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1.  Progression-Free Survival (PFS) as a Surrogate Endpoint of Overall Survival (OS) in Patients with Metastatic Renal Cell Carcinoma (mRCC) 
Cancer  2013;120(1):10.1002/cncr.28221.
To investigate the dependence between PFS and OS in mRCC patients and to explore whether PFS can be used as an intermediate endpoint of OS in this patient population.
Patients and Methods
A total of 1,381 patients from two prospective phase III trials (CALGB 90206 and AVOREN) of interferon with or without bevacizumab were used in this analysis. Both trials recruited previously-untreated clear-cell mRCC patients with an ECOG performance status 0–2, adequate bone marrow, hepatic, cardiac and renal function and controlled blood pressure. The CALGB study served as the training dataset, and the AVOREN study as the testing dataset. The dependence between PFS and OS was investigated using Kendall’s tau for bivariate time-to-event endpoints.
In the training dataset, the median OS among patients who experienced progressive disease at 3 or 6 months were 6 and 8 months, respectively, compared to 25 and 30 (p-value<0.001) months in patients who did not progress. The adjusted hazard ratios were 2.6 (p-value <0.001) and 2.8 (p-value <0.001) for patients who did and did not progress at 3- or 6-months. The dependence between PFS and OS was 0.53. These associations were confirmed in the testing dataset.
In mRCC patients treated with interferon with or without bevacizumab, PFS at 3-and 6-months predicts OS. A high dependence between PFS and OS was observed suggesting that PFS may be used as a surrogate endpoint for OS. This is a novel observation for RCC; however these findings require validation in mRCC patients treated with other targeted-agents.
PMCID: PMC3869105  PMID: 24347384
2.  Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium 
Investigational new drugs  2010;30(1):382-386.
Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease.
Patients and methods
We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologicallyconfirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2 on days 1, 8 and 15 of a 28 day cycle.
Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%.
Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.
PMCID: PMC4319645  PMID: 20803052
Pancreatic cancer; Phase II trial; Gemcitabine; Sorafenib
3.  Cediranib in patients with malignant mesothelioma: A phase II trial of the University of Chicago Phase II Consortium 
Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors -1, -2, and -3.
We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily.
Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR + SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥ grade 3 hypertension (8.5 vs. 4.1 months, p=0.024).
This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated.
PMCID: PMC4319647  PMID: 22831987
Mesothelioma; cediranib; vascular endothelial growth factor; hypertension
4.  Dasatinib in previously treated metastatic colorectal cancer: a phase II trial of the University of Chicago Phase II Consortium 
Investigational new drugs  2011;30(3):1211-1215.
Treatment options for metastatic colorectal cancer (CRC) are limited after a fluoropyrimi-dine, oxaliplatin and irinotecan; novel agents need to be explored in this setting. Dasatinib, an oral inhibitor of Src family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models.
Patients and methods
We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic CRC patients. No more than 2 prior chemotherapy regimens were permitted, which must have contained a fluoropyrimidine, oxaliplatin and irinotecan. The primary endpoint was progression-free survival (PFS) at 4 months. The Simon two-stage design required that at least 5 of the first 19 patients be progression-free at 4 months to expand to a second stage.
Nineteen patients enrolled at 9 centers. The study was terminated after the first stage due to lack of efficacy. There were no objective responses; 1 patient (5%) had stable disease for 7.3 months. The PFS rate at 4 months was 5.3% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Grade 3/4 toxicities included fatigue in 16% of patients, and anemia, anorexia, nausea/vomiting and dyspnea in 11%.
Dasatinib is inactive as a single agent in previously treated metastatic CRC patients.
PMCID: PMC4317401  PMID: 21552992
Colorectal cancer; Phase II trial; Dasatinib
5.  A randomized phase II study of pazopanib in hormone sensitive prostate cancer: a University of Chicago Phase II Consortium/ Department of Defense Prostate Cancer Clinical Trials Consortium study 
Intermittent androgen suppression 1 is an increasingly popular treatment option for hormone sensitive prostate cancer. Based on previous data with anti-angiogenic strategies, we hypothesized that pan-inhibition of the vascular endothelial growth factor receptor (VEGFR) using pazopanib during the IAS off period would result in prolonged time to PSA failure.
Men with biochemically recurrent prostate cancer whose PSA was < 0.5 ng/mL after 6 months of androgen deprivation therapy (ADT) were randomized to pazopanib 800 mg daily or observation. The planned primary outcome was time to PSA progression >4.0 ng/mL.
Thirty-seven patients were randomized. Of 18 randomized to pazopanib, at the time of study closure, 4 had progressive disease (PD), 1 remained on treatment, and 13 (72%) electively disenrolled, the most common reason being patient request due to grade 1/2 toxicity (8 patients). Two additional patients were removed from treatment due to adverse events. Of 19 patients randomized to observation, at the time of study closure, 4 had PD, 7 remained under protocol defined observation, and 8 (42%) had disenrolled, most commonly due to non-compliance with protocol visits (3 patients). Due to high dropout rates in both arms, the study was halted.
IAS is a treatment approach that may facilitate investigation of novel agents in the hormone sensitive state. This trial attempted to investigate the role of antiangiogenic therapy in this setting, but encountered several barriers, including toxicities and patient non-compliance, which can make implementation of such a study difficult. Future investigative efforts in this arena should carefully consider drug toxicity and employ a design that maximizes patient convenience in order to reduce the drop out rate.
PMCID: PMC4312616  PMID: 22006050
Prostate cancer; Intermittent Androgen Suppression; Tyrosine Kinase Inhibitors
6.  Phase II Study of the Oral Mek Inhibitor Selumetinib in Advanced Acute Myeloid Leukemia (AML): A University of Chicago Phase II Consortium Trial 
The clinical relevance of targeting RAS/RAF/MEK/ERK pathway, activated in 70-80% of acute myeloid leukemia (AML) patients, is unknown.
Experimental Design
Selumetinib is an oral small molecule inhibitor of MEK1/2 kinase. Forty-seven patients with relapsed/refractory AML or ≥60 years old with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial and minor). Leukemia cells were analyzed for ERK and mTOR phosphorylation.
Common drug-related toxicities were grade I-II diarrhea, fatigue, nausea, vomiting and skin rash. In the FLT3 wild type cohort, 6/36 (17%) patients had a response [1 partial response, 3 minor responses, 2 unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single nucleotide polymorphism (SNP) rs3733542 in exon 18 of KIT gene was detected in significantly higher number of patients with response/stable disease compared with non-responders (60% vs 23%; p=0.027).
Selumetinib is associated with modest single agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials.
PMCID: PMC4310865  PMID: 24178622
7.  The Combination of Insulin-Like Growth Factor Receptor 1 (IGF1R) Antibody Cixutumumab and Mitotane as a First-Line Therapy for Patients with Recurrent/Metastatic Adrenocortical Carcinoma: a Multi-institutional NCI-Sponsored Trial 
Hormones & cancer  2014;5(4):232-239.
Adrenocortical carcinoma (ACC) is an aggressive malignancy, which lacks an effective systemic treatment. Abnormal activation of insulin-like growth factor receptor 1 (IGF1R) has been frequently observed. Preclinical studies demonstrated that pharmacological inhibition of IGF1R signaling in ACC has antiproliferative effects. A previous phase I trial with an IGF1R inhibitor has demonstrated biological activity against ACC. The objective of this study is to assess the efficacy of the combination of the IGF1R inhibitor cixutumumab (IMC-A12) in association with mitotane as a first-line treatment for advanced/metastatic ACC. We conducted a multicenter, randomized double-arm phase II trial in patients with irresectable recurrent/metastatic ACC. The original protocol included two treatment groups: IMC-A12 + mitotane and mitotane as a single agent, after an initial single-arm phase for safety evaluation with IMC-A12 + mitotane. IMC-A12 was dosed at 10 mg/kg intravenously every 2 weeks. The starting dose for mitotane was 2 g daily, subsequently adjusted according to serum levels/symptoms. The primary endpoint was progression-free survival (PFS) according to RECIST (Response Evaluation Criteria in Solid Tumors). This study was terminated before the randomization phase due to slow accrual and limited efficacy. Twenty patients (13 males, 7 females) with a median age of 50.2 years (range 21.9–79.6) were enrolled for the single-arm phase. Therapeutic effects were observed in 8/20 patients, including one partial response and seven stable diseases. The median PFS was 6 weeks (range 2.66–48). Toxic events included two grade 4 (hyperglycemia and hyponatremia) and one grade 5 (multiorgan failure). Although the regimen demonstrated activity in some patients, the relatively low therapeutic efficacy precluded further studies with this combination of drugs.
PMCID: PMC4298824  PMID: 24849545
8.  Quantitative characterization of androgen receptor protein expression and cellular localization in circulating tumor cells from patients with metastatic castration-resistant prostate cancer 
Many current therapies for metastatic castration-resistant prostate cancer (mCRPC) are aimed at AR signaling; however, resistance to these therapies is inevitable. To personalize CRPC therapy in an individual with clinical progression despite maximal AR signaling blockade, it is important to characterize the status of AR activity within their cancer. Biopsies of bone metastases are invasive and frequently fail to yield sufficient tissue for further study. Evaluation of circulating tumor cells (CTCs) offers an alternative, minimally invasive mechanism to characterize and study late-stage disease. The goal of this study was to evaluate the utility of CTC interrogation with respect to the AR as a potential novel therapeutic biomarker in patients with mCRPC.
Fifteen mL of whole blood was collected from patients with progressive, metastatic mCRPC, the mononuclear cell portion was isolated, and fluorescence-activated cell sorting (FACS) was used to isolate and evaluate CTCs. A novel protocol was optimized to use ImageStreamX to quantitatively analyze AR expression and subcellular localization within CTCs. Co-expression of AR and the proliferation marker Ki67 was also determined using ImageStreamX.
We found inter-patient and intra-patient heterogeneity in expression and localization of AR. Increased AR expression and nuclear localization are associated with elevated co-expression of Ki-67, consistent with the continued role for AR in castration-resistant disease. Despite intra-patient heterogeneity, CTCs from patients with prior exposure to abiraterone had increased AR expression compared to CTCs from patients who were abiraterone-naïve.
As our toolbox for targeting AR function expands, our ability to evaluate AR expression and function within tumor samples from patients with late-stage disease will likely be a critical component of the personalized management of advanced prostate cancer. AR expression and nuclear localization varies within patients and between patients; however it remains associated with markers of proliferation. This supports a molecularly diverse AR-centric pathobiology imparting castration-resistance.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0313-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4252013  PMID: 25424879
Prostate neoplasms; Androgen receptor; Circulating tumor cells; Castration-resistant prostate cancer
9.  The Effect of Prior Androgen Synthesis Inhibition on Outcomes of Subsequent Therapy with Docetaxel in Patients with Metastatic Castrate Resistant Prostate Cancer: Results from a Retrospective Analysis of a Randomized Phase 3 Clinical Trial (CALGB 90401) (Alliance) 
Cancer  2013;119(20):3636-3643.
Preliminary data suggests a potential decreased benefit of docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients previously treated with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). CALGB 90401 (Alliance), a phase 3 trial of mCRPC patients treated with docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes following docetaxel.
CALGB 90401 randomized 1050 men with chemotherapy-naïve, mCRPC to treatment with docetaxel and prednisone with either bevacizumab or placebo. 1005 men (96%) had data available regarding prior ketoconazole therapy. The effect of prior ketoconazole on overall survival (OS), progression-free survival (PFS), PSA decline, and objective response rate (ORR) observed was assessed using proportional hazards and Poisson regression method adjusted for validated prognostic factors and treatment arm.
Baseline characteristics between patients with (N=277) and without (N=728) prior ketoconazole therapy were similar. There were no statistically significant differences between patients with and without prior ketoconazole therapy with respect to OS (median OS 21.1 vs. 22.3 months, stratified log-rank p-value=0.635); PFS (median PFS 8.1 vs. 8.6 months, stratified log-rank p-value=0.342); ≥50% PSA decline (61% vs. 66%, relative risk=1.09, adjusted p-value=0.129); or ORR (39% vs. 43%, relative risk=1.11, adjusted p-value=0.366).
As measured by OS, PFS, PSA and ORR, there is no evidence that prior treatment with ketoconazole impacts clinical outcomes in mCRPC patients treated with subsequent docetaxel-based therapy. Prospective studies are needed to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC.
PMCID: PMC3795898  PMID: 23913744
10.  Axitinib in Metastatic Renal Cell Carcinoma: Results of a Pharmacokinetic and Pharmacodynamic Analysis 
Journal of clinical pharmacology  2013;53(5):491-504.
Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2-compartment model with first-order absorption and a lag time, with estimated mean systemic clearance (CL) of 14.6 L/h and central volume of distribution (Vc) of 47.3 L. Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas Vc increased with body weight. However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments. Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression-free and overall survivals and higher probability of partial response in metastatic RCC patients. These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy.
PMCID: PMC4175417  PMID: 23553560
axitinib; metastatic renal cell carcinoma; population pharmacokinetics and pharmacodynamics; VEGF receptor inhibitor; diastolic blood pressure
11.  Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials 
European urology  2012;63(4):717-723.
Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10 g/dl, and liver metastasis (LM).
The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. Design, setting, and participants: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n = 570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine plus BSC (n = 352).
Outcome measurements and statistical analysis
Cox proportional hazards regression was used to evaluate the association of factors, with overall survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures.
Results and limitations
ECOG-PS >0, LM, Hb <10 g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic = 0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable.
Shorter TFPC enhances prognostic classification independent of ECOG-PS>0, Hb<10 g/ dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.
PMCID: PMC4127896  PMID: 23206856
Urothelial carcinoma; Second line; Prognosis; Time from prior chemotherapy; Hemoglobin; Liver metastasis; Performance status
12.  Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma 
Journal of Clinical Oncology  2012;30(20):2509-2515.
Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM.
Patients and Methods
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m2 on days 1 and 8 every 21 days, cisplatin 75 mg/m2 every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression.
One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater.
The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.
PMCID: PMC3397785  PMID: 22665541
13.  Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing Docetaxel and Prednisone With or Without Bevacizumab in Men With Metastatic Castration-Resistant Prostate Cancer: CALGB 90401 
Journal of Clinical Oncology  2012;30(13):1534-1540.
A randomized, placebo-controlled study based on preclinical and clinical data that supports the potential role of vascular endothelial growth factor in prostate cancer was performed to evaluate the addition of bevacizumab to standard docetaxel and prednisone therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods
Patients with chemotherapy-naive progressive mCRPC with Eastern Cooperative Oncology Group performance status ≤ 2 and adequate bone marrow, hepatic, and renal function were randomly assigned to receive docetaxel 75 mg/m2 intravenously (IV) over 1 hour for 21 days plus prednisone 5 mg orally twice per day (DP) with either bevacizumab 15 mg/kg IV every 3 weeks (DP + B) or placebo. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), 50% decline in prostate-specific antigen, objective response (OR), and toxicity.
In total, 1,050 patients were randomly assigned. The median OS for patients given DP + B was 22.6 months compared with 21.5 months for patients treated with DP (hazard ratio, 0.91; 95% CI, 0.78 to 1.05; stratified log-rank P = .181). The median PFS time was superior in the DP + B arm (9.9 v 7.5 months, stratified log-rank P < .001) as was the proportion of patients with OR (49.4% v 35.5%; P = .0013). Grade 3 or greater treatment-related toxicity was more common with DP + B (75.4% v 56.2%; P ≤ .001), as was the number of treatment-related deaths (4.0% v 1.2%; P = .005).
Despite an improvement in PFS and OR, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC and was associated with greater toxicity.
PMCID: PMC3383121  PMID: 22454414
14.  Phase III Study of Molecularly Targeted Adjuvant Therapy in Locally Advanced Urothelial Cancer of the Bladder Based on p53 Status  
Journal of Clinical Oncology  2011;29(25):3443-3449.
Retrospective studies suggest that p53 alteration is prognostic for recurrence in patients with urothelial bladder cancer and predictive for benefit from combination methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) adjuvant chemotherapy.
Patients and Methods
Patients with pT1/T2N0M0 disease whose tumors demonstrated ≥ 10% nuclear reactivity on centrally performed immunohistochemistry for p53 were offered random assignment to three cycles of adjuvant MVAC versus observation; p53-negative patients were observed. By using a log-rank test with one-sided α = .05 and β = .10, 190 p53-positive patients were planned to be randomly assigned to detect an absolute improvement in probability of recurring by 3 years from 0.50 to 0.30.
A total of 521 patients were registered, 499 underwent p53 assessment, 272 (55%) were positive, and 114 (42%) were randomly assigned. Accrual was halted on the basis of the data and safety monitoring board review of a futility analysis. Overall 5-year probability of recurring was 0.20 (95% CI, 0.16 to 0.24) with no difference on the basis of p53 status. Only 67% of patients randomly assigned to MVAC received all three cycles with 12 patients receiving no treatment. There was no difference in recurrence in the randomly assigned patients (hazard ratio, 0.78; 95% CI, 0.29 to 2.08; P = .62).
Neither the prognostic value of p53 nor the benefit of MVAC chemotherapy in patients with p53-positive tumors was confirmed, but the high patient refusal rate, lower than expected event rate, and failures to receive assigned therapy severely compromised study power.
PMCID: PMC3164246  PMID: 21810677
15.  Estimation of Progression-Free Survival for All Treated Patients in the Randomized Discontinuation Trial Design 
The American statistician  2012;66(3):155-162.
The randomized discontinuation trial (RDT) design is an enrichment-type design that has been used in a variety of diseases to evaluate the efficacy of new treatments. The RDT design seeks to select a more homogeneous group of patients, consisting of those who are more likely to show a treatment benefit if one exists. In oncology, the RDT design has been applied to evaluate the effects of cytostatic agents, that is, drugs that act primarily by slowing tumor growth rather than shrinking tumors. In the RDT design, all patients receive treatment during an initial, open-label run-in period of duration T. Patients with objective response (substantial tumor shrinkage) remain on therapy while those with early progressive disease are removed from the trial. Patients with stable disease (SD) are then randomized to either continue active treatment or switched to placebo. The main analysis compares outcomes, for example, progression-free survival (PFS), between the two randomized arms. As a secondary objective, investigators may seek to estimate PFS for all treated patients, measured from the time of entry into the study, by combining information from the run-in and post run-in periods. For t ≤ T, PFS is estimated by the observed proportion of patients who are progression-free among all patients enrolled. For t > T, the estimate can be expressed as Ŝ(t) = p̂OR × ŜOR(t − T) + p̂SD × ŜSD(t − T), where p̂OR is the estimated probability of response during the run-in period, p̂SD is the estimated probability of SD, and ŜOR(t − T) and ŜSD(t − T) are the Kaplan–Meier estimates of subsequent PFS in the responders and patients with SD randomized to continue treatment, respectively. In this article, we derive the variance of Ŝ(t), enabling the construction of confidence intervals for both S(t) and the median survival time. Simulation results indicate that the method provides accurate coverage rates. An interesting aspect of the design is that outcomes during the run-in phase have a negative multinomial distribution, something not frequently encountered in practice.
PMCID: PMC3769804  PMID: 24039273
Confidence limits; Enrichment design; Negative multinomial distribution; Phase II clinical trials
16.  Estimation of renal cell carcinoma treatment effects from disease progression modeling 
To improve future drug development efficiency in renal cell carcinoma (RCC), a disease progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib, and incorporated baseline tumor size, a linear disease progression component, and an exponential drug effect parameter. With the model-estimated effect of sorafenib on RCC growth we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater drug effect than sorafenib would have 82% power (one-sided α = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with CT imaging offers a scaffold on which to develop new, more efficient, phase II trial endpoints and analytic strategies for RCC.
PMCID: PMC3791430  PMID: 23443753
Antineoplastic Agents; Antiangiogenic Agents; Carcinoma; Renal/drug therapy; Decision Making; Drugs; Investigational; Humans; Models; Statistical; Renal Neoplasms/drug therapy
17.  FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer 
Cancer Medicine  2013;2(4):545-552.
The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([18F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37–80). Median pre- and 2-week treatment average SUVmax were 6.6 (1–17.9) and 4.2 (1–13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (−32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability.
In this phase II trial, FDG-PET was explored as a predictive biomarker for response to everolimus (mTOR inhibition) in metastatic renal cell carcinoma. Everolimus therapy decreased SUVs on follow-up FDG-PET scans in these patients. SUV changes were modestly correlated with changes in tumor size and baseline average SUVmax values were correlated with overall survival.
PMCID: PMC3799289  PMID: 24156027
Kidney carcinoma; mTOR protein; pharmacological biomarkers; positron emission tomography
18.  A Randomized Phase I Study of Testosterone Replacement for Patients with Low Risk Castrate Resistant Prostate Cancer 
European urology  2009;56(1):97-103.
The androgen pathway remains biologically relevant even in castration resistant prostate cancer (CRPC). In preclinical models, androgen therapy for CRPC leads to growth arrest, apoptosis, and tumor shrinkage. This study determined the toxicity and feasibility of a testosterone therapy in early CRPC.
Prostate cancer patients with progressive disease following androgen ablation, antiandrogen therapy and withdrawal, with none to minimal metastatic disease were randomized to treatment with transdermal testosterone, at 2.5, 5.0 or 7.5 mg/day. Toxicity, PSA, imaging, quality of life, and strength were monitored. Treatment was discontinued for significant toxicity, clinical progression, or a 3-fold increase in PSA.
Fifteen men, median age 73 (62–92), median PSA 11.1 ng/ml (5.2–63.6), were treated. Testosterone increased from castrate, to median concentrations of 305, 308, 297 ng/dL for 2.5mg (n=4), 5.0mg (n=5), and 7.5mg (n=5) doses, respectively. One patient was taken off study at 53 weeks due to grade 4 cardiac toxicity. There were no other grade 3 or 4 toxicities related to the study medication, and the grade 2 toxicities were minimal. Only one patient experienced symptomatic progression, and 3 (20%) demonstrated a decrease in PSA (largest =43%). Median time to progression was 9 weeks (range 2–96), with no detectable difference in the three dose cohorts. There was no significant change in QOL or hand-grip strength with treatment.
Testosterone is a feasible and reasonably well tolerated therapy for men with early CRPC. A larger, randomized trial is underway to further characterize efficacy and impact on QOL measures.
PMCID: PMC2885777  PMID: 19282098
19.  Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacodynamic Biomarker Study of Sorafenib in Metastatic Renal Carcinoma 
Journal of Clinical Oncology  2008;26(28):4572-4578.
Sorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamic biomarker.
Patients and Methods
Patients were randomly assigned to placebo or 200 or 400 mg twice per day of sorafenib. DCE-MRI was performed at baseline and 4 weeks. DCE-MRI parameters, area under the contrast concentration versus time curve 90 seconds after contrast injection (IAUC90), and volume transfer constant of contrast agent (Ktrans) were calculated for a metastatic site selected in a blinded manner. Primary end point was change in Ktrans.
Of the 56 assessable patients, 48 underwent two MRIs; 44 MRIs were assessable for study end points. Mean Ktrans log ratios were 0.131 (standard deviation [SD], 0.315), −0.148 (SD, 0.382), −0.271 (SD, 0.499) in placebo, 200- and 400-mg cohorts, respectively (P = .0077 for trend) corresponding to changes of +14%, −14%, and −24%. IAUC90 log ratios were 0.041 (SD, 0.197), −0.040 (SD, 0.132), −0.356 (SD, 0.411), respectively (P = .0003 for trend), corresponding to changes of +4%, −4%, and −30%. Using a log-rank test, IAUC90 and Ktrans changes were not associated with progression-free survival (PFS). Patients with high baseline Ktrans had a better PFS (P = .027).
IAUC90 and Ktrans are pharmacodynamic biomarkers for sorafenib, but variability is high and magnitude of effect is less than previously reported. Changes in DCE-MRI parameters after 4 weeks of sorafenib are not predictive of PFS, suggesting that these biomarkers are not surrogate end points. The value of baseline Ktrans as a prognostic or predictive biomarker requires additional study.
PMCID: PMC2736992  PMID: 18824708
20.  A University of Chicago Consortium Phase II Trial of SB-715992 in Advanced Renal Cell Cancer 
Clinical genitourinary cancer  2008;6(1):21-24.
Advanced renal cell cancer (RCC) continues to have a poor overall prognosis despite new FDA-approved therapies. Although taxane-based therapies are generally ineffective in RCC, research into the role of the von Hippel-Lindau protein has shown an association with microtubule dynamics. Mitotic kinesins are a class of molecular motors that also interact with microtubules and are required for proper mitotic function. SB-715992 is a new agent that inhibits the function of a mitotic kinesin known as kinesin spindle protein and leads to cell death.
Patients and Methods
Twenty previously treated advanced RCC patients were enrolled in this phase II trial of SB-715992, with response rate as a primary endpoint.
No patients responded with complete or partial remission. Six patients had stable disease, and one patient continues on therapy after 12 cycles. Common toxicities included anemia (80%), elevated creatinine (70%), lymphopenia (45%), fatigue (50%), hyperglycemia (50%), and dyspnea (45%). Reported grade 3/4 toxicities included dyspnea, fatigue, neutropenia with skin infection, dizziness, hyperuricemia, and hypertension.
This dose and schedule of SB-715992 does not appear to have a significant cytotoxic effect for patients with previously treated advanced RCC.
PMCID: PMC2704464  PMID: 18501078
Kinesin spindle inhibitor; Multidrug resistance–associated protein 2; von Hippel-Lindau protein
21.  Pharmacogenomics in Early Phase Oncology Clinical Trials: Is There a Sweet Spot in Phase II? 
Clinical Cancer Research  2012;18(10):2809-2816.
Many clinical trials of oncology drugs now include at least a consideration of pharmacogenomics, the study of germline or acquired genetic factors governing a drug's response and toxicity. Besides the potential benefit to patients from the consideration of personalized pharmacogenomic information when making treatment decisions, there is a clear incentive for oncology drug developers to incorporate pharmacogenomic factors in the drug development process since pharmacogenomic biomarkers may allow predictive characterization of sub-populations within a disease that may particularly respond, or may allow preidentification of patients at highest risk for adverse events. There is, however, a lack of agreement in actual practice as to where in the oncology clinical drug development process pharmacogenomic studies should be incorporated. In this article, we examine the recent growth of pharmacogenomics in oncology clinical trials, especially in early phase studies, and examine several critical questions facing the incorporation of pharmacogenomics in early oncologic drug development. We show that phase II clinical trials in particular have a favorable track record for demonstrating positive pharmacogenomic signals, worthy of additional follow-up and validation, and that the phase II setting holds significant promise for potentially accelerating and informing future phase III trials. We conclude that phase II trials offer an ideal “sweet spot” for routine incorporation of pharmacogenomic questions in oncology drug development.
PMCID: PMC3354016  PMID: 22427349
phase II; oncology; clinical trials; pharmacogenomics; biomarker development
22.  The Role of Chemotherapy in Upper Tract Urothelial Carcinoma 
Advances in Urology  2009;2009:419028.
Locally advanced upper tract urothelial carcinoma has a poor prognosis. While surgery represents the only potentially curable therapeutic intervention, recurrences are common and typically systemic in nature. It is thus reasonable to consider perioperative chemotherapy in an effort to decrease the risk of recurrence. There are very little direct data providing clinical guidance in this scenario. For urothelial cancer of the bladder, there are randomized phase III data demonstrating a survival advantage with neoadjuvant cisplatin-based combination chemotherapy. Although arguments favoring adjuvant chemotherapy could be made for upper tract urothelial cancer, the loss of renal function that occurs with nephrectomy can complicate administration of appropriate perioperative treatment. Therefore, by analogy to urothelial carcinoma of the lower tract, it is argued that cisplatin-based neoadjuvant chemotherapy should be the standard of care for patients with locally advanced upper tract urothelial cancer.
PMCID: PMC2630419  PMID: 19190766
23.  Resampling phase III data to assess phase II trial designs and endpoints 
Clinical Cancer Research  2012;18(8):2309-2315.
The best phase II design and endpoint for growth inhibitory agents is controversial. We simulated phase II trials by resampling patients from a positive (sorafenib vs. placebo; TARGET) and a negative (AE941 vs. placebo) phase III trial in metastatic renal cancer to compare the ability of various designs and endpoints to predict the known results.
Experimental design
770 and 259 patients from TARGET and the AE 941 trial, respectively, were resampled (5,000 replicates) to simulate phase II trials with alpha = 0.10 (one-sided). Designs/endpoints: single arm, two-stage with response rate (RR) by RECIST (37 patients); and randomized, two arm (20–35 patients/arm) with RR by RECIST, mean log ratio of tumor sizes (log ratio), PFS rate at 90 days (PFS-90), and overall PFS.
Single arm trials were positive with RR by RECIST in 55% and 1% of replications for sorafenib and AE 941, respectively. Randomized trials versus placebo with 20 patients per arm were positive with RR by RECIST in 55% and 7%, log ratio in 88% and 25%, PFS-90 in 64% and 15%, and overall PFS in 69% and 9% of replications for sorafenib and AE 941, respectively.
Compared with the single arm design and the randomized design comparing PFS, the randomized phase II design with the log ratio endpoint has greater power to predict the positive phase III result of sorafenib in renal cancer, but a higher false positive rate for the negative phase III result of AE 941.
PMCID: PMC3328614  PMID: 22287601
resampling; phase II; randomized; single arm; tumor size
24.  A Phase I Study of Continuous Infusion Cilengitide in Patients with Solid Tumors 
Investigational New Drugs  2010;30(2):604-610.
Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3-5 hours with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide.
Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 hours after infusion bag change.
Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/hr. Toxicities were limited to grade ≤ 2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose.
Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/hr, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion.
PMCID: PMC3059335  PMID: 20839028
Randomized data have supported the use of long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) for men with high-risk prostate cancer. The present study reviewed the outcomes of intermediate- and high-risk men treated with RT and short-term ADT.
Materials and Methods
A total of 184 men with any single risk factor of prostate-specific antigen ≥10 ng/mL, clinical Stage T2b or greater, or Gleason score ≥7 were treated with primary external beam RT for nonmetastatic adenocarcinoma of the prostate. The median radiation dose was 74 Gy; 55% were treated with intensity-modulated RT. All patients received ADT for 1 to 6 months (median, 4), consisting of a gonadotropin-releasing hormone analog. Univariate and multivariable analyses were performed for risk factors, including T stage, Gleason score, radiation dose, and prostate-specific antigen level.
With a median follow-up of 51 months, the 4-year freedom from biochemical failure (FFBF) using the nadir plus 2 ng/mL definition was 83% for all patients. Clinical Stage T3 disease was the only variable tested associated with FFBF on univariate (4-year FFBF rate, 46% vs. 87% for Stage T1-T2c disease; p = .0303) and multivariable analysis (hazard ratio, 3.9; p = .0016). On a subset analysis of high-risk patients (National Comprehensive Cancer Network criteria), those with clinical Stage T3 disease (4-year FFBF rate, 46% vs. 80%; p = .0303) and a radiation dose <74 Gy (4-year FFBF rate, 64% vs. 80%) had a poorer outcome on univariate analysis. However, clinical Stage T3 disease and radiation dose were not significant on multivariable analysis, although a statistical multivariable trend was seen for both (p = .0650 and p = .0597, respectively).
Short-term ADT and RT might be acceptable for men with intermediate- and high-risk prostate cancer, especially for clinically localized disease treated with doses of ≥74 Gy.
PMCID: PMC3049990  PMID: 19695789
Prostate cancer; radiotherapy; hormonal therapy

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