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ABSTRACT: The central role played by the class I(A) phosphatidylinositol-3-kinase (PI3K) signaling node in human cancer is highlighted in the multiple mechanisms by which these signals become dysregulated. Many studies suggest that constitutive PI3K activation in human cancer contributes to drug resistance, including targeted agents and standard cytotoxic therapy. The combination of activation mechanisms and the multiple downstream cascades that emanate from the PI3K node contributes to the difficulty in measuring PI3K activation as a biomarker. Although many agents suppress the pathway in models, the challenge remains to translate this biology into a patient selection strategy (i.e., identify patients with "PI3K activated" tumors) and subsequently link this biomarker definition to drug responses in patients. The various genetic and epigenetic lesions resulting in pathway activation necessitate combined approaches using genetic, genomic, and protein biomarkers to accurately characterize "PI3K activated" tumors. Such a combined approach to pathway status can be assessed using a statistical stratification of patients in a randomized trial into "pathway on" and "pathway off" subsets to compare the treatment effect in each arm. Instead of considering individual biomarkers for their predictive ability, this strategy proposes the use of a collection of biomarkers to identify a specific "pathway on" patient population predicted to have clinical benefit from a pathway inhibitor. Here, we review the current understanding of the mechanisms of PI3K activation in breast cancer and discuss a pathway-based approach using PI3K as a predictive biomarker in clinical development, which is currently in use in a global phase 3 setting.
Breast Cancer Research and Treatment 11/2010; 124(1):1-11. · 4.43 Impact Factor
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ABSTRACT: For patients with advanced cancers, it is important that treatment improves the quality as well as the quantity of survival. This quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) analysis provides a combined measure of both the overall survival interval and the quality of survival for patients with advanced renal cell carcinoma (RCC) receiving temsirolimus, interferon (IFN)-alpha or the combination of these agents, using data from a phase III clinical trial.
Overall survival was partitioned into three distinct health states: time with serious toxicity (TOX), time after progression (REL) and time without symptoms of progression or toxicity (TWiST). Health states were quality weighted by patient-reported EQ-5D measures collected while receiving treatment.
All 626 patients from the trial were included in computation of health-state durations. EQ-5D questionnaires were obtained from 260 patients upon progression and from 230 after a grade 3 or 4 adverse event, and from 278 patients in the TWiST state. Patients receiving temsirolimus had 38% longer TWiST than those receiving IFNalpha (6.5 vs 4.7 months, respectively; p = 0.0005). Patients receiving temsirolimus had 25% longer quality-adjusted survival in terms of Q-TWiST than those receiving IFNalpha (7.0 vs 5.6 months, respectively; p = 0.0015). Differences between the combination (temsirolimus + IFNalpha) and IFNalpha groups were not statistically significant. Threshold utility analysis indicated that temsirolimus was the preferred alternative for all possible utility weights for REL and TOX health states.
Temsirolimus resulted in significantly longer Q-TWiST (quality-adjusted survival) in patients with advanced RCC than IFNalpha therapy.
PharmacoEconomics 01/2010; 28(7):577-84. · 2.66 Impact Factor
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Georg Hess,
Raoul Herbrecht,
Jorge Romaguera,
Gregor Verhoef,
Michael Crump,
Christian Gisselbrecht,
Anna Laurell,
Fritz Offner, Andrew Strahs,
Anna Berkenblit,
Orysia Hanushevsky,
Jill Clancy,
Becker Hewes,
Laurence Moore,
Bertrand Coiffier
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ABSTRACT: Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease.
In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment.
Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia.
Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.
Journal of Clinical Oncology 09/2009; 27(23):3822-9. · 18.37 Impact Factor
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Robert A. Figlin MD,
Paul de Souza MBBS,
David McDermott MD,
Janice P. Dutcher MD,
Anna Berkenblit MD,
Alexandra Thiele PhD,
Mizue Krygowski MS,
Andrew Strahs PhD,
PhD Jay Feingold MD,
Joseph Boni PhD, [......],
Paul de Souza,
David McDermott,
Janice P. Dutcher,
Anna Berkenblit,
Alexandra Thiele,
Mizue Krygowski, Andrew Strahs,
Jay Feingold,
Joseph Boni,
Gary Hudes
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ABSTRACT: BACKGROUND:Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 α correlated with efficacy in patients treated with temsirolimus (Torisel) versus interferon-α (IFN).METHODS:Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 α baseline levels were measured in archived tumor specimens by immunohistochemistry.RESULTS:There was no correlation between baseline PTEN and HIF1 α levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors.CONCLUSIONS:The baseline status of the molecular markers PTEN and HIF1 α did not correlate with efficacy in renal cell carcinoma patients treated with temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with temsirolimus regardless of PTEN and HIF1 α status. Thus, baseline PTEN and HIF-1 levels may not predict response to temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to temsirolimus in patients with advanced renal cell carcinoma. Cancer 2009. © 2009 American Cancer Society.
Cancer 08/2009; 115(16):3651 - 3660. · 4.77 Impact Factor
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Robert A Figlin,
Paul de Souza,
David McDermott,
Janice P Dutcher,
Anna Berkenblit,
Alexandra Thiele,
Mizue Krygowski, Andrew Strahs,
Jay Feingold,
Joseph Boni,
Gary Hudes
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ABSTRACT: Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 alpha correlated with efficacy in patients treated with temsirolimus (Torisel) versus interferon-alpha (IFN).
Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 alpha baseline levels were measured in archived tumor specimens by immunohistochemistry.
There was no correlation between baseline PTEN and HIF1 alpha levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors.
The baseline status of the molecular markers PTEN and HIF1 alpha did not correlate with efficacy in renal cell carcinoma patients treated with temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with temsirolimus regardless of PTEN and HIF1 alpha status. Thus, baseline PTEN and HIF-1 levels may not predict response to temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to temsirolimus in patients with advanced renal cell carcinoma.
Cancer 07/2009; 115(16):3651-60. · 4.77 Impact Factor
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ABSTRACT: Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with temsirolimus (Torisel) or interferon-alpha (IFN). Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units [MU] subcutaneously three times weekly, escalating to 18 MU) or temsirolimus (25 mg intravenously weekly). Results Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology. Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.
Medical Oncology 03/2009; 26(2):202-9. · 2.14 Impact Factor
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Michael E Burczynski,
Ron L Peterson,
Natalie C Twine,
Krystyna A Zuberek,
Brendan J Brodeur,
Lori Casciotti,
Vasu Maganti,
Padma S Reddy, Andrew Strahs,
Fred Immermann,
Walter Spinelli,
Ulrich Schwertschlag,
Anna M Slager,
Monette M Cotreau,
Andrew J Dorner
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ABSTRACT: Ulcerative colitis (UC) and Crohn's disease (CD) are common inflammatory bowel diseases producing intestinal inflammation and tissue damage. Although emerging evidence suggests these diseases are distinct, approximately 10% of patients remain classified as indeterminate inflammatory bowel disease even after invasive colonoscopy intended for diagnosis. A molecular diagnostic assay using a clinically accessible tissue would greatly assist in the classification of these diseases. In the present study we assessed transcriptional profiles in peripheral blood mononuclear cells from 42 healthy individuals, 59 CD patients, and 26 UC patients by hybridization to microarrays interrogating more than 22,000 sequences. Supervised analysis identified a set of 12 genes that distinguished UC and CD patient samples with high accuracy. The alterations in transcript levels observed by microarray were verified by real-time polymerase chain reaction. The results suggest that a peripheral blood mononuclear cell-based gene expression signature can provide a molecular biomarker that can complement the standard diagnosis of UC and CD.
Journal of Molecular Diagnostics 03/2006; 8(1):51-61. · 3.58 Impact Factor
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ABSTRACT: The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 mug of recombinant human interleukin-12 (rhIL-12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL-12 were evaluated. Recombinant human IL-12 was well tolerated in these healthy male and female subjects. The most frequently reported adverse events were flu-like symptoms, which exhibited a dose-response relationship. Pharmacokinetic analysis suggested that serum IL-12 levels increased with dose. Analysis of serum levels indicated that interferon-gamma increased with the dose of rhIL-12, whereas IL-6 levels showed no changes with rhIL-12 treatment. The messenger ribonucleic acid expression of signal transducer and activator of transcription was significantly increased 24 hours after the administration of rhIL-12 for all dose groups versus placebo, and results indicated that the magnitude of increase may be dose dependent. This study suggests that interferon-gamma and signal transducer and activator of transcription are biomarkers of rhIL-12 activity.
The Journal of Clinical Pharmacology 07/2005; 45(6):649-58. · 2.91 Impact Factor
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Michael E Burczynski,
Natalie C Twine,
Gary Dukart,
Bonnie Marshall,
Manuel Hidalgo,
Walter M Stadler,
Theodore Logan,
Janice Dutcher,
Gary Hudes,
William L Trepicchio, Andrew Strahs,
Fred Immermann,
Donna K Slonim,
Andrew J Dorner
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ABSTRACT: Given their accessibility, surrogate tissues, such as peripheral blood mononuclear cells (PBMC), may provide potential predictive biomarkers in clinical pharmacogenomic studies. In leukemias and lymphomas, the prognostic value of peripheral blast expression profiles is clear; however, it is unclear whether circulating mononuclear cells of patients with solid tumors might yield profiles with similar prognostic associations.
In this study, we evaluated the association of expression profiles in PBMCs with clinical outcomes in patients with advanced renal cell cancer. Transcriptional patterns in PBMCs of 45 renal cell cancer patients were compared with clinical outcome data at the conclusion of a phase II study of the mTOR kinase inhibitor CCI-779 to determine whether pretreatment transcriptional patterns in PBMCs were correlated with eventual patient outcomes.
Unsupervised hierarchical clustering of the PBMC profiles using all expressed genes identified clusters of patients with significant differences in survival. Cox proportional hazards modeling showed that the expression levels of many PBMC transcripts were predictors for the patient outcomes of time to progression and overall survival (time to death). Supervised class prediction approaches identified multivariate expression patterns in PBMCs capable of assigning favorable outcomes of time to death and time to progression in a test set of renal cancer patients, with overall performance accuracies of 72% and 85%, respectively.
The present study provides the first example of gene expression profiling in peripheral blood, a clinically accessible surrogate tissue, for identifying patterns of gene expression associated with higher likelihoods of positive outcome in patients with a solid tumor.
Clinical Cancer Research 03/2005; 11(3):1181-9. · 7.74 Impact Factor
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ABSTRACT: A study in healthy men and women was performed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered recombinant human interleukin-11 (oprelvekin) (OAO). Four cohorts of 10 subjects each received 3, 5, 10 or 30 mg (8:2/OAO:placebo ratio), first as a single dose with a 7-day washout period, then 7 consecutive daily doses. Safety was assessed by ongoing evaluation of adverse events (AEs) and laboratory values. PK samples were collected on the first and last day of dose administration. The established effects of subcutaneous oprelvekin on C-reactive protein (CRP, upward arrow), platelet count (upward arrow), fibrinogen (upward arrow) and hemoglobin (downward arrow), were evaluated. PK analysis showed that most subjects (27/34, 79%) had undetectable serum levels of IL-11. PD measures showed no changes from baseline between any OAO group and the placebo group. Orally administered oprelvekin was safe and well tolerated at all doses. A total of five AEs (abdominal pain, diarrhea, headache, rhinitis, grade 3 alanine aminotransferase elevation) were reported across all groups. Evaluations of serum IL-11 levels indicate that OAO is not systemically absorbed at levels above the lower limit of the bioanalytic assay. These data in addition to the lack of effect on PD measures suggest that there is a decreased potential of systemic adverse events with OAO.
Biopharmaceutics & Drug Disposition 11/2004; 25(7):291-6. · 2.07 Impact Factor
