Phase II trial of the combination of gemcitabine and 131I-MIBG therapy in paediatric patients with relapsed or progressive neuroblastoma

Pediatric tumors are rare and neuroblastoma accounts for 10% of all childhood
cancers. Neuroblastoma can present in different stages, stage IV in patients
older than 1 year of age represents the most frequent form. This stage is
diagnosed in the Netherlands in 25 patients per year. The overall cure rate for
childhood cancer with current treatment protocols is approximately 70%, buit
cancer is still the leading cause of death due to disease in children. Despite
intensive treatment for neuroblastoma stage IV disease cure rate is far worse:
a 5-year survival rate of only 30-40%. Therefore, we urgently need new drug to
improve prognosis.

In this study we aim at assessing the efficacy and toxicity of the combination
of gemcitabine and 131I-MIBG in children with relapsed or progressive
neuroblastoma. Children will be divided in 2 strata: MIBG pretreated and
MIBG-naive.
Gemcitabine is a type of drug (anti-metabolite) which is currently not
available in the treatment protocols. Its activity is extensively shown in
solid tumours in adults. Furthermore, since gemcitabine has a radiosensitizing
effect, it is part of the combination treatment with external beam radiotherapy
in the treatment of some adult tumours. Extensively preclinical evidence has
proven that gemcitabine as a single drug is quite effective in neuroblastoma
cell lines. In phase I studies with gemcitabine in children, a mild toxicity
profile was seen. The maximum tolerated dose (MTD) of gemcitabine single agent
in children with solid tumors is 1200 mg/m2/dose (3 weeks, 1 weeks rest). The
dosages at which gemcitabine shows radiosensitizing effect are much lower than
the MTD. In this study, we will use a startdose of gemcitabine of 375 mg/m2/
dose. See further design.
131I-MIBG single agent has shown its efficacy in patients with neuroblastoma
both in upfront and in relapse setting with response rates in relapse setting
of 10-43%. Given the radiosensitising effect and the mild toxicity profile we
feel the combination of gemcitabine and 131I-MIBG warrants further clinical
investigation.

To evaluate the efficacy and toxicity of gemcitabine in combination wth
131I-MIBG in pediatric patients with relapsed or progressive neuroblastoma.

This multi-center study will be performed in collaboration with German
Pediatric Oncology Hematology Group (GPOH) in 10-12 different centres in the
Netherlands, Germany and Hong-Kong. It is a single-arm study according to a
2-stage design with stopping rules for efficacy and toxicity. We start with a
dose of 375 mg/m2/dose of gemcitabine. When 6 patients have been treated at the
first dose-level a safety analysis will be performed. If dose-limiting toxicity
is encountered in 2 or more patients, the trial stops or will be amended
(dosing, interval). Otherwise, enrolment will be continued until 19 patients
have been treated. Then an interim analysis will be performed after which, in
case of intermediate reponse and no severe toxicity, study will be continued
with an escalated dose (500 mg/m2). If response rates are very high at interim
analysis and there's limited toxicity, enrollment will be continued at the same
dose of gemcitabine (375 mg/m2) up to 47 patients. If study is continued at the
escalated dose level, another safety analysis will be performed after treating
the first 6 patients and an interim analysis will be perfomed after 19 patients
at that dose.
Patient numbers will be balanced per stratum based on previous MIBG-treatment,
enrollment will be continued until a minimum of patients are included per
stratum.
(see the protocol for statistical details)

Treatment consists of gemcitabine 375 mg/m2 IV in 30 minutes, followed by
131I-MIBG 444 Mbq/kg IV over 1 hour on day 1 in a cycle of 28 days. On Day 8
gemcitabine 375 mg/m2 IV in 30 minutes is given.
Following the treatment with 131I-MIBG the child will be admitted and isolated
to a nuclear medicine ward for 3-5 days at the beginning of the cycle. Children
may be released from the nuclear medicine ward if exposure rate is below a
treshold. On Day 8 gemcitabine infusion will be given at the day-care unit
after which the child can go home.
After 1 cycles response will be assessed. If the patient has clinical benefit
and toxicity is mild, combination treatment can be continued until a maximum of
6 cycles.

Treatment consists of 1-2 x 3-5 days admission to a nuclear medicine ward and
2-4x administration of chemotherapy at the day-care unit. Additional visits to
the hospital may be needed for tumor evalution.

At inclusion we will perform physical examination, tumor evaluation (scans),
blood tests and urine sampling.
During treatment blood tests will be done and chemotherapy is given
Follow-up: tumor evaluation and blood tests will be done.

Common risks during chemotherapy: nausea and vomiting, leukocytopenia and
thrombocyotpenia