Personalized Patient Derived Xenograft (pPDX) Modeling to Test Drug Response in Matching Host

Study Overview
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Brief Summary
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By obtaining clinical specimens from participants with triple negative breast cancer (TNBC), colorectal cancer (CRC), high grade serous ovarian cancer (HGSOC), and other select tumor types to establish and profile as freshly implanted tumors in mice, the aim of this study is to identify agents with predicted activity in the host patient while also potentially providing them with personalized cancer treatment options

Detailed Description
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Personalized patient-derived xenografts (pPDX) are increasingly used as tools for drug development in pre-clinical settings, and have been shown to recapitulate the histology and behavior of the cancers from which they are derived. Although, they have been commonly used productively as pre-clinical disease models to study disease biology and drug response, they have not been used prospectively to inform clinical management. pPDX have been employed to inform clinical decision-making in small studies, which have shown high concordance between individual pPDX and patient responses to therapy. While encouraging, the role of this approach in breast, colorectal, ovarian, and other cancer populations and in the context of genomic drug matching strategies remains undefined. This has created an opportunity to evaluate the utility of pPDX as clinical predictors to direct the use of chemo- and targeted therapies in combination with comprehensive genomic and epigenetic analysis for patients with TNBC, CRC, HGSOC and other selected tumor types.

Official Title
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Prospective Evaluation of Freshly Implanted Cancers in Mice to Test Drug Response in Matching Host

Conditions
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Colorectal Neoplasms, Colorectal Cancer, Breast Cancer, Breast Neoplasms, Ovarian Cancer, Ovarian Neoplasm

Intervention / Treatment
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* Other: Molecular Profiling & In Vivo drug testing in pPDX and organoid cultures


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years. Patient diagnosis must be categorized as either (I) OR (II) OR (III) OR (IV): (I) Histologically confirmed Triple Negative Breast Cancer by Institutional and American Society of Clinical Oncology (ASCO)/Cancer of American Pathologists (CAP) guidelines, either: Stage IV (metastatic) disease that has not been treated with systemic therapy in the metastatic setting or Stage I to III (non-metastatic) with residual mass by clinical exam and/or breast imaging following anthracycline + taxane-containing neoadjuvant chemotherapy OR (II) Histologically-confirmed Stage IV colorectal cancer treated with ≤ 1 line of systemic therapy in the metastatic setting, either: Undergoing surgical resection of liver metastases or With metastatic lesions amenable to biopsy OR (III) Histologically-confirmed advanced High Grade Serous Ovarian Cancer, either: Recurrent disease with a life expectancy of at least 12 months or Stage III or IV with residual disease following neoadjuvant chemotherapy, or at risk of high recurrence OR (IV) Histologically confirmed solid tumor not meeting criteria for (I), (II) or (III) above, for which evaluation of investigational therapies is of particular interest or where clinical need exists, at the discretion of the PI Disease amenable to biopsy or surgery for tissue procurement Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Willingness and ability of patient to provide signed voluntary informed consent. Exclusion Criteria: Clinically significant hepatic, renal, cardiac or other organ dysfunction likely to limit participation in clinical trials. Known brain metastasis Any condition that could interfere with a patient's ability to provide informed consent such as dementia or severe cognitive impairment. Any contraindication to undergoing a biopsy procedure.

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Triple Negative Breast Cancer<br>Triple negative breast cancer patients with residual invasive disease following neoadjuvant chemotherapy (n= up to 15) or with newly diagnosed metastatic disease (n=up to 30). After the screening procedures confirms patient eligibility: Molecular Profiling will be performed on clinical sample pPDX generation for in vivo drug testing In vitro organoid culture generation (if sufficient fresh tissue available) Identifying an actionable genomic alteration and drug making a matched treatment therapy recommendation. | Other: Molecular Profiling & In Vivo drug testing in pPDX and organoid cultures<br>* Molecular profiling of host tumour sample and pPDX will be performed and analyzed by an expert panel. In vitro organoid culture generation may also be performed if sufficient fresh tissue is available. Matched treatment recommendation based on profiling and in vivo pPDX drug testing results will be made, if available. This recommendation will be communicated to the primary oncologist.<br>|
| Colorectal Cancer<br>Colorectal cancer patients with metastatic disease undergoing resection of liver metastases, or with lesions amenable to biopsy (n=up to 15). After the screening procedures confirms patient eligibility: Molecular Profiling will be performed on clinical sample pPDX generation for in vivo drug testing In vitro organoid culture generation (if sufficient fresh tissue available) Identifying an actionable genomic alteration and drug making a matched treatment therapy recommendation. | Other: Molecular Profiling & In Vivo drug testing in pPDX and organoid cultures<br>* Molecular profiling of host tumour sample and pPDX will be performed and analyzed by an expert panel. In vitro organoid culture generation may also be performed if sufficient fresh tissue is available. Matched treatment recommendation based on profiling and in vivo pPDX drug testing results will be made, if available. This recommendation will be communicated to the primary oncologist.<br>|
| High Grade Serous Ovarian Cancer<br>High grade serous ovarian cancer patients with recurrent disease with a life expectancy of at least 12 months (n=up to 15), or Stage III or IV with residual disease following neoadjuvant chemotherapy, or at risk of high recurrence (n=up to 15). After the screening procedures confirms patient eligibility: Molecular Profiling will be performed on clinical sample pPDX generation for in vivo drug testing In vitro organoid culture generation (if sufficient fresh tissue available) Identifying an actionable genomic alteration and drug making a matched treatment therapy recommendation. | Other: Molecular Profiling & In Vivo drug testing in pPDX and organoid cultures<br>* Molecular profiling of host tumour sample and pPDX will be performed and analyzed by an expert panel. In vitro organoid culture generation may also be performed if sufficient fresh tissue is available. Matched treatment recommendation based on profiling and in vivo pPDX drug testing results will be made, if available. This recommendation will be communicated to the primary oncologist.<br>|
| Other tumor types<br>Other selected tumor types at the discretion of the PI (n= up to 30) After the screening procedures confirms patient eligibility: Molecular Profiling will be performed on clinical sample pPDX generation for in vivo drug testing In vitro organoid culture generation (if sufficient fresh tissue available) Identifying an actionable genomic alteration and drug making a matched treatment therapy recommendation. | Other: Molecular Profiling & In Vivo drug testing in pPDX and organoid cultures<br>* Molecular profiling of host tumour sample and pPDX will be performed and analyzed by an expert panel. In vitro organoid culture generation may also be performed if sufficient fresh tissue is available. Matched treatment recommendation based on profiling and in vivo pPDX drug testing results will be made, if available. This recommendation will be communicated to the primary oncologist.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of drug sensitive pPDX to a panel of drugs as a predictor of clinical response in matched host | Sensitivity measured by tumor growth inhibition (>80%) or objective tumor response (regression) as per Response Evaluation Criteria In Solid Tumors (RECIST) criteria. | up to 5 years | 
| Rate of results reporting |  | up to 5 years | 
| Rate of pPDX engraftment |  | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of actionable alterations identified in clinical and pPDX samples | Genomic alterations identified using the Ion Proton System for Next-Generation Sequencing (NGS). | up to 5 years | 
| Number of patients with molecular abnormalities in pPDX as identified via NGS eliciting clinical responses while receiving matched treatments. | Overall accuracy of clinical responses as assessed by RECIST criteria in patient tumor. | up to 5 years | 
| Correlation between pPDX and organoid drug sensitivities |  | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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personalized patient-derived xenografts (pPDX), molecular profiling, epigenetic analysis, drug sensitivity testing, triple negative, metastatic, serous