Treatment Resistance Following Anti-cancer Therapies

Not Applicable

Terminated

• Conditions: Disease Progression
• Interventions: Procedure: De novo tumor tissue biopsy; Procedure: 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.

Study Timeline

• Study Start: 2019-02-13
• Study First Submitted: 2020-06-09
• Study First Submitted QC: 2020-06-16
• Study First Posted: 2020-06-17
• Primary Completion: 2020-12-14
• Study Completion: 2020-12-14
• Results First Submitted: 2021-11-29
• Status Verified: 2024-11
• Results First Submitted QC: 2024-11-25
• Last Update Submitted: 2024-11-25
• Results First Posted: 2024-12-03
• Last Update Posted: 2024-12-03

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 38

Inclusion Criteria

• 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.

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Exclusion Criteria

• 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.

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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; 🇺🇸 Anchorage, Alaska, United States

Clínica Viedma S.A.; 🇦🇷 Viedma, RIO Negro, Argentina

Sanatorio de la Mujer; 🇦🇷 Rosario, Santa FÉ, Argentina

Hospital Britanico de Buenos Aires; 🇦🇷 Caba, Argentina

Grand Hôpital de Charleroi - Site Notre Dame; 🇧🇪 Charleroi, Belgium

AZ Maria Middelares; 🇧🇪 Gent, Belgium

Clinique Saint-Pierre Ottignies; 🇧🇪 Ottignies, Belgium

Southern Cancer Center, PC; 🇺🇸 Mobile, Alabama, United States

Seattle Cancer Care Alliance; 🇺🇸 Seattle, Washington, United States

University of Washington Medical Center; 🇺🇸 Seattle, Washington, United States

Southern Cancer Center, P.C.; 🇺🇸 Daphne, Alabama, United States

The Oncology Institute of Hope Innovation; 🇺🇸 Santa Ana, California, United States

Arizona Oncology Associates, PC - HOPE; 🇺🇸 Tucson, Arizona, United States

UCI Medical Center-Chao Family Comprehensive Cancer Center; 🇺🇸 Orange, California, United States

Sansum Clinic; 🇺🇸 Solvang, California, United States

The Oncology Institute of Hope and Innovation; 🇺🇸 Whittier, California, United States

ICRI-Administrative and Supplies Only; 🇺🇸 Whittier, California, United States

Woodlands Medical Specialists PA; 🇺🇸 Pensacola, Florida, United States

Centro de Educacion Medica e Investigaciones Clinicas"Norberto Quirno" CEMIC; 🇦🇷 Ciudad Autónoma de Bs As, Argentina

UZ Gent; 🇧🇪 Gent, Belgium

Hôpital de Jolimont; 🇧🇪 Haine-Saint-Paul, Belgium

Hôpitaux Civils de Colmar, Centre Hospitalier Louis Pasteur; 🇫🇷 Colmar, France

Centre Jean Perrin; 🇫🇷 Clermont Ferrand, France

CHU Henri Mondor; 🇫🇷 Créteil, France

Institut Jean Godinot; 🇫🇷 Reims Cedex, France

Hôpital La Croix du Sud; 🇫🇷 Quint Fonsegrives, France

Hopital Bégin; 🇫🇷 Saint-Mande, France

Royal Cornwall Hospital; 🇬🇧 Cornwall, United Kingdom

Arizona Oncology Associates, PC-HOPE; 🇺🇸 Tucson, Arizona, United States