Two-stage stratified designs with survival outcomes and adjustment for misclassification in predictive biomarkers.

Biomarker stratified clinical trial designs are versatile tools to assess biomarker clinical utility and address its relationship with clinical endpoints. Due to imperfect assays and/or classification rules, biomarker status is prone to errors. To account for biomarker misclassification, we consider a two-stage stratified design for survival outcomes with an adjustment for misclassification in predictive biomarkers. Compared to continuous and/or binary outcomes, the test statistics for survival outcomes with an adjustment for biomarker misclassification is much more complicated and needs to take special care. We propose to use the information from the observed biomarker status strata to construct adjusted log-rank statistics for true biomarker status strata. These adjusted log-rank statistics are then used to develop sequential tests for the global (composite) hypothesis and component-wise hypothesis. We discuss the power analysis with the control of the type-I error rate by using the correlations between the adjusted log-rank statistics within and between the design stages. Our method is illustrated with examples of the recent successful development of immunotherapy in nonsmall-cell lung cancer.

Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes.

BACKGROUND: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established. METHODS: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo. CONCLUSIONS: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).

SURPASS-ET: phase III study of ropeginterferon alfa-2b versus anagrelide as second-line therapy in essential thrombocythemia.

Patients diagnosed with high-risk essential thrombocythemia (ET) have limited treatment options to reduce the risk of thrombosis and lessen the progression of the disease by targeting the molecular source. Hydroxyurea is the recommended treatment, but many patients experience resistance or intolerance. Anagrelide is an approved second-line option for ET, but concerns of a higher frequency of disease transformation may affect its role as a suitable long-term option. Interferons have been evaluated in myeloproliferative neoplasms for over 30 years, but early formulations had safety and tolerability issues. SURPASS-ET (NCT04285086) is a phase III, open-label, multicenter, global, randomized, active-controlled trial that will evaluate the safety, efficacy, tolerability and pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide as second-line therapy in high-risk ET.

Essential thrombocythemia (ET) is a condition characterized by having more platelets than normal. The high number of platelets increases the risk of a life-threatening blood clot and/or bleeding. Patients with ET and at a high risk for these events are usually treated first with hydroxyurea (HU), but some patients do not respond properly or may develop significant side effects. Anagrelide is an approved medication used in patients who do not respond to HU. Ropeginterferon alfa-2b is a disease-specific, long-acting interferon with a good safety profile approved in polycythemia vera, another type of myeloproliferative neoplasm. The SURPASS-ET clinical trial will evaluate the safety, efficacy, tolerability and pharmacokinetics of ropeginterferon alfa-2b compared with anagrelide in patients with ET who are resistant or cannot tolerate HU. Clinical Trial Registration: NCT04285086 (ClinicalTrials.gov).

Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial.

AIMS/HYPOTHESIS: In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). METHODS: Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed. RESULTS: A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were -16.2% (-23.9, -7.6) and 2.6 ml min-1 [1.73 m]-2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups. CONCLUSIONS/INTERPRETATION: Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR. TRIAL REGISTRATION: ClinicalTrials.gov NCT01986881.

Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease: Results of the VERTIS CV Trial.

BACKGROUND: In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes. METHODS: VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events. RESULTS: A total of 8246 patients were randomly assigned to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pretrial ejection fraction (EF) available, including n=959 with EF ≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75-1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54-0.90]; P=0.006). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44-0.90]; no HF: HR, 0.79 [95% CI, 0.54-1.15]; P interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF ≤45% versus preserved EF >45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF ≤45% (HR, 0.48 [95% CI, 0.30-0.76]) versus EF >45% (HR, 0.86 [95% CI, 0.58-1.29]). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate <60 mL·min-1·1.73 m-2, albuminuria, and diuretic use (each P interaction <0.05). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56-0.87]) and total HHF/CV death (rate ratio, 0.83 [95% CI, 0.72-0.96]). CONCLUSIONS: In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.

Plasma, Prostate and Urine Levels of Tocopherols and Metabolites in Men after Supplementation with a γ-Tocopherol-Rich Vitamin E Mixture.

The vitamin E forms γ- and δ-tocopherols (T) inhibit carcinogenesis in animal models; nevertheless, their cancer preventive activities in humans are uncertain. As an initial step to address this issue, we conducted a pilot phase 0 trial to determine the levels of tocopherols and their metabolites in prostate cancer patients undergoing radical prostatectomy. The patients were randomized to no supplementation or two capsules of a γ-T-rich vitamin E mixture daily for 7 or 14 day prior to prostatectomy. Blood and urine samples were collected before supplementation and on the day of surgery, along with prostate tissue, for analysis of tocopherols and their metabolites. Estimated blood loss during surgery was not significantly different across treatment arms and there were no reported adverse events. Prostate tissue levels of γ-T and δ-T were increased after 14 day of supplementation. Their side-chain degradation metabolites (CEHCs and CMBHCs) were significantly elevated in plasma, prostate and urine samples after supplementation for 7 or 14 day. In conclusion, supplementation with γ-T-rich vitamin E increased the prostate levels of γ-T and δ-T. The use of pure γ-T, δ-T or tocopherol mixtures with higher ratio of γ-T or δ-T to α-T is recommended for future studies.

Two-stage enrichment clinical trial design with adjustment for misclassification in predictive biomarkers.

A two-stage enrichment design is a type of adaptive design, which extends a stratified design with a futility analysis on the marker negative cohort at the first stage, and the second stage can be either a targeted design with only the marker positive stratum, or still the stratified design with both marker strata, depending on the result of the interim futility analysis. In this paper, we consider the situation where the marker assay and the classification rule are possibly subject to error. We derive the sequential tests for the global hypothesis as well as the component tests for the overall cohort and the marker-positive cohort. We discuss the power analysis with the control of the type I error rate and show the adverse impact of the misclassification on the powers. We also show the enhanced power of the two-stage enrichment over the one-stage design and illustrate with examples of the recent successful development of immunotherapy in non-small-cell lung cancer.

Tocopherols inhibit estrogen-induced cancer stemness and OCT4 signaling in breast cancer.

Estrogen plays an important role in breast cancer development. While the mechanism of the estrogen effects is not fully elucidated, one possible route is by increasing the stem cell-like properties in the tumors. Tocopherols are known to reduce breast cancer development and progression. The aim of the present study is to investigate the effects of tocopherols on the regulation of breast cancer stemness mediated by estrogen. To determine the effects of tocopherols on estrogen-influenced breast cancer stem cells, the MCF-7 tumorsphere culture system, which enriches for mammary progenitor cells and putative breast cancer stem cells, was utilized. Treatment with estrogen resulted in an increase in the CD44+/CD24- subpopulation and aldehyde dehydrogenase activity in tumorspheres as well as the number and size of tumorspheres. Tocopherols inhibited the estrogen-induced expansion of the breast cancer stem population. Tocopherols decreased the levels of stem cell markers, including octamer-binding transcription factor 4 (OCT4), CD44 and SOX-2, as well as estrogen-related markers, such as trefoil factor (TFF)/pS2, cathepsin D, progesterone receptor and SERPINA1, in estrogen-stimulated tumorspheres. Overexpression of OCT4 increased CD44 and sex-determining region Y-box-2 levels and significantly increased cell invasion and expression of the invasion markers, matrix metalloproteinases, tissue inhibitors of metalloproteinase and urokinase plasminogen activator, and tocopherols inhibited these OCT4-mediated effects. These results suggest a potential inhibitory mechanism of tocopherols in estrogen-induced stemness and cell invasion in breast cancer.

Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV).

BACKGROUND: Ertugliflozin is an inhibitor of sodium-glucose co-transporter-2 (SGLT2), approved in the United States and European Union to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). The VERTIS cardiovascular (CV) outcomes trial (NCT01986881) has a primary objective to demonstrate non-inferiority of ertugliflozin versus placebo on major adverse CV events: time to the first event of CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary objectives are to demonstrate superiority of ertugliflozin versus placebo on time to: 1) the composite outcome of CV death or hospitalization for heart failure (HF); 2) CV death; and 3) the composite outcome of renal death, dialysis/transplant, or doubling of serum creatinine from baseline. METHODS: Patients ≥40 years old with T2DM (HbA1c 7.0-10.5%) and established atherosclerotic cardiovascular disease (ASCVD) of the coronary, cerebral, and/or peripheral arterial systems, were randomized 1:1:1 to once daily double-blind placebo, ertugliflozin 5 mg or 15 mg added to existing therapy. RESULTS: 8246 patients were randomized and 8238 received at least 1 dose of investigational product. Mean age was 64.4 years, 11.0% were ≥75 years old, and mean diabetes duration was 12.9 years with screening HbA1c of 8.3%. At entry, coronary artery disease, cerebrovascular disease, and peripheral arterial disease were present in 76.3%, 23.1%, and 18.8% of patients, respectively. HF was present in 23.1%, and Stage 3 kidney disease in 21.6% of patients. CONCLUSION: The results from the VERTIS-CV trial will define the CV and renal safety and efficacy of ertugliflozin in patients with T2DM and ASCVD.

Phase I trial of selenium plus chemotherapy in gynecologic cancers.

PURPOSE: Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. METHODS: Chemo-naïve patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RESULTS: Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 µg to 5000 µg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. CONCLUSION: Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 µg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

Relative efficiency of precision medicine designs for clinical trials with predictive biomarkers.

Prospective randomized clinical trials addressing biomarkers are time consuming and costly, but are necessary for regulatory agencies to approve new therapies with predictive biomarkers. For this reason, recently, there have been many discussions and proposals of various trial designs and comparisons of their efficiency in the literature. We compare statistical efficiencies between the marker-stratified design and the marker-based precision medicine design regarding testing/estimating 4 hypotheses/parameters of clinical interest, namely, treatment effects in each marker-positive and marker-negative cohorts, marker-by-treatment interaction, and the marker's clinical utility. As may be expected, the stratified design is more efficient than the precision medicine design. However, it is perhaps surprising to find out how low the relative efficiency can be for the precision medicine design. We quantify the relative efficiency as a function of design factors including the marker-positive prevalence rate, marker assay and classification sensitivity and specificity, and the treatment randomization ratio. It is interesting to examine the trends of the relative efficiency with these design parameters in testing different hypotheses. We advocate to use the stratified design over the precision medicine design in clinical trials with predictive biomarkers.

Effects of Soybean Lipid Infusion on Unbound Free Fatty Acids and Unbound Bilirubin in Preterm Infants.

OBJECTIVE: To assess the effects of a soybean lipid emulsion infusions on levels of unbound (free) bilirubin (Bf) and unbound free fatty acids (FFAu) as well as changes in Bf and total serum bilirubin (TSB) during phototherapy in infants born preterm. STUDY DESIGN: Ninety-seven infants born preterm (birth weight: 500-2000 g; gestational age: 23-34 weeks) were enrolled to investigate the effect of 0, 1, 2, and 3 g/kg/d of intralipid infusion on Bf and FFAu. Pre- and postphototherapy TSB, FFAu, and Bf also were analyzed in 91 infants to assess the effects of phototherapy. FFAu levels were measured with the fluorescent probe ADIFAB2 and Bf by the fluorescent Bf sensor BL22P1B11-Rh during intralipid infusion and at start and end of phototherapy. TSB and plasma albumin were measured by the diazo and bromcresol green techniques, respectively. Bilirubin-albumin dissociation constants were calculated based on Bf and plasma albumin. RESULTS: Bf and FFAu increased with increasing intralipid dosage across all gestational ages. TSB and Bf were correlated significantly when infants received 0 or 1 g/kg/d of intralipid but not at greater doses of intralipid (2 and 3 g/kg/d). Although phototherapy effectively reduced both TSB and Bf in the total phototherapy group (by 32% and 12%, respectively), it reduced TSB, but not Bf, in infants less than 28 weeks of gestation. CONCLUSIONS: Increasing intralipid doses result in increasing FFAu levels, which are associated with increased Bf independent of TSB. In infants born extremely preterm (<28 weeks of gestation), phototherapy effectively reduces TSB but not Bf.

Comments on the three papers by the FDA/CDER research team on the regulatory perspective of the missing data problem.

This communication comments on the three papers by the FDA CDER research team on the regulatory perspective of the missing data problem. The focus is on two topics: causal estimand and sensitivity analysis. Copyright © 2016 John Wiley & Sons, Ltd.

Extension of a Cox proportional hazards cure model when cure information is partially known.

When there is evidence of long-term survivors, cure models are often used to model the survival curve. A cure model is a mixture model consisting of a cured fraction and an uncured fraction. Traditional cure models assume that the cured or uncured status in the censored set cannot be distinguished. But in many practices, some diagnostic procedures may provide partial information about the cured or uncured status relative to certain sensitivity and specificity. The traditional cure model does not take advantage of this additional information. Motivated by a clinical study on bone injury in pediatric patients, we propose a novel extension of a traditional Cox proportional hazards (PH) cure model that incorporates the additional information about the cured status. This extension can be applied when the latency part of the cure model is modeled by the Cox PH model. Extensive simulations demonstrated that the proposed extension provides more efficient and less biased estimations, and the higher efficiency and smaller bias is associated with higher sensitivity and specificity of diagnostic procedures. When the proposed extended Cox PH cure model was applied to the motivating example, there was a substantial improvement in the estimation.

Potential Association of Urinary N7-(2-Carbamoyl-2-hydroxyethyl) Guanine with Dietary Acrylamide Intake of Smokers and Nonsmokers.

Acrylamide (AA), a rodent carcinogen, is widely used in industry and present in cigarette smoke as well as in foods processed at high temperatures. The metabolic activation of AA to glycidamide (GA) could be critical for AA carcinogenicity since GA causes DNA adduct formation in vivo. N7-(2-carbamoyl-2-hydroxyethyl) guanine (N7-GAG), the most abundant DNA adduct of AA, is subjected to spontaneous and enzymatic depurination and excreted through urine. Urinary N7-GAG analysis can confirm AA genotoxicity and identify active species of AA metabolites in humans, thereby serving as a risk-associated biomarker for molecular epidemiology studies. This study aimed to develop an isotope-dilution solid-phase extraction liquid chromatography tandem mass spectrometry method to comparatively analyze urinary N7-GAG levels in nonsmokers and smokers. Urinary N-acetyl-S-(propionamide)-cysteine (AAMA), a metabolite of AA, was also analyzed as a biomarker for current AA exposure. Urinary N7-GAG was quantified by monitoring m/z 239 → 152 for N7-GAG and m/z 242 → 152 for (13)C3-labeled N7-GAG under positive electron spray ionization and multiple reaction mode. The median urinary N7-GAG level was 0.93 µg/g creatinine in nonsmokers (n = 33) and 1.41 µg/g creatinine in smokers (n = 30). Multiple linear regression analysis of data revealed that N7-GAG levels were only significantly associated with AAMA levels. These results demonstrate that urinary N7-GAG of nonsmokers and smokers is significantly associated with a very low level of dietary AA intake, assessed by analyzing urinary AAMA.

Surgical removal of the parametrial fat pads stimulates apoptosis and inhibits UVB-induced carcinogenesis in mice fed a high-fat diet.

Removal of the parametrial fat pads (partial lipectomy) from female SKH-1 mice fed a high-fat diet inhibited UVB-induced carcinogenesis, but this was not observed in mice fed a low-fat chow diet. Partial lipectomy in high-fat-fed mice decreased the number of keratoacanthomas and squamous cell carcinomas per mouse by 76 and 79%, respectively, compared with sham-operated control mice irradiated with UVB for 33 wk. Immunohistochemical analysis indicated that partial lipectomy increased caspase 3 (active form) positive cells by 48% in precancerous epidermis away from tumors, by 68% in keratoacanthomas, and by 224% in squamous cell carcinomas compared with sham-operated control mice. In addition, partial lipectomy decreased cell proliferation away from tumors and in tumors. RT-PCR analysis for adipokines revealed that mRNAs for TIMP1, MCP1, and SerpinE1 (proinflammatory/antiapoptotic cytokines) in the parametrial fat pads of sham-operated control mice were 54- to 83-fold higher than levels in compensatory fat that returned after surgery in partially lipectomized mice at the end of the tumor study. Feeding mice high-fat diets for 2 wk increased levels of TIMP1 and other adipokines in serum and epidermis, and these increases were inhibited by removal of the parametrial fat pads. Our results are a unique demonstration that surgical removal of a specific tissue fat results in inhibition of carcinogenesis in obese mice. This inhibition was associated with an increase in apoptosis and a decrease in proliferation in tumors and in precancerous areas away from tumors.

Methods of designing two-stage winner trials with survival outcomes.

In drug development, especially for oncology studies, a recent proposal is to combine a costly phase II dose selection study with a subsequent phase III study into a single trial that compares the selected (winning) dose from the first stage with the control group. This design may also be used in phase III trials, in which the winning active treatment regimen, selected at the first stage, is compared with the control group at the second stage. This design is known as a two-stage winner design, as proposed by Shun et al. (2008) for continuous outcomes. Time-to-event data are often analyzed in oncology trials. In order to derive the critical value and power of this design, per Shun et al. (2008), it is essential to calculate the asymptotic covariance and correlation of the log-rank statistics for survival outcomes between the two stages. In this paper, we derive the asymptotic covariance and correlation, and provide additional approximate design parameters. Examples are given to illustrate the method, and simulations are performed to evaluate the veracity of these approximate design parameters.

Multi-regional clinical trial design and consistency assessment of treatment effects.

We can apply both fixed and random effects models to multi-regional clinical trial (MRCT) design and data analysis. Thoroughly, understanding the features of these models in an MRCT setting will help assessing their applicability to an MRCT. In this paper, we discuss the interpretations of trial results from these models. We also evaluate the impact of the number of regions and the sample size configuration across the regions on the required total sample size for the overall treatment effect assessment. For quantifying treatment effects of individual regions, the empirical shrinkage estimator and the James-Stein type shrinkage estimator associate with smaller variability compared with the regular sample estimator. We conduct computation and simulation to compare the performance of these estimators when they are applied to assess consistency of treatment effects across regions. We use a multinational trial example to illustrate the application of these methods.

Phase 2 trial of paclitaxel, 13-cis retinoic acid, and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer.

OBJECTIVE: Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. MATERIALS AND METHODS: Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. RESULTS: Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. CONCLUSIONS: Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.