Treatment Resistance Following Anti-cancer Therapies
- Conditions
- Disease Progression
- Interventions
- Procedure: De novo tumor tissue biopsyProcedure: Research blood draws
- Registration Number
- NCT04436120
- Lead Sponsor
- Pfizer
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 38
- Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors treated as follows:
- Non small cell lung carcinoma (NSCLC) monotherapy: Disease progression (PD) on 1st line monotherapy anti PD-1/ L1.
- NSCLC combination: PD on 1st line anti PD-1/ L1 plus standard doublet platinum containing regimen; or PD on 1st-line anti-PD-1/-L1 plus standard doublet platinum-containing regimen followed by continuation of single agent anti-PD-1/-L1).
- Renal cell carcinoma (RCC) with clear cell component: PD on 2nd line monotherapy anti PD-1/ L1; or PD on 1st line combination of doublet anti-PD-1/ L1 with anti-CTLA-4; or PD on 1st-line combination of avelumab with axitinib or pembrolizumab with axitinib.
- HR+ HER2 adenocarcinoma of the breast: PD on 1st line combination of doublet palbociclib with hormonal therapy.
- Castrate resistant adenocarcinoma of the prostate: PD on enzalutamide monotherapy.
- Castrate resistant adenocarcinoma of the prostate: PD on abiraterone in combination with prednisone.
- germline mutated BRCA (gBRCAm), HER2- breast cancer: PD on a PARP inhibitor monotherapy in patients previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.
- Radiographic evidence of PD, including the target lesion being subjected to biopsy for the study, on the most recent regimen that requires a change in anti-cancer treatment.
- Tumor biopsy taken from a bone or an irradiated target lesion.
- Discontinuation of current or most recent anti cancer therapy due to toxicity and not progressive disease.
- Initiation of new anti-cancer therapy after disease progression prior to planned biopsy.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Tumor biopsy and blood draw De novo tumor tissue biopsy Tumor biopsy and blood draw Tumor biopsy and blood draw Research blood draws Tumor biopsy and blood draw
- Primary Outcome Measures
Name Time Method Change in the Frequency of Gene Alterations Between Pre-treatment Tumor Samples (Archival) and Post-progression (De Novo) Tumor Biopsies Through study completion, approximately 3 months 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With Fully Evaluable Archival and Post-Progression Tumor Biopsy by Cohort Through study completion, approximately 3 months 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
Overall Agreement Rate of Gene Alterations Between Post-Progression Tumor Biopsy and Blood NGS Results Through study completion, approximately 3 months 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.
Change in Frequency of RB1 Gene Alterations Between Pre-Treatment Archival and Post-Progression Samples Through study completion, approximately 3 months 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).Percentage of Participants Who Carried the RB1 Gene Alterations in Post-Progression Blood cfDNA Through study completion, approximately 3 months 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.
Change in Frequency of AR Gene Alterations Between Pre-Treatment Archival and Post-Progression Samples Through study completion, approximately 3 months 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.Percentage of Participants Who Carried the AR Gene Alterations in Post-Progression Blood cfDNA Through study completion, approximately 3 months 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.Change in Expression of Nuclear Hormone Receptors Between Pre-Treatment Archival and Post-Progression Samples Through study completion, approximately 3 months 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.
Trial Locations
- Locations (29)
Alaska Urological Institute dba Alaska Clinical Research Center
馃嚭馃嚫Anchorage, Alaska, United States
Cl铆nica Viedma S.A.
馃嚘馃嚪Viedma, RIO Negro, Argentina
Sanatorio de la Mujer
馃嚘馃嚪Rosario, Santa F脡, Argentina
Hospital Britanico de Buenos Aires
馃嚘馃嚪Caba, Argentina
Grand H么pital de Charleroi - Site Notre Dame
馃嚙馃嚜Charleroi, Belgium
AZ Maria Middelares
馃嚙馃嚜Gent, Belgium
Clinique Saint-Pierre Ottignies
馃嚙馃嚜Ottignies, Belgium
Southern Cancer Center, PC
馃嚭馃嚫Mobile, Alabama, United States
Seattle Cancer Care Alliance
馃嚭馃嚫Seattle, Washington, United States
University of Washington Medical Center
馃嚭馃嚫Seattle, Washington, United States
Southern Cancer Center, P.C.
馃嚭馃嚫Daphne, Alabama, United States
The Oncology Institute of Hope Innovation
馃嚭馃嚫Santa Ana, California, United States
Arizona Oncology Associates, PC - HOPE
馃嚭馃嚫Tucson, Arizona, United States
UCI Medical Center-Chao Family Comprehensive Cancer Center
馃嚭馃嚫Orange, California, United States
Sansum Clinic
馃嚭馃嚫Solvang, California, United States
The Oncology Institute of Hope and Innovation
馃嚭馃嚫Whittier, California, United States
ICRI-Administrative and Supplies Only
馃嚭馃嚫Whittier, California, United States
Woodlands Medical Specialists PA
馃嚭馃嚫Pensacola, Florida, United States
Centro de Educacion Medica e Investigaciones Clinicas"Norberto Quirno" CEMIC
馃嚘馃嚪Ciudad Aut贸noma de Bs As, Argentina
UZ Gent
馃嚙馃嚜Gent, Belgium
H么pital de Jolimont
馃嚙馃嚜Haine-Saint-Paul, Belgium
H么pitaux Civils de Colmar, Centre Hospitalier Louis Pasteur
馃嚝馃嚪Colmar, France
Centre Jean Perrin
馃嚝馃嚪Clermont Ferrand, France
CHU Henri Mondor
馃嚝馃嚪Cr茅teil, France
Institut Jean Godinot
馃嚝馃嚪Reims Cedex, France
H么pital La Croix du Sud
馃嚝馃嚪Quint Fonsegrives, France
Hopital B茅gin
馃嚝馃嚪Saint-Mande, France
Royal Cornwall Hospital
馃嚞馃嚙Cornwall, United Kingdom
Arizona Oncology Associates, PC-HOPE
馃嚭馃嚫Tucson, Arizona, United States