Temsirolimus Infusion for Brain Tumor

Overseen By Phase 0 Navigator

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Nader Sanai

Disqualifiers: Interstitial lung disease, Pregnancy, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on another investigational drug, you must stop it at least 30 days before starting the trial treatment.

What data supports the effectiveness of the drug Temsirolimus for brain tumors?

Temsirolimus, an mTOR inhibitor, has shown promise in treating various cancers, including breast cancer and renal cell carcinoma, with response rates of 10-20% in some studies. It is also being evaluated for melanoma and has shown effectiveness in mantle-cell lymphoma with a 40% response rate. ^{1 2 3 4 5}

Is temsirolimus safe for humans?

Temsirolimus has been studied in various clinical trials, showing some side effects like rash, mouth sores, and fatigue. In combination with other drugs, it can cause low platelet counts, which are cells that help blood clot. The maximum tolerated dose varies depending on the formulation and combination with other treatments. ^{1 2 4 6 7}

How is the drug Temsirolimus unique for treating brain tumors?

Temsirolimus is unique because it is an mTOR inhibitor, which means it blocks a specific protein that helps cancer cells grow. It is given through an infusion (a slow injection into a vein) and is being studied for its potential to treat brain tumors, which is different from many standard treatments that might not target this specific pathway. ^{1 2 5 8 9}

What is the purpose of this trial?

This is a single-center, open-label, dose-escalating Phase 0 trial that will enroll participants with a confirmed diagnosed recurrent high-grade glioma (grade 3 or 4 per WHO criteria) targeting the mTOR pathway. Eligible participants will be administered a single infusion of temsirolimus through super-selective intra-arterial infusion or intravenous infusion. Participants will receive the study drug administration on the same day as the planned surgical resection of the tumor.

Research Team

Nader Sanai, MD

Principal Investigator

Chief Scientific Officer/Director

Eligibility Criteria

Adults over 18 with a specific type of brain tumor called high-grade glioma that's come back after initial treatment can join. They must have completed the Stupp regimen, not be pregnant or able to become pregnant, and agree to use effective contraception. People with serious medical conditions like active infections or lung disease, recent other trials, or live vaccinations are excluded.

Inclusion Criteria

My cancer shows specific genetic changes related to mTOR signaling.

My bone marrow and organs are functioning well.

I have a tumor that can be measured and is at least 1 cm in size.

Exclusion Criteria

Participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, active infection, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance]

Pregnancy or lactation

Known hypersensitivity to temsirolimus or its metabolites, polysorbate 80, or to any other component of temsirolimus

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of temsirolimus via super-selective intra-arterial infusion or IV on the same day as the planned surgical resection of the tumor

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Temsirolimus

Trial Overview This trial tests Temsirolimus delivered directly into the artery feeding the tumor or through an IV on the same day as surgery to remove the tumor. It's for those whose tumors show certain changes in their mTOR pathway and is designed to find out how different doses affect patients.

Participant Groups

Group I: Single infusion of Temsirolimus Experimental Treatment 1 Intervention

Single infusion of Temsirolimus via super-selective intra-arterial infusion or IV

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

Approved in European Union as Torisel for:

• Renal cell carcinoma

Approved in United States as Torisel for:

• Advanced renal cell carcinoma

Who Is Running the Clinical Trial?

Nader Sanai

Lead Sponsor

Trials

11

Recruited

440+

Barrow Neurological Institute

Collaborator

Trials

27

Recruited

7,100+

Ivy Brain Tumor Center

Collaborator

Trials

12

Recruited

910+

Findings from Research

In a study involving 63 patients with advanced cancer, temsirolimus was found to be generally well tolerated, with a maximum tolerated dose established at 15 mg/m²/day for heavily pretreated patients and 19 mg/m²/day for minimally pretreated patients.

The treatment showed promising preliminary antitumor activity, with one patient achieving a confirmed partial response lasting 12.7 months, and several others showing stable disease for over 24 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Hidalgo, M., Buckner, JC., Erlichman, C., et al.[2014]

In a Phase 1 study involving 10 Japanese patients with advanced solid tumors, the maximum-tolerated dose of temsirolimus was determined to be 15 mg/m², with significant toxicities observed at higher doses, including Grade 3 stomatitis and diarrhea.

Temsirolimus demonstrated dose-dependent pharmacokinetics, with peak blood concentrations of both temsirolimus and its active metabolite sirolimus increasing with higher doses, indicating a need for careful dose management in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 clinical study of temsirolimus (CCI-779) in Japanese patients with advanced solid tumors. Fujisaka, Y., Yamada, Y., Yamamoto, N., et al.[2014]

Temsirolimus, an intravenous drug that targets the mTOR kinase, shows immunosuppressive and antiproliferative effects, particularly in cancers like breast cancer, glioblastoma, and renal cell carcinoma, with response rates between 10% to 20%.

In mantle-cell lymphoma, temsirolimus has a higher response rate of 40%, indicating its potential effectiveness, especially when used in combination with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Update on clinical activity of CCI779 (temsirolimus), mTOR inhibitor]. Mounier, N., Vignot, S., Spano, JP.[2021]

Temsirolimus demonstrated an objective response rate of 9.2% in patients with advanced breast cancer, indicating some level of antitumor activity, particularly in a heavily pretreated population of 109 patients.

The lower dose of 75 mg showed a more tolerable safety profile compared to the higher 250 mg dose, which was associated with increased toxicity, including a notable incidence of grade 3 or 4 depression in 10% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. Chan, S., Scheulen, ME., Johnston, S., et al.[2022]

Temsirolimus, an mTOR inhibitor, significantly enhances the anti-tumor effects of cancer vaccines in murine models for renal cell carcinoma and melanoma, indicating its potential as a powerful adjunct in immunotherapy.

The combination of temsirolimus with HSP-based cancer vaccines leads to stronger immune responses, including increased production of interferon-γ and enhanced formation of CD8 memory T cells, suggesting a robust immune-mediated mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Wang, Y., Wang, XY., Subjeck, JR., et al.[2021]

The maximum tolerated dose of oral temsirolimus for patients with advanced cancer was determined to be 75 mg, with some patients experiencing dose-limiting toxicities such as elevated liver enzymes and rash at higher doses.

Despite some adverse events like mucositis and fatigue, two patients showed minor tumor responses at the 75 mg dose, suggesting potential efficacy that warrants further investigation in metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer. Buckner, JC., Forouzesh, B., Erlichman, C., et al.[2021]

The combination therapy of sorafenib and temsirolimus was found to have a maximum tolerated dose (MTD) of 800 mg daily for sorafenib and 25 mg weekly for temsirolimus, with grade 3 thrombocytopenia being the main dose-limiting toxicity.

Despite the safety established in the phase I component, the phase II component showed minimal efficacy, with no patients remaining progression-free at 6 months and a median progression-free survival of only 8 weeks, leading to the study's early termination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02. Lee, EQ., Kuhn, J., Lamborn, KR., et al.[2023]

Temsirolimus is effective for treating relapsed/refractory mantle cell lymphoma (MCL), but it has a different safety profile compared to its use in renal cell carcinoma, with hematological adverse events being the most common but manageable through dose adjustments.

Gastrointestinal toxicities, particularly diarrhea, are frequent but usually mild, and serious adverse events like grade 3 pneumonitis are rare, especially when temsirolimus is used alone rather than in combination with rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temsirolimus in the treatment of mantle cell lymphoma: frequency and management of adverse effects. Bouabdallah, K., Ribrag, V., Terriou, L., et al.[2022]

This study developed the first population pharmacokinetic (PK) model for temsirolimus and its metabolite sirolimus in pediatric patients with recurrent solid tumors, based on data from 19 patients.

The findings indicate that body weight significantly affects the clearance of temsirolimus, which will help in personalizing dosing for children and improving future clinical trial designs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of temsirolimus and sirolimus in children with recurrent solid tumours: a report from the Children's Oncology Group. Mizuno, T., Fukuda, T., Christians, U., et al.[2021]

References

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

A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. [2014]

2. England pubmed.ncbi.nlm.nih.gov

A Phase 1 clinical study of temsirolimus (CCI-779) in Japanese patients with advanced solid tumors. [2014]

3. France pubmed.ncbi.nlm.nih.gov

[Update on clinical activity of CCI779 (temsirolimus), mTOR inhibitor]. [2021]

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

Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. [2022]

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

Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. [2021]

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

Phase I, pharmacokinetic study of temsirolimus administered orally to patients with advanced cancer. [2021]

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

Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02. [2023]

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

Temsirolimus in the treatment of mantle cell lymphoma: frequency and management of adverse effects. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of temsirolimus and sirolimus in children with recurrent solid tumours: a report from the Children's Oncology Group. [2021]