IA Carboplatin + Radiotherapy in Relapsing GBM
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorUniversité de Sherbrooke
About this trial
Treatment of glioblastoma involves an optimal surgery, followed by a combination of radiation and temozolomide chemotherapy. Progression-free survival (PFS) with this treatment is only 6.9 months and relapse is the norm. The rationale behind the fact that limited chemotherapy agents are available in the treatment of malignant gliomas is related to the blood-brain barrier (BBB), which limits drug entry to the brain. Intraarterial (IA) chemotherapy allows to circumvent this. Using IA delivery of carboplatin, the investigators have observed responses in 70% of patients for a median PFS of 5 months. Median survival from study entry was 11 months, whereas the overall survival 23 months. How can this be improved? By coupling radiation with a chemotherapeutic which is also a potent radiosensitizer such as carboplatin.
Study design: In this phase I/II trial, patients will be treated at recurrence; a surgery will be performed for cytoreduction and to obtain tumor sample, followed with a combination of re-irradiation and IA carboplatin chemotherapy. A careful escalation scheme from 1.5Gy/fraction up to 3.5Gy/fraction will allow the investigators to determine the optimal re-irradiation dose (10 fractions of radiation over 2 weeks). Toxicity will be assessed according to the NCIC common toxicity criteria. Combined with radiation, patients will receive 2 treatments of IA carboplatin, 400 mg/m2, 4 hours prior to the first and the sixth radiation fraction. IA treatments will then be continued on a monthly basis, up to a total of 12 months, or until progression.
Outcome measurements: Tumor response will be evaluated using the RANO criteria by magnetic resonance imaging monthly. The investigators will also acquire a sequence that enables the measurement of cerebral blood flow, cerebral blood volume and blood vessel permeability that are all relevant to understand the delivery of therapeutics to the CNS. Primary outcome will be OS and PFS. Secondary outcome will be QOL, neurocognition, and carboplatin delivery.
In vitro intracellular carboplatin accumulation: Tumor samples from re-operation will be be analyzed for intracellular Pt concentration by ICP-MS. The amount of Pt bound to DNA will be measured. The level of apoptosis will be determined for each of the sample.
Putting together these data will allow to correlate clinical and radiological response to QOL, NC (MOCA), and to delivery surrogates for the IA infusion and intracellular penetration of carboplatin.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Histological diagnosis of glioblastoma multiforme
Radiological progression on an MRI scan, according to the RANO criteria, in the context of a known glioblastoma multiforme, already treated with the Stupp protocol of combined radiotherapy-Temozolomide, and progressing. This implies a measurable disease on MRI.
Prior radiotherapy and temozolomide, as per the Stupp protocol, no sooner than 4 weeks, is permitted.
18 of age and over
Disqualifiers
Presence of a severe psychiatric or medical condition that would interfere with treatment administration or study enrolment.
Presence of an active auto-immune disease.
Occurrence of another malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
Pregnancy (as objectivated by a positive b-HCG) or actively nursing
Trial design
Design model
Sequential
Treatments tested in this trial
IA Carbo+ Radiation
Drugcombination of intraarterial carboplatin + radiation in dose escalation
Treatment groups
35 Participants
are divided into 6 treatment groups6
Treatment groupsSee each treatment group below.
Group A: Arm 1: IA Carbo + radiationExperimental treatment 1 intervention
Group B: Arm 2: IA Carbo + radiationExperimental treatment 1 intervention
Group C: Arm 3: IA Carbo + radiationExperimental treatment 1 intervention
Group D: Arm 4: IA Carbo + radiationExperimental treatment 1 intervention
Group E: Arm 5: IA Carbo + radiationExperimental treatment 1 intervention
Group F: Arm 6: IA Carbo + radiationExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Response on MRI using the RANO Criteria
T1, T2, FLAIR and a new diffusion protocol
Time frame
every 4 weeks until progression per RANO criteriaSecondary outcomes
1
Incidence of treatment related Neurocognitive decline
MOCA questionnaire (Montreal Cognitive Assessment)
Time frame
Every 4 weeks until progression per RANO criteria2
Quality of life (QOL) using SNAS questionnaire (Sherbrooke neuro assessment scale for quality of life). Scale range from 30 to 120; the lower scores indicate better quality of life.
SNAS Questionnaire
Time frame
Every 4 weeks until progression per RANO criteria3
In vitro intracellular carboplatin accumulation
samples will then be analysed at one hour intervals for intracellular Pt concentration by Inductively Coupled Plasma Mass Spectrometer (ICP-MS). The amount of Pt bound to DNA will also be measured by ICP-MS. The level of apoptosis will be determined for each of the analysed sample
Time frame
Once, 40 hours after surgerySponsors and contacts
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Source ClinicalTrials.gov