True Response Rate Research Articles

Estimating Response Ratios from Continuous Outcome Data

Several methods for imputing the number of responders from summary continuous outcome data in randomized controlled trials exist. A method by Furukawa and others was used in the quite common case that only such summary continuous outcome measures, but not the actual numbers of responders, are reported in order to estimate response rates (probabilities) for different treatments and response ratios between treatments in such trials. The authors give some empirical justification, but encourage search for theoretical support and further empirical exploration. In particular, a problem that needs to be addressed is that randomness in baseline score is not taken into consideration. This will be done in the present paper. Assuming a binormal model for the data, we compare theoretically the true response rate for a single treatment arm to the theoretical response rate underlying two versions of the suggested imputation method. We also assess the performance of the method numerically for some choices of model parameters. We show that the method works satisfactorily in some cases, but can be seriously biased in others. Moreover, assessing the uncertainty of the estimates is problematic. We suggest an alternative Bayesian estimation procedure, based directly on the normal model, which avoids these problems and provides more precise estimates when applied to simulated data sets.

Abstract OT3-2-08: A phase 2 single-arm study of the clinical activity and safety of enzalutamide in patients with advanced androgen receptor-positive triple-negative breast cancer

Abstract Background: Androgen receptor (AR) expression by IHC is observed in 10-30% of patients (pts) with triple-negative breast cancer (TNBC). Molecular profiling of TNBC has identified a subtype, luminal AR, so called as it clusters with luminal A or B on PAM50 profiling. This AR positive (AR+) subtype of TNBC expresses high levels of AR mRNA and is heavily enriched in hormone-regulated pathways, yet lacks expression of estrogen and progesterone receptors. Experiments using AR+ TNBC cell lines have demonstrated enhanced growth, both in vitro and in vivo, in response to androgen stimulation that can be inhibited by enzalutamide (ENZA), a potent inhibitor of AR signaling that lacks the agonist activity observed with bicalutamide. AR+ TNBC may represent a novel clinical subtype of breast cancer, driven by AR signaling and which may respond to ENZA. Trial design: ENZA will be administered orally at 160mg daily to pts with AR+ TNBC until disease progression or intolerability. The primary endpoint is clinical benefit rate (CBR), defined as the proportion of pts with complete response (CR), partial response (PR), or stable disease (SD) at ≥16 weeks (wks). A Simon 2-stage design is used to ensure that a minimum threshold for activity is met. If the CBR at 16 wks exceeds 2 in 26 pts, the sample size will increase to enroll 62 evaluable pts. AR testing may be performed locally for eligibility, but central testing is required in all pts. This trial is currently enrolling pts. Eligibility criteria: Eligible pts are adult women with advanced AR+ (any nuclear staining by IHC) TNBC. TNBC is determined locally and defined as <1% IHC staining for both ER and PgR and 0 or 1+ IHC staining for Her2 or negative for Her2 amplification in IHC 2+ disease. Advanced is defined as metastatic or locally advanced disease not amenable to curative surgery or radiotherapy. Bone-only non-measurable disease is permitted. Pts must have adequate organ and bone marrow function and ECOG status ≤1. Pts with current or previously treated brain metastases or a history of seizure are excluded, as are pts who received prior AR targeted agents for 28 or more days. Specific aims: The primary objective is to determine CBR at ≥16 wks. Secondary objectives include CBR at ≥24 wks, response rates and duration of response, progression-free survival, pharmacokinetics of ENZA, and safety and tolerability. Exploratory endpoints include overall survival and evaluation of the relationship between AR expression and signaling in breast tissue and ENZA activity. Statistical methods: Efficacy analyses will be conducted on all enrolled pts with centrally defined AR+ TNBC and at least 1 available post-baseline tumor assessment. Efficacy analyses will use investigator-assessed outcomes according to RECIST 1.1. The null hypothesis (H0), that the true CBR is 8%, will be tested against a 1-sided alternative; if CBR is <3 in 26 pts in Stage 1, enrollment will stop. If CBR exceeds 9 in 62 pts in Stage 2, H0 will be rejected. This design yields a 1-sided type 1 error rate of 5% and 85% power when the true response rate is 20%. Contact information: For more information on this trial, please contact Amy Peterson at Medivation (amy.peterson@medivation.com). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-08.

Final results of phase II trial of doxorubicin HCl liposome injection followed by bexarotene in advanced cutaneous T-cell lymphoma

High response rates for doxorubicin HCl liposome injection (DLI) in cutaneous T-cell lymphoma (CTCL) have been reported with vague criteria until recently. Approximately 50% of CTCL patients respond to bexarotene (Bex). A phase II trial was carried out to clarify the true overall response rate (ORR) for DLI and to assess the role of sequential Bex. Patients were treated with DLI 20 mg/m(2) i.v. every 2 weeks for 16 weeks (8 doses) followed by 16 weeks with Bex 300 mg/m(2) orally. Response assessments were carried out after 16 (DLI) and 32 weeks (Bex). Skin responses were measured by the modified Severity-Weighted Assessment Tool (mSWAT) and the Composite Assessment of Index Lesion Severity (CA). Thirty-seven patients were treated: stage IV (22, 8 with Sézary syndrome), IIB (10), earlier stage refractory to skin-directed therapies or radiation therapy (5). For 34 assessable patients: ORR 14/34 [41%: partial response (PR) 12, clinical complete response (CCR) 2]. Maximum responses were all seen after 16 weeks DLI. Median progression-free survival (PFS) was 5 months. There were 22 deaths: 21 of disease and 1 of heart failure. Twenty-seven grade 3 and 5 grade 4 toxic events were observed. With strict criteria, DLI ORR is among the highest reported for single agents in CTCL. Sequential Bex did not increase the response rate or duration.

The Established Status Epilepticus Trial 2013

Benzodiazepine-refractory status epilepticus (established status epilepticus, ESE) is a relatively common emergency condition with several widely used treatments. There are no controlled, randomized, blinded clinical trials to compare the efficacy and tolerability of currently available treatments for ESE. The ESE treatment trial is designed to determine the most effective and/or the least effective treatment of ESE among patients older than 2years by comparing three arms: fosphenytoin (fPHT) levetiracetam (LVT), and valproic acid (VPA). This is a multicenter, randomized, double-blind, Bayesian adaptive, phase III comparative effectiveness trial. Up to 795 patients will be randomized initially 1:1:1, and response-adaptive randomization will occur after 300 patients have been recruited. Randomization will be stratified by three age groups, 2-18, 19-65, and 66 and older. The primary outcome measure is cessation of clinical seizure activity and improving mental status, without serious adverse effects or further intervention at 60min after administration of study drug. Each subject will be followed until discharge or 30days from enrollment. This trial will include interim analyses for early success and futility. This trial will be considered a success if the probability that a treatment is the most effective is >0.975 or the probability that a treatment is the least effective is >0.975 for any treatment. Proposed total sample size is 795, which provides 90% power to identify the most effective and/or the least effective treatment when one treatment arm has a true response rate of 65% and the true response rate is 50% in the other two arms.

What Do Child Daycare Center Teachers Know About Atopic Dermatitis?

Atopic dermatitis (AD) is the most common childhood inflammatory skin disorder. The purpose of this study was to elucidate the knowledge level of daycare center teachers about AD and related factors. Study subjects were 297 teachers (287 female, 10 male) from 20 randomly selected daycare centers in Istanbul. The knowledge level of teachers was assessed using a questionnaire with 21 questions about AD. The teachers were asked nine additional questions about demographic and other characteristics of the child care centers and about themselves. The mean age of the teachers was 26.4 ± 8.1 years (range 20-53 yrs). The mean score for the 21 questions was 71.4 ± 12.1 (68%) from a maximum of 105 points. The response rate of teachers rate for each question ranged from 54% to 90%. The completely true response rate for each question ranged from 3.0% to 66.7%. The knowledge level of the teachers was related to the number of children in the daycare center, but not to sex, age, education level, family history of atopy, teacher's monthly salary, location, or whether the daycare center was public or private. Although teachers in daycare centers have some knowledge about AD, widespread educational programs for teachers about AD may help to improve the understanding of the disease and the quality of life of affected children in daycare centers.

Repigmentation of vitiligo-associated leukotrichia after autologous, non-cultured melanocyte-keratinocyte transplantation

Many cases of leukotrichia are associated with vitiligo. Hair follicles are believed to be the source of melanocytes for skin repigmentation using standard medical therapy for vitiligo. Vitiliginous areas with overlying leukotrichia usually fail to achieve repigmentation by conventional medical treatments as a result of a deficient melanocyte reservoir. Even after the successful repigmentation of vitiliginous skin by medical therapies, leukotrichia hairs may remain depigmented, causing a major psychological impact to the patient. In such cases, surgical treatments may help to achieve the repigmentation of leukotrichia hairs. Reports of successful repigmentation in leukotrichia using different surgical treatments for vitiligo are few. This study reports the benefit of autologous non-cultured melanocyte-keratinocyte transplantation (MKT) in patients with vitiligo-associated leukotrichia. We report four cases of vitiligo-associated leukotrichia treated with MKT. All four patients showed significant repigmentation in vitiligo-associated leukotrichia after MKT. Melanocyte-keratinocyte transplantation may represent a good therapeutic option for the repigmentation of vitiligo-associated leukotrichia. This series includes only four responsive cases. Larger prospective studies are needed to determine the true response rate and mechanism of repigmentation.

Sample size calculation for studies comparing binary outcomes using historical controls

In historical control trials (HCTs), the experimental therapy is compared with a control therapy that has been evaluated in a previously conducted trial. Makuch and Simon developed a sample size formula where the observations from the HC group were considered not subject to sampling variability. Many researchers have pointed out that the Makuch-Simon sample size formula does not preserve the nominal power and type I error. We develop a sample size calculation approach that properly accounts for the uncertainty in the true response rate of the HC group. We demonstrate that the empirical power and type I error, obtained over the simulated HC data, have extremely skewed distributions. We then derive a closed-form sample size formula that enables researchers to control percentiles, instead of means, of the power and type I error accounting for the skewness of the distributions. A simulation study demonstrates that this approach preserves the operational characteristics in a more realistic scenario where the true response rate of the HC group is unknown. We also show that the controlling percentiles can be used to describe the joint behavior of the power and type I error. It provides a new perspective on the assessment of HCTs.

A phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in patients with advanced hepatocellular carcinoma (HCC).

4099 Background: There is strong rationale to combine an m-TOR inhibitor (TEM) with a VEGF inhibitor (BEV) as a potentially active and well tolerated treatment for HCC. Both agents have shown modest single agent activity in HCC and so evaluated here in a phase II trial. Methods: A modified 2-stage Simon design planned 25 or 50 patients (pts) to test the null hypothesis that true tumor response rate is at most 10% andtrue 6-mo progression-free survival rate (PFS) (by RECIST) is at most 65%, or no better than single agent BEV (6 mo PR >2 pts or PFS 6 mo >18 out of 25.) Toxicity, TTP, PFS and survival were 2nd endpoints. Eligible pts had confirmed HCC with disease unresectable or amenable to other localised therapies, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR class of agents. TEM was administered at starting dose 25 mg IV d1,8,15,22 with BEV at 10mg/kg IV d 1, 15, all q 28 days (1 cycle). Imaging was q 8 wks. Results: From 09/09 to 09/11, 27 eligible pts were enrolled with 25 evaluable for toxicity and efficacy. Med age 59 yrs, 85% male, PS 0/1: 35/65, 58% metastatic, >85% BCLC stage C. With med 6 cycles (range 1-14) delivered, most pts (88%) experienced a grade 3+ adverse event (a/e.) Common grade 3 a/es related to treatment included thrombocytopenia (40%), neutropenia (20%), leucopenia (12%), fatigue (8%), anemia, mucositis, dyspnea, diarrhea, bleeds, fistula, infections (4% each). There was one possible treatment related death. Per protocol dose reductions/discontinuation for TEM-related a/es were most common. There were 2 confirmed PRs and 16 pts progression-free by 6 mos. A third pt developed a late PR at cycle 13. Median TTP on study was 6 mos, median PFS was 7.4 mos and median survival was 8.3 mos, with 13 pts still alive. Accrual closed at end of stage 1 as neither the number of responses nor the PFS at 6 mos passed the futility stopping rule set for this combination. Conclusions: This multicenter study is the first HCC trial evaluating the BEV/TEM doublet. Despite manageable toxicity, the ORR and 6 mo PFS did not surpass assumptions based on single agent BEV in HCC. Further study of BEV/TEM combination in this advanced HCC population is not recommended.

Phase II trial of temsirolimus and bevacizumab for initial recurrence of endometrial cancer.

5025 Background: We report the interim results of the endometrial arm of a multi-tumor protocol using temsirolimus and bevacizumab in endometrial cancer (EMCA) patients at the time of their initial recurrence. The primary aim of this trial is to assess treatment efficacy in terms of both confirmed tumor response and 6-month progression free survival (PFS). Methods: Women with a performance status of 0 or 1 who have had their first recurrence for EMCA were eligible. Subjects who had chemotherapy as part of their adjuvant treatment after front line surgical staging were also eligible. The regimen included Temsirolimus 25 mg IV weekly followed by bevacizumab 10mg/kg IV on days 1 and 15 of a 28 day cycle. A modified two-stage Simon design with fixed sample size was adopted with the null hypothesis being that the true tumor response rate is at most 25% and the true 6 month PFS rate is at most 50%. Results: We enrolled 26 evaluable subjects to the first stage of which one did not proceed with treatment. The median age at enrollment was 60 (range 40-80). 22 (85%) were white and 19 (73%) were not Hispanic/Latino. 19 (73%) of subjects had prior raditation therapy, with 4 having a prior para-aortic boost. 5 (20%) subjects had a confirmed PR and 12 (48%) were progression-free at 6 months, which fell short of the futility stopping rule. An additional 5 (20%) subjects had a best response of confirmed SD, so 10 (40%) had overall clinical benefit from this regimen. AEs attributable to treatment were modest and included 16 grade 3 adverse events, of which the most common ones included hypertension, hyperglycemia, and neutropenia. There were 2 grade 4 events that were possibly treatment related including a duodenal perforation and an anorectal infection. Conclusions: While there was clinical benefit of this regimen in women at the time of their first recurrence of EMCA, the combination of temsirolimus and bevacizumab did not achieve our prespecified efficacy assumptions. This differs from what has been reported with this combination as a second line therapy for recurrent EMCA, where prespecified response assumptions differ. Also, the regimen had comparable safety and toxicity to other cytotoxic chemotherapy regimens used in this setting.

A multi-institutional phase II trial of pazopanib monotherapy in advanced anaplastic thyroid cancer.

5544 Background: Pazopanib, an orally bioavailable multitargeted inhibitor of kinases including VEGF-R, demonstrated impressive activity in metastatic differentiated thyroid cancer (49% durable RECIST PRs) and promising preclinical activity in anaplastic thyroid cancer (ATC) models, prompting its evaluation also as a candidate therapeutic in advanced ATC. Methods: A multicenter single arm phase II trial of 800 mg pazopanib daily was undertaken with the primary endpoint of RECIST response rate. The trial was designed such that there would be a 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true tumor response rate is >5%. A pre-specified stopping rule designated that enrollment would cease unless 1 or more RECIST PRs+CRs were observed in the first 14 of 33 potential patients. Eligibility required informed consent, >18 years of age, performance status ECOG 0-2, systolic blood pressure (BP) <140 mm Hg and diastolic BP <90 mm Hg at entry, QTc interval <480 msecs, and measurable disease by RECIST criteria. Anatomical imaging and toxicity evaluations were required every 4 weeks. Results: Sixteen patients were enrolled. One patient withdrew prior to therapy, leaving 15 evaluable patients – 33.3% were male, with a median age of 66 years (range 45-77); 11 of 15 patients had progressed through prior systemic therapy. Four patients required 1-2 dose reductions, with the most common severe toxicities (CTC-AE version 3.0 grades 3-5) hypertension (13%) and pharyngolaryngeal pain (13%). Reasons for treatment discontinuation included: disease progression (12 pts), death on study due to a vascular event possibly related to treatment (1 pt.), and intolerability (radiation recall tracheitis – 1 pt, and uncontrolled hypertension – 1 pt). Although transient disease regression was observed in several patients, there were no confirmed RECIST tumor responses, triggering study closure at time of interim analysis. Two patients are alive with disease 9.9 months and 2.9 years post-registration; the remaining 13 died of disease. The median time to progression was 62 days and the median survival time was 111 days. Conclusions: Pazopanib has poor single agent activity in advanced anaplastic thyroid cancer.

Final results of a phase II trial of weekly nab-paclitaxel with GM-CSF as chemoimmunotherapy for platinum-resistant epithelial ovarian cancer.

5082^ Background: Ovarian cancer patients with an anti-tumor immune response have a prolonged survival, suggesting that augmenting anti-tumor immunity may be therapeutic. We hypothesized that weekly nab paclitaxel (nabP) followed by GM-CSF may enhance anti tumor immunity and prolong time to progression (TTP). Methods: Eligible subjects had platinum resistant ovarian, primary peritoneal or fallopian tube cancer, and an elevated CA125. Conditional power estimate after 11 subjects showed 22 subjects had 80% power to show a response rate (RR) >21% if the true study RR is 35%. Study end points were RR and TTP. Progression (DP) was doubling of CA125 above the nadir. Complete response (CR) was a decline of CA125 below institutional normal. Partial response (PR) was a decline of >50% from baseline. Stable disease (SD) was all other scenarios. Subjects received nabP, 100mg/m2 days 1,8,15 followed by GM-CSF 250mcg days 16-26 of a 28 day cycle until progression or 6 cycles were complete. Responding subjects received up to 6 more cycles of GM-CSF on days 14-28. Results: 21 subjects received at least one dose of study medications. Median age was 61 (30-91) and had a median of 3 (1-13) prior regimens. Among those completing the study, the median TTP was 132 days vs. 272 days on the prior platinum regimen. 9/21 (43%) had a PR and 4/21 (19%) had a CR. Subjects with a response had a median TTP of 140 days. Assay of serial T-lymphocyte counts against CEA, MUC1, CA125 and tt and influenza controls are planned. Conclusions: Weekly nabP with GM-CSF had manageable toxicity and induced a high response rate (62% by CA125) in patients with platinum resistant ovarian cancer, however this regimen did not prolong the TTP beyond the TTP observed in the prior platinum regimen.

Gemcitabine (G) and cisplatin (C) as first-line treatment of metastatic breast cancer (MBC): Results of phase II trial.

e11528 Background: G has been studied in combination with a variety of agents known to be active in cancer. G has a mild toxicity profile. GC is active in various advanced tumors. Splitting of C dose (d1 + d8) is better tolerated and can be a good alternative to once a cycle in pts with advanced breast cancer. This phase II trial evaluates G (1000 mg/m2) C (35 mg/ m2) d1+d8 repeated every 21 d in the 1st-line treatment of metastatic breast cancer (MBC). The primary objective of the study was to determine the objective tumor response rate (ORR) of 1st-line GC in patients with metastatic breast cancer. The one-stage design tested the null hypothesis that the true response rate for this population should be equal to 50% for efficacy. Overall survival (OS), time to progression (TTP) and toxicity were evaluated. Methods: 70 female MBC pts with the median age of 49.8 yrs (range 29.6-80.0) were enrolled. Tumor assessment was performed every other cycle by standard criteria including CT or MRI. 67 pts received a total of 310 cycles GC, out of these 54 pts were evaluable for efficacy. Results: Complete and partial responses were observed in 7/54 (13.0%) and 19/54 (35.2%) evaluable pts, respectively with an overall response of 48.1%. Disease stabilization was noticed in 19/54 (35.2%) pts. Progression was observed in 5/54 (9.3%) pts. Median TTP was 33.9 weeks (95% CI, 23.9-48.0). Median OS was 84.0 weeks (95% CI, 58.6-119.3). 1-year overall survival rate was 68.4% (95% CI, 53.6-79.3%). Hematological toxicity G4 was neutropenia in 14.9% (10/67), and no G4 thrombocytopenia. Hypotension G4 (1.5%) was the only severe non-hematological toxicity. Conclusions: GC in the first-line treatment of MBC demonstrated a substantial overall response rate and had a good toxicity profile. GC is a suitable option for first-line MBC in selected pts.

OT1-02-10: Phase I-II Study of HER2 Vaccination with Poly(I) • Poly(C12U) (Ampligen®) as an Adjuvant in Optimally Treated Breast Cancer Patients.

Abstract Background Despite improved response rates and overall survival, many HER2+ breast cancer (BC) patients have disease relapse suggesting residual microscopic disease. HER2 vaccines given with adjuvants that can enhance, sustain, and skew antigen immunogenicity toward a Th1 phenotype could induce robust tumor-specific Th1 immunity resulting in immunologic eradication of residual tumor cells and potentially prevent relapse. One such adjuvant is Ampligen which is highly selective as a TLR-3 agonist. Our pre-clinical studies show a dose effect in the tumor prevention efficacy of Ampligen when given as an adjuvant with vaccines. We hypothesize HER2 peptide vaccination given with standard adjuvant 100mcg GMCSF and Ampligen can induce a higher incidence and magnitude of protective HER2−specific Th1 immunity than with GMCSF alone. Trial design: Phase I-II randomized 2-stage HER2 vaccine study. Stage I will enroll 40 patients (10/arm) into one of 4 Ampligen dose arms (4, 20, 79, or 495 mcg + HER2 vaccine). The Ampligen “maximum biologic dose” (MBD), the dose with the highest incidence/magnitude of immune response and lowest incidence of toxicity will be defined. Stage II will enroll 48 patients (24/arm) receiving Ampligen MBD + HER2 vaccine + GMCSF or HER2 vaccine + GMCSF to evaluate if Ampligen MBD increases the incidence and magnitude of immunity vs HER2 vaccine + GMCSF alone. Patients will be enrolled sequentially and randomized equally into all arms via a permuted block design. Patients will receive 3 monthly vaccines. Toxicity and immune response will be assessed. Aims: 1) To evaluate toxicity and define the MBD of Ampligen as an adjuvant with HER2 vaccination 2) determine if Ampligen MBD when combined with GMCSF as adjuvant and HER2 vaccination increases incidence/magnitude of HER2 Th1 immunity compared to standard GMCSF alone. Eligibility criteria: Stage II–IV HER2+ BC patients who: 1) have completed definitive standard treatment, and in clinical remission 2) 14 days post chemotherapy and steroids 3) have adequate blood counts 4) are off trastuzumab 5) have no active autoimmune disease. Statistical methods: In aim 1, we expect mild toxicity between the 4 dose arms, thus lack of efficacy based on incidence of immune response will be evaluated. Six responses must be observed within a dose arm to move forward based on historical 60% response rate (RR) with standard GMCSF (probability of continuing if true RR is 40% and 70% is 0.17, 0.85, respectively). In aim 2, 24 patients/arm provides 80% power to detect 40% difference in incidence of immune response between the 2 groups (Pearson chi-square test, two-sided alpha of 0.05) and 82% power to assess a 0.85 SD unit difference in change between control and MBD, based on a 2-sample t-test (p=0.05) and effect size defined as the difference in the means divided by the common SD. Incidences of HER2 Th1 immunity will be compared across treatment arms via Pearson chi-square test; magnitude of immune response will be compared across groups via linear regression model. Study Accrual: Target accrual is 88 patients: Stage 1 (n=40) and Stage II (n=48). There has been no accrual at this time. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-02-10.

S5 The prevalence of asthma among cleaners in the UK

BackgroundA number of epidemiological studies have shown a significant association between asthma and working as cleaner but reporting schemes and workforce surveys have identified typical features of occupational asthma in...

A phase II evaluation of trabectedin in the treatment of advanced, persistent, or recurrent uterine leiomyosarcoma: A gynecologic oncology group study

ObjectiveTo estimate activity and safety of trabectedin 1.5mg/m2 IV over 24hours every 3weeks (1 cycle) in uterine leiomyosarcoma. MethodsPatients with chemotherapy naive, advanced, persistent or recurrent uterine leiomyosarcoma, acceptable organ function and PS≤2 were eligible. A two-stage design was utilized. Three responses were required in the first stage to initiate the second stage; the target sample size was 40 for the combined stages. If the true response rate was 10%, the study design provided a 95% chance of correctly classifying the treatment as “inactive.” Conversely, if the true response rate was 30%, then the average probability of correctly classifying the treatment as active would be 90%. ResultsTwenty patients were eligible and evaluable. The median number of cycles was 10 (123 total cycles, range 2–29). The number of patients with partial responses was 2 (10%; 95% confidence interval of 1.2%–31.7%). Response durations were 3.3 and 5.7months. Ten patients had stable disease (50%). The median progression-free survival (PFS) and overall survival were 5.8months and greater than 26.1months (median not reached), respectively. Observed grade 3/4 toxicity included: neutropenia 16/20 (1 infection); thrombocytopenia 3/20; metabolic 3/20; anemia, gastrointestinal and vascular 1/20 each. There were no treatment related deaths nor cases of liver failure. ConclusionsAlthough a second stage of accrual was not indicated based on the overall response rate, the drug was well tolerated.

Current Practice and Perception of Screening for Medication Adherence in Inflammatory Bowel Disease

BackgroundAdherence to medication in inflammatory bowel disease (IBD) improves outcomes. Current practices of screening for adherence to IBD medications are unknown. The goal of this study was to determine current practice and perception of screening for medication adherence among US-based gastroenterologists.MethodsA survey was mailed electronically to gastroenterologists whose electronic-mail address was listed in the American College of Gastroenterology database. Physicians who cared for IBD patients were invited to answer.ResultsAbout 6830 surveys were sent to gastroenterologists nationwide, and 395 physicians who cared for IBD patients completed the survey. The true response rate is unknown, as the number of physicians caring for IBD patients in the database is unknown. About 77% (n=303) of physicians who responded stated they screen for adherence to medication. Of the 77% of physicians who screened for adherence, only 19% (n=58) use accepted measures of screening for adherence (pill counts, prescription refill rates, or adherence surveys). The remaining 81% used patient interview to screen for adherence, a measure considered least accepted to determine adherence, as it overestimates adherence. The average number of IBD patients observed in 1 week had no statistical significance in predilection for screening (P=0.82). Private practice physicians (P=0.05), younger physicians (P=0.03), and physicians with fewer years of experience (P=0.02) all were more likely to screen. About 95% of responders thought determining a low adherer to medicine was important because an intervention can increase adherence.ConclusionsThe majority of gastroenterologists surveyed recognize that adherence to medication is important and improves outcomes. The majority of physicians in this study are screening for nonadherence in IBD, but are not using accepted measures for adherence detection. If this study truly reflects the majority of physicians nationwide, changing the way physicians screen for adherence, may detect more low adherers to medication.

Gemcitabine (G) and cisplatin (C) as first-line treatment of metastatic breast cancer (MBC): Results of phase II trial.

273 Background: G has been studied in combination with a variety of agents known to be active in cancer. G has a mild toxicity profile. GC is active in various advanced tumors. Splitting of C dose (D 1 + d8) is better tolerated and can be a good alternative to once a cycle in pts with advanced breast cancer. This phase II trial evaluates G (1000 mg/m2) C (35 mg/ m2) d1+8 repeated every 21 d in the 1st-line treatment of metastatic breast cancer (MBC). The primary objective of the study was to determine the objective tumor response rate (ORR) of 1st-line GC in patients with metastatic breast cancer.The one-stage design tested the null hypothesis that the true response rate for this population should be equal to 50% for efficacy. Overall survival (OS), time to progression (TTP) and toxicity were evaluated. Methods: 70 female MBC pts with the median age of 49.8 ys (range 29.6-80.0) were enrolled. Tumor assessment was performed every other cycle by standard criteria including CT or MRI. 67 pts received a total of 310 cycles GC, out of these 54 pts were evaluable for efficacy. Results: Complete and partial responses were observed in 7/54 (13.0%) and 19/54 (35.2%) evaluable pts, respectively with an overall response of 48.2%. Disease stabilization was noticed in 19/54 (35.2%) pts. Progression was observed in 5/54 (9.3%) pts. TTP was 33.9 weeks (95% CI, 23.9-48.0). OS was 84.0 weeks (95% CI, 58.6-119.3). 1-year overall survival rate was 68.4% (95% CI, 53.6-79.3%). Hematological toxicity G4 was neutropenia in 14.9% (10/67), and no G4 thrombocytopenia. Hypotension G4 (1.5%) was the only severe non-hematological toxicity. Conclusions: GC in the first-line treatment of MBC, demonstrated a substantial overall response rate and had a good toxicity profile. GC is a suitable option for first-line MBC in selected pts.

Two-Stage Designs with Additional Futility Tests for Phase II Clinical Trials with Heterogeneous Patient Populations

The patient population for a phase II clinical trial sometimes consists of multiple subgroups categorized by different prognostic factors such as age, disease stage, etc. Response rates across such subgroups often are heterogeneous; that is, the therapy under study may be inefficacious in some groups but efficacious in others. In this article, we propose a two-stage testing procedure consisting of futility tests and efficacy tests. The futility test is performed first within each subgroup. If there is strong evidence that the therapy is inefficacious in some subgroups, these subgroups are excluded from further consideration. The test then is performed across only the remaining subgroups. We carefully define and compute the Type I error rate and powers under various alternative hypotheses. Our numerical studies show that with proper designs, the addition of futility tests causes little loss of power under the alternative hypothesis that the study therapy is efficacious in all subgroups. Simultaneously, the proposed testing procedure detects inefficacious subgroups with a moderate or high probability when true response rates in these subgroups are low. Finally, we present an application to a Children's Oncology Group phase II clinical trial in relapsed neuroblastoma patients.

Induction chemotherapy with cisplatin, 5-fluorouracil, and cetuximab followed by radiotherapy and cetuximad in head and neck cancers: Preliminary results of a modern integrated approach.

e16030 Background: To determine feasibility and efficacy of induction chemotherapy (ICT) with cisplatin, 5-fluorouracil and cetuximab, followed by concurrent cetuximab and radiotherapy (RTCT), in patients with stage III-IV, non metastatic, head and neck cancer. Methods: ICT consisted of two cycles of cisplatin 100 mg/m2 and 5-FU 1,000 mg/m2i.v.c. d1-4 q28, and weekly cetuximab 250 mg/m2 (after loading dose of 400 mg/m2) followed by RTCT. Staging and restaging procedures include CT, MRI and 18F-FDG PET scan. All patients received IMRT. The total dose delivered was 70/60/50 Gy in 2Gy/fx to macroscopic and metabolic active disease/nodal high-risk areas of microscopic disease/nodal low risk areas. Toxicity was recorded and scored according to the NCI-CTC 3.0 scale. A one-stage design tested the null hypothesis that the true objective response rate is <= 60% versus the alternative hypothesis that it exceeds 60%. Assuming a type I error rate of 5% and a power of 80%, this trial required 37 response-evaluable patients. Actually 19 have completed the whole treatment and results are show below. Results: From October 2008 to July 2010, 19 patients have been evaluated. The median age was 58 years (range 37-70 years). All patients had a good performance status (ECOG Score 0-1). Stage was III/IVa-b in 3/16. Tumor location was oral cavity/pharynx/larynx in 5/10/4. During induction chemotherapy grade 3-4 hemathological toxicity was: NEU/PLT/HB in 5/2/1 patients. Only one neutropenic fever have been recorded. Hypomagnesemia was mild (Grade 1) in 10 patients. Overall response rate to ICT was 17/19 (89.4%). During RTCT grade 2-3 skin toxicity and mucositis was in 11 and 12 patients respectively. One patient drop off treatment due to declining in performance status. Thus 18 patients are evaluable for clinical response. Complete response rate was recorded in 14/19 patients (73.7%). After a median of follow-up of 13 mounths, only 2 patients experienced progression (one local the other pulmonary). Conclusions: This regimen seems safer than those that include docetaxel induction schemes.

Type I error rate control in adaptive designs for confirmatory clinical trials with treatment selection at interim

Interest in confirmatory adaptive combined phase II/III studies with treatment selection has increased in the past few years. These studies start comparing several treatments with a control. One (or more) treatment(s) is then selected after the first stage based on the available information at an interim analysis, including interim data from the ongoing trial, external information and expert knowledge. Recruitment continues, but now only for the selected treatment(s) and the control, possibly in combination with a sample size reassessment. The final analysis of the selected treatment(s) includes the patients from both stages and is performed such that the overall Type I error rate is strictly controlled, thus providing confirmatory evidence of efficacy at the final analysis. In this paper we describe two approaches to control the Type I error rate in adaptive designs with sample size reassessment and/or treatment selection. The first method adjusts the critical value using a simulation-based approach, which incorporates the number of patients at an interim analysis, the true response rates, the treatment selection rule, etc. We discuss the underlying assumptions of simulation-based procedures and give several examples where the Type I error rate is not controlled if some of the assumptions are violated. The second method is an adaptive Bonferroni-Holm test procedure based on conditional error rates of the individual treatment-control comparisons. We show that this procedure controls the Type I error rate, even if a deviation from a pre-planned adaptation rule or the time point of such a decision is necessary.