scholarly journals Early-Phase Platform Trials: A New Paradigm for Dose Finding and Treatment Screening in the Era of Precision Oncology

2019 ◽  
pp. 1-8
Author(s):  
Mei-Yin C. Polley ◽  
Ying Kuen Cheung
Keyword(s):  
Early Phase ◽  
Cytotoxic Agents ◽  
Dose Finding ◽  
Stopping Rules ◽  
Precision Oncology ◽  
Cancer Therapies ◽  
New Paradigm ◽  
Cancer Trial ◽  
Targeted Cancer Therapies ◽  
Statistical Designs

Applications in early-phase cancer trials have motivated the development of many statistical designs since the late 1980s, including dose-finding methods, futility screening, treatment selection, and early stopping rules. These methods are often proposed to address the conventional cytotoxic therapeutics for neoplastic diseases and cancer. Recent advances in precision medicine have motivated novel trial designs, most notably the idea of master protocol (eg, platform trial, basket trial, umbrella trial, N-of-1 trial), for the evaluation of molecularly targeted cancer therapies. In this article, we review the concepts and methodology of early-phase cancer trial designs with a focus on dose finding and treatment screening and put these methods in the context of platform trials of molecularly targeted cancer therapies. Because most cancer trial designs have been developed for cytotoxic agents, we will discuss how these time-tested design principles hold relevance for targeted cancer therapies, and we will delineate how a master protocol may serve as an efficient platform for safety and efficacy evaluations of novel targeted therapies.

scholarly journals Bayesian Adaptive Design for Finding the Maximum Tolerated Sequence of Doses in Multicycle Dose-Finding Clinical Trials

2018 ◽  
pp. 1-19 ◽  
Author(s):  
Jiaying Lyu ◽  
Emily Curran ◽  
Yuan Ji
Keyword(s):  
Adaptive Design ◽  
Decision Rules ◽  
Dose Finding ◽  
Patient Specific ◽  
Precision Oncology ◽  
Operating Characteristics ◽  
Time Saving ◽  
Bayesian Adaptive Design ◽  
Statistical Designs ◽  
Dosing Strategy

Purpose Statistical designs for traditional phase I dose-finding trials consider dose-limiting toxicity in the first cycle of treatment. In reality, patients often go through multiple cycles of treatment and may experience toxicity events in more than one cycle. Therefore, it is desirable to identify the maximum tolerated sequence of three doses across three cycles of treatment. Methods Motivated by a three-cycle dose-finding clinical trial for a rare cancer with a JAK inhibitor, we proposed and implemented a simple Bayesian adaptive dose-cycle finding (BaSyc) design that allows intercycle and intrapatient dose modification. Because of the patient-specific dosing strategy over cycles, the BaSyc design is suited as a method in precision oncology. Results BaSyc is simple and transparent because its algorithm can be summarized as two tabulated decision rules before the trial starts, allowing physicians to visually examine these rules. In addition, BaSyc employs a time-saving enrollment scheme that speeds up the trial. Extensive simulation studies show that BaSyc has desirable operating characteristics in identifying the maximum tolerated sequence. Conclusion The BaSyc design provides a first-of-kind multicycle approach for dose finding and will likely lead to better and safer patient care and drug development.

Tumor-targeting drug delivery of chemotherapeutic agents

2011 ◽  
Vol 83 (9) ◽  
pp. 1685-1698 ◽  
Author(s):  
Iwao Ojima
Keyword(s):  
Drug Delivery ◽  
Tumor Targeting ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Cancer Therapies ◽  
Molecular Approaches ◽  
Tumor Recognition ◽  
Targeted Cancer Therapies

Despite the significant progress in the development of cancer detection, prevention, surgery, and therapy, there is still no common cure for this disease. In addition, the long-standing problem of chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, including tumor-targeting drug delivery systems (TTDDS). In general, a TTDDS consists of a tumor recognition moiety and a cytotoxic “warhead” connected through a “smart” linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a “Trojan horse” approach becomes possible for mass delivery of cytotoxic warheads to maximize the efficacy. This account presents the progress in the molecular approaches to the design and development of novel drug delivery systems for tumor-targeting chemotherapy in our laboratory.

scholarly journals Collateral Responses to Classical Cytotoxic Chemotherapies are Heterogeneous and Sensitivities are Sparse

2021 ◽  
Author(s):  
Simona Dalin ◽  
Douglas A. Lauffenburger ◽  
Michael T. Hemann
Keyword(s):  
Rational Design ◽  
Chemotherapy Resistance ◽  
Resistant Cell ◽  
Cytotoxic Agents ◽  
Cancer Therapies ◽  
Combination Drug ◽  
Collateral Sensitivity ◽  
Targeted Cancer Therapies ◽  
Drug Regimens ◽  
Combination Regimens

AbstractChemotherapy resistance is a major obstacle to curing cancer patients. Combination drug regimens have shown promise as a method to overcome resistance; however, to date only some cancers have been cured with this method. Collateral sensitivity – the phenomenon whereby resistance to one drug is co-occurrent with sensitivity to a second drug – has been gaining traction as a promising new concept to guide rational design of combination regimens. Here we survey collateral responses to acquisition of resistance to four classical chemotherapy agents. Although collateral sensitivities have been documented for antibiotics and targeted cancer therapies, we did not observe collateral sensitivities to any of the cytotoxic agents we studied. Interestingly, we did observe heterogeneity in the phenotypic response to acquisition of resistance to each drug, suggesting the existence of multiple different states of resistance for each drug. Surprisingly, this phenotypic heterogeneity was unrelated to transcriptomic heterogeneity in the resistant cell lines. These features of phenotypic and transcriptomic heterogeneity must be taken into account in future studies of treated tumor subclones and in design of chemotherapy combinations.

scholarly journals Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 723
Author(s):  
Valerie J. Carpenter ◽  
Tareq Saleh ◽  
David A. Gewirtz
Keyword(s):  
Cancer Therapy ◽  
Tumor Cell ◽  
Cancer Therapies ◽  
Cell Models ◽  
Future Directions ◽  
Targeted Cancer Therapies

Senolytics represent a group of mechanistically diverse drugs that can eliminate senescent cells, both in tumors and in several aging-related pathologies. Consequently, senolytic use has been proposed as a potential adjuvant approach to improve the response to senescence-inducing conventional and targeted cancer therapies. Despite the unequivocal promise of senolytics, issues of universality, selectivity, resistance, and toxicity remain to be further clarified. In this review, we attempt to summarize and analyze the current preclinical literature involving the use of senolytics in senescent tumor cell models, and to propose tenable solutions and future directions to improve the understanding and use of this novel class of drugs.

Unified exact design with early stopping rules for single arm clinical trials with multiple endpoints

2021 ◽  
pp. 096228022110130
Author(s):  
Wei Wei ◽  
Denise Esserman ◽  
Michael Kane ◽  
Daniel Zelterman
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
Decision Rules ◽  
Stopping Rules ◽  
Multiple Endpoints ◽  
Shiny App ◽  
R Shiny ◽  
Early Phase Clinical Trials ◽  
User Friendly ◽  
Exact Design

Adaptive designs are gaining popularity in early phase clinical trials because they enable investigators to change the course of a study in response to accumulating data. We propose a novel design to simultaneously monitor several endpoints. These include efficacy, futility, toxicity and other outcomes in early phase, single-arm studies. We construct a recursive relationship to compute the exact probabilities of stopping for any combination of endpoints without the need for simulation, given pre-specified decision rules. The proposed design is flexible in the number and timing of interim analyses. A R Shiny app with user-friendly web interface has been created to facilitate the implementation of the proposed design.

scholarly journals The reimbursement of targeted cancer therapies in Bulgaria: is it evidence-based?

2015 ◽  
Vol 25 (suppl_3) ◽  
Author(s):  
T Vekov ◽  
R Koleva-Kolarova ◽  
S Aleksandrova-Yankulovska ◽  
N Veleva
Keyword(s):  
Evidence Based ◽  
Cancer Therapies ◽  
Targeted Cancer Therapies
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