PHASE I-II TRIAL OF METRONOMIC TEMOZOLAMIDE WITH INTERMITTENT INTENSIFICATION AND IRINOTECAN IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Study Design: Open label, phase I - II trial. Phase I trial: TMZ will be administered in a
fixed schedule as follows:
- 50 mg/m2/day divided in three daily doses (approx. 17 mg/m2/8 hours) on days 1-7, 9-21,
- 100 mg/m2 in a morning single dose on days 8 and 22
CPT-11 starting dose:
.100 mg/m2 on days 8 and 22, administered 3 to 6 hours after TMZ.(Level 1).One cycle = 28
days. CPT-11 will be escalated in successive cohorts of 3 patients as follows: 115, 130,
145, 160 mg/m2 .
Three patients will be treated at dose level 1. If there is no DLT, 3 new patients will be
treated at dose level 2, and so on. If 1 or 2 of the 3 patients initially recruited at each
treatment level experience DLT, 3 additional patients will be included at the same level. If
DLT is registered in less than 3 of the 6 patients treated at this level, 3 new patients
will be included in the next dose level. If 3 or more of the 6 patients experience DLT, the
phase I trial will be closed and the previous treatment level will be chosen for the phase
II trial. If all 3 initial patients at one level experience DLT, the previous dose level
will be used in the phase II trial.
If DLT is found at dose level 1, phase I trial will be re-started at level -2 (70 mg/m2 )
and -1 (85 mg/m2).
Definition of DLT:
- Absolute neutrophil count (ANC) < 500/ μl > 7 days
- Platelet count < 25000/ μl
- A delay in starting a new cycle by > 7 days to allow recovery from toxicity (ANC ≥
1500/ μl and platelet count ≥ 100000/ μl
- Febrile Neutropenia
- Non-haematological toxicity grade 3-4, except alopecia and nausea/vomiting or diarrhea
without adequate prophylaxis or treatment.
Phase II trial: Patients will receive the treatment schedule at the dose level stated in the
phase I study. Treatment will be maintained until progression or excessive toxicity.
Patient evaluation: A physical examination, blood count, and basic biochemistry assessment
will be performed within 3 weeks before treatment and at each study visit. Tumor recurrence
or progression has to be demonstrated by MRI scan performed within 3 weeks before the first
treatment course and after every second course of chemotherapy. The assessment of tumor
response will be based on criteria defined by Macdonald et al. Study visits will be
performed on days 1, 8, 15 and 22 of first and second treatment course, and on days 8 and 22
thereafter, if no significant toxicity has been observed.
Complementary studies: The immunohistochemical expression of PTEN and MGMT will be assessed
in paraffin sections of tumor tissue of all patients.
Blood samples for enzyme immunoassay of TSP1, sVEGFR-1 and VEGF-A will be collected within
3 weeks before treatment, after course 1 and every 3 treatment courses thereafter.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Efficacy of the treatment (Phase I)
To determine the maximum tolerated dose (MTD) of CPT-11 administered on days 8 and 22 in combination with a fixed, continuous and metronomic regimen of TMZ, given in 28-days cycles to use the Recommended Dose in phase II
every patient should receive at least one cycle ( 28 days)
Reynés Gaspar, Dr
Hospital Universitario La Fe de Valencia
Spain: Spanish Agency of Medicines