Intraarterial Carboplatin Combinations for Glioblastoma

Overseen By Marie-Andrée Roy, Nurse

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Université de Sherbrooke

Disqualifiers: Severe psychiatric, Autoimmune, Cardiac, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 48-72 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

The standard of care for glioblastoma (GBM) treatment involves maximal resection followed by concomitant radiotherapy and temozolomide. Progression-free survival (PFS) with this treatment is only 6.9 months and relapse is inevitable. At relapse, there is no consensus regarding the optimal therapeutic strategy. 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 impedes drug entry to the brain. Intraarterial (IA) chemotherapy allows to circumvent this. Using IA delivery of carboplatin, can produce responses in 70% of patients for a median PFS of 5 months. Median survival from study entry was 11 months, whereas the overall survival (OS) 23 months. How can the OS and PFS be improved? By combining chemotherapeutic agents with different mechanisms of action. Study design: In this phase II trial, treatment will be offered at relapse. Surgery will be performed for cytoreduction if it is warranted, followed with a combination IA carboplatin + IA Cealyx (liposomal doxorubicin) or IA carboplatin + IA etoposide phosphate. Toxicity will be assessed according to the NCIC common toxicity criteria. Treatment will consist in either IA carboplatin (400 mg/m\^2) + IA Cealyx (30 mg/m\^2) or IA carboplatin (400 mg/m\^2) + IA etoposide phosphate (400 mg/m\^2) every 4-6 weeks (1 cycle). Up to twelve cycles will be offered. Outcome measurements: Tumor response will be evaluated using the RANO criteria by magnetic resonance imaging monthly. Primary outcome will PFS and tumor response. Secondary outcome will include median OS, toxicity, quality of life (QOL), neurocognition (NC). Putting together these data will allow to correlate clinical and radiological response to QOL and NC.

Will I have to stop taking my current medications?

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 combination used in the clinical trial for glioblastoma?

Research shows that pegylated liposomal doxorubicin (Caelyx) can penetrate the blood-brain barrier better than standard doxorubicin, making it more effective for treating high-grade gliomas, a type of brain tumor. Additionally, combining Caelyx with carboplatin has shown promising activity in treating various solid tumors. ^{1 2 3 4 5}

Is intraarterial carboplatin with pegylated liposomal doxorubicin safe for humans?

Pegylated liposomal doxorubicin (Caelyx) has been shown to have reduced toxicity compared to standard doxorubicin, with fewer cases of severe low white blood cell counts and hair loss. However, it can cause skin-related side effects like hand-foot syndrome, which can range from mild to severe. ^{1 2 6 7 8}

How does intraarterial carboplatin differ from other glioblastoma treatments?

Intraarterial carboplatin is unique because it is delivered directly into the arteries supplying the brain, which can increase drug concentration in the tumor and reduce systemic side effects compared to traditional intravenous methods. This approach may enhance the effectiveness of the drug while minimizing toxicity, making it a promising option for treating glioblastoma. ^{1 9 10 11 12}

Research Team

David Fortin, MD

Principal Investigator

Estrie University Integrated Health and Social Services Center - University Hospital of Sherbrooke

Eligibility Criteria

This trial is for individuals with glioblastoma that has recurred or is relapsing. Participants must have already undergone standard treatment including surgery, radiotherapy, and temozolomide. They should be eligible for additional surgery if needed and able to receive intraarterial chemotherapy.

Inclusion Criteria

Patients should be either sterile or else use a contraceptive strategy (for at least 2 months prior to study accruals)

Written informed consent obtained

I have been diagnosed with glioblastoma multiforme.

Exclusion Criteria

Pregnancy (as confirmed by a positive b-HCG) or actively nursing

Presence of an active autoimmune disease

I haven't had any cancer except for certain skin cancers or cervical cancer in situ in the last 5 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intraarterial carboplatin combined with either Caelyx or etoposide phosphate every 4-6 weeks for up to 12 cycles

48-72 weeks

Monthly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Monthly MRI scans and assessments

Treatment Details

Interventions

• IA Caelyx
• IA Carboplatin
• IA Etoposide Phosphate

Trial Overview The study tests two combinations of intraarterial chemotherapy: Carboplatin with Caelyx versus Carboplatin with Etoposide Phosphate in patients whose glioblastoma has progressed after initial treatment. The goal is to improve progression-free survival (PFS) and overall survival (OS).

Participant Groups

Group I: IA Carboplatin + IA Etoposide Phosphate Experimental Treatment 1 Intervention

Participants will be treated with IA carboplatin + IA etoposide phosphate on each cycle (4-6 weeks), for up to 12 cycles.

Group II: IA Carboplatin + IA Caelyx Experimental Treatment 1 Intervention

Participants will be treated with IA carboplatin + IA liposomal doxorubicin on each cycle (4-6 weeks), for up to 12 cycles.

Who Is Running the Clinical Trial?

Université de Sherbrooke

Lead Sponsor

Trials

317

Recruited

79,300+

Findings from Research

In a study of 22 patients with advanced solid tumors, the combination of Carboplatin and Caelyx was found to have a maximum tolerated dose of Caelyx at 35 mg/m2, with dose-limiting toxicities primarily being hematological, such as febrile neutropenia and thrombocytopenia.

The treatment showed promising antitumor activity, particularly in relapsing ovarian cancer, with three patients responding to therapy, including two complete responses, suggesting that further investigation in phase II studies is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of pegylated liposomal doxorubicin (Caelyx) in combination with carboplatin in patients with advanced solid tumors. Gonçalves, A., Braud, AC., Viret, F., et al.[2013]

Pegylated liposomal doxorubicin, used alone or with tamoxifen, showed moderate efficacy in treating recurrent high-grade glioma, with a 40% overall response rate and 15% progression-free survival at 6 months in trials involving 40 patients.

Both treatment regimens were well tolerated, with palmoplantar erythrodysesthesia as the main side effect, and no significant predictors of clinical response were identified, indicating the need for further research to understand treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Hau, P., Fabel, K., Baumgart, U., et al.[2022]

In a phase II study involving 35 patients with locally advanced breast cancer, the combination of paclitaxel and pegylated liposomal doxorubicin showed significant efficacy, with 71% of patients responding to treatment, including a 17% complete response rate.

The primary side effect observed was skin toxicity, particularly palmar-plantar erythrodysesthesia, but these effects were manageable, and there were no treatment-related deaths, indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin (Caelyx) and paclitaxel in locally advanced breast cancer: a phase II study by the Hellenic Cooperative Oncology Group. Gogas, H., Papadimitriou, C., Kalofonos, HP., et al.[2020]

Polyethylene-glycol-liposomal doxorubicin (Caelyx) has shown promising efficacy in treating high-grade glioma patients, with results comparable to other successful Phase II studies, indicating its potential as a viable treatment option.

Encapsulation of doxorubicin in polyethylene-glycol liposomes significantly enhances its ability to penetrate the blood-brain barrier, which is crucial for effective treatment of brain tumors, and allows for the use of lower doses compared to conventional liposomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in the therapy of high-grade glioma at relapse: pegylated liposomal doxorubicin. Hau, P., Dietrich, J., Fabel, K., et al.[2009]

In a study of 15 patients with recurrent high-grade gliomas, liposomal doxorubicin treatment led to disease stabilization in 54% of patients, indicating moderate efficacy in this challenging condition.

The treatment was well tolerated, with manageable side effects, and resulted in a median overall survival of 40 weeks after therapy, which is promising compared to other studies on recurrent glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin. Fabel, K., Dietrich, J., Hau, P., et al.[2022]

In a phase I study involving 26 patients with advanced solid tumors, the combination of pegylated liposomal doxorubicin (Caelyx) and paclitaxel was found to be feasible, with a maximum tolerated dose established at 15 mg/m2 for Caelyx and 115 mg/m2 for paclitaxel, administered every two weeks.

The treatment regimen showed acceptable toxicity levels, with mild hematologic side effects and no significant cardiotoxicity, while achieving a complete response in one patient and partial responses in four, particularly among breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of paclitaxel (taxol) and pegylated liposomal doxorubicin (caelyx) administered every 2 weeks in patients with advanced solid tumors. Mavroudis, D., Kouroussis, Ch., Kakolyris, S., et al.[2018]

In a study involving 28 patients with advanced androgen-insensitive prostate cancer (AIPC), liposomal PEG-coated doxorubicin (Caelyx) showed limited efficacy, with only three patients achieving biochemical responses and one reporting subjective improvement.

Caelyx demonstrated a low toxicity profile, with no severe Grade 4 toxicities reported, suggesting it could be a safe option for combination therapies in treating this chemotherapy-resistant cancer, although clinicians should monitor for potential delays in PSA response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal doxorubicin (Caelyx) in symptomatic androgen-independent prostate cancer (AIPC)--delayed response and flare phenomenon should be considered. Fosså, SD., Vaage, S., Letocha, H., et al.[2019]

In a trial involving 94 patients with advanced soft-tissue sarcoma, CAELYX (pegylated liposomal doxorubicin) demonstrated a significantly lower incidence of severe myelosuppression and alopecia compared to standard doxorubicin, indicating a better safety profile.

Both CAELYX and doxorubicin showed similar antitumor activity, with response rates of 10% and 9% respectively, suggesting that CAELYX is a viable alternative for treatment with reduced toxicity, warranting further investigation in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Judson, I., Radford, JA., Harris, M., et al.[2022]

Intraarterial chemotherapy with carboplatin resulted in a lower response rate of 12.5% for malignant gliomas compared to 45% for ACNU, indicating that carboplatin is less effective in achieving remission.

Carboplatin treatment was associated with a higher incidence of neurotoxicities, including serious side effects like hemiparesis and blindness, suggesting it may pose greater risks compared to ACNU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of intraarterial carboplatin and ACNU for the treatment of gliomas. Fujiwara, T., Matsumoto, Y., Honma, Y., et al.[2022]

Encapsulating platinum drugs like carboplatin in liposomes significantly reduces toxicity and enhances their anti-cancer effects, allowing for higher doses to be used safely in glioblastoma treatment.

Intra-arterial administration of carboplatin or its liposomal formulation Lipoxal™, especially when combined with blood-brain barrier disruption, leads to improved tumor control and increased survival time in Fischer rats with glioma, outperforming traditional intravenous methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain. Charest, G., Sanche, L., Fortin, D., et al.[2021]

In a Phase I study involving 15 patients with various brain tumors, intracarotid carboplatin showed some efficacy, with one patient experiencing partial remission and others showing stable disease, although the median survival was only 9 weeks.

The treatment was associated with mild to moderate nausea and some hematological side effects, but severe complications occurred in patients with pre-existing vascular issues, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of intracarotid administration of carboplatin. Stewart, DJ., Belanger, JM., Grahovac, Z., et al.[2019]

In a phase II study involving 23 patients with malignant gliomas, intraarterial infusion of carboplatin showed promising results, with 26% of evaluable patients achieving a partial response lasting between 3 to 10 months.

Carboplatin demonstrated a favorable safety profile, with mild side effects such as nausea and myelosuppression, and no significant renal or auditory toxicity, suggesting it may be a less toxic alternative to cisplatin for treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraarterial infusion of carboplatin in the treatment of malignant gliomas: a phase II study. Follézou, JY., Fauchon, F., Chiras, J.[2016]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Phase I study of pegylated liposomal doxorubicin (Caelyx) in combination with carboplatin in patients with advanced solid tumors. [2013]

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

Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin (Caelyx) and paclitaxel in locally advanced breast cancer: a phase II study by the Hellenic Cooperative Oncology Group. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Advances in the therapy of high-grade glioma at relapse: pegylated liposomal doxorubicin. [2009]

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

Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Phase I study of paclitaxel (taxol) and pegylated liposomal doxorubicin (caelyx) administered every 2 weeks in patients with advanced solid tumors. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Liposomal doxorubicin (Caelyx) in symptomatic androgen-independent prostate cancer (AIPC)--delayed response and flare phenomenon should be considered. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. [2022]

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

A comparison of intraarterial carboplatin and ACNU for the treatment of gliomas. [2022]

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

Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain. [2021]

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

Phase I study of intracarotid administration of carboplatin. [2019]

12. Slovakia pubmed.ncbi.nlm.nih.gov

Intraarterial infusion of carboplatin in the treatment of malignant gliomas: a phase II study. [2016]