Trial Information

Phase 2 Single- Arm Studies of Temozolomide in Combination With Topotecan in Refractory and Relapsed Neuroblastoma and Other Paediatric Solid Tumours

Current treatments for malignant paediatric solid tumors involve a combination of
chemotherapy, surgery and, in certain cases, radiotherapy. This multidisciplinary approach
leads to an overall cure of approximately 70%. Nevertheless, cancer mortality remains the
leading cause of disease-related death in children and adolescents between 1 and 19 years.
This is due to diseases with a poor prognosis, such as metastatic neuroblastoma, sarcoma in
soft tissue and bone and brain tumors. New effective treatments must be found in order to
continue to increase the cure rate of children and adolescents treated for cancer, as well
as to improve the cured patients' quality of life

Neuroblastoma (NB) is a malignant paediatric tumour derived from primordial neural crest
cells. This tumor accounts for 8% to 10% of all cancers with a median age of onset of 22
months. The primary tumor may be located in different anatomic sites such as abdomen (65%),
thorax (19%), pelvis (2%), and cervix (1%). The strongest prognostic factors are age and
stage. Localized NB and those occuring in infants have a 90% survival rate when the
biological profile is favorable. Conversely, in case of Myc-N amplification, survival is
around 30% after conventional treatment and 70% after intensification. More than 50% of
patients have a disseminated tumor at diagnosis, and Stage 4 neuroblastoma in patients older
than 1 year of age represents the most frequent form. Neuroblastoma is a chemosensitive
tumor. Chemotherapy is indicated in large primary tumours to reduce the volume and attempt a
safe surgical resection and to eradicate tumour metastases in disseminated NB. The most
frequently used drugs are alkylating and platinum agents (cyclophosphamide, melphalan,
cisplatin, carboplatin), topoisomerase II inhibitors (doxorubicin, etoposide) and
vinca-alkaloids (vincristine). High-dose chemotherapy (busulfan, melphalan, carboplatin,
etoposide) with autologous bone marrow stem cell support is used as a consolidation
treatment in patients with metastatic disease, as well as maintenance therapy with retinoid
acid. Although such an intensive strategy, the probability of survival of patients over 1
year of age with Stage 4 neuroblastoma is less than 40%. New drugs are urgently needed for
patients with recurrent neuroblastoma.

Central nervous system (CNS) tumors as an entity represent the second most frequent
malignancy in childhood and adolescents. The incidence rate of childhood primary benign and
malignant brain tumors is 3.9 cases per 100,000 person-years, and appears to be increasing.
Two thirds of the new cases are in children less than 15 years of age. The morbidity
associated with CNS tumors exceeds those of other malignancies and is undoubtedly a result
of the neurological and cognitive deficits associated with both the tumor itself and
aggressive multimodal therapy. Current treatment involves surgical resection, mostly
combined with irradiation and/or chemotherapy. This multidisciplinary approach leads to a
cure in about 55% of all brain tumour patients. However, the outcome in small children and
certain malignancies, such as high grade astrocytomas, brain stem glioma and atypical
teratoid/rhabdoid tumors and metastatic primary neuroectodermal tumors
(PNET)/medulloblastoma is still dismal. In addition, treatment with irradiation and/or the
combination of different chemotherapeutic agents is at the limit of tolerance inducing
renal, hepatic, auditory, or hematological toxicity. Moreover, irradiation to the cerebral
hemispheres, especially in small children, induces devastating sequelae. Clinical resistance
to anticancer agents is the primary reason for treatment failure in childhood cancer and the
development of new agents with a new profile of anti-tumour activity and toxicity is highly
warranted.

Other relapsed/refractory non-CNS solid tumors include nephroblastoma, osteosarcoma, Ewing's
sarcoma, rhabdomyosarcoma and soft-tissue sarcomas, and rarer tumours, such as
hepatoblastoma, retinoblastoma, nasopharyngeal carcinoma, and germ-cell tumours. For most of
these tumors, treatment protocols are available for first-line therapy; to a lesser extent,
treatment recommendations are proposed in case of relapse. Depending on the disease, type,
and localization of relapse, treatment may include combinations of salvage chemotherapy,
including high-dose chemotherapy with stem cell rescue, radiotherapy, and surgery.

In several of these diseases, temozolomide (as well as topoisomerase I inhibitors, such as
irinotecan and Topotecan) have shown single agent activity and may be used in combination
schedules.