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Metronomic Temozolamide in Patients With Recurrent Glioblastoma

Study Purpose

Indication: Subjects with glioblastoma at first relapse after surgery, radiotherapy and first-line temozolomide (TMZ). Objectives: 1. Phase I endpoint:

  • - 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-day cycles.
2. Phase II endpoints: Primary endpoint: Progression-free survival at 6 months. Secondary endpoints: Response rate, toxicity profile, overall survival. Complementary studies: To assess the effect of treatment on plasma concentration of thrombospondin-1 (TSP1), soluble VEGF receptor 1 (sVEGF-1) and VEGF-A, and their correlation with clinical outcome.
  • - To assess the correlation between immunohistochemical expression of PTEN and MGMT proteins, and clinical outcomes.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion Criteria

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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT01308632
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 2/Phase 3
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Grupo Español de Investigación en Neurooncología
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Reynés Gaspar, Dr
Principal Investigator Affiliation Hospital Universitario La Fe de Valencia
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Unknown status
Countries
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Glioblastoma
Additional Details

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.

Arms & Interventions

Arms

Experimental: Temozolamide, irinotecan

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 .

Interventions

Drug: - Temozolamide, irinotecan

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 .

Contact Information

This trial has no sites locations listed at this time. If you are interested in learning more, you can contact the trial's primary contact:

For additional contact information, you can also visit the trial on clinicaltrials.gov.