Who can enter
- Children and teenagers with cancer in whom the disease has returned (relapse) or responded insufficiently to treatment (refractory).
- Age: up to 18 years.
The goal of this study is to assess how safe and effective a drug (or a combination of drugs) is that matches a molecular alteration in the tumor of children with cancer.
Cancer arises by the accumulation of multiple changes in the DNA, also called molecular alterations. These changes can for example result in uncontrolled growth and division of tumor cells, or insufficient sensitivity to chemotherapy. Therefore, more and more drugs are being developed that are specifically aimed at certain molecular alterations in the tumor.
Previously, the iTHER-study determined which alterations are present in the tumor (the so-called ‘molecular profile’) of children with relapsed or refractory disease. When such an alteration is present, treatment with a drug directly targeting this alteration may be possible in certain cases. This is also called ‘precision medicine’ or ‘targeted therapy’. These treatments are part of the clinical study ESMART.
The ESMART study is divided into different treatment options (so-called ‘arms’). In doing so, we try to choose a drug that matches the molecular alteration in the tumor.
The following ‘arms’ have started:
Arm A: Ribociclib in combination with topotecan and temozolomide (TOTEM)
Ribociclib is a drug that inhibits so-called CDK enzymes. These enzymes enable tumor cells to proliferate. Ribociclib is already used for the treatment of women with breast cancer, but has not yet been registered for the treatment of children. TOTEM has already been used in children, especially in neuroblastoma. By adding ribociclib to the treatment with TOTEM we hope that the treatment will be more effective.
Arm C: AZD1775 in combination with carboplatin
AZD1775 will be given in combination with carboplatin, a chemotherapeutic drug. Chemotherapy causes DNA damage in tumor cells. In order to repair that damage, tumor cells use the so-called WEE1-kinase. AZD1775 inhibits the WEE1-kinase, thus preventing DNA repair and enhancing the effect of chemotherapy.
Arm D: Olaparib in combination with irinotecan
Irinotecan is a chemotherapeutic drug that causes DNA-strand brakes. Olaparib blocks the so-called PARP enzyme, involved in DNA repair, thus preventing damaged cancer cells from repairing themselves. This way, the cancer cells die. Adding olaparib to the treatment with irinotecan may enhance its efficacy. In a recent study among adults with colon cancer, combination of olaparib with irinotecan resulted in stable disease in a number of patients.
Arm I: Enasidenib
A mutation of the IDH gene contributes to the development of tumor cells. This mutation has been found in different types of brain tumors and leukemia. Enasidenib is a drug that inhibits the effect of the IDH mutation. This drug has been studied in adults with a specific type of leukemia (AML), but has not yet been evaluated in children.
Arm J: Lirilumab in combination with nivolumab
The drugs lirilumab and nivolumab are both antibodies, each targeting a different so-called ‘immune checkpoint’. Tumor cells use these immune checkpoints to put a brake on the immune system. Lirilumab and nivolumab release this brake, and enhance the activity of the immune system against tumor cells. Combining lirilumab with nivolumab may be more effective. Nivolumab has been used in children before, but in a different setting. Lirilumab has not yet been used in children, but has been used in adults, also in combination with nivolumab.
This study was initiated by ITCC, an international collaboration that promotes drug research for children with cancer in Europe.
‘European proof-of-concept therapeutic stratification trial of molecular anomalies in relapsed or refractory tumors.’
- Hematologic malignancies
- Solid tumors
1/2, multi arm
Maximum number of patients
280, of whom 25 are expected to participate in the Netherlands
April 5, 2018
Open (Arms A and C are closed for inclusion)
Local principal investigator
Dr. N. van Eijkelenburg
Institut Gustave Roussy, Villejuif, France
The study of this new treatment has been reviewed by an accredited medical research ethics committee. This committee has decided that it is justified to ask patients to participate in this study. More information can be found at: CCMO.
Trial registry number
EudraCT number 2016-000133-40
In order to participate in a study please refer to your/your child’s doctor.
February 21, 2022