Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 459-459
Author(s):  
Filip Janku ◽  
Aung Naing ◽  
Gerald Steven Falchook ◽  
Apostolia Maria Tsimberidou ◽  
Vanda M. T. Stepanek ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Early Phase ◽  
Advanced Colorectal Cancer ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Kras Mutations ◽  
Pik3ca Mutations ◽  
Molecular Abnormalities ◽  
Early Phase Clinical Trials

459 Background: Therapeutic matching based on underlying molecular abnormalities showed promising results in patients with diverse advanced cancers in early phase clinical trials. PIK3CA mutations may predict response to therapies with PI3K/AKT/mTOR inhibitors. Methods: Tumors from patients with colorectal cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Results: Of 194 patients analyzed, 31 (16%) had PIK3CA mutations. Of 194 patients 175 (90%) were assessed for the presence of KRAS mutation. Patients with PIK3CA mutations had higher prevalence of simultaneous KRAS mutations than patients with wild-type (wt) PIK3CA (21/30, 70% vs. 63/145, 43%; p=0.009). Of the 31 patients with PIK3CA mutations, 17 (55%) were treated in clinical trials containing a PI3K/AKT/mTOR pathway inhibitor (median age, 57; median number of prior therapies, 4). Of these 17 patients, none achieved a partial or complete response (PR/CR) and only 1 (6%, 95% CI 0.01-0.27) patient had stable disease for more than 6 months (SD>6), which was not significantly different from the SD>6/PR/CR rate of 16% (11/67; 95% CI 0.09-0.27) in colorectal cancer patients without PIK3CA mutations treated on the same protocols targeting the PI3K/AKT/mTOR pathway (p=0.44). The median progression-free survival was only 1.9 months (95% CI 1.5-2.3). Conclusions: Heavily pretreated patients with PIK3CA-mutant advanced colorectal cancer do not seem to benefit from protocols incorporating PI3K/AKT/mTOR inhibitors. PIK3CA mutations are associated with simultaneous KRAS mutations, which might account for therapeutic resistance.

scholarly journals Target-Based Therapeutic Matching in Early-Phase Clinical Trials in Patients with Advanced Colorectal Cancer and PIK3CA Mutations

2013 ◽  
Vol 12 (12) ◽  
pp. 2857-2863 ◽  
Author(s):  
Prasanth Ganesan ◽  
Filip Janku ◽  
Aung Naing ◽  
David S. Hong ◽  
Apostolia M. Tsimberidou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Early Phase ◽  
Advanced Colorectal Cancer ◽  
Pik3ca Mutations ◽  
Early Phase Clinical Trials

Monitoring event times in early phase clinical trials: some practical issues

2005 ◽  
Vol 2 (6) ◽  
pp. 467-478 ◽  
Author(s):  
Peter F Thall ◽  
Leiko H Wooten ◽  
Nizar M Tannir
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Event Times ◽  
Early Phase Clinical Trials

scholarly journals Bayesian adaptive design of early-phase clinical trials for precision medicine based on cancer biomarkers

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shinjo Yada
Keyword(s):  
Neural Network ◽  
Clinical Trials ◽  
Precision Medicine ◽  
Early Phase ◽  
Patient Specific ◽  
Specific Gene ◽  
Cancer Type ◽  
Background Characteristics ◽  
Number Of Patients ◽  
Early Phase Clinical Trials

Abstract Cancer tissue samples obtained via biopsy or surgery were examined for specific gene mutations by genetic testing to inform treatment. Precision medicine, which considers not only the cancer type and location, but also the genetic information, environment, and lifestyle of each patient, can be applied for disease prevention and treatment in individual patients. The number of patient-specific characteristics, including biomarkers, has been increasing with time; these characteristics are highly correlated with outcomes. The number of patients at the beginning of early-phase clinical trials is often limited. Moreover, it is challenging to estimate parameters of models that include baseline characteristics as covariates such as biomarkers. To overcome these issues and promote personalized medicine, we propose a dose-finding method that considers patient background characteristics, including biomarkers, using a model for phase I/II oncology trials. We built a Bayesian neural network with input variables of dose, biomarkers, and interactions between dose and biomarkers and output variables of efficacy outcomes for each patient. We trained the neural network to select the optimal dose based on all background characteristics of a patient. Simulation analysis showed that the probability of selecting the desirable dose was higher using the proposed method than that using the naïve method.

scholarly journals Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components

Vaccine ◽  
2019 ◽  
Vol 37 (47) ◽  
pp. 6951-6961 ◽  
Author(s):  
Sofiya Fedosyuk ◽  
Thomas Merritt ◽  
Marco Polo Peralta-Alvarez ◽  
Susan J Morris ◽  
Ada Lam ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Adenovirus Vector ◽  
Simple Method ◽  
Simian Adenovirus ◽  
Early Phase Clinical Trials

scholarly journals Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders

2021 ◽  
Vol 22 (4) ◽  
pp. 1615
Author(s):  
Maurits F. J. M. Vissers ◽  
Jules A. A. C. Heuberger ◽  
Geert Jan Groeneveld
Keyword(s):  
Clinical Trials ◽  
Failure Rate ◽  
Neurodegenerative Disorders ◽  
Early Phase ◽  
Proof Of Concept ◽  
Mesh Terms ◽  
Disease Modifying ◽  
Early Phase Clinical Trials ◽  
Pharmacodynamic Biomarkers ◽  
Response Biomarkers

The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date.

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