Trial Summary
What is the purpose of this trial?This study assesses cardiovascular injury and cardiac fitness in patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced) receiving model based personalized chemoradiation. The goal of this study is to learn more about the risk of developing heart disease as a result of chemoradiation treatment for lung cancer. Researchers also want to learn if the risk can be reduced by using a patient's individual risk profile to guide cancer treatment and help protect the heart.
Is the drug Model Based Personalized Chemoradiation (Tecentriq, MPDL3280A, RG7446) a promising treatment for lung cancer?Yes, Model Based Personalized Chemoradiation is a promising treatment for lung cancer. Research shows that personalized approaches, like using patient-derived models, can help tailor treatments to individual patients, improving outcomes. This drug is part of a new wave of treatments that aim to be more effective by targeting specific characteristics of a patient's cancer.356810
What safety data exists for personalized chemoradiation for lung cancer?The provided research does not directly address the safety data for personalized chemoradiation using Tecentriq, MPDL3280A, or RG7446. However, it includes studies on the safety and toxicity of chemoradiotherapy in lung cancer, such as intensified high-dose chemoradiotherapy and concurrent chemoradiotherapy with trametinib. These studies analyze toxicity profiles and safety in the context of lung cancer treatment, which may offer insights into the safety considerations for similar treatments.1291113
Do I have to stop taking my current medications for the trial?The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.
What data supports the idea that Personalized Chemoradiation for Lung Cancer is an effective treatment?The available research shows that personalized chemoradiation for lung cancer can be effective because it uses patient-specific information to tailor the treatment. For example, the use of genomic biomarkers to personalize radiotherapy can improve control and cure rates by matching the treatment to the tumor's characteristics. This approach is more precise compared to standard treatments, which often use a one-size-fits-all method. Additionally, a patient-derived model has been developed to predict how well a patient will respond to radiation and chemotherapy, which can help improve survival and quality of life for lung cancer patients.47121314
Eligibility Criteria
Adults with locally advanced non-small cell lung cancer who can sign consent, undergo thoracic radiation and systemic therapy (like chemo), and perform cardiac tests. They must have a Karnofsky performance status of 70 or above, indicating they are able to care for themselves. Excluded are those with prior chest radiation, pregnant or breastfeeding women, renal failure patients on dialysis, or anyone unable to do the required heart imaging tests.Inclusion Criteria
I am willing and able to undergo heart imaging tests.
I have been diagnosed with non-small cell lung cancer.
I am able to care for myself but may not be able to do active work.
I can and am willing to do a 6-minute walking test.
I am 18 years old or older.
Exclusion Criteria
I have had radiation therapy to my chest area before.
I am on dialysis due to kidney failure.
I cannot do the tests required by the study.
Treatment Details
The trial is studying how personalized chemoradiation treatment affects heart health in lung cancer patients. It involves various cardiac fitness assessments like walking tests and heart scans using techniques such as SPECT and echocardiography before and after treatment to see if tailoring therapy based on individual risk can protect the heart.
2Treatment groups
Experimental Treatment
Group I: Standard Treatment Plan (Cohort One)Experimental Treatment7 Interventions
Patients undergo SPECT/CT with stress test and echocardiogram with strain before RT, 6-8 weeks and 12 months after completion of RT. Patients also participate in 6 MWT before RT, 2-3 and 6-7 weeks during RT, then 6-8 weeks, 4-6 months and 12 months after completion of RT. Patients undergo blood sample collection and complete questionnaires over 3-5 minutes before RT, 2-3, 4-5, 6-7 weeks after the initiation of RT, then at 3, 6, 12, and 24 months after completion of RT.
Group II: Model Based Personalized Treatment Plan (Cohort Two)Experimental Treatment7 Interventions
Patients undergo SPECT/CT with stress test and echocardiogram with strain before RT, 6-8 weeks and 12 months after completion of RT. Patients also participate in 6 MWT before RT, 2-3 and 6-7 weeks during RT, then 6-8 weeks, 4-6 months and 12 months after completion of RT. Patients undergo blood sample collection and complete questionnaires over 3-5 minutes before RT, 2-3, 4-5, 6-7 weeks after the initiation of RT, then at 3, 6, 12, and 24 months after completion of RT.
Model Based Personalized Chemoradiation is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as Tecentriq for:
- Urothelial carcinoma
- Non-small cell lung cancer
- Small cell lung cancer
- Hepatocellular carcinoma
- Alveolar soft part sarcoma
🇺🇸 Approved in United States as Tecentriq for:
- Non-small cell lung cancer
- Small cell lung cancer
- Hepatocellular carcinoma
- Melanoma
- Alveolar soft part sarcoma
Find a clinic near you
Research locations nearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who is running the clinical trial?
M.D. Anderson Cancer CenterLead Sponsor
National Heart, Lung, and Blood Institute (NHLBI)Collaborator
References
Intensified high-dose chemoradiotherapy with induction chemotherapy in patients with locally advanced non-small-cell lung cancer-safety and toxicity results within a prospective trial. [2018]To analyze the toxicity profile of an intensified definitive chemoradiotherapy (CRT) schedule in patients with locally advanced non-small-cell lung cancer (Stage IIIA N2/selected IIIB) treated within a prospective multicenter trial.
Prospective study of epidermal growth factor receptor tyrosine kinase inhibitors concurrent with individualized radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. [2018]To establish the safety profile and efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) concurrent with individualized radiotherapy (RT) in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC).
Integrative oncology drug discovery accompanied by preclinical translational research as prerequisite for clinical development. [2015]The molecular heterogeneity of cancer calls for individualized therapies to become the standard of care. It is now generally accepted that target-specific compounds require specific new development programs. But, even for new drugs with general mode of action (i.e., chemotherapy), tailored treatment approaches, such as specific schedules or combinations, have been shown to improve the therapeutic outcome. Therefore, the preclinical development of new therapeutic agents needs, next to the "classical pharmacodynamic studies", the implementation of integrative translational research (TR) as early as possible. New TR approaches, starting already at target identification and validation (TIV) will allow to defining the optimal patient population for clinical development, to tailor individual treatment of the tumor disease and to choose a rational basis among the manifold options for treatment combinations. We will discuss several examples from TR studies, which have initially been started to evaluate the molecular mode of action and to recognize mechanisms which can lead to resistance. Research was extended later to identify predictive response biomarkers and establish a rationale for combination with different therapies. A detailed gene expression analysis of lung cancer cells and apoptotic pathway interference studies in colon cancer cells provided insight in the molecular mechanisms of action. These new findings are correlated with results from other studies performed during the preclinical development program. We discuss pros and cons, successes and failures of our integrative preclinical development program and provide recommendations for future oncology projects.
An instrument dedicated for modelling of pulmonary radiotherapy. [2018]Radiotherapy plays a pivotal role in lung cancer treatment. Selection of patients for new (radio)therapeutic options aiming at improving outcomes requires reliable and validated prediction models. We present the implementation of a prospective platform for evaluation and development of lung radiotherapy (proPED-LUNG) as an instrument enabling multidimensional predictive modelling.
Establishing a colorectal cancer liver metastasis patient-derived tumor xenograft model for the evaluation of personalized chemotherapy. [2022]In order to suggest optimal anticancer drugs for patient-tailored chemotherapy, we developed a colorectal cancer (CRC)-liver metastasis patient-derived tumor xenograft (PDTX) model.
Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation. [2019]Preclinical models that can better predict therapeutic activity in clinical trials are needed in this era of personalized cancer treatment. Herein, we established genomically and clinically annotated patient-derived xenografts (PDXs) from non-small-cell lung cancer (NSCLC) patients and investigated whether these PDXs would faithfully recapitulate patient responses to targeted therapy.
Novel Genomic-Based Strategies to Personalize Lymph Node Radiation Therapy. [2019]Current standard radiotherapy doses have been derived from empiric methods rather than a scientific framework. Subclinical nodal dosing remains relatively uniform across most disease sites, despite heterogeneity in patient and tumor biology. It is now clear that there are subsets of patients who will benefit from genomically-informed radiotherapy planning, and there are increasing efforts toward prescribing radiation dose to match the radiosensitivity of the tumor. By using novel genomic biomarkers to personalize delivery of radiotherapy, there is an opportunity to improve loco-regional control and cure rates. We survey the current landscape of personalized radiation oncology across commonly treated disease sites.
Integrative Pharmacogenomics Analysis of Patient-Derived Xenografts. [2019]Identifying robust biomarkers of drug response constitutes a key challenge in precision medicine. Patient-derived tumor xenografts (PDX) have emerged as reliable preclinical models that more accurately recapitulate tumor response to chemo- and targeted therapies. However, the lack of computational tools makes it difficult to analyze high-throughput molecular and pharmacologic profiles of PDX. We have developed Xenograft Visualization & Analysis (Xeva), an open-source software package for in vivo pharmacogenomic datasets that allows for quantification of variability in gene expression and pathway activity across PDX passages. We found that only a few genes and pathways exhibited passage-specific alterations and were therefore not suitable for biomarker discovery. Using the largest PDX pharmacogenomic dataset to date, we identified 87 pathways that are significantly associated with response to 51 drugs (FDR < 0.05). We found novel biomarkers based on gene expressions, copy number aberrations, and mutations predictive of drug response (concordance index > 0.60; FDR < 0.05). Our study demonstrates that Xeva provides a flexible platform for integrative analysis of preclinical in vivo pharmacogenomics data to identify biomarkers predictive of drug response, representing a major step forward in precision oncology. SIGNIFICANCE: A computational platform for PDX data analysis reveals consistent gene and pathway activity across passages and confirms drug response prediction biomarkers in PDX.See related commentary by Meehan, p. 4324.
Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development. [2022]Radiotherapy is an effective anticancer treatment, but combinations with targeted agents that maximize efficacy while sparing normal tissue are needed. Here, we assess the radiopotentiation profiles of DNA damage response inhibitors (DDRi) olaparib (PARP1/2), ceralasertib (ATR), adavosertib (WEE1), AZD0156 (ATM), and KU-60648 (DNA-PK). We performed a radiotherapy combination screen and assessed how drug concentration and cellular DDR deficiencies influence the radiopotentiation ability of DDRi. We pre-selected six lung cancer cell lines with different genetic/signaling aberrations (including mutations in TP53 and ATM) and assessed multiple concentrations of DDRi in combination with a fixed radiotherapy dose by clonogenic assay. The effective concentration of DDRi in radiotherapy combinations is lower than that required for single-agent efficacy. This has the potential to be exploited further in the context of DDR deficiencies to increase therapeutic index and we demonstrate that low concentrations of AZD0156 preferentially sensitized p53-deficient cells. Moreover, testing multiple concentrations of DDRi in radiotherapy combinations indicated that olaparib, ceralasertib, and adavosertib have a desirable safety profile showing moderate increases in radiotherapy dose enhancement with increasing inhibitor concentration. Small increases in concentration of AZD0156 and particularly KU-60648, however, result in steep increases in dose enhancement. Radiopotentiation profiling can inform on effective drug doses required for radiosensitization in relation to biomarkers, providing an opportunity to increase therapeutic index. Moreover, multiple concentration testing demonstrates a relationship between drug concentration and radiotherapy effect that provides valuable insights that, with future in vivo validation, can guide dose-escalation strategies in clinical trials.
Screening and Validation of Molecular Targeted Radiosensitizers. [2022]The development of molecular targeted drugs with radiation and chemotherapy is critically important for improving the outcomes of patients with hard-to-treat, potentially curable cancers. However, too many preclinical studies have not translated into successful radiation oncology trials. Major contributing factors to this insufficiency include poor reproducibility of preclinical data, inadequate preclinical modeling of intertumoral genomic heterogeneity that influences treatment sensitivity in the clinic, and a reliance on tumor growth delay instead of local control (TCD50) endpoints. There exists an urgent need to overcome these barriers to facilitate successful clinical translation of targeted radiosensitizers. To this end, we have used 3-dimensional (3D) cell culture assays to better model tumor behavior in vivo. Examples of successful prediction of in vivo effects with these 3D assays include radiosensitization of head and neck cancers by inhibiting epidermal growth factor receptor or focal adhesion kinase signaling, and radioresistance associated with oncogenic mutation of KRAS. To address the issue of tumor heterogeneity, we leveraged institutional resources that allow high-throughput 3D screening of radiation combinations with small-molecule inhibitors across genomically characterized cell lines from lung, head and neck, and pancreatic cancers. This high-throughput screen is expected to uncover genomic biomarkers that will inform the successful clinical translation of targeted agents from the National Cancer Institute Cancer Therapy Evaluation Program portfolio and other sources. Screening "hits" need to be subjected to refinement studies that include clonogenic assays, addition of disease-specific chemotherapeutics, target/biomarker validation, and integration of patient-derived tumor models. The chemoradiosensitizing activities of the most promising drugs should be confirmed in TCD50 assays in xenograft models with or without relevant biomarker and using clinically relevant radiation fractionation. We predict that appropriately validated and biomarker-directed targeted therapies will have a higher likelihood than past efforts of being successfully incorporated into the standard management of hard-to-treat tumors.
Phase I Trial of Definitive Concurrent Chemoradiotherapy and Trametinib for KRAS-Mutated Non-Small Cell Lung Cancer. [2023]This phase I trial (NCT01912625) evaluated the safety and pharmacokinetics of definitive concurrent chemoradiotherapy (cCRT) and the radiosensitizer trametinib (MEK1/2 inhibitor) for KRAS-mutated nonmetastatic non-small cell lung cancer (NSCLC).
Patient-Derived Tumoroid for the Prediction of Radiotherapy and Chemotherapy Responses in Non-Small-Cell Lung Cancer. [2023]Radiation therapy and platinum-based chemotherapy are common treatments for lung cancer patients. Several factors are considered for the low overall survival rate of lung cancer, such as the patient's physical state and the complex heterogeneity of the tumor, which leads to resistance to the treatment. Consequently, precision medicines are needed for the patients to improve their survival and their quality of life. Until now, no patient-derived tumoroid model has been reported to predict the efficiency of radiation therapy in non-small-cell lung cancer. Using our patient-derived tumoroid model, we report that this model could be used to evaluate the efficiency of radiation therapy and cisplatin-based chemotherapy in non-small-cell lung cancer. In addition, these results can be correlated to clinical outcomes of patients, indicating that this patient-derived tumoroid model can predict the response to radiotherapy and chemotherapy in non-small-cell lung cancer.
Effects of EGFR driver mutations on pathologic regression in resectable locally advanced non-small cell lung cancer treated with neoadjuvant chemoradiation and completion surgery. [2023]We hypothesized that driver mutations in epidermal growth factor receptor (EGFR) are associated with decreased pathologic response to neoadjuvant chemoradiation (NA-ChRT) in locally advanced non-small cell lung cancer (LA-NSCLC).
ROE (Radiotherapy Outcomes Estimator): An open-source tool for optimizing radiotherapy prescriptions. [2023]Radiotherapy prescriptions currently derive from population-wide guidelines established through large clinical trials. We provide an open-source software tool for patient-specific prescription determination using personalized dose-response curves.