Ignite Creation Date:
2024-05-06 @ 8:06 PM
Last Modification Date:
2024-10-26 @ 3:20 PM
Study NCT ID:
NCT06250829
Status:
RECRUITING
Last Update Posted:
2024-02-09
First Post:
2024-02-01
Brief Title:
Model to Predict pCR and IrAEs in Early Stage Non-small Cell Lung Cancer
Sponsor:
Lawson Health Research Institute
Organization:
Lawson Health Research Institute
Study Overview
Official Title:
Analysis of Variables Predicting Pathological Complete Response and Immune Related Adverse Events in Patients With Resectable Non-Small Cell Lung Cancer Receiving Neoadjuvant Immunotherapy With Chemotherapy - A Prospective Cohort Study
Status:
RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Pre-PLaN
Brief Summary:
Lung cancer is the chief cause of cancer death The new standard-of-care SOC in operable lung cancer combines chemotherapy and an immune-stimulating drug before the surgery neoadjuvant approach This results in a large increase in complete cancer clearance rates compared to chemotherapy alone 30 with combination vs 4 with chemotherapy alone leading to much better long-term survival and probably many more cures However most still dont achieve complete clearance and a few have increases in or spread of their tumors while on treatment Therefore we need to understand why some patients benefit responders and others dont benefit non-responders on an immunotherapy-based treatment Also some patients unpredictably develop severe immune-type side effects related to the immunotherapy drug although such side effects may be associated with improved anti-cancer effects In short the same treatment can result in complete cancer clearance in one patient and in a worst-case scenario may result in severe toxicity or fail to control spreadgrowth thus precluding surgery The immune system obviously plays a key role in both benefit and harm yet most of the research in this field has focused only on the cancer We plan an in-depth study in 60 patients focusing on the cancer as well as the patients immune system pre-surgery This will enable us to identify factors predicting complete cancer clearance and the occurrence of immune-type side effects Using highly sophisticated resources available to us here in London we will develop predictive models enabling better patient management including possible avoidance of surgery and identification of key biological differences between major responders and non-responders to highlight important new targets for the development of even newer and better therapies
Detailed Description:
RATIONALE For patients pts with stage I-IIIA NSCLC surgical resection is the SOC Adjuvant chemotherapy chemo offers modest survival benefit and there remains equipoise in the relative value of adjuvant vs neo-adjuvant chemo Recently Health Canada approved neo-adjuvant immunotherapy nivolumab with platinum-based chemo chemonivo in pts with resectable IB-IIIA non-small cell lung cancer NSCLC based on a prospective trial CM816 showing better event-free EFS and overall survival OS and pathological complete responses pCR making this approach as the new SoC pCR rates in CM816 were 24 neoadjuvant nivochemo compared to 22 neoadjuvant chemo alone In these trials OS benefit was especially seen in pts with tumors expressing programmed death-ligand 1 PD-L1 and those with pCR
We propose a prospective single cohort study to analyze the predictors of pCR in a similar-sized cohort of our pts on the same neo-adjuvant chemonivo but employing a range of parameters that are both broader and in some cases more sophisticated We intend to make use of parameters that reflect both the tumor itself as well as the integrity of immune system of the host obviously a critical determinant of immune-mediated efficacy yet strangely neglected in the literature We will then seek to develop an initial predictive model for pCR with a good sensitivityspecificity as a prelude to refiningtesting the model in future work with a much larger sample
Noting that immune-related adverse events IrAEs are strongly associated with efficacy with immunotherapy we will not only be including the emergence of early on-treatment IrAEs in our pCR modeling but also develop an additional model as a subsidiary aim to predict IrAEs themselves Note the incidence of grade3 AEs was 335 in CM816 and there is currently no available way to predict their occurrence This is not to suggest such a model if successful should be used to deny such pts immune checkpoint inhibitors but it would allow a more informed consent process as well as more intensive pro-active monitoring to avoid the worst outcomes of serious IrAEs which are occasionally fatal by early intervention
Major Aim Development of a model predicting pCR after neo-adjuvant chemonivo in pts with resectable NSCLC
Hypothesis That an initial model combining predictive variables from baseline tumor characteristics baseline factors likely to be associated with host immunity as well as treatment-emergent events in pts with resectable NSCLC on neoadjuvant chemonivo can predict a pCR with an area under the Receiver Operator Characteristic ROC curve of at least 08
Objectives Primary Objectives 1 To explore the feasibility of acquiring a combination of baseline and treatment-emergent potentially predictive variables in pts with early-stage NSCLC subject to neoadjuvant chemonivo 2 To curate these variables and by uni-and multi-variate analyses to identify those independently useful in predicting pCR in these pts 3 To combine these independently predictive factors into a model with adequate sensitivity and specificity
Secondary Objectives 1 To assess outcomes in patients with resectable NSCLC treated with neoadjuvant chemoimmuno 2 To evaluate exploratory and potential biomarkers for predicting pCR major pathological responses MPR overall response rate ORR event-free survival EFS overall survival OS and IrAEs 3 To assess if a post-treatment but pre-surgery metabolic response by F18-FluorodeoxyglucoseFDG-Positron emission tomographyPETCT and a blood-only molecular residual disease assay ctDNA clearance can accurately predict a pCR added to or instead of a more complex model
Endpoints Primary 1 To determine the predictive power sensitivity specificity ROC characteristic curves of a model combining variables in predicting pCR 2 To determine whether a similar model can be constructed to predict IrAEs
Secondary Endpoints 1 Assess pCR MPR clinical objective response rates ORR EFS and OS and IrAEs 2 Exploratory the feasibility of acquiring novel potential biomarkers - eg Lymphocyte-activation gene 3 LAG3 Lysine-specific histone demethylase1A LSD1 Leukemia inhibitory factor LIF Interleukin 6 IL6 Interleukin 7 IL7
Study Population Participants with histologically confirmed Stage IB-IIIA NSCLC who are considered to have a resectable disease with available baseline tumor tissue for immunohistochemistry IHC and next-generation sequencing NGS except those with known epidermal growth factor receptor EGFR mutations anaplastic lymphoma kinase ALK or receptor tyrosine kinase ROS1 translocation or active known or suspected autoimmune disease
Study Design A prospective single cohort N60 study
Treatment Details Patients with resectable stage Ib-IIIa NSCLC will be treated with new SoC 3 cycles of neoadjuvant nivolumab immunotherapy plus platinum doublet chemo
Sample Size Our planned accrual of 60 patients will result in approximately 15 pCRs assuming an event rate of 25 This will allow us to explore our potential predictors and their univariable associations with pCR andor no-pCR outcomes The top predictors identified in univariable analyses could be used as candidate predictors in a multivariable prediction model This framework would allow for an exploratory multivariable model predicting no-pCR with up to 9 of the top candidate predictors identified in univariable analyses andor up to 3- 4 of the top candidates predicting pCR This assumes a two-sided type I error rate of 00516
Feasibility Our centre treats an average 60 patients per year with resectable NSCLC who are eligible for neoadjuvant therapy As such we should be able to meet our enrollment goal in approximately 12-14 months
Significance A model that can predict pCR could help in identifying pts most likely to benefit from neo-adjuvant chemonivo If subsequently validated such a model would have several applications including pt selection for neo-adjuvant chemoimmuno potential avoidance of surgery in reliably-predicted pCR pts of morbid thoracotomy identification of pts needing additional treatments eg CTLA4 inhibitors or radiotherapy acquisition of important insights into the biological underpinnings of resistance and most crucially identification of novel targets or strategies to overcome resistance
We propose a prospective single cohort study to analyze the predictors of pCR in a similar-sized cohort of our pts on the same neo-adjuvant chemonivo but employing a range of parameters that are both broader and in some cases more sophisticated We intend to make use of parameters that reflect both the tumor itself as well as the integrity of immune system of the host obviously a critical determinant of immune-mediated efficacy yet strangely neglected in the literature We will then seek to develop an initial predictive model for pCR with a good sensitivityspecificity as a prelude to refiningtesting the model in future work with a much larger sample
Noting that immune-related adverse events IrAEs are strongly associated with efficacy with immunotherapy we will not only be including the emergence of early on-treatment IrAEs in our pCR modeling but also develop an additional model as a subsidiary aim to predict IrAEs themselves Note the incidence of grade3 AEs was 335 in CM816 and there is currently no available way to predict their occurrence This is not to suggest such a model if successful should be used to deny such pts immune checkpoint inhibitors but it would allow a more informed consent process as well as more intensive pro-active monitoring to avoid the worst outcomes of serious IrAEs which are occasionally fatal by early intervention
Major Aim Development of a model predicting pCR after neo-adjuvant chemonivo in pts with resectable NSCLC
Hypothesis That an initial model combining predictive variables from baseline tumor characteristics baseline factors likely to be associated with host immunity as well as treatment-emergent events in pts with resectable NSCLC on neoadjuvant chemonivo can predict a pCR with an area under the Receiver Operator Characteristic ROC curve of at least 08
Objectives Primary Objectives 1 To explore the feasibility of acquiring a combination of baseline and treatment-emergent potentially predictive variables in pts with early-stage NSCLC subject to neoadjuvant chemonivo 2 To curate these variables and by uni-and multi-variate analyses to identify those independently useful in predicting pCR in these pts 3 To combine these independently predictive factors into a model with adequate sensitivity and specificity
Secondary Objectives 1 To assess outcomes in patients with resectable NSCLC treated with neoadjuvant chemoimmuno 2 To evaluate exploratory and potential biomarkers for predicting pCR major pathological responses MPR overall response rate ORR event-free survival EFS overall survival OS and IrAEs 3 To assess if a post-treatment but pre-surgery metabolic response by F18-FluorodeoxyglucoseFDG-Positron emission tomographyPETCT and a blood-only molecular residual disease assay ctDNA clearance can accurately predict a pCR added to or instead of a more complex model
Endpoints Primary 1 To determine the predictive power sensitivity specificity ROC characteristic curves of a model combining variables in predicting pCR 2 To determine whether a similar model can be constructed to predict IrAEs
Secondary Endpoints 1 Assess pCR MPR clinical objective response rates ORR EFS and OS and IrAEs 2 Exploratory the feasibility of acquiring novel potential biomarkers - eg Lymphocyte-activation gene 3 LAG3 Lysine-specific histone demethylase1A LSD1 Leukemia inhibitory factor LIF Interleukin 6 IL6 Interleukin 7 IL7
Study Population Participants with histologically confirmed Stage IB-IIIA NSCLC who are considered to have a resectable disease with available baseline tumor tissue for immunohistochemistry IHC and next-generation sequencing NGS except those with known epidermal growth factor receptor EGFR mutations anaplastic lymphoma kinase ALK or receptor tyrosine kinase ROS1 translocation or active known or suspected autoimmune disease
Study Design A prospective single cohort N60 study
Treatment Details Patients with resectable stage Ib-IIIa NSCLC will be treated with new SoC 3 cycles of neoadjuvant nivolumab immunotherapy plus platinum doublet chemo
Sample Size Our planned accrual of 60 patients will result in approximately 15 pCRs assuming an event rate of 25 This will allow us to explore our potential predictors and their univariable associations with pCR andor no-pCR outcomes The top predictors identified in univariable analyses could be used as candidate predictors in a multivariable prediction model This framework would allow for an exploratory multivariable model predicting no-pCR with up to 9 of the top candidate predictors identified in univariable analyses andor up to 3- 4 of the top candidates predicting pCR This assumes a two-sided type I error rate of 00516
Feasibility Our centre treats an average 60 patients per year with resectable NSCLC who are eligible for neoadjuvant therapy As such we should be able to meet our enrollment goal in approximately 12-14 months
Significance A model that can predict pCR could help in identifying pts most likely to benefit from neo-adjuvant chemonivo If subsequently validated such a model would have several applications including pt selection for neo-adjuvant chemoimmuno potential avoidance of surgery in reliably-predicted pCR pts of morbid thoracotomy identification of pts needing additional treatments eg CTLA4 inhibitors or radiotherapy acquisition of important insights into the biological underpinnings of resistance and most crucially identification of novel targets or strategies to overcome resistance
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None