Treatment Resistance Following Anti-cancer Therapies

TREATMENT RESISTANCE FOLLOWING ANTI-CANCER THERAPIES (TRANSLATE)

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.

Study Overview

• Status: Terminated
• Conditions: Disease Progression
• Intervention / Treatment: Procedure: De novo tumor tissue biopsy; Procedure: Research blood draws

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 Type: Interventional
• Enrollment (Actual): 38
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1280AEB
    • Hospital Britanico de Buenos Aires
  • Ciudad Autónoma de Bs As, Argentina, C1431FWO
    • Centro de Educacion Medica e Investigaciones Clinicas"Norberto Quirno" CEMIC
  • RIO Negro
    • Viedma, RIO Negro, Argentina, 8500
      • Clinica Viedma S.A.
  • Santa FÉ
    • Rosario, Santa FÉ, Argentina, S2000ORE
      • Sanatorio de la Mujer
• Belgium
  • Charleroi, Belgium, 6000
    • Grand Hopital de Charleroi - Site Notre Dame
  • Gent, Belgium, 9000
    • UZ Gent
  • Gent, Belgium, 9000
    • AZ Maria Middelares
  • Haine-Saint-Paul, Belgium, 7100
    • Hôpital de Jolimont
  • Ottignies, Belgium, 1340
    • Clinique Saint-Pierre Ottignies
• France
  • Clermont Ferrand, France, 63011
    • Centre Jean Perrin
  • Colmar, France, 68024
    • Hôpitaux Civils de Colmar, Centre Hospitalier Louis Pasteur
  • Créteil, France, 94010
    • Chu Henri Mondor
  • Quint Fonsegrives, France, 31130
    • Hôpital La Croix du Sud
  • Reims Cedex, France, 51056
    • Institut Jean Godinot
  • Saint-Mande, France, 94160
    • Hopital Bégin
• United Kingdom
  • Cornwall, United Kingdom, TR1 3IJ
    • Royal Cornwall Hospital
• United States
  • Alabama
    • Daphne, Alabama, United States, 36526
      • Southern Cancer Center, P.C.
    • Mobile, Alabama, United States, 36608
      • Southern Cancer Center, PC
    • Mobile, Alabama, United States, 36607
      • Southern Cancer Center, PC
  • Alaska
    • Anchorage, Alaska, United States, 99503
      • Alaska Urological Institute dba Alaska Clinical Research Center
  • Arizona
    • Tucson, Arizona, United States, 85711
      • Arizona Oncology Associates, PC - HOPE
    • Tucson, Arizona, United States, 85704
      • Arizona Oncology Associates, PC-Hope
  • California
    • Glendale, California, United States, 91204
      • The Oncology Institute of Hope Innovation
    • Long Beach, California, United States, 90805
      • The Oncology Institute of Hope Innovation
    • Orange, California, United States, 92868-3201
      • UCI Medical Center-Chao Family Comprehensive Cancer Center
    • Santa Ana, California, United States, 92705
      • The Oncology Institute of Hope Innovation
    • Santa Barbara, California, United States, 93105
      • Sansum Clinic
    • Solvang, California, United States, 93463
      • Sansum Clinic
    • Whittier, California, United States, 90602
      • The Oncology Institute of Hope and Innovation
    • Whittier, California, United States, 90603
      • ICRI-Administrative and Supplies Only
  • Florida
    • Pensacola, Florida, United States, 32503
      • Woodlands Medical Specialists PA
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Tumor biopsy and blood draw	Procedure: De novo tumor tissue biopsy; De novo tissue biopsy performed following disease progression; Procedure: Research blood draws; Blood biospecimens collected following disease progression

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Through study completion, approximately 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	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).	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.	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.	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.	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.	Through study completion, approximately 3 months

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2019
• Primary Completion (Actual): December 14, 2020
• Study Completion (Actual): December 14, 2020

Study Registration Dates

• First Submitted: June 9, 2020
• First Submitted That Met QC Criteria: June 16, 2020
• First Posted (Actual): June 17, 2020

Study Record Updates

• Last Update Posted (Actual): December 3, 2024
• Last Update Submitted That Met QC Criteria: November 25, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Non Small Cell Lung Cancer; Castrate-Resistant Prostate Cancer; Renal Cell Carcinoma; HR+ HER2- Breast Cancer; Germline mutated BRCA, HER2- Breast Cancer
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease Progression
• Other Study ID Numbers: A9001502; TRANSLATE (Alias Study Number); 2018-003612-45 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No