Childhood Cancer Combination Immunotherapy in Hypermutant Cancers

Trial Begins February, 2021
Meet Our Pediatric Team

Uri Tabori, MD

Staff Physician Haematology/OncologyThe Hospital for Sick ChildrenView Bio

Dr. Uri Tabori is a Pediatric Hematologist Oncologist at the Hospital for Sick Children and a Professor for Pediatrics and Medical Biophysics at the University of Toronto.

Dr. Tabori holds the Garron Family Chair in Childhood Cancer Research and maintains an active clinical practice in the treatment of children with cancer, focusing particularly on those with brain tumors.

He is especially interested in translating basic genomic and genetic discoveries for early detection and precision therapeutics in individuals determined to be at high-risk of developing cancers at a young age. As such, he also leads the International Replication Repair Deficiency Consortium.

Daniel Morgenstern, MD

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

Dr. Morgenstern trained in the U.K. with a combined medical/PhD qualification from the University of Cambridge, and then completed paediatric training in London. He was an academic clinical lecturer based at UCL Institute of Child Health and undertook research relating to cancer immunology. Morgenstern subsequently undertook a fellowship in drug development at the Royal Marsden Hospital, Sutton, U.K. and then moved to SickKids as the first Sears Foundation / Garron Cancer Centre Fellow in Neuroblastoma in 2012.

He was a consultant in paediatric oncology at Great Ormond Street Hospital for Children in London before returning to SickKids in 2016 as Staff Oncologist and Director of the New Agent and Innovative Therapies (NAIT) program. His current focus in on the treatment of neuroblastoma and the development of novel therapeutic approaches for hard-to-treat childhood cancers through early phase clinical trials.

View Full Team

Uri Y. Tabori, MD, The Hospital for Sick Children
Daniel Morgenstern, MD, The Hospital for Sick Children
Crystal Mackall, MD, Stanford University
John Maris, MD, Children’s Hospital of Philadelphia

Patient Advocates:
Denise Bebenek
Jenell Holstead

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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.

We Need You

Why Your Participation Matters

Completion of this program will enable us to discover and develop the optimal therapies for a high-risk subset of pediatric cancers with high unmet needs. This will be executed in a rigorous biomarker directed approach and will also uncover novel biomarkers for both the prediction and monitoring of disease response to immunotherapy for eligible patients. The success of this program could be expanded to common adult malignancies which harbor hypermutation.

Key Insights for Participants

This trial consists of two parts. In Part l, patients undergo collection of tumour samples (or analysis of existing samples) to determine their tumour mutation level. Patients with elevated TMB (≥10 mut/mb) may be eligible for Part II. In Part II, patients will receive treatment.

Patients who have had their tumours previously tested by Foundation Medicine and found to have a TMB of ≥10 mut/mb may immediately enter screening for Part 2 of the trial.


Key criteria are summarized below and can be found in detail on 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
Male or female
Age Range:
patients must be ≥12 months and ≤25 years of age at the time of pre-screening enrollment
Relapse, recurrent or refractory hypermutant pediatric cancer


Patients must have recovered from the acute toxic effects of all prior anti-cancer therapies prior to starting treatment.

Patients with history of autoimmune disease are not eligible

Patients with history of interstitial lung disease or pneumonitis are not eligible

Patients who have received a solid organ transplant or allogenic stem cell transplant are not eligible

Patients who have been previously treated with a combination of anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors are not eligible

Patients with brain tumors are not eligible if their tumour is greater than 6 cm in single maximal dimension or there are other concerns about potential toxicity from the treatment if the tumour swells as a result of therapy.

Previous treatment with nivolumab and/or other anti-PD-1/PD-L1 inhibitors is permitted

Previous treatment with ipilimumab and/or other anti-CTLA-4 inhibitors is permitted

All patients who enroll in Part 1 will receive a copy of their Foundation Medicine report. This report will list other mutations in the cancer, which may benefit your child’s treatment.


You play a vital role.

Here are the locations where you can currently participate in this clinical trial. If you or a loved one is interested in enrolling and learning more about this study, please contact the patient coordinator below. The patient coordinator is there to help you understand every aspect of the clinical trial process and answer any questions you may have.

Once you contact the patient coordinator, he or she will start by reviewing your medical history with you to see whether you meet all the criteria to participate. The coordinator will then guide you through a review of the study and detailed “informed consent” documents that you are required to sign when you enroll in a clinical trial.

Toronta, Ontario, Canada

The Hospital for Sick Children
Daniel Morgenstern, MD
P: 416-813-7654 x227565

Vancouver, British Columbia, Canada

British Columbia Children's Hospital
Kirk Schultz, MD, MD

Aurora, Colorado, United States

Children's Hospital Colorado
Lia Gore, MD

Philadelphia, Pennsylvania, United States

<Children's Hospital of Philadelphia (CHOP)
Emily Blauel, MD

Bethesda, Maryland, United States

<National Cancer Institute
Rosandra N. Kaplan, MD

Seattle, Washington, United States

<Seattle Children’s Hospital

Palo Alto, California, United States

<Stanford Children’s Health
Allison Pribnow, MD

Houston, Texas, United States

<Texas Children's Hospital
Shoba A. Navai, MD

Madison, Wisconsin, United States

<University of Wisconsin Hospital and Clinics
Kenneth B. DeSantes, MD

St. Louis, Missouri, United States

<St. Louis Children’s Hospital
Mohamed Abdelbaki, MD
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