Trial Information

A Phase I Trial Using Irinotecan, Vincristine, and Dexamethasone In Children With Relapsed And/Or Refractory Hematologic Malignancies

TREATMENT PLAN

Treatment This is a phase I trial of irinotecan, vincristine, and dexamethasone administered
over a 2-week period. Each treatment course will be a minimum of 21 days from the first
day of irinotecan. Cycles may be repeated after hematologic recovery every 21 days if in
the opinion of the primary physician the patient received some benefit from the
chemotherapy. Irinotecan pharmacokinetic studies for each patient will be performed with
the first course of therapy. From 4 to 18 patients will be treated to determine the MTD,
irinotecan pharmacokinetics, and biologic effects of this combination of chemotherapeutic
agents.

Drug Dosages for Each Course Irinotecan, 20 mg/m2/day IV, Days 1-5, 8-12

**Dexamethasone Days 6-10 Vincristine 1.5 mg/m2/day IV (max 2 mg), Days 1, 8 (patients < 1
year of age or < 10kg in weight: Vincristine 0.05 mg/kg)

CNS Chemotherapy

No intrathecal therapy will be given during the first course for any patients. Triple
intrathecal chemotherapy (MHA) will be given on day 1 of subsequent courses (if patient is
eligible) for patients with NHL or ALL. The age adjusted dosages are as follows:

<12 months Methotrexate 6 mg, Hydrocortisone 12 mg, Ara-C 18 mg 12 -24 months Methotrexate 8
mg, Hydrocortisone 16 mg, Ara-C 24 24-35 months Methotrexate 10 mg, Hydrocortisone 20 mg,
Ara-C 30 ≥36 months Methotrexate 12 mg, Hydrocortisone 24 mg, Ara-C 36

**Dose Escalation for Dexamethasone

The doses for irinotecan and vincristine are fixed. The starting dose for dexamethasone
will be 10 mg/m2/day po divided TID for 5 days. Intra-patient dose escalation will not be
allowed.

Dose Level Dose (mg/m2/day) Dose Level 1 10 Dose Level 2 20
Dose Level 3 30 If the MTD is exceeded at the first dose level, then the subsequent
cohort of patients will be treated at a dose that is 50% (5 mg/m2) lower than the starting
dose.

Inter-Patient Escalation

Escalations are planned in groups of three patients, with up to three additional patients to
be added at the first indication of DLT.

When 3 patients who are evaluable for toxicity have completed 3 weeks of therapy at a dose
level without evidence of dose-limiting toxicity (DLT) subsequent patients may be enrolled
at the next dose level.

If a dose-limiting toxicity is observed in 1 patient from the initial cohort of 3 patients
at a given dose level, up to 3 additional patients will be entered at that dose level. If
none of these additional patients experience a DLT (1/6 with DLT), the dose level will be
escalated.

At the time a second patient has a DLT at a dose level (≥ 2 out of 2 to 6 patients), the MTD
has been exceeded and the next lower dose will be considered the MTD.

If the MTD is exceeded at the first dose level, then the subsequent cohort of patients will
be treated at a dose that is 50% (5 mg/m2) lower than the starting dose. If the MTD is
exceeded at this lower level then the protocol will be stopped.

If the MTD is not reached, the maximum dose level studied will be considered the recommended
dose.

The exception to the above escalation is if the dose-limiting toxicity is diarrhea in both
patients required to define a MTD, then another cohort of patients will be treated at the
same dose level with the addition of oral cefixime. If there are no dose-limiting
toxicities in the cohort that receives cefixime, then dose escalation will continue as above
with all further patients receiving oral cefixime.

Additional Courses

Patients may receive additional courses if in the opinion of the primary physician the
patient received some benefit from the chemotherapy at intervals of 21 days as soon as
hematologic recovery from the therapy has occurred. In addition, patients may receive
intrathecal therapy as directed by the primary physician during these subsequent courses.
Intra-patient escalation will not be allowed.