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Childhood Cancer Combination Immunotherapy in Hypermutant Cancers

Trial Begins January 28, 2021
Meet Our Pediatric Team

Uri Tabori, MD

Staff Physician Haematology/OncologyThe Hospital for Sick ChildrenView Bio

Dr. Uri Tabori maintains an active clinical practice in the treatment of children with cancer, focusing particularly on those with brain tumours. Based on his clinical and research interests, he participates in the development of systems for early detection and intervention in individuals determined to be at high-risk of developing brain tumours. This includes patients with neurofibromatosis type 1 and 2, Li-Fraumeni syndrome and mismatch repair genes.

Daniel Morgenstern, MB, BChir, PHD

Staff Physician, Solid Tumour Section, Haematology/OncologyThe Hospital for Sick ChildrenView Bio

Daniel Morgenstern is a Staff Oncologist at Hospital for Sick Children, Toronto and Assistant Professor at the University of Toronto. He originally trained and worked in the UK, primarily at Great Ormond Street Hospital in London where he was clinical lead for the neuroblastoma and autograft programs, and an active member of SIOPEN. Dr Morgenstern moved to SickKids, Toronto in 2016 as Director of the New Agent and Innovative Therapy (NAIT) and Therapeutic mIBG Programs, and co-lead of the neuroblastoma service. He is also Medical Director of the Oncology/BMT Clinical Trials Support Unit. Dr Morgenstern’s clinical activities are focussed on neuroblastoma and solid tumour patients participating in early phase clinical trials. His research interests are in early phase trials and, in particular, the use of immune checkpoint inhibitors in paediatric cancers and the development of precision medicine approaches for paediatric solid tumours.

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About This SU2C Catalyst Clinical Trial

Cancers that have an unusually high number of genetic mutations are referred to as hypermutant. Hypermutant tumors occur in around 5% of cases and can arise in any type of cancer from any organ. These cancers are extremely aggressive. They usually do not respond to currently available therapies, such as chemotherapy and radiation. This is problematic for the treating team and more importantly the patient.

Our team has discovered that hypermutant cancers in children are often caused by inherited mistakes in the genes responsible for repairing errors that may arise in a cell’s DNA as it divides and the DNA is replicated. Hypermutation can also be exacerbated or caused by previous chemotherapy. We were the first to demonstrate that children with hypermutant cancers respond to a particular type of immunotherapy called immune checkpoint inhibition. More importantly, we were able to observe long-term survivorship and improvement in the quality of life. In the last 3 years, we have created mouse models of hypermutant cancers that develop cancers that are similar to the human condition. We are using these models to look for combinations of treatment to test before giving to patients, and through these efforts, we have already established the first international clinical trial for children with hypermutant cancers. In this project, we will work towards two groundbreaking initiatives in the advancement of childhood hypermutant cancer treatment:

1) test new promising drug candidates in combination with immunotherapy on these mouse models and patient derived cell lines and

2) establish the first clinical trial using combination therapy through the new childhood cancer immunotherapy network (PED-CITN).

For the first time, these initiatives will offer a possible cure for children with hypermutant cancers. Through rigorous preclinical testing, we will be able to inform the next clinical trials. Through this iterative process, we will identify the right therapy for the right patient. Not all children will respond to the same therapies, but through these initiatives we will be able to find the right therapies for the right children until all children with hypermutant cancers have a chance at a childhood.

Eligibility

Key criteria are summarized below and can be found in detail on ClinicalTrials.gov. Interested patients will need to review their medical histories with clinical trial patient coordinators before they can be accepted to participate in this trial.

 

  1. A tumor tissue specimen must be available for molecular profiling, which includes TMB analysis
  2. To enter Part 1, Patients do not need to have prior proof of hypermutation. However, they must have evidence of one or more of the following:
    1. Microsatellite Instability (MSI-H)
    2. Mutation causing functional loss of mismatch repair gene expression (MLH1, MSH2, MSH6, PMS2, EPCAM, MSH3)
    3. Functional mutation of POLE or POLD1 genes
    4. A syndrome linked to hypermutant cancer predisposition such as congenital mismatch repair deficiency (CMMRD), Lynch syndrome, or xeroderma pigmentosum (XP).
    5. Other factors or sequencing evidence not listed above but which may be predictive of hypermutant cancer may be permitted after discussion with the protocol principal investigator
    6. A hypermutant tumours
  3. Patients must have measurable disease
  4. To enter Part 2, Patients must have confirmation of cancer with a TMB of >= 10 mutations (mut)/megabase (Mb) as determined by an next generation sequencing (NGS) targeted cancer gene panel performed by Foundation Medicine Inc. (FMI). Proof of TMB eligibility can be from Part 1 participation or a previously acquired FMI report
Gender:
Male or female
Age Range:
patients must be ≥12 months and ≤25 years of age at the time of pre-screening enrollment
Diagnosis:
Relapse, recurrent or refractory hypermutant pediatric cancer
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