The TRANSLATE study aims to better understand why tumors become resistant to standard anti-cancer therapies. New tumor biopsy and blood samples are collected after disease progression on standard-of-care anti-cancer treatment and compared to the initial (archival) tumor biopsy sample taken from the same patient. Annotated reports of results from clinical Next Generation Sequencing (NGS) gene panel tests of both tumor and blood are sent directly from the testing lab to the study physician for discussion with the patient during the study. Patients may participate in interventional treatment clinical trials at the same time as participating in the TRANSLATE study. Primary data will be publicly available after the study to support further research.
Background: Development of new cancer treatments requires better understanding of why tumors develop resistance to standard-of-care (SOC) therapies. However, post-progression tumor biopsies are not routinely collected, limiting the tissue available to characterize mechanisms of treatment resistance. The TRANSLATE clinical study is specifically designed to address these critical gaps. Trial design: TRANSLATE is a global, multicenter, translational study designed to collect and compare archival pre-treatment tumor tissue with paired de novo tumor and blood samples obtained following disease progression on SOC therapies, targeting therapeutically important areas of cancer biology. Eligible Tumor Type and Most Recent SOC Therapy: * Non-small-cell lung and Anti-PD-1/-L1 monotherapy * Non-small-cell lung and Anti-PD-1/-L1 + platinum * Clear cell renal cell carcinoma and Anti-PD-1/-L1 monotherapy * Clear cell renal cell carcinoma and Doublet anti-PD-1/-L1 + anti-CTLA-4 * Clear cell renal cell carcinoma and Pembrolizumab + axitinib * Clear cell renal cell carcinoma and Avelumab + axitinib * HR+ HER2- breast and Palbociclib + hormonal therapy * germline mutated BRCA breast and Olaparib or talazoparib monotherapy * Castration-resistant prostate and Enzalutamide * Castration-resistant prostate and Abiraterone + prednisone Eligibility criteria include adults with locally advanced or metastatic tumors; radiographic evidence of progressive disease during the most recent SOC regimen; sufficient archival tumor tissue; and a post-progression tumor lesion that is safely accessible for a new biopsy. The results from clinical NGS panel testing may help inform subsequent treatment plan or identification of relevant interventional clinical trials. Patients are enrolled after disease progression on SOC and before change in treatment and participate in 3 study visits within approximately 3 months. Next-generation sequencing results from analysis of tumor tissue and blood will be returned to the study physician and patient for review at a subsequent study visit within this timeframe. The primary endpoint is the change in frequency of gene alterations between pre-treatment and post-progression tumor biopsies. Secondary endpoints address prioritized scientific hypotheses specific to each target area of biology and indication. Primary data will be publicly available after the study to support further research. Sponsored by Pfizer Inc.; EudraCT: 2018-003612-45.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
38
De novo tissue biopsy performed following disease progression
Blood biospecimens collected following disease progression
Southern Cancer Center, P.C.
Daphne, Alabama, United States
Southern Cancer Center, PC
Mobile, Alabama, United States
Southern Cancer Center, PC
Mobile, Alabama, United States
Alaska Urological Institute dba Alaska Clinical Research Center
Anchorage, Alaska, United States
Arizona Oncology Associates, PC-HOPE
Tucson, Arizona, United States
Change in the Frequency of Gene Alterations Between Pre-treatment Tumor Samples (Archival) and Post-progression (De Novo) Tumor Biopsies
Change in frequency is calculated by (frequency in de novo samples) - (frequency in archival samples). The frequency of each gene alteration is calculated as number of patients who harbored the alteration divided by the total number of patients in the cohort. Only gene alterations with variant allele frequency of 5% or greater were included in the analysis. Two different sequencing techniques were applied so 2 analysis sets were repeated for each cohort: targeted panel next-generation sequencing (NGS) and whole exome sequencing NGS.
Time frame: Through study completion, approximately 3 months
Number of Participants With Fully Evaluable Archival and Post-Progression Tumor Biopsy by Cohort
Estimating the number of fully biomarker evaluable population by cohort to evaluate the success rate in obtaining paired archival and post-progression tumor biopsies that were adequate to meet the objectives of the study
Time frame: Through study completion, approximately 3 months
Overall Agreement Rate of Gene Alterations Between Post-Progression Tumor Biopsy and Blood NGS Results
Genetic alterations detected in blood were compared to those detected in tissue. Only gene alterations with frequency of 5% or greater based on assessment of tumor biopsy were included in the analysis.
Time frame: Through study completion, approximately 3 months
Change in Frequency of RB1 Gene Alterations Between Pre-Treatment Archival and Post-Progression Samples
Mutations in RB1 gene associated with immune function, have also been shown to impact tumor immunogenicity and related with CDK4/6 inhibition. CDK4 or CDK6 complexed with cyclin D1 (CCND1) phosphorylates the retinoblastoma gene product (Rb), releasing the E2F and DP transcription factors that regulate the expression of genes required for entry into the S phase of the cell cycle. Calculation of change in frequency was decribed in the primary endpoint (Outcome Measure 1).
Time frame: Through study completion, approximately 3 months
Percentage of Participants Who Carried the RB1 Gene Alterations in Post-Progression Blood cfDNA
Mutations in RB1 gene associated with immune function, have also been shown to impact tumor immunogenicity and related with CDK4/6 inhibition. CDK4 or CDK6 complexed with cyclin D1 (CCND1) phosphorylates the retinoblastoma gene product (Rb), releasing the E2F and DP transcription factors that regulate the expression of genes required for entry into the S phase of the cell cycle. Percentage of Participants Who Carried the RB1 Gene Alterations in Post Progression Blood cfDNA analysis was only conducted for Cohort 4 as per protocol.
Time frame: Through study completion, approximately 3 months
Change in Frequency of AR Gene Alterations Between Pre-Treatment Archival and Post-Progression Samples
Pre-treatment archival tumor samples and post-progression de novo tumor biopsies were analyzed to identify molecular markers of resistance to selected anti-cancer therapies. Calculation of change in frequency was described for in the primary endpoint (Outcome Measure 1). AR gene Alterations analysis was only conducted for the Cohorts 5 \& 6 as per protocol.
Time frame: Through study completion, approximately 3 months
Percentage of Participants Who Carried the AR Gene Alterations in Post-Progression Blood cfDNA
Androgen receptor (AR) gene alterations can be evaluated as mechanisms of resistance to enzalutamide or abiraterone. Percentage of Participants Who Carried the AR Gene Alterations in Post-Progression Blood cfDNA analysis was conducted as it was only applicable to Cohorts 5 \&6.
Time frame: Through study completion, approximately 3 months
Change in Expression of Nuclear Hormone Receptors Between Pre-Treatment Archival and Post-Progression Samples
The differences in the expression of nuclear hormone receptor (HR) reflecting nuclear receptor pathway activity between the archival and de novo samples. Using HTG panel in BET \[targeted tumor RNA (TTR)\] population and Tempus RNAseq in BET \[whole transcriptome tumor RNA (WTTR)\] population. The unit of HTG expression data for nuclear hormone receptors is normalized expression counts. This Outcome Measure analysis was only conducted for Cohorts 5 \& 6 as per protocol.
Time frame: Through study completion, approximately 3 months
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Arizona Oncology Associates, PC - HOPE
Tucson, Arizona, United States
The Oncology Institute of Hope Innovation
Glendale, California, United States
The Oncology Institute of Hope Innovation
Long Beach, California, United States
UCI Medical Center-Chao Family Comprehensive Cancer Center
Orange, California, United States
The Oncology Institute of Hope Innovation
Santa Ana, California, United States
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