Treatment Resistance Following Anti-cancer Therapies

Study Overview
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Brief Summary
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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
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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.

Official Title
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TREATMENT RESISTANCE FOLLOWING ANTI-CANCER THERAPIES (TRANSLATE)

Conditions
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Disease Progression

Intervention / Treatment
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* Procedure: De novo tumor tissue biopsy
* Procedure: Research blood draws


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Tumor biopsy and blood draw<br>Tumor biopsy and blood draw | Procedure: De novo tumor tissue biopsy<br>* De novo tissue biopsy performed following disease progression<br>Procedure: Research blood draws<br>* Blood biospecimens collected following disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the frequency of gene alterations between pre treatment tumor samples and post progression tumor biopsies |  | Through study completion, approximately 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with fully evaluable archival and post progression tumor biopsy (eg, sample sufficient for all intended analyses at all measured time points) |  | Through study completion, approximately 3 months | 
| Concordance of gene alterations between post progression biopsy tissue and blood NGS results |  | Through study completion, approximately 3 months | 
| Change in the frequency of alterations in genes encoding HLA, Beta-2 Microglobulin, STAT1, JAK1, JAK2, IFN-gamma and IFN- gamma R between pre treatment archival and post progression samples |  | Through study completion, approximately 3 months | 
| Frequency of alterations in genes encoding HLA, Beta 2 Microglobulin, STAT1, JAK1, JAK2, IFN-gamma and IFNGR in cfDNA |  | Through study completion, approximately 3 months | 
| Change in the frequency of RB1 gene alterations between pre treatment archival and post progression samples |  | Through study completion, approximately 3 months | 
| Frequency of RB1 gene alterations in cfDNA |  | Through study completion, approximately 3 months | 
| Change in the frequency of AR gene alterations between pre treatment archival and post progression samples |  | Through study completion, approximately 3 months | 
| Frequency of AR gene alterations in cfDNA |  | Through study completion, approximately 3 months | 
| Changes in the expression of nuclear hormone receptors or related RNA signatures reflecting nuclear receptor pathway activity between pre treatment archival and post progression samples |  | Through study completion, approximately 3 months | 
| Change in the frequency of somatic reversion alterations in gBRCA mutant allele between pre treatment archival and post progression samples |  | Through study completion, approximately 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Germline mutated BRCA, HER2- Breast Cancer, Non Small Cell Lung Cancer, Renal Cell Carcinoma, HR+ HER2- Breast Cancer, Castrate-Resistant Prostate Cancer