuals with preclinical ADAD and will foster an improved understanding of AD biomarkers and their relationship to clinical outcomes.

Introduction Autosomal-dominant Alzheimer's disease (ADAD) represents a crucial population for identifying prevention strategies that might modify disease course for cognitively unimpaired individuals at high imminent risk for developing symptoms due to Alzheimer's disease (AD), that is, who have “preclinical” AD. Crenezumab is an antiamyloid monoclonal antibody that binds monomeric and aggregated forms of amyloid β, with highest affinity for oligomers; it is in development for early stages of sporadic AD and for ADAD. Methods This is a prospective, randomized, double-blind, placebo-controlled phase 2 study of the efficacy of crenezumab versus placebo in asymptomatic PSEN1 E280A mutation carriers from family kindreds with ADAD in Colombia. Participants were randomized to receive either crenezumab or placebo for 260 weeks. The study was designed to enroll a planned total of 300 participants, including 200 preclinical mutation carriers (approximately 100 treatment, 100 placebo) and an additional control group of mutation noncarriers from the same family kindreds included to mask mutation carrier status (100 placebo only). The primary outcome is change in the Alzheimer's Prevention Initiative ADAD Composite Cognitive Test Score from baseline to week 260. Secondary outcomes include time to progression to mild cognitive impairment due to AD or dementia due to AD; changes in dementia severity, memory, and overall neurocognitive functioning; and changes in amyloid–positron emission tomography, fluorodeoxyglucose–positron emission tomography, magnetic resonance imaging volumes, and cerebrospinal fluid levels of β amyloid, tau, and p-tau. Safety and tolerability are assessed. Results Two hundred fifty-two participants were enrolled between December 2013 and February 2017. Discussion We describe the first large-scale, potentially label-enabling clinical trial of a preclinical treatment for ADAD. Results from this trial will inform on the efficacy of crenezumab for delaying onset of, slowing decline in, or preventing cognitive impairment in individuals with preclinical ADAD and will foster an improved understanding of AD biomarkers and their relationship to clinical outcomes.

In the past decade, the cost of drug development has increased significantly. The estimates vary widely but frequently quoted numbers are staggering-it takes 10-15 years and billions of dollars to bring a drug to patients. To a large extent this is due to many long, expensive and ultimately unsuccessful drug trials. While one approach to combat the low yield on investment could be to continue searching for new blockbusters, an alternative method would lead us to focus on testing new targeted treatments that have a strong underlying scientific rationale and are more likely to provide enhanced clinical benefit in population subsets defined by molecular diagnostics. Development of these new treatments, however, cannot follow the usual established path; new strategies and approaches are required for the co-development of novel therapeutics and the diagnostic. In this paper we will review, from the point of view of industry, the approaches to, and challenges of drug development strategies incorporating predictive biomarkers into clinical programs. We will outline the basic concepts behind co-development with predictive biomarkers and summarize the current regulatory paradigm. We will present guiding principles of personalized health care (PHC) development and review the statistical, strategic, regulatory and operational challenges that statisticians regularly encounter on development programs with a PHC component. Some practical recommendations for team statisticians involved in PHC drug development are included. The majority of the examples and recommendations are drawn from oncology but broader concepts apply across all therapeutic areas.

Background Mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety and pharmacokinetics of GDC-0449, a small-molecule inhibitor of SMO, and responses of metastatic or locally advanced basal-cell carcinoma to the drug. Methods We selected 33 patients with metastatic or locally advanced basal-cell carcinoma to receive oral GDC-0449 at one of three doses; 17 patients received 150 mg per day, 15 patients received 270 mg per day, and 1 patient received 540 mg per day. We assessed tumor responses with the use of Response Evaluation Criteria in Solid Tumors (RECIST), physical examination, or both. Molecular aspects of the tumors were examined. Results The median duration of the study treatment was 9.8 months. Of the 33 patients, 18 had an objective response to GDC-0449, according to assessment on imaging (7 patients), physical examination (10 patients), or both (1 p...

We identify three properties of the standard oncology phase I trial design or 3 + 3 design. We show that the standard design implicitly uses isotonic regression to estimate a maximum tolerated dose. We next illustrate the relationship between the standard design and a Bayesian design proposed by Ji et al. (2007). A slight modification to this Bayesian design, under a particular model specification, would assign treatments in a manner identical to the standard design. We finally present calculations revealing the behavior of the standard design in a worst case scenario and compare its behavior with other 3 + 3-like designs.

Purpose We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin. Patients and Methods No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST). Results Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment. Conclusion Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.

Few data exist on the occurrence of metastatic basal cell carcinoma (mBCC). To identify all cases of mBCC in Denmark over a 14-year period. We searched the Danish National Patient Registry covering all Danish hospitals, the Danish Cancer Registry, the National Pathology Registry and the Causes of Death Registry during the period 1997 to 2010 for potential cases of mBCC registered according to the International classification of diseases ICD-10 and the International Systemized Nomenclature of Medicine (SNOMED). We identified 126,627 patients with a history of primary basal cell carcinoma (BCC) in the registries during the 14-year study period. Using case identifications from the four registries, a total of 170 potential mBCC cases were identified. However, after a pathology review, only five cases could be confirmed, of which three were basosquamous carcinomas. The 14-year cumulative incidence proportion of mBCC was 0.0039% (95% CI 0.0016-0.0083) among individuals with a history of previous BCC (n = 126,627) and 0.0001% (95% CI 0.0000-0.0002) in the general population. MBCC is a rare disease and only a small proportion of potential cases identified in automated clinical databases or registries can be confirmed by pathology and medical record review.

Background: Understanding of immune tolerance mechanisms of cancer has prompted the development of cancer immunotherapies such as atezolizumab (anti-PD-L1, MPDL3280A). Robust, durable responses have been observed, leading to Breakthrough status designation by the FDA for atezolizumab for previously treated NSCLC and bladder cancer (UBC) patients. Roche/Ventana have developed a companion diagnostic (CDx) for atezoliziumab using a robust immunohistochemistry (IHC) assay and antibody clone (SP142), optimized to detect PD-L1 expression in both tumor cells (TC) and tumor-infiltrating immune cells (IC). Here we describe the characteristics of the SP142 assay, PD-L1 expression patterns observed by immunohistochemistry in TC and IC compartments, and their association with clinical efficacy for NSCLC and UBC patients. Methods: The anti-human PD-L1 rabbit monoclonal antibody SP142 was optimized for detection of both TC and IC expression of PD-L1 with the Ventana OptiView DAB IHC Detection Kit on the automated BenchMark ULTRA platform. The VENTANA PD-L1 (SP142) CDx assay was validated for use in formalin-fixed, paraffin-embedded samples of NSCLC and UBC in a series of studies addressing sensitivity, specificity, robustness, and precision. Formalin fixed, paraffin embedded tumor specimens were obtained from patients prescreened and/or enrolled into Genentech Ph I study PCD4989g, and PD-L1 expression was measured using the SP142 assay and PCR gene expression assays. Results: The SP142 assay met pre-defined acceptance criteria for TC and IC assessment of PD-L1 expression in NSCLC and UBC tumors, including >90% inter-reader concordance between pathologist readers. Rapid and durable responses were observed in the Ph I study (PCD4989g), and correlated with PD-L1 expression patterns observed by immunohistochemistry in TC and IC. In the same Ph I study (PCD4989g), PD-L1 expression as measured by PCR did not demonstrate the same predictive value as observed for IHC. Conclusions: The PD-L1 IHC (SP142) CDx is a robust assay to measure PD-L1 expression in both IC and TC. Further, the high reproducibility of results between pathologists shows that the scoring algorithms in UBC and NSCLC are precise, reproducible, and practical in the diagnostic setting. The results indicate that favorable atezolizumab efficacy for UBC is strongly associated with higher IC levels as assessed by the sensitive and specific PD-L1 IHC (SP142) CDx assay. In NSCLC, favorable atezolizumab efficacy is associated with tumors expressing either high TC or high IC levels by the PD-L1 IHC (SP142) CDx assay. These data support the predictive value of tumor PD-L1 levels by IHC for NSCLC and UBC patients receiving atezoliziumab. Citation Format: Zachary S. Boyd, Dustin Smith, Brian Baker, Bharathi Vennapusa, Hartmut Koeppen, Marcin Kowanetz, Sanjeev Mariathasan, Jean-Marie Bruey, Howard Mackey, Gregg Fine, Simonetta Mocci, Priti Hegde, J. Andrew Williams, Ian McCaffery. Development of a PD-L1 companion diagnostic IHC assay (SP142) for atezolizumab. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B001.

Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma.In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted.Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).

e13544 Background: A large burden is placed on clinical trials that simultaneously investigate efficacy of a new therapeutic agent along with the relevance of a potential predictive biomarker. Ofte...

e14000 Background: For predictive biomarkers that are not binary in nature (eg. non-mutation based), Mackey and Bengtsson (Contemporary Clinical Trials, 2013) illustrate the substantial statistical...

2575 Background: The investigation of predictive biomarkers in clinical trials often involves estimation of the biomarker by treatment interaction effect (Royston and Sauerbrei, Journal of Clinical...

3530 Background: GDC-0449 is an HPI that has shown clinical activity in advanced basal cell carcinoma and preclinical activity in CRC. Methods: 199 previously untreated mCRC patients (pts), receive...

3516 Background: Aberrant Hh signaling pathway activation has been implicated in a variety of cancers via both Hh ligand-independent and ligand-dependent overexpression. GDC-0449 is a first-in-huma...

Background: Aberrant Hedgehog signaling due to PATCHED or SMOOTHENED mutations is critical to the development of both hereditary and sporadic human basal cell carcinomas (BCCs). GDC-0449 is a first-in-class, potent, oral systemic inhibitor of Hedgehog signal transduction. A dose escalation Phase I trial for refractory solid tumors was conducted. Because of activity seen in initial patients with BCC, an expansion cohort was added to evaluate activity in locally advanced, multifocal, or metastatic BCC patients. Methods: Patients were enrolled in a first-in-human, 3+3 design Phase I study with modified dose doubling to evaluate safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics. In the dose escalation portion, patients received 150, 270, or 540 mg GDC-0449 administered orally as a single dose on day 1, followed by a 1-week pharmacokinetics break, and then once daily on a continuous 28-day schedule (cycle 1=35 days). The expansion cohort BCC patients received 150 mg GDC-0449 daily without interruption beginning day 1. Surrogate tissues were assessed for expression levels of Hedgehog target gene, GLI1. Results: Eight of 9 BCC patients enrolled have been evaluated. In 4 patients with measurable met disease, 2 confirmed RECIST partial responses, 1 stable disease, and 1 progressive disease have been observed. In 4 patients with clinically evaluable locally advanced or multifocal disease, 2 patients had complete response in subcutaneous masses by physical exam and 2 patients had stable disease in skin lesions. One met BCC patient is too early to assess. Metabolic responses by EORTC positron emission tomography (PET) criteria were achieved in 5 out of 5 patients to date. Durable clinical benefit (range 56+ to 375+ days, median 112+ days) was achieved in 8 out of 9 patients. GLI1 expression in skin biopsies was reduced >2-fold in all patients tested to date. Conclusions: GDC-0449 was evaluated in locally advanced, multifocal, and metastatic BCC patients on a continuous daily oral schedule and without significant toxicities. Antitumor activity was observed in almost all BCC patients enrolled, thereby confirming the importance of inhibiting aberrant Hedgehog signaling in BCC. Table 1.BCC Patient Data for GDC-0449 Phase I StudyPt #Disease State (Site)Dose [mg] (Cohort)GLI1 Reduction (>2-fold)PET ResponseRECIST ResponseComments1met150 (DE)++PR*375+ days on study, improved dyspnea, decreased bone pain2LA (ear)270 (DE)++CR (physical exam184+ days, reduced ear canal drainage, mutant PATCHED3met540 (DE)NDNDPD45 days on study, ear lesion healing4met150 (EC)++PR126+ days, improved dyspnea, reduced fatigue5LA (ear)150 (EC++CR (physical exam)112+ days, decreased ear bleeding6MF150 (EC)++SD113+ days, skin lesions healing7met150 (EC)NDNDSD67+ days, improved dyspnea8MF150 (EC)NDPET negSD60+ days, skin lesions healing9met150 (EC)NDTETE56+ days*PR, partial response; CR, complete response; SD, stable disease; PD, progressive disease.

5006 Background: Bevacizumab (BV), a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor, has demonstrated clinical benefit in multiple tumor types. Activity in ovarian cancer (OC) has been reported in phase II studies in patients (pts) with recurrent disease. We now describe the activity/safety of BV in pts with platinum-resistant OC (PROC) that progressed after topotecan or liposomal doxorubicin (LD). Methods: Eligibility criteria for this multicenter, Phase II study included primary or secondary PROC that progressed within 3 months of topotecan or LD, 3 or fewer prior chemotherapy regimens, and a performance status (PS) 0 or 1. BV was dosed at 15 mg/kg q 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as defined by RECIST. A two-stage design was utilized with H1 set at 15%. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), and safety. Results: The study enrolled 44 of the intended 53 pts, closing early due to a higher than expected rate of gastrointestinal perforations (GIP). Baseline characteristics included median age 60 yrs (range 31–87); PS 0 in 26 pts, 1 in 18 pts; 2 prior chemotherapy regimens in 20 pts, 3 in 24 pts. Preliminary efficacy: ORR (CR+PR), 7/44 (16%). Median duration of response was 12 weeks, with 2 pts continuing on study >5 months. Serious adverse events (SAEs) were reported in 18/44 pts (41%). Selected SAEs included GIP 5 (11%; one occurred more than 30 days after coming off study while on paclitaxel and commercial Avastin®), bowel obstruction 5 (11%), arterial thromboembolic events 4 (9%), delayed wound healing 2 (5%), and one case each of pulmonary hypertension, hypertensive encephalopathy, and hypoxia. Conclusions: BV has single agent activity in women with PROC, but is associated with substantial toxicity in this population. Trials are ongoing in less heavily treated, newly diagnosed pts with OC to evaluate the efficacy and safety of BV in these disease settings. Identification of risk factors for BV-associated adverse events requires further study. [Table: see text]