Ex Vivo Drug Sensitivity Testing and Mutation Profiling

Study Overview
=================
Brief Summary
-----------------
This study is a prospective, non-randomized feasibility study. Freshly isolated tumor cells from patients will be screened using state-of-the-art viability assay designed for ex vivo high-throughput drug sensitivity testing (DST). In addition, genetic information will be obtained from cancer and normal (germline) tissue and correlated with drug response. This study will provide the platform for informing treating physician about individualized treatment options. The main outcome of this study will be the proportions of the patients whose treatment was guided by the personalized medicine approach.

Detailed Description
-----------------
PRIMARY OBJECTIVE: The primary objective of the study is to determine feasibility of providing pediatric cancer patients with access to personalized treatment options and clinical management recommendations based on ex vivo drug sensitivity testing (DST) and genomic profiling. SECONDARY OBJECTIVE: The secondary objective of the study is to compare individual outcomes (response and disease-free survival) in patients with pediatric cancers treated with DST-guided therapy as compared to non-DST guided (conventional) therapy. EXPLORATORY OBJECTIVE: To explore associations between genetic abnormalities in malignancies and ex vivo drug response.

Official Title
-----------------
Personalized Ex Vivo Drug Screening and Genomics Profiling to Guide Individualized Treatments for Children With Relapsed or Refractory Solid Tumors and Leukemias

Conditions
-----------------
Recurrent Childhood Acute Myeloid Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Large Cell Lymphoma, Refractory Childhood Acute Lymphoblastic Leukemia, Refractory Childhood Hodgkin Lymphoma, Refractory Childhood Malignant Germ Cell Neoplasm, Recurrent Childhood Brain Tumor, Recurrent Childhood Brainstem Glioma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Childhood Ependymoma, Recurrent Childhood Lymphoblastic Lymphoma, Recurrent Childhood Gliosarcoma, Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients aged 21 years or younger at the time of enrollment on this study of any gender, race or ethnicity. Subjects with suspected or confirmed diagnosis of recurrent or refractory cancer Subjects who are scheduled for or have recently had biopsy or tumor excised (solid tumors) or bone marrow aspirate (blood cancers) Subjects willing to have a blood draw or buccal swab done for the purposes of genetic testing Subjects or their parents or legal guardians willing to sign informed consent Subjects aged 7 to 17 willing to sign assent Exclusion Criteria: Subjects who do not have malignant tissue available and accessible The amount of excised malignant tissue is not sufficient for the ex vivo drug testing and/or genetic profiling. Patients with newly diagnosed tumors and tumors that have high (>90%) cure rate with safe standard therapy.

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Chemorefractory or relapsed patients<br>We intend to enroll chemorefractory or relapsed pediatric patients with all types of cancers where tumor tissue would be available for ex vivo drug screening and genomic profiling. The results of the drug sensitivity assay and genetic screening will be used to inform treating physician about patient-specific drug sensitivity or resistance guiding best therapy choices. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients that receive DST-guided treatmens | This study will be considered successful (feasibility demonstrated) if it is possible to choose and initiate a monotherapy or combination drug regimen based on functional and/or genomics data within 4 weeks in at least 16 out of 25 patients (64%). To achieve at least 90% power, the null hypothesis will be rejected when at least 16 out of 25 patients receive treatment recommendations through functional and/or genomics data within 4 weeks on the study. With that outcome, we would have 95% confidence that the true feasibility rate is at least 30% (95% CI: 0.425, 1). | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessing Objective Response Rate | We will assess changes in cohort Objective Response Rate (ORR) by comparing ORR in patients treated with FPM-guided therapy versus ORR in patients treated with non-FPM guided conventional therapy (standard of care) | Up to 4 years | 
| Assessing Progression-Free Survival (PFS) | We will assess changes in cohort PFS by comparing PFS in patients treated with FPM-guided therapy versus PFS in patients treated with non-FPM guided conventional therapy (standard of care) | Up to 4 years | 
| Assessing Previous vs Trial PFS Ratio (PFS2/PFS1) | We will assess changes in PFS from each patient's previous treatment versus their PFS from the treatment assigned during the trial. Assessments will be made both in the FPM-guided cohort and the non-FPM-guided conventional therapy cohort. Analysis will include both the raw ratio as well as the number of incidences of 30% improved PFS on trial versus previous regimen (PFS2/PFS1 > 1.3x). | Up to 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ex vivo drug sensitivity assay, genomic profiling