Treatment Resistance Following Anti-cancer Therapies

TREATMENT RESISTANCE FOLLOWING ANTI-CANCER THERAPIES (TRANSLATE)

Status

Terminated

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04436120

Enrollment

Registered

2020-06-17

Start date

2019-02-13

Completion date

2020-12-14

Last updated

2024-12-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Disease Progression

Keywords

Non Small Cell Lung Cancer, Renal Cell Carcinoma, HR+ HER2- Breast Cancer, Castrate-Resistant Prostate Cancer, Germline mutated BRCA, HER2- Breast Cancer

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.

Interventions

PROCEDUREDe novo tumor tissue biopsy

De novo tissue biopsy performed following disease progression

PROCEDUREResearch blood draws

Blood biospecimens collected following disease progression

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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
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.
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.

Countries

Argentina, Belgium, France, United Kingdom, United States

Participant flow

Pre-assignment details

A total of 38 participants were enrolled into 7 cohorts. The Safety Analysis (SA) population included 36 participants who had de novo biopsy or research blood draw performed.

Participants by arm

Arm	Count
Cohort 1: NSCLC Monotherapy Progressive disease on 1st line monotherapy anti-PD-1/-L1.	1
Cohort 2: NSCLC Combination Progressive disease on 1st line anti-PD-1/-L1 plus standard doublet platinum-containing regimen; or progressive disease on 1st line anti-PD-1/-L1 plus standard doublet platinum-containing regimen followed by continuation of single agent anti-PD-1/-L1.	4
Cohort 3: RCC With Clear Cell Component Progressive disease on 2nd line monotherapy anti-PD-1/-L1; or progressive disease on 1st line combination of doublet anti-PD-1/-L1 with anti-CTLA-4; or progressive disease on 1st line combination of avelumab with axitinib or pembrolizumab with axitinib.	5
Cohort 4: HR+ HER2- Adenocarcinoma of the Breast Progressive disease on 1st line combination of doublet palbociclib with hormonal therapy.	10
Cohort 5: Castrate-resistant Adenocarcinoma of the Prostate Progressive disease on enzalutamide monotherapy.	5
Cohort 6: Castrate-resistant Adenocarcinoma of the Prostate Progressive disease on abiraterone in combination with prednisone.	10
Cohort 7: gBRCAm HER2- Adenocarcinoma of the Breast Progressive disease on a PARP inhibitor monotherapy in participants previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.	1
Total	36

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006
Overall Study	neither a de novo biopsy nor a research blood draw	0	0	0	1	0	1	0

Baseline characteristics

Characteristic	Cohort 7: gBRCAm HER2- Adenocarcinoma of the Breast	Total	Cohort 1: NSCLC Monotherapy	Cohort 2: NSCLC Combination	Cohort 3: RCC With Clear Cell Component	Cohort 4: HR+ HER2- Adenocarcinoma of the Breast	Cohort 5: Castrate-resistant Adenocarcinoma of the Prostate	Cohort 6: Castrate-resistant Adenocarcinoma of the Prostate
Age, Continuous	43.0 Years	67.1 Years STANDARD_DEVIATION 8.99	73.0 Years	70.8 Years STANDARD_DEVIATION 6.9	65.0 Years STANDARD_DEVIATION 9.11	66.6 Years STANDARD_DEVIATION 6.88	76.0 Years STANDARD_DEVIATION 9.85	64.7 Years STANDARD_DEVIATION 6.62
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	6 Participants	1 Participants	0 Participants	1 Participants	3 Participants	1 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants	18 Participants	0 Participants	3 Participants	3 Participants	6 Participants	3 Participants	3 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants	12 Participants	0 Participants	1 Participants	1 Participants	1 Participants	1 Participants	7 Participants
Race/Ethnicity, Customized Multiracial	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Not reported	1 Participants	7 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants	4 Participants
Race/Ethnicity, Customized White	0 Participants	28 Participants	1 Participants	4 Participants	3 Participants	10 Participants	4 Participants	6 Participants
Sex: Female, Male Female	1 Participants	12 Participants	0 Participants	0 Participants	1 Participants	10 Participants	0 Participants	0 Participants
Sex: Female, Male Male	0 Participants	24 Participants	1 Participants	4 Participants	4 Participants	0 Participants	5 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk
deaths Total, all-cause mortality	0 / 1	0 / 4	0 / 5	0 / 10	0 / 5	0 / 10	0 / 1
other Total, other adverse events	0 / 1	0 / 4	0 / 5	1 / 10	1 / 5	0 / 10	0 / 1
serious Total, serious adverse events	0 / 1	0 / 4	0 / 5	0 / 10	0 / 5	0 / 10	0 / 1

Outcome results

Primary

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.