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Dose‐ranging studies are a crucial part of the phase II drug development process. They complement the understanding gained from exposure‐response analyses. However, the statistical design issues related to dose‐ranging studies are not always keenly understood and a poorly designed study can be costly for later development. In this tutorial, we review five key statistical principles in designing such a study. We also describe some popular statistical approaches, including pairwise comparison, modeling, and Multiple Comparison Procedure modeling in the context of principles.

BackgroundCystic fibrosis (CF) is a genetic, multisystemic, progressive and life-shortening disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Different genotypes have been linked to variations in disease progression among people with CF. The burden of illness (BOI) in children with CF is incompletely characterised, particularly as it relates to CFTR genotypes prior to the availability of the first CFTR modulators. This retrospective, cross-sectional, descriptive study evaluated the BOI in US children with CF MethodsData from the US Cystic Fibrosis Foundation Patient Registry from 2011 were used to summarise key patient and disease characteristics using descriptive statistics, overall and grouped by age (0 to F508del/F508del, F508del/minimal function (MF), MF/MF, gating mutation on ≥1 allele, residual function mutation on ≥1 allele and R117H on ≥1 allele) group.ResultsThe analysis included 9185 children. Among 6-year-olds to 1 in 1 s was 92.6% (17.5%). Among all children ConclusionsPrior to the approval of the first CFTR modulator therapies in children

The drop-the-losers design combines a phase 2 trial of k treatments and a confirmatory phase 3 trial under a single adaptive protocol, thereby gaining efficiency over a traditional clinical development approach. Such designs may be particularly useful in the rare disease setting, where conserving sample size is paramount, and control arms may not be feasible. We propose an unconditional exact likelihood (UEL) testing and inference procedure for these designs for a binary endpoint using small sample sizes, comparing its operating characteristics to existing methods. Additional practical considerations are evaluated, including the choice of stagewise sample sizes and effect of ties.

In phase I oncology trials, dose-limiting toxicity (DLT) is often used as the endpoint during early cycles in dose escalation studies to find the maximum tolerated dose (MTD). Bayesian adaptive designs such as the Escalation with Overdose Control (EWOC; Babb et al., Stat Med 17:1103–1120, 1998) methods have been introduced to protect patients from overdosing and account for variability in toxicity estimates.

Personalized medicine, or tailored therapy, has been an active and important topic in recent medical research. Many methods have been proposed in the literature for predictive biomarker detection and subgroup identification. In this article, we propose a novel decision tree-based approach applicable in randomized clinical trials. We model the prognostic effects of the biomarkers using additive regression trees and the biomarker-by-treatment effect using a single regression tree. Bayesian approach is utilized to periodically revise the split variables and the split rules of the decision trees, which provides a better overall fitting. Gibbs sampler is implemented in the MCMC procedure, which updates the prognostic trees and the interaction tree separately. We use the posterior distribution of the interaction tree to construct the predictive scores of the biomarkers and to identify the subgroup where the treatment is superior to the control. Numerical simulations show that our proposed method performs well under various settings comparing to existing methods. We also demonstrate an application of our method in a real clinical trial.

This paper concerns using modified weighted Schoenfeld residuals to test the proportionality of subdistribution hazards for the Fine-Gray model, similar to the tests proposed by Grambsch and Therneau for independently censored data. We develop a score test for the time-varying coefficients based on the modified Schoenfeld residuals derived assuming a certain form of non-proportionality. The methods perform well in simulations and a real data analysis of breast cancer data, where the treatment effect exhibits non-proportional hazards.

A Bayesian approach to finding the maximum tolerated dose (MTD) is presented. The approach is flexible, allowing inclusion of covariates, and enables transparent dose recommendations based on comprehensive inferential summaries on the probability of dose-limiting toxicities (DLT). A case study is presented for a Phase I combination of two oncology drugs, nilotinib and imatinib. Data obtained and decisions made during the study are described. Final determination of the MTD pair is outlined, along with discussion regarding the use and interpretability of within- and end-of-study data.

Purpose: LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In this phase I study, LBH589 was administered i.v. as a 30-minute infusion on days 1 to 7 of a 21-day cycle. Experimental Design: Fifteen patients (median age, 63 years; range, 42-87 years) with acute myeloid leukemia (13 patients), acute lymphocytic leukemia (1 patient), or myelodysplastic syndrome (1 patient) were treated with LBH589 at the following dose levels (mg/m2): 4.8 (3 patients), 7.2 (3 patients), 9.0 (1 patient), 11.5 (3 patient), and 14.0 (5 patients). The levels of histone acetylation were measured using quantitative flow cytometry and plasma LBH589 concentrations were assayed. Results: Four dose-limiting toxicities (grade 3 QTcF prolongation) were observed, four at 14.0 mg/m2 and one at 11.5 mg/m2. QTcF prolongation was asymptomatic and reversed on LBH589 discontinuation. Other potentially LBH589-related toxicities included nausea (40%), diarrhea (33%), vomiting (33%), hypokalemia (27%), loss of appetite (13%), and thrombocytopenia (13%). In 8 of 11 patients with peripheral blasts, transient reductions occurred with a rebound following the 7-day treatment period. H3 acetylation increase was significant in B-cells (CD19+; P = 0.02) and blasts (CD34+; P = 0.04). The increase in H2B acetylation was highest in CD19+ and CD34+ cells [3.8-fold (P = 0.01) and 4.4-fold (P = 0.03), respectively]. The median acetylation of histones H2B and H3 in CD34+ and CD19+ cells significantly increased on therapy as did apoptosis in CD14+ cells. Area under the curve increased proportionally with dose with a terminal half-life of ∼11 hours. Conclusion: Intravenous administration of LBH589 was well tolerated at doses

Many jail inmates have a history of mental illness, substance use, and drug-related crime. This article assesses the effect of psychiatric comorbidity on retention in jail-based substance abuse treatment. Secondary data from five jail-based substance abuse treatment programs were studied using descriptive and multivariate analyses. Controlling for age, sex, race, education, and program, the odds of an offender with a history of mental illness being terminated from treatment were nearly three times that of those with no such history. The data suggest that psychiatric comorbidity may be an important correlate of retention in jail-based substance abuse treatment.

By generalizing the proportional hazards model, we introduce a new function β( t ), which we call the proportionality function, and which we show plays a role in studying aspects of the randomly censored model. We develop an asymptotically efficient nonparametric estimator of β( t ), establish its uniform consistency, and obtain a weak convergence result. Furthermore, a confidence band for β( t ), based on the bootstrap, is developed. The results are applied to an actual dataset.

The maximum likelihood estimator (MLE) for the survival function STunder the proportional hazards model of censorship is derived and shown to differ from the Abdushukurov-Cheng-Lin estimator when the class of allowable distributions includes all continuous and discrete distributions. The estimators are compared via an example. The MLE is calculated using a Newton-Raphson iterative procedure and implemented via a FORTRAN algorithm.

Many jail inmates have a history of substance use and “abuse”; few, however, receive comprehensive treatment for substance use disorders while in jail. The authors offer a longitudinal reanalysis of data from five jail-based substance user treatment programs. Survival analysis was used to identify client characteristics associated with length of time in treatment. Survival curves for the five programs were compared, indicating which ones retained inmates the longest. Results from a model stratified by jail site revealed that inmates over 25 years of age and those already sentenced had significantly longer treatment stays. The Substance Abuse Intervention Division (SAID) program, a modified therapeutic community in a New York jail, and the Deciding, Educating, Understanding, Counseling, and Evaluation (DEUCE) program, a curriculum-based intervention, had the longest survival curves and were, therefore, most effective at retaining inmates in treatment.

7584 Background: CT- 322 is a pegylated protein engineered from the tenth type III human fibronectin domain thatspecifically blocks VEGFR-2 signaling by all known ligands. This international randomized study assessed the efficacy and safety of PC + CT-322 compared to PC + Bev as first-line treatment for advanced non-squamous NSCLC. Methods: In addition to paclitaxel 200 mg/m2and carboplatin AUC 6 given on day 1 of a 21 day cycle(maximum 6 cycles), subjects, stratified by ECOG performance status, disease stage, and site, were randomized 1:1 to receive either CT-322 2 mg/kg on days 1, 8, and 15 (arm A) or Bev 15 mg/kg on day 1 and placebo on days 8 and 15 (arm B). CT -322 and Bev/placebo were continued as maintenance until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and safety. Results: 255 subjects were randomized to arm A (n=127) or arm B (n=128). Baseline characteristics were wellbalanced. After a median follow- up of 13.8 months, 9 subjects on arm A and 24 on arm B remained on study treatment. The median treatment duration was 19 weeks in arm A and 26.3 weeks on arm B. The median PFS in arm A was 5.6 months compared to 6.8 months in arm B (HR 1.51, 1 -sided p=0.997). In all prespecified subgroups, PFS was favored in arm B. The response rate was 25.2% in arm A compared to 32.8% in arm B. Median OS was 12.5 months in arm A compared to 15.2 months in arm B. The most common grade ≥ 3 adverse events (Arm A vs B) were neutropenia (47.2% vs 49.2%), thrombocytopenia (11.8% vs 6.3%), and fatigue (10.2% in both arms). Grade ≥ 3 hypertension was more frequently reported in arm A (8.7% vs 3.1%). Grade ≥ 3 venous thrombosis (5.5% vs 6.3%), proteinuria (1.6% vs 2.3%), and bleeding events (0.8% vs 1.6%) were similar. Conclusions: PC + CT-322 failed to improve PFS, OS, or response rate compared to PC + Bev. However, thesafety profile in the PC + CT-322 arm was consistent with the anti-angiogenic mechanism of action, suggesting that CT-322 has biological activity as an inhibitor of VEGFR-2.

Panobinostat (LBH589) is a novel and potent pan-deacetylase inhibitor (DACi) with broad preclinical activity in models of hematologic malignancies. This trial is evaluating panobinostat in patients (pts) with advanced hematologic malignancies with 2 schedules of oral administration: Monday/Wednesday/Friday (MWF) every week or MWF every other week. Each schedule is being assessed in 2 pt groups that differ by disease and the definition of hematologic dose-limiting toxicity (DLT): pts with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM); and pts with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic idiopathic myelofibrosis (CIMF), acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), or chronic lymphocytic leukemia (CLL). A 3-parameter Bayesian logistic regression model guides dose escalation, and a minimum of 6 evaluable pts at each dose level is required prior to dose escalation. To date, 128 pts have been enrolled: 79 pts with weekly dosing at 20, 30, 40, 60, and 80 mg/dose; and 49 pts dosed every other week with 30, 45, 60, and 80 mg/dose. The most common diseases have included AML (65 pts), HL (23 pts), and MM (12 pts). Panobinostat has rapid oral absorption (median Tmax 1 h, range 0.5–3 h), AUC and Cmax are dose-related, and mean effective t½ is 16.7 h. The adverse-event (AE) profile has been similar between the 2 schedules; the most common grade 3/4 AEs (≥10%) have been thrombocytopenia (43%), neutropenia (22%), febrile neutropenia (20%), fatigue (20%), and anemia (11%). In pts with lymphoma and myeloma, the principal DLT is thrombocytopenia, whereas in patients with AML, in whom grade 4 thrombocytopenia is not considered dose-limiting, the principal DLT is fatigue. With weekly dosing, the maximum tolerated dose (MTD) is 40 mg/dose in pts with lymphoma and myeloma, whereas the MTD is 60 mg/dose in pts with AML. The MTD has not been established for dosing every other week in either group of pts, but this regimen is not expected to provide greater dose intensity than weekly treatment. Anti-tumor activity has been observed in a group of 13 response-evaluable pts with relapsed/refractory HL, treated at doses ≥30 mg with both schedules: PR by computed tomography (CT), 5/13 pts (38%); metabolic PR by positron emission tomography (PET), 7/12 pts (58%) (PET assessment not performed in 1 pt); symptom improvement in 7 of the 9 pts with disease-related symptoms at baseline (78%); and disease control for up to 16+ cycles. Anti-tumor activity has also been observed in a group of 26 response-evaluable pts with AML, treated at doses ≥40 mg on the weekly schedule: 2 CRs, including 1 pt ongoing >1 yr; 1 pt aleukemic (marrow not assessable due to fibrosis) >10 months; 2 pts ongoing with decreased marrow blasts and disease control for 9 and 12 months. Activity has also been observed with panobinostat doses ≥30 mg in pts with other hematologic malignancies: CIMF (2 pts, both ongoing, 1 pt with decreased splenomegaly and transfusion independence >20 months, 1 pt with decreased splenomegaly >3 months); MDS (1 pt PR); MM (1 pt PR); and CD4+/56+ hematodermic neoplasm (1 pt PR). For future studies of single-agent panobinostat in HL, the recommended regimen is 40 mg p.o. MWF every week. A regimen of 60 mg p.o. MWF every week is recommended for further evaluation of panobinostat’s single-agent activity in AML.

8555 Background: Panobinostat (LBH589) is a potent pan-deacetylase inhibitor (DACi) which has demonstrated activity in patients (pts) with CTCL in a phase I study (Prince et al, ASCO 2007). This phase II study aims to confirm that activity. Methods: This open-label study enrolled pts with CTCL (stage IB-IVA), including Mycosis fungoides (MF) and Sezary syndrome (SS), who have failed ≥2 prior systemic therapies, have adequate organ function and ECOG PS ≤2. Pts with significant cardiovascular abnormalities or QTcF >450 msec on screening ECG were excluded. Pts were accrued to Group 1 (Grp 1, previously treated with oral bexarotene) or Group 2 (Grp 2, bexarotene naive); both following a Simon 2-stage design. Panobinostat (20 mg) was administered orally on days 1, 3, and 5 weekly until disease progression or intolerance. Primary endpoint is the response rate measured using a composite score derived from assessment of skin disease using modified Severity-Weighted Assessment Tool [mSWAT], evaluation of visceral ...

3131 Introduction: LAQ824, a novel cinnamic acid hydroxamate, inhibits HDAC activity (IC50, 0.03 μM) and the hERG channel(IC50, 10 μM). Methods: In 3 phase I studies, LAQ824 was administered as a 3-hr intravenous infusion on several dosing schedules, principally days 1–3 of a 21-day cycle, to adult pts with advanced solid (studies 2102 and 2107) or hematologic (study 2101) malignancies. Pts with impaired cardiac function were excluded; drugs known to prolong QT interval were prohibited. Serial digital ECGs were performed at baseline (4 ECGs), on days of dosing and post-dose each cycle. ECG data were processed in a core lab by manual analysis. Cardiac enzymes were assessed on days of dosing. LVEF was assessed by MUGA scan or echocardiogram each cycle. Results: 77 pts (median age: 60 yrs; 48 males, 29 females) were treated at 11 dose levels, range 6 - 200 mg/m2/day. PK analysis showed dose proportionality, T1/2of 6 - 26 hrs, and 1.5 fold accumulation at steady state. There was considerable inter-patient var...

3106 Introduction: LBH589 is a novel cinnamic acid hydroxamate that inhibits HDAC activity, IC50 of 0.03 μM, and inhibits hERG channel with an IC50 of 3.9 μM. Methods: In 2 phase I studies, LBH589 was administered as a 30 minute intravenous infusion on 2 schedules, days 1–3 and 8–10 of a 21 day cycle or days 1–3 and 15–17 of a 28 day cycle to adult pts with advanced solid malignancies (study 2101) or on a schedule of days 1–7 of a 21 day cycle to adult pts with hematologic malignancies (study 2102). Patients with impaired heart function were excluded, and drugs known to prolong QT interval were prohibited. Serial digital ECGs were performed at baseline (6 ECGs), and on days of dosing. ECG data were processed in a core lab by manual analysis. Results: 45 pts (median age: 60 yrs; 23 males, 22 females) were treated at 10 dose levels, range 1.2 - 20.0 mg/m2/day. PK analysis showed dose proportionality, T1/2 of 6 - 26 hr, and approximately 1.5 fold accumulation at steady state (day 3). PD analysis of PBL showe...

LBH589 is a novel HDAC inhibitor which activates p21 and inhibits proliferation and induces apoptosis in tumor cell lines at nanomolar concentrations. In this study, LBH589 was administered IV as a 30-minute infusion on days 1–7 of a 21 day cycle. Fourteen pts. (median 61 years [range 42–87], performance status 0 (2 pts) or 1 (12 pts), de novo AML (2 pts), relapsed /refractory AML (10 pts), refractory ALL (1 pt), MDS (RAEB) (1 pt) have been treated at dose levels (mg/m2): 4.8 (3 pts), 7.2 (3 pts), 9.0 (1 pt), 11.5 (2 pts), 14.0 (5 pts). Four DLT’s (G3 QTcF prolongation) have been observed − 3 at 14.0 mg/m2 and one at 11.5 mg/m2 (a total of 357 ECG’s were performed during the study). One patient treated at 14.0 mg/m2 died of pulmonary hemmorhage resulting from sepsis while on study. Treatment with LBH589 as well as the patient’s underlying disease (MDS) were considered a contributing factors to the sepsis. A white cell differentiation syndrome (which was sucessfully treated with high-dose steroids) was observed in one patient with refractory AML treated at 14.0 mg/m2. Other LBH589-related toxicities included: Grade 1 ST-T wave abnormality, palpitations, hypokalemia; Grade 2 diarrhea, nausea, vomiting, loss of appetite, headache, atrial fibrillation, and QT prolongation. In 9 of 12 patients (2 patients were aleukemic), treatment with LBH589 resulted in reductions in peripheral blasts, WBC and platelets during treatment. Counts rebounded following the 7-day treatment period (generally by day 15). Bone marrow blast counts generally continued to increase during treatment. The levels of histone acetylation in bone marrow and peripheral blood cells were measured using quantitative flow cytometry and antibodies against histones H2B and H3. The median acetylation of histones H2B and H3 in CD34+ cells increased on therapy from 4463 to 17185 and from 11540 to 66224, respectively. Despite this increase in histone acetylation a significant change in apoptosis (measured by annexin V or mitochondrial potential) or proliferation (measured by BrdU incorporation) in CD34+ cells was not demonstrated. However, peripheral blood lymphocytes showed significant increase in apoptosis on day 7 as compared with the levels of apoptosis before therapy. PK samples were collected on days 1 and 7 of cycle 1 and analyzed using a noncompartmental analysis. Plasma LBH589 concentrations were determined using HPLC/MS/MS assay. AUC increased proportionally with dose and mean AUCs (0–24h) were 139.47, 131.46, 189.12, and 344.28 ng.h/mL, respectively, for 4.8, 7.2, 9.0, and 14.0 mg/M2 dose levels on Day 1. Terminal half-life was approximately 11 hrs. LBH589 given IV appears well tolerated at doses below 11.5 mg/m2 with consistent transient antileukemic and PD effects.