Phase II single-arm studies of gemcitabine in combination with oxaliplatin in refractory and relapsed pediatric solid tumors

Pediatric tumors are rare and can be divided in hematlogical malignancies and
solid tumors. In the Netherlands approximately 280 children per year are
diagnosed with a solid tumor. Solid tumors are very heterogeneous and consist
of many small subgroups (less than 20 new patients per year). The overall cure
rate is approximately 70%. In soem subrgoups, such as stage 4 neuroblastoma or
pontine glioma, prognosis is much worse, and cancer is still the leading cause
of death due to disease in children. Therefore, we urgently need new drugs to
improve the prognosis.
In this study we aim at assessing the response rate to a combination of
gemcitabin and oxaliplatin in children with relapsed/refractory solid tumors
who have failed standard treatment. Five different strata will be included:
neuroblastoma, osteosarcoma, medulloblastoma, other brain tumors and other
solid non-brain tumors. For the first 2 cohorts some activity was seen in phase
I studies (oxaliplatin, see the protocol). Medulloblastoma is included because
it is in general the most chemo-sensitive brain tumor. The other 2 groups aim
at screening efficacy in a larger group of children, and are descrptive in
nature.
Gemcitabien showed limited activity in phase I studie sin children, but
in-vitro synergy with oxaliplatin has been dmeonstrated, and this drug is an
anti-metabolite, which are currently not available to childen with solid
tumors. Given its activity in adults (althuogh in carcinomas which are rare in
children) we feel thsi warrants further clinical investigation. Oxaliplatin did
show some activity in phase I studies, is not cross-resistant with cisplatin,
en has a different toxicty profile when compared with cisplatin (no auditory or
renal toxicity).
A 2-weekly schedule was chosen as it is patient friednly and it may caus eless
hematological toxiicty. Both drugs can be combined full-dose in adult studies,
and there are no differences in PK between adults and children. Because of teh
risk of peripheral neuropathy with oxaliplatin currently 12 courses are
planned, however, in case of individual benefit more courses may be given.

To assess the response rate to the combination of gemcitabin plus oxlaiplatin
in 5 different strata of relapsed/refractory pediatric solid tumors, in whom
standard treatment has failed. Secondary objectives are the safety, the
duration of response, the time to progression and survival, and the value of
PET-scans in the response evaluation of osteosarcoma.

This multi-center study will be performed with the ITCC-consortium, with 32
centra in several European countries. It si a single-arm study with 29 subjects
pe arm at maximum. Only in the miscelleneous solid tumor arm 40 patienst may be
included. A 2-stage design is used, hence if no responses occur in the first
9-12 patients (see the protocol for statistical details) an arm may be closed.

Treatment consists of 12 courses of GemOx (or more in case of individual
benefit), which consists of gemcitabine 1000 mg/m2 IV in 100 minutes followed
by oxaliplatin 100 mg/m2 IV in 120 minutes on one day, every 14 days. This
infusions can be given at the day-care unit.

Treatment consists of 12 days of chemotherapy administration at the day-care
unit over a 6-months treatmnet period. Additional visits to the hospital may be
needed for tumor evaluation.

At inclusion we will perform physical examination, tumor-evaluation (scans),
blood tests and a pregnancy test for females with child-bearing potential.
During treatment pateints will have regular blood sampling, and will experience
general side-effects from chemotherapy such as hair loss, nausea and vomiting.
cytopenia, and possibly peripheral neuropathy.
Follow-up tumor evaluations are needed.

For patients with osteosarcoma a tumor biopsy may be necessary. There is a
separate question in this patient group regarding the value of PET-scans for
response evaluation.