IA Carboplatin + Radiotherapy in Relapsing GBM

Summary

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.

Timeline

Start

2018-07-10

Primary completion

2025-12-10

Completion

2026-06-10

Publications

• Background Mathieu D, Fortin D. The role of chemotherapy in the treatment of malignant astrocytomas. Can J Neurol Sci. 2006 May;33(2):127-40. doi: 10.1017/s0317167100004881.
• Background Drapeau A, Fortin D. Chemotherapy Delivery Strategies to the Central Nervous System: neither Optional nor Superfluous. Curr Cancer Drug Targets. 2015;15(9):752-68. doi: 10.2174/1568009615666150616123548.
• Background Shi M, Fortin D, Sanche L, Paquette B. Convection-enhancement delivery of platinum-based drugs and Lipoplatin(TM) to optimize the concomitant effect with radiotherapy in F98 glioma rat model. Invest New Drugs. 2015 Jun;33(3):555-63. doi: 10.1007/s10637-015-0228-4. Epub 2015 Mar 18.
• Background Blanchette M, Tremblay L, Lepage M, Fortin D. Impact of drug size on brain tumor and brain parenchyma delivery after a blood-brain barrier disruption. J Cereb Blood Flow Metab. 2014 May;34(5):820-6. doi: 10.1038/jcbfm.2014.14. Epub 2014 Feb 12.
• Results Charest G, Paquette B, Fortin D, Mathieu D, Sanche L. Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation. J Neurooncol. 2010 Apr;97(2):187-93. doi: 10.1007/s11060-009-0011-5. Epub 2009 Sep 17.
• Results Goffaux P, Boudrias M, Mathieu D, Charpentier C, Veilleux N, Fortin D. Development of a concise QOL questionnaire for brain tumor patients. Can J Neurol Sci. 2009 May;36(3):340-8. doi: 10.1017/s0317167100007095.
• Results Charest G, Sanche L, Fortin D, Mathieu D, Paquette B. Glioblastoma treatment: bypassing the toxicity of platinum compounds by using liposomal formulation and increasing treatment efficiency with concomitant radiotherapy. Int J Radiat Oncol Biol Phys. 2012 Sep 1;84(1):244-9. doi: 10.1016/j.ijrobp.2011.10.054. Epub 2012 Jan 26.
• Results Dea N, Fournier-Gosselin MP, Mathieu D, Goffaux P, Fortin D. Does extent of resection impact survival in patients bearing glioblastoma? Can J Neurol Sci. 2012 Sep;39(5):632-7. doi: 10.1017/s0317167100015377.
• Results Daigle K, Fortin D, Mathieu D, Saint-Pierre AB, Pare FM, de la Sablonniere A, Goffaux P. Effects of surgical resection on the evolution of quality of life in newly diagnosed patients with glioblastoma: a report on 19 patients surviving to follow-up. Curr Med Res Opin. 2013 Oct;29(10):1307-13. doi: 10.1185/03007995.2013.823858. Epub 2013 Jul 30.
• Results Charest G, Sanche L, Fortin D, Mathieu D, Paquette B. Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain. J Neurooncol. 2013 Dec;115(3):365-73. doi: 10.1007/s11060-013-1238-8. Epub 2013 Sep 13.
• Results Fortin D, Morin PA, Belzile F, Mathieu D, Pare FM. Intra-arterial carboplatin as a salvage strategy in the treatment of recurrent glioblastoma multiforme. J Neurooncol. 2014 Sep;119(2):397-403. doi: 10.1007/s11060-014-1504-4. Epub 2014 Jun 20.

Drugs

Indications