Studies of Temozolomide in Combination With Topotecan in Refractory and Relapsed Paediatric Solid Tumours
Condition: Neuroblastoma; Brain Tumors; Solid Tumors
MeSH terms: Neoplasms; Neuroblastoma
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of the study is to determine whether the combination of Hycamtin (Topotecan) and
      Temozolomide is effective in the treatment of relapsed and refractory neuroblastoma and other
      paediatric solid tumors.
    

Detailed description: 
      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.
    

Intervention name(s): Temozolomide/Hycamtin (Topotecan)
Intervention type(s): Drug
Intervention description(s): Temozolomide: bottles containing 5 capsules of 5, 20, 100 and 250 mg
Hycamtin (Topotecan): a lyophilisate for infusion in vials containing 4 mg
Patients receive during 5 days (Day 1 to Day 5):
Temozolomide 150 mg/m2/day per os, dose will be adjusted to the closest 5 mg, followed one hour later by Hycamtin(Topotecan) 0.75 mg/m2/day as an intravenous infusion over 30 minutes
Other intervention name(s): Hycamtin:Topotecan
Intervention MeSH terms: Temozolomide; Topotecan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Temozolomide; Topotecan; paediatric solid tumours; Miscellaneous other solid tumours