NeuroblastomaPhase 2TOTEM2NCT00918320
Studies of Temozolomide in Combination With Topotecan in Refractory and Relapsed Paediatric Solid Tumours
A Phase 2 study testing Temozolomide/Hycamtin (Topotecan) in people with Neuroblastoma and Brain Tumors, run by Gustave Roussy, Cancer Campus, Grand Paris at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 6 months to 20 years
- Conditions the study is for
- Neuroblastoma, Brain Tumors, Solid Tumors
- What is being tested?
- Temozolomide/Hycamtin (Topotecan)
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 129 participants
- Where
- 1 siteFrance
- Study dates
- Jun 2009to Aug 2015
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months to 20 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Histologically or cytologically confirmed neuroblastoma, brain tumor or other solid tumor (at diagnosis)
- Relapsed or refractory tumors in which correct standard treatment approaches have failed
- No more than 2 lines of prior chemotherapy
- Measurable primary and/or metastatic disease on CT/MRI at least one bi-dimensionally measurable lesion.
- For patients with neuroblastoma, measurable disease will be defined by the modified International Neuroblastoma Staging System (Brodeur et al.1993) completed with MIBG scoring.
- Age at inclusion: 6 months to ≤ 20 years
Show all 19Show fewer
- Lansky play score ≥ 70% or ECOG performance status ≤ 1
- Life expectancy ≥ 3 months
- Adequate organ function:
- Adequate haematological function: haemoglobin ≥ 80 g/l, neutrophil count ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L; in case of bone marrow disease: neutrophils ≥ 0.5 x 109/l and platelets ≥ 75 x 109/l;
- Adequate renal function: normal creatinine related to patient's age:
- 0 - 1 year: ≤ 40 µmol/L
- 1 - 15 years: ≤ 65 µmol/L
- 15 - 20 years: ≤ 110 µmol/L Adequate hepatic function: bilirubin ≤ 1.5 x ULN; AST and ALT ≤ 2.5 x ULN (AST, ALT ≤5xULN in case of liver metastases)
- Wash-out of 4 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas, 2 weeks in case of vincristine alone; 6 weeks in case of prior radiotherapy (except palliative radiotherapy on non measurable lesions). Patients must have recovered from the acute toxic effects of all prior therapy before enrolment into the study.
- Patients previously treated with only one of the 2 drugs are eligible.
- Able to comply with scheduled follow-up and with management of toxicity.
- All patients with reproductive potential must practice an effective method of birth control while on study. Female patients aged > 12 years must have a negative pregnancy test within 7 days before study treatment.
- Written informed consent from patient, parents or legal guardian.
Who cannot join
- Concurrent administration of any other anti-tumour therapy.
- Serious concomitant systemic disorder (for example, active infection including HIV or cardiac disease) that in the opinion of the investigator, would compromise the patient's ability to complete the study.
- History of allergic reaction to the compounds or their solvents.
- History of allergic reaction to Dacarbazine (DITC).
- Galactosemia, Glucose-galactose malabsorption or lactase deficiency.
- Pregnant or breast feeding young women.
- Presence of symptomatic brain metastases in patients with solid non-CNS tumors.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase 2 Single- Arm Studies of Temozolomide in Combination With Topotecan in Refractory and Relapsed Neuroblastoma and Other Paediatric Solid Tumours
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.
Read the 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.
- Conditions
- Neuroblastoma, Brain Tumors, Solid Tumors
- Being tested
- Temozolomide/Hycamtin (Topotecan)
- Keywords
- Temozolomide, Topotecan, paediatric solid tumours, Miscellaneous other solid tumours
- Medical subject headings
- Neuroblastoma, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Temozolomide/Hycamtin (Topotecan)Drug
Also called Hycamtin:Topotecan
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
| Study group | Role | What they receive |
|---|---|---|
| Toptecan + temozolomide | Experimental | Not described Receives: Drug: Temozolomide/Hycamtin (Topotecan) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Response rate
Measured: after 2 cycles=8 weeks of therapy
Secondary outcomes (2)
safety and adverse event profile of the combination safety and adverse event
Measured: 28 days
time-to-event endpoints: duration of response, time to progressive disease, time to treatment failure and overall survival
Measured: every 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jun 2009 (estimated)
- Study startJun 2009
- Primary completionOct 2013
- Study completionAug 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for NeuroblastomaStudies of the same condition, open and under way.
- More trials run by Gustave Roussy, Cancer Campus, Grand ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 129 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gustave Roussy, Cancer Campus, Grand Paris
- Sponsor type
- University, hospital or other
- Collaborators
- St. Anna Kinderkrebsforschung, Catholic University of the Sacred Heart, Erasmus Medical Center
- Responsible party
- Sponsor
- Investigators
- Birgit Geoerger, MD, PHD, Principal investigator, Gustave Roussy, Cancer Campus, Grand Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00918320
- Sponsor's protocol ID
- CSET 2008/1378
- Acronym
- TOTEM2
- Status last verified
- Aug 2026
- First submitted
- 8 Jun 2009
- Last updated
- 19 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Le Teuff G, Castaneda-Heredia A, Dufour C, Jaspan T, Calmon R, Devos A, McHugh K, Leblond P, Frappaz D, Aerts I, Zwaan CM, Ducassou S, Chastagner P, Verschuur A, Corradini N, Casanova M, Rubie H, Riccardi R, Le Deley MC, Vassal G, Geoerger B; European consortium Innovative Therapies for Children with Cancer (ITCC). Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study. Pediatr Blood Cancer. 2020 Jan;67(1):e28032. doi: 10.1002/pbc.28032. Epub 2019 Oct 8.
PubMed 31595663
Study at a glance
From the registry record, last updated by the sponsor on 19 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 2 Single- Arm Studies of Temozolomide in Combination With Topotecan in Refractory and Relapsed Neuroblastoma and Other Paediatric Solid Tumours
- ClinicalTrials.gov ID
- NCT00918320
- Acronym / sponsor ID
- TOTEM2 / CSET 2008/1378
- Conditions
- Neuroblastoma, Brain Tumors, Solid Tumors
- Keywords
- Temozolomide, Topotecan, paediatric solid tumours, Miscellaneous other solid tumours
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 129 participants (actual)
- Lead sponsor
- Gustave Roussy, Cancer Campus, Grand ParisUniversity, hospital or other
- Collaborators
- St. Anna Kinderkrebsforschung, Catholic University of the Sacred Heart, Erasmus Medical Center
- Study start
- Jun 2009
- Primary completion
- Oct 2013 (actual)
- Study completion
- Aug 2015 (actual)
- First posted
- 11 Jun 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Toptecan + temozolomide | Experimental | Drug: Temozolomide/Hycamtin (Topotecan) |
Who may qualify
- Ages
- 6 months to 20 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (19 listed)
- Histologically or cytologically confirmed neuroblastoma, brain tumor or other solid tumor (at diagnosis)
- Relapsed or refractory tumors in which correct standard treatment approaches have failed
- No more than 2 lines of prior chemotherapy
- Measurable primary and/or metastatic disease on CT/MRI at least one bi-dimensionally measurable lesion.
- For patients with neuroblastoma, measurable disease will be defined by the modified International Neuroblastoma Staging System (Brodeur et al.1993) completed with MIBG scoring.
Key exclusion criteria (7 listed)
- Concurrent administration of any other anti-tumour therapy.
- Serious concomitant systemic disorder (for example, active infection including HIV or cardiac disease) that in the opinion of the investigator, would compromise the patient's ability to complete the study.
- History of allergic reaction to the compounds or their solvents.
- History of allergic reaction to Dacarbazine (DITC).
- Galactosemia, Glucose-galactose malabsorption or lactase deficiency.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Temozolomide/Hycamtin (Topotecan)Also: Hycamtin:TopotecanTemozolomide: 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 | Drug | Toptecan + temozolomide |
Primary outcome
Response rate
Time frame: after 2 cycles=8 weeks of therapy
2 secondary outcomes
safety and adverse event profile of the combination safety and adverse event
Time frame: 28 days
time-to-event endpoints: duration of response, time to progressive disease, time to treatment failure and overall survival
Time frame: every 8 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Aug 2026.
- Results publication: PubMed 31595663Le Teuff G, Castaneda-Heredia A, Dufour C, Jaspan T, Calmon R, Devos A, McHugh K, Leblond P, Frappaz D, Aerts I, Zwaan CM, Ducassou S, Chastagner P, Verschuur A, Corradini N, Casanova M, Rubie H, Riccardi R, Le Deley MC, Vassal G, Geoerger B; European consortium Innovative Therapies for Children with Cancer (ITCC). Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study. Pediatr Blood Cancer. 2020 Jan;67(1):e28032. doi: 10.1002/pbc.28032. Epub 2019 Oct 8.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Birgit Geoerger, MD, PHD principal investigator
Gustave Roussy, Cancer Campus, Grand Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Temozolomide/Hycamtin (Topotecan) in people with Neuroblastoma and Brain Tumors, run by Gustave Roussy, Cancer Campus, Grand Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Response rate (time frame: after 2 cycles=8 weeks of therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00918320, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Aug 2026.