Lorem Sit Amet Dolor
Researcher: Lorem Sit Amet

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Pilot Trial to Evaluate the Feasibility and Clinical Utility of Tumor Molecular Profiling to Formulate a Personalized Maintenance Treatment Plan for De Novo Metastatic High Risk and Refractory Pediatr
Translational
Sarcoma
Lay Summary

Abstract: Outcomes in children with solid tumors that are already spread at the time of diagnosis or that do not respond with chemotherapy are generally poor and attempts to intensify treatment have not improved survival.  Personalized medicine is an emerging field of medicine that uses genetic information obtained from the tumor itself to treat one’s cancer.  The role of personalized medicine is being investigated in solid tumors in adults and early results have shown improvement in outcomes for certain cancer types in adults such as breast and ovarian cancer.  Many cancer drugs that can target certain cancer cells but not normal cells are now approved by the FDA and are being used in several solid tumor types in children.  We propose a pilot trial to determine the clinical benefit of analyzing tumor tissue DNA and RNA to help determine an individualized (aka personalized) treatment plan for children with high risk solid tumors.

Relevance: Cancer is the second most common cause of death in children following accidental trauma. Solid tumors account for two-thirds of all cancer-related deaths in children. Advances in medical therapy have resulted in significant progress in the treatment of pediatric solid tumors over the last four decades.  Whereas those with early disease that has not spread have experienced the greatest benefit, there has been little improvement in survival for children whose solid tumors have already spread at time of diagnosis. Children whose tumors fail to respond to standard chemotherapy regimens have even worse outcomes and attempts to further increase the doses of chemotherapy have failed to make any difference.

The role of personalized medicine is being investigated in solid tumors in adults and early results have shown improvement in outcomes for certain adult cancer types such as breast and ovarian cancer.  Many targeted cancer drugs are now approved by the FDA and are being used in several solid tumor types in children such as brain tumors and infantile fibrosarcoma, a type of cancer in infants and young children that forms in fibrous tissue and are often large and fast-growing.  These newer targeted agents are different than chemotherapy and act on specific molecules that are involved in growth and spread of cancer cells.  Unlike chemotherapy which targets all rapidly dividing (both healthy and cancer) cells, these targeted cancer agents generally carry fewer side effects.  By using a personalized medicine approach, we hope to extend and provide a better quality of life for children with advanced solid tumors.

We propose a pilot trial to determine the clinical benefit of analyzing tumor tissue DNA and RNA to help formulate an individualized (aka personalized) treatment plan for children with high risk solid tumors.  Based on the tumor genetic information obtained, we intend to come up with a personalized treatment plan using a combination of up to 3 different FDA approved targeted cancer drugs for each case.  Whereas most currently open trials investigating personalized medicine strategies are aimed towards relapsed cancer, our study is unique in that we intend to use a personalized medicine treatment plan to try to prevent cancer from coming back.

Executive Summary

PI: Michael A. Huang, MD

Co-investigators: Kerry McGowan, MD, Mustafa Barbour, MD, Jun Zhao, DO

Scientific Abstract

The prognosis of metastatic and refractory pediatric solid tumors is generally poor and attempts to intensify therapy have not resulted in improved outcomes.  The role of molecular guided therapy strategies is currently being explored in different adult solid tumors and has resulted in significant improvement in progression free survival (PFS) in certain cancer types (e.g. breast, ovarian CA).  Many targeted cancer drugs are now commercially available and some are already in clinical use for several pediatric solid tumors (e.g. larotrectinib for infantile fibrosarcoma, dabrafenib and trametinib for gliomas).  We therefore propose a pilot trial to evaluate the feasibility and clinical utility of tumor molecular profiling to formulate a personalized (individualized) maintenance treatment plan for newly diagnosed metastatic high risk and refractory pediatric solid tumors. We also seek to determine the impact of this approach on patient quality of life (QoL).

Background and Clinical Significance

Cancer is the second most common cause of pediatric mortality following accidental trauma. Pediatric solid tumors account for two-thirds of all cases. Advances in medical therapy have resulted in significant progress in the treatment of pediatric solid tumors over the last four decades.  Whereas patients with localized disease have experienced the largest benefit, there has been little improvement in survival for patients with metastatic disease.  Patients whose tumors are refractory to conventional treatment regimens fare even worse with attempts to intensify therapy failing to improve outcomes.

In recent years, personalized medicine has come to the forefront owing mainly to the progressive decline in the cost of tumor molecular sequencing, the increase in the number of tumor genes tested in a typical sequencing panel, and the rapidly increasing number of commercially available FDA approved targeted cancer drugs. Whereas further intensification of traditional chemotherapeutic regimens carries a significant burden for both acute and long-term toxicities, adjunctive therapy using targeted cancer drugs have the added attraction of generally carrying reduced risk of treatment complications. Early phase clinical trials have met with encouraging results and have resulted in significant improvement in progression free survival (PFS) in certain cancer types (e.g. breast, ovarian CA).  Several FDA-approved targeted cancer drugs have proven safety and efficacy in pediatric solid malignancies (e.g. larotrectinib for infantile fibrosarcoma, dabrafenib and trametinib for gliomas) while others are being studied in clinical trials. 

Our study is innovative in that we will investigate the feasibility and clinical benefit of tumor molecular profiling to formulate a personalized maintenance treatment approach in de novo pediatric metastatic high risk and refractory solid tumors. Although the role of tumor molecular profiling in directing targeted therapy has been previously investigated in several single US-based institutional studies, all but one of those studies’ primary population was composed of relapsed/refractory cases, the time point at which the disease is expected to be much harder to treat.  Most currently open clinical trials including the COG Pediatric MATCH study are investigating the role of targeted cancer drugs primarily in the relapsed/recurrent setting as well.  By studying the use of personalized medicine approach in newly diagnosed metastatic high risk and refractory pediatric solid tumors, we hope to extend high quality life by delaying or outright preventing the need to apply more deleterious treatments (e.g. high dose alkylator-based chemotherapy, bone marrow transplantation) in the event of likely disease recurrence or progression.  

Another common pitfall of most current personalized medicine trials is the use of single targeted agents.  Our study intends to use combination therapy to mitigate the possibility of treatment resistance.  The proposed study will utilize whole exome (tumor DNA) and matched deep whole transcriptome sequencing (RNA-seq) together with pharmacogenomics analysis thru the Nantomics GPS Cancer platform.  Children with either metastatic high risk (defined as presence of metastatic disease at diagnosis with an estimated 2yr PFS of < 50%) or refractory solid tumors are eligible. Based on the tumor molecular profile, there will be a designated molecular tumor board (composed of at least 3 pediatric oncologists and 1 pediatric oncology pharmacist) that will meet and formulate a personalized maintenance treatment plan that includes up to 3 FDA approved targeted cancer drugs.  Each patient receiving personalized maintenance therapy will be periodically assessed for toxicity. Toxicity data will be collected and assessed according to the NCI CTCAE v5.0 criteria. Dose adjustments will be made according to the organ systems showing the greatest degree of toxicity.

Specific Aims

Aim 1. To evaluate the feasibility of tumor molecular profiling to formulate a personalized maintenance treatment plan for newly diagnosed pediatric metastatic high risk and refractory solid tumors

Hypothesis: Tumor molecular profiling will result in the identification of at least one targetable alteration to incorporate into a personalized maintenance treatment plan in at least two-thirds of newly diagnosed pediatric metastatic high risk and refractory solid tumor cases.

Rationale: Based on previous reports, up to 32-56% of pediatric patients with solid tumors had targetable genomic alterations. We expect that by using more robust molecular DNA and RNA sequencing thru GPS Cancer, we will have similar if not higher chances of incorporating a targeted agent into a personalized maintenance treatment plan for children with metastatic high risk and refractory solid tumors.

Approach: The proposed study will utilize whole exome (tumor DNA) and matched deep whole transcriptome sequencing (RNA-seq) together with pharmacogenomics analysis thru the Nantomics GPS Cancer platform.  Children with either metastatic high risk (defined as presence of metastatic disease at diagnosis with an estimated 2yr PFS of < 50%) or refractory solid tumors are eligible. Based on the tumor molecular profile, the molecular tumor board will determine a personalized maintenance treatment plan that includes up to 3 FDA approved drugs.

Aim 2. To determine disease control rates at 6, 12, 18 and 24 months of pediatric metastatic high risk and refractory solid tumor patients treated according to a personalized maintenance treatment plan.

Hypothesis: Children with metastatic high risk and refractory solid tumors treated according to a personalized maintenance treatment plan will have durable (lasting >6 months) and improved disease control rates (DCR), as well as improved overall survival (OS) and median time to progression (MTP) compared to their non-treated counterparts.

Rationale: The prognoses of metastatic and refractory pediatric solid tumors are generally poor and attempts to intensify therapy have not resulted in improved outcomes.  Early results from the PEDS-MIONCOSEQ study utilizing molecular guided therapy are promising and includes some durable responses. While the primary study population in the above study is composed of refractory/relapsed cases, our study utilizes a more upfront approach for newly diagnosed metastatic high risk and refractory disease. 

Additionally, use of single targeted therapies has been shown to result in treatment resistance over time.  While treatment with the selective BRAF V600e inhibitor demonstrated an initial response in the majority of melanoma cases, PFS was limited due to developed resistance seen within 6-9 months. Our study intends to use combination therapy using up to 3 FDA approved drugs to mitigate this concern.

Approach: We will determine disease control rates (DCR), defined by the percentage of patients with at least stable disease, at 6, 12, 18 and 24 months from initiation of a personalized maintenance treatment regimen for children with metastatic high risk and refractory solid tumors. We will also monitor other clinical outcomes including but not limited to OS and MTP.

Aim 3. To determine the impact of a personalized maintenance treatment strategy on quality of life (QofL) in newly diagnosed pediatric metastatic high risk and refractory solid tumor patients.

Hypothesis: Utilizing a personalized maintenance treatment plan for children with metastatic high risk and refractory solid tumors will result in improved quality of life (QofL) compared to their non-treated counterparts.

Rationale: Further intensification of traditional chemotherapeutic regimens generally results in diminishing returns and significantly increases risk for both acute and long-term toxicities. Adjunctive therapy using targeted cancer drugs, on the other hand, generally carry reduced risk of treatment complications. 

Approach: We will utilize a modified version of the Functional Assessment of Cancer Therapy – General (FACT-G) to measure the impact of this approach on patient QofL.  Only oral agents will be utilized to promote improvement in patient quality of life

Exploratory Aim: To investigate the utility of serial circulating tumor DNA (ctDNA) analysis as a biomarker of treatment response and disease progression in pediatric solid tumor patients.

Hypothesis: Circulating tumor (ctDNA) levels will directly correlate with tumor disease burden and plasma levels will act as sensitive markers of treatment response and disease relapse in pediatric solid tumor patients.

Rationale: ctDNA has potential as a biomarker of treatment response and disease progression in several cancer types.  ctDNA levels have been demonstrated to correlate with tumor burden, with declining levels seen with treatment response.  In addition, ctDNA has shown promise as a non-invasive method for real-time determination of tumor progression. However, there is a lack of standardized methods for ctDNA processing and analysis, which serves as a large hindrance to incorporating ctDNA surveillance into routine clinical practice.

Approach: Using SOPs optimized for downstream ctDNA analysis, plasma samples will be collected prior to initiation of personalized maintenance therapy in children with high risk and refractory solid tumor patients, and every 3 months thereafter until 2 years out or at time of progression/relapse, whichever occurs sooner.

Expertise 

Dr. Michael Angelo Huang is a pediatric oncologist at the Norton Children’s Cancer Institute (affiliate of the University of Louisville, Louisville, KY) whose field of expertise is in neuro-oncology and bone marrow transplantation. He has a vested interest in immunotherapy and molecular targeted therapy.   He completed General Pediatrics residency training at Albert Einstein Medical Center in Philadelphia, PA and subspecialty training in Pediatric Hematology/Oncology/Bone Marrow Transplantation at Penn State Hershey Children's Hospital in Hershey, PA.  He subsequently pursued further training in Pediatric Neuro-Oncology at Penn State Hershey Children's Hospital.

As the Co-Director of the Neuro-Oncology Program of the Norton Children’s Cancer Institute. Dr. Huang has implemented universal molecular profiling for all pediatric gliomas at our institution and has been integral in jump-starting a statewide neuro-oncology molecular tumor board collaboration with the University of Kentucky.  He is the very first grant funding recipient of the Kentucky Pediatric Cancer Research Trust Fund (KPCRTF), a countrywide first-of-its-kind legislation passed in 2015 to support pediatric cancer research and treatment, with an bi-annual allotted budget of $5 million.  He has initiated an early phase clinical trial for molecular high risk medulloblastoma thru the Beat Childhood Consortium (formerly the Neuroblastoma and Medulloblastoma Translational Research Consortium or NMTRC), a worldwide research network of 40+ universities and children's hospitals that offers novel therapies for high-risk pediatric cancers.

Dr. Kerry McGowan is a pediatric oncologist at the Norton Children’s Cancer Institute (affiliate of the University of Louisville, Louisville, KY) whose field of expertise is in solid tumors.   As the Inpatient and Outpatient Medical Director for Norton Children's Cancer Institute, one of her main clinical focus areas is in patient safety and improvement of patient processes.  She also serves as the Director of the Solid Tumor Program at the Norton Children’s Cancer Institute and provides oversight for the children's hospital's Chemotherapy Safety Committee. She completed General Pediatrics residency training at the University of Miami in Miami, FL and subspecialty training in Pediatric Hematology/Oncology/Bone Marrow Transplantation at Nationwide Children's Hospital in Columbus, OH.

 

 

Description of Research Proposal

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Budget

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Integer gravida non felis non euismod. Fusce finibus aliquet consequat. Nam ac metus bibendum, iaculis purus sed, suscipit ligula. Proin et nisi libero. Mauris non urna urna. Nullam augue eros, fringilla sed mauris vitae, porta tincidunt risus. Aliquam sed tincidunt sem. Quisque lacinia quam tortor, imperdiet efficitur odio iaculis in. Sed ultricies condimentum volutpat. Vivamus dignissim faucibus porta.

Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.

Morbi orci urna, ornare non pretium eget, pulvinar eget magna. Ut consectetur efficitur varius. Fusce ac aliquet mauris, at mattis ligula. Quisque est libero, interdum id orci et, ornare luctus diam. Proin commodo lectus id accumsan blandit. Nulla eu turpis interdum, luctus ante ac, imperdiet tellus. In semper enim eu tristique aliquam.

Collaborations and Conflicts of Interest

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Curabitur ut ipsum non odio malesuada vulputate. Morbi maximus, est eu lobortis molestie, tortor sapien hendrerit nisi, in cursus odio diam ut odio. Fusce pulvinar volutpat velit. Aliquam erat volutpat. Integer rhoncus mollis suscipit. Praesent non ipsum mollis, finibus nunc a, scelerisque nibh. In feugiat iaculis velit, eu semper lacus dignissim nec. Praesent vitae nisi leo. Cras venenatis dictum magna ut semper. Sed eget eros nibh. Sed vitae quam sed dolor faucibus elementum. Curabitur interdum porttitor finibus. Nullam tincidunt odio lectus, sit amet rhoncus libero dapibus sed. Sed mollis egestas enim, vel porta tortor volutpat eget.