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Dr. Obumneke Amadi-Onuoha -Transcript 37_ clinical trail design
- 1. First comprehensive report of impact of genomic alterations, chemotherapy, targeted therapy and immunotherapy on outcomes in the genomics driven squamous master protocol LungMAP:Umbrella design Trial Obumneke A. Amadi-Onuoha, DrPH, MPH, MSHS November 21, 2020
- 2. Video: LungMap https://www.youtube.com/watch?v=jrihzTXKUO8 Targets Squamous cell lung to match therapy.
- 3. Umbrella Clinical Trail Design and Real-World Drug/Medical Device Study Overview • Umbrella design Trial • Lung Map Biomarker Driven Sub-studies Model (Redman et al. 2020).
- 4. Lung Map Biomarker Driven Sub-Studies: Schema (Redman et al. 2020).
- 5. Advantages 1. Overall the risk/benefit ratio for performing the study appeared to be within acceptable considerations, treatment-by-biomarker marker interaction can be computed, that would promote improved predictive homogeneity (all patients from same tumor group) when randomization against a control treatment 2. The threats to external validity may not be apparent in this study because the comparison of the treatment arms results was randomly assigned to participants, and the Findings is representative of a real-world setting, in relation to the investigated disease histology, moreover, the study design was flexible and can easily add or drop arm. (Redman et al. 2020).
- 6. Disadvantages 1. The study result may not apply/generalize to the world at large because of the difficulty in enrolling rare molecular subtypes of a single tumor type, therefore, it may affect the external validity of the study result. 2. Scientific validity of the study may encounter bias from the enrollment of patients whose tumors have multiple mutations in treatments matching a single mutation , this may be controversial and result in a drug approval without confirmed efficacy. (Redman et al. 2020).
- 7. Conclusions The Lung Map trial has the prospective to change and accelerate the way investigational biomarker-defined therapies are confirmed and approved for lung cancer and potential to support many other diseases.
- 8. References NIH(2020). Lung-MAP: Biomarker-Targeted Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer. Retrieved from https://clinicaltrials.gov/ct2/show/NCT02154490 Papadimitrakopoulou, V., Redman, M. W., Gandara, D. R., Hirsch, F. R., Mack, P. C., Langer, C. J., ... & Waqar, S. N. (2018). First comprehensive report of impact of genomic alterations, chemotherapy, targeted therapy and immunotherapy on outcomes in the genomics driven squamous master protocol LungMAP. Redman, M. W., Papadimitrakopoulou, V. A., Minichiello, K., Hirsch, F. R., Mack, P. C., Schwartz, L. H., ... & Miao, J. (2020). Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol. The Lancet Oncology, 21(11). (Redman et al. 2020).
Editor's Notes
- Hi everyone, this is Dr. Obumneke Amadi-Onuoha, this presentation is to give an overview of an innovative clinical trail study design. The topic presentenced is an umbrella design clinical trail study, titled: First comprehensive report of impact of genomic alterations, chemotherapy, targeted therapy and immunotherapy on outcomes in the genomics driven squamous master protocol LungMAP. by(Redman, et al., 2020). The clinical trial is a two sub-study component, i.e., the biomarker-driven sub-study and the non-match sub-studies, however, my presentation focus will be leveraged only on the biomarker driven sub-study, the purpose being to describe the innovative lung-Map master protocol of using a biomarker-driven therapy that uses genomic screening to target specific cancer cells and assign the proper chemotherapy drugs to it. The strategy will help personalize treatment therapies for non-small lung cancer patients. Also, the rational for presentation, it because of the limited slide requirement for the assignment. In continuation, the components of the slide will include: 1) An Overview of the : Umbrella design Trial, & its constructed visual Lung Map Biomarker Driven Sub-studies Model 2)The schema visual and components 3)The study advantages and disadvantages, concluding remarks and references.
- This is an umbrella clinical trail design for the study. The master protocol where all patients in the sub trial share a common tumor type evaluated by multiple therapeutic treatments and a biomarker enrichment strategy. The Lung-Map model uses a multi-drug targeted approach to match patients with sub-studies to test investigational new treatments based on their specific tumor profile, this was achieved by using a tissue-based comprehensive genomic profiling assay of genes (FoundationOne CDX)that targets the genomic alterations, or mutations found as a driver of these cancer cells growth(Redman, et al., 2020). The Biomaker-driven therapies for the squamous non–small cell lung cancer types evaluate in this sub-study with reported out come include : 1) Taselisib, this is a potent selective PI3KFC inhibitor, with preclinical activity in relevant mutant PIK3CA models. 2) Palbociclib, this is a selective inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. CDK family have been found to be overexpressed frequently secondary to amplification or translocation in lung cancers, potentially leading to uncontrolled activation of the cell cycle(Redman, et al., 2020). 3) AZD4547, this is a potent inhibitor of FGFR has shown anti-tumor activity in preclinical models in patients with amplified SCC. The drug, Docetaxel is a chemotherapy used to treat a few types of cancer that include lung cancer used as (Standard of care) as the study comparison group(Redman, et al., 2020).
- Eligibility and Inclusion Criteria: The studies' eligibility criteria included patients 18yrs and older with lung cancer or have been previously treated with a platinum- based chemotherapy, and an eastern cooperative performance status 0-2. There are many inclusions criteria for this study into the sub-study stage, however, the basic was, patients must be screened at progression on prior treatment or to be pre-screened prior to progression while on treatment(Redman, et al., 2020). In the previous slide, I describe the method used for genomic profiling to match squamous metastatic lung cancer cells biomarkers to therapies, thereafter, eligible participants will receive sub-study assignment. The sub-study assignment is a single –arm phase 2 design, patients detected with a biomarker are assigned, those with multiple biomarkers are randomized into a sub-study(Redman, et al., 2020). With protocol for genomic profiling, biomarker results were reported with 16 days from tissue submission for all patients. For treatment arms, Patients with tumors positive are randomized to Arm II receive therapies PO 1-21 days in the absence of disease progression or unacceptable toxicity, other specifications applied. Initial documentation of progression is assessed by local review up to 18 months since end of growth(NIH,2020,Redman, et al., 2020). Endpoints: The co-primary endpoints for the study includes: -To identify a series of molecular targets/biomarkers for which there will be a new drug match, leading to appropriate sub-study assignment and drug treatment Overall survival and progression free survival with therapy examined, with time frame up to 3years. The comparison of the treatment arms was conducted using a randomization stratification factors-log-rank test to test the primary hypotheses, a Cox PH model was used to estimate the hazard ration and confidence intervals, adjusting for performance status, lines of therapy, age, and gender (Redman, et al., 2020). Evaluation of test drugs were compared with Docetaxel. The result/outcomes with targeted therapies biomarker treatment showed some efficacy.