PHASE I-II TRIAL OF METRONOMIC TEMOZOLAMIDE WITH INTERMITTENT INTENSIFICATION AND IRINOTECAN IN PATIENTS WITH RECURRENT GLIOBLASTOMA
18 Years
N/A
Both
Glioblastoma
Trial Information
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:
TMZ
- 50 mg/m2/day divided in three daily doses (approx. 17 mg/m2/8 hours) on days 1-7, 9-21,
and 23-28.
- 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.
Inclusion Criteria:
1. Patients > 18 years old
2. Histological confirmed GB at first relapse, assessed by MRI scan, after surgical
resection or biopsy, radiotherapy, and first-line chemotherapy with TMZ. A TMZ
treatment duration of at least 3 months is required. Previous chemotherapy with
CPT-11 is not allowed.
3. Karnofsky performance status ≥ 70.
4. ANC ≥ 1500/ μl, platelet count ≥ 100000/ μl, haemoglobin > 10 g/dl, serum creatinine
and total bilirubin < 1.5 times the upper limit of laboratory normal, transaminases <
3.0 times the upper limit of laboratory normal.
5. Stable or descending corticosteroid dose ≥ 72 hours before baseline MRI and study
treatment.
6. Life expectancy greater than 3 months
7. Written informed consent.
Exclusion Criteria:
1. Pregnancy or breastfeeding.
2. Neurological impairment that precludes comprehension or treatment administration
3. Vomiting or other condition that interfere with oral administration of TMZ
4. Previous or concurrent malignancy, excluding basal cell carcinomas or in situ
cervical cancer.
5. Concurrent disease that could interfere with treatment
6. Concurrent treatment with enzyme-inducing drugs. Patients under enzyme-inducing
anticonvulsants should discontinue treatment at least one week before study treatment
and begin a new anti-epileptic treatment with non enzyme-inducing drugs if indicated.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Efficacy of the treatment (Phase I)
Outcome Description:
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
Outcome Time Frame:
every patient should receive at least one cycle ( 28 days)
Safety Issue:
Yes
Principal Investigator
Reynés Gaspar, Dr
Investigator Role:
Principal Investigator
Investigator Affiliation:
Hospital Universitario La Fe de Valencia
Authority:
Spain: Spanish Agency of Medicines
Study ID:
GENOM-007
NCT ID:
NCT01308632
Start Date:
November 2007
Completion Date:
June 2012
Related Keywords:
- Glioblastoma
- glioblastoma
- temozolamide
- radiotherapy
- TMZ
- irinotecan
- Glioblastoma
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