Carboplatin + Radiotherapy for Relapsing Glioblastoma

Overseen By David Fortin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Université de Sherbrooke

Disqualifiers: Severe psychiatric, Auto-immune, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 11

Duration: 2 weeks for initial radiation, followed by monthly IA carboplatin for up to 12 months

35 Participants Needed

Trial Summary

What is the purpose of 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.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Carboplatin combined with Radiotherapy for treating relapsing glioblastoma?

Carboplatin has been shown to enhance the effects of radiation therapy in treating brain tumors, acting as a radiation sensitizer to improve cell killing. In studies, it has demonstrated some effectiveness in stabilizing or partially reducing tumor size in glioblastoma patients, although survival benefits compared to traditional treatments were not significant. ^{1 2 3 4 5}

Is the combination of carboplatin and radiotherapy safe for treating glioblastoma?

Carboplatin combined with radiotherapy has been studied for glioblastoma and other brain tumors, showing mild side effects like nausea and low blood platelet counts, but no significant kidney or hearing issues. Overall, this combination appears to be generally safe in humans. ^{2 4 6 7 8}

How does the drug carboplatin combined with radiotherapy differ from other treatments for relapsing glioblastoma?

Carboplatin, when used with radiotherapy, acts as a radiation sensitizer, meaning it enhances the effectiveness of radiation in killing cancer cells. This combination is unique because it leverages carboplatin's ability to make cancer cells more vulnerable to radiation, which is different from standard treatments that may not use this sensitizing approach. ^{2 3 4 9 10}

Research Team

David Fortin, MD

Principal Investigator

CRC-CHUS

Eligibility Criteria

This trial is for adults over 18 with glioblastoma multiforme that has relapsed after initial treatment with radiotherapy and temozolomide. Participants must have a Karnofsky performance status of 60-100% and adequate blood counts, without impaired bone marrow function or significantly elevated bilirubin levels.

Inclusion Criteria

Hemoglobin > 8 g/dL

Bilirubin ≤ 2 times normal value

My glioblastoma has worsened on MRI after treatment with radiotherapy and Temozolomide.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery

Surgery for cytoreduction and tumor sample collection

1 week

1 visit (in-person)

Treatment

Combination of re-irradiation and intraarterial carboplatin chemotherapy

2 weeks for initial radiation, followed by monthly IA carboplatin for up to 12 months

10 visits (in-person) for radiation, monthly visits for IA carboplatin

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Monthly MRI and assessments

Treatment Details

Interventions

• Carboplatin
• Radiation

Trial Overview The study tests intraarterial (IA) carboplatin combined with re-irradiation in patients whose glioblastoma has recurred. The goal is to find the optimal radiation dose alongside IA chemotherapy, assessing tumor response, quality of life, neurocognition, and drug delivery within the brain.

Participant Groups

Group I: Arm 6: IA Carbo + radiation Experimental Treatment 1 Intervention

400 mg/m\^2 carbo + 35 Gy

Group II: Arm 5: IA Carbo + radiation Experimental Treatment 1 Intervention

400 mg/m\^2 carbo + 30 Gy

Group III: Arm 4: IA Carbo + radiation Experimental Treatment 1 Intervention

400 mg/m\^2 carbo + 25 Gy

Group IV: Arm 3: IA Carbo + radiation Experimental Treatment 1 Intervention

400 mg/m\^2 carbo + 20 Gy

Group V: Arm 2: IA Carbo + radiation Experimental Treatment 1 Intervention

400 mg/m\^2 carbo + 18 Gy

Group VI: Arm 1: IA Carbo + radiation Experimental Treatment 1 Intervention

400 mg/m\^2 carbo + 15 Gy

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Université de Sherbrooke

Lead Sponsor

Trials

317

Recruited

79,300+

Findings from Research

The addition of temozolomide to radiotherapy has shown a statistically significant survival benefit for patients with glioblastoma, marking a notable success in treatment.

Despite previous treatment strategies failing to improve outcomes, this combination therapy has minimal acute toxicity, highlighting its potential as a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Radiotherapy for glioblastomas: from radiobiology to concomitant chemotherapy]. Simon, JM., Toubiana, T., Lang, P., et al.[2018]

In a clinical trial involving 14 patients with newly diagnosed glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), low-dose carboplatin was safely administered alongside radiotherapy without significant toxicities, suggesting a tolerable treatment approach.

Despite the safety of the combined therapy, the results showed no improvement in survival time compared to historical data for patients treated with radiotherapy alone, indicating that carboplatin may not enhance the effectiveness of radiation in these types of brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma. Peterson, K., Harsh, G., Fisher, PG., et al.[2020]

In a study of 25 patients with glioblastoma multiforme, neoadjuvant carboplatin chemotherapy showed promising results, with 6 partial responses and 1 complete response among those with assessable tumors, indicating its potential efficacy before radiation therapy.

The treatment was found to be feasible with modest side effects, and the median survival of 19.2 months suggests that carboplatin could be a valuable option in the management of newly diagnosed glioblastoma multiforme, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin chemotherapy before irradiation in newly diagnosed glioblastoma multiforme. Gruber, ML., Glass, J., Choudhri, H., et al.[2019]

In a study of 56 patients with newly diagnosed glioblastoma, treatment with radiotherapy and concurrent carboplatin plus teniposide followed by carmustine resulted in a median survival time of 12.5 months and a time to progression of 7.5 months.

The treatment was generally well-tolerated, with acceptable levels of toxicity, although 7.1% of patients experienced radiation necrosis, indicating that while the regimen is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and teniposide concurrent with radiotherapy in patients with glioblastoma multiforme: a phase II study. Brandes, AA., Rigon, A., Zampieri, P., et al.[2020]

Combining radiation therapy with intracerebral administration of carboplatin significantly improved survival in F98 glioma-bearing rats, achieving a mean survival time of 107.7 days and a 43% cure rate, compared to 30-35 days for radiation alone.

The study found that using a pump for carboplatin delivery combined with radiation therapy was more effective than convection enhanced delivery (CED), but both methods showed promise, with CED yielding survival rates comparable to those achieved with higher radiation doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy combined with intracerebral administration of carboplatin for the treatment of brain tumors. Yang, W., Barth, RF., Huo, T., et al.[2021]

In a study involving 44 patients with recurrent childhood brain tumors, carboplatin was found to have a disease-specific response rate of 43% in medulloblastoma, indicating its potential effectiveness in treating this type of cancer.

Carboplatin demonstrated a favorable safety profile with mild side effects, such as low emetic effects and no significant auditory or renal toxicity, making it a promising candidate for further studies in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and recurrent childhood brain tumors. Allen, JC., Walker, R., Luks, E., et al.[2017]

Fractionated stereotactic re-irradiation shows a 12-month overall survival rate of 33.1% and a progression-free survival rate of 13.4% in patients with recurrent glioblastoma, based on a meta-analysis of eight studies involving 307 patients.

The treatment has a low incidence of radiation necrosis, indicating it is a relatively safe option for patients, with factors like age and radiation dose affecting survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fractionated stereotactic re-irradiation for recurrent glioblastoma: A systematic review and meta-analysis. Luo, T., Feng, J., Sun, P.[2023]

In a study of 32 patients with recurrent glioma who had previously undergone radiation and chemotherapy, 50% showed a response or stabilization of their disease after two infusions of carboplatin, indicating its efficacy in this challenging patient population.

The median time to tumor progression was 19 weeks and the median survival duration was 38 weeks, with thrombocytopenia being the main side effect, affecting one-third of patients, but no significant neurological or renal toxicities were observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of intravenous carboplatin for the treatment of recurrent gliomas. Warnick, RE., Prados, MD., Mack, EE., et al.[2022]

In a study of 15 patients with relapsed high-grade glioma, carboplatin and iproplatin demonstrated some effectiveness, with one patient from each treatment achieving partial remission based on CT scans.

However, the study was halted due to significant toxicity, including severe myelosuppression and fatal neurotoxicity in one patient, highlighting safety concerns with these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and toxicity of carboplatin and iproplatin in relapsed high-grade glioma. Twelves, CJ., Ash, CM., Miles, DW., et al.[2019]

In a study of 20 patients with high-grade glioma, those treated with high doses of carboplatin had a mean survival time of 10.45 months, which was better than the control group treated with BCNU, who had a mean survival time of 9.85 months.

The high-dose carboplatin treatment was generally well tolerated, and 10% of patients survived beyond 18 months, compared to 0% in the control group, suggesting that carboplatin may be a more effective option for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous administration of high doses of carboplatin in multimodal treatment of high grade gliomas: a phase II study. Lunardi, P., Osman Farah, J., Mastronardi, L., et al.[2019]

References

1. France pubmed.ncbi.nlm.nih.gov

[Radiotherapy for glioblastomas: from radiobiology to concomitant chemotherapy]. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Carboplatin chemotherapy before irradiation in newly diagnosed glioblastoma multiforme. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Carboplatin and teniposide concurrent with radiotherapy in patients with glioblastoma multiforme: a phase II study. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Radiation therapy combined with intracerebral administration of carboplatin for the treatment of brain tumors. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Carboplatin and recurrent childhood brain tumors. [2017]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Fractionated stereotactic re-irradiation for recurrent glioblastoma: A systematic review and meta-analysis. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

A phase II study of intravenous carboplatin for the treatment of recurrent gliomas. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Activity and toxicity of carboplatin and iproplatin in relapsed high-grade glioma. [2019]

10. Austria pubmed.ncbi.nlm.nih.gov

Intravenous administration of high doses of carboplatin in multimodal treatment of high grade gliomas: a phase II study. [2019]