Topotecan for Brain Cancer

(TPT CED rHGG Trial)

Overseen By Jeffrey Bruce, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jeffrey N. Bruce

Must not be taking: Antiretrovirals, CYP3A4/5 substrates

Disqualifiers: CSF disease, Cerebellum tumors, HIV, others

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

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

Compensation: Varies

Number of Visits: 4

Duration: 23-29 days

6 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety of a new method for delivering the chemotherapy drug Topotecan directly to brain tumors in individuals with recurring malignant glioma, a type of brain cancer with a specific mutation. The method, called Convection Enhanced Delivery (CED), uses a pump to send the drug directly to the tumor site, aiming to improve drug distribution and tumor response. Suitable candidates for this trial have already undergone standard treatments for their glioma and show signs of disease progression. Participants will undergo four treatment sessions over approximately one month, with monitoring throughout. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications that are metabolized solely through CYP3A4/5 with a narrow therapeutic index, strong CYP2C8 inhibitors, or those that risk QT prolongation and are CYP3A substrates. If you're on such medications, you must stop them at least two weeks before starting the trial.

What prior data suggests that Convection Enhanced Delivery of Topotecan is safe for patients with recurrent malignant glioma?

A previous study safely administered Topotecan to patients with a specific type of brain cancer using convection-enhanced delivery (CED). This method delivers the drug directly to the brain tumor, reducing side effects in other parts of the body. However, Topotecan can still cause side effects, with myelosuppression being the most common. This condition lowers blood cell counts and weakens the immune system.

The current study aims to assess the safety of using this drug over a longer period. As an early-phase trial, the primary focus is on ensuring the treatment's safety for humans. Early-phase trials closely monitor safety, so participants receive careful monitoring. Patients in the study will undergo regular check-ups and imaging tests to detect and manage any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Topotecan is unique because it is delivered directly to the brain using a method called Convection-Enhanced Delivery (CED). Unlike traditional chemotherapy that circulates throughout the body, this technique allows for targeted delivery of the drug right where it's needed, potentially reducing side effects and enhancing effectiveness. Researchers are excited because this approach could offer a more precise and powerful attack on brain cancer, potentially leading to better outcomes for patients.

What evidence suggests that Convection Enhanced Delivery of Topotecan is effective for brain cancer?

Research has shown that delivering Topotecan directly into the brain using Convection Enhanced Delivery (CED) can effectively target brain tumors. This technique allows Topotecan to bypass the blood-brain barrier, which typically prevents drugs from reaching brain tumors. In earlier trials, patients with recurrent glioblastoma, a type of brain cancer, responded well to this treatment with Topotecan. Specifically, these patients experienced safe delivery of the drug and some reduction in tumor size. In this trial, participants will receive long-term CED of Topotecan. While information on long-term effectiveness is still being gathered, early results suggest that CED could enhance Topotecan's effectiveness against brain tumors. ^{6 7 8 9 10}

Who Is on the Research Team?

Jeffrey Bruce, MD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

This trial is for patients with recurrent malignant glioma, a type of brain tumor that has returned after treatment. Participants must have a specific genetic change in their tumor called an IDH mutation. The study excludes individuals who do not meet these criteria or have other health conditions that could interfere with the trial.

Inclusion Criteria

I am using birth control and, if female, will have a pregnancy test before joining the study.

I can understand and agree to the study's procedures and risks.

My MRI shows a tumor smaller than 32 cc that can be reached with precise tools.

Exclusion Criteria

I do not have an active infection or a fever without a known cause.

I have been treated with topotecan for my cancer.

Women who are breast-feeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive four 48-hour infusions of Topotecan over 23-29 days with 5-7 day rest periods between infusions

23-29 days

4 infusions, regular monitoring through imaging and exams

Follow-up

Participants are monitored for safety and effectiveness after treatment, including tumor response assessment

4-6 weeks

Follow-up MRI and exams

Long-term follow-up

Participants are contacted every 3-6 months to assess progression-free survival and overall survival

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Topotecan

Trial Overview The trial tests chronic Convection Enhanced Delivery (CED) of Topotecan directly to the brain tumor over four infusions across approximately one month. CED involves placing a pump under the skin connected by a catheter to deliver the drug to the tumor site.

How Is the Trial Designed?

Group I: Long-term CED of Topotecan Experimental Treatment 1 Intervention

Six patients will be treated with Topotecan by Convection-Enhanced Delivery. Four 48-hour Topotecan infusions will be carried out over the course of 23-29 days (with five to seven-day drug holiday after the first three infusions). Infusions will take place using Synchromed II infusion pumps with the same infusion parameters and experimental conditions used in our previous Phase I clinical trial and other short-term studies.

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

Approved in European Union as Hycamtin for:

• Ovarian cancer
• Small cell lung cancer
• Cervical cancer

Approved in United States as Hycamtin for:

• Ovarian cancer
• Small cell lung cancer
• Cervical cancer

Who Is Running the Clinical Trial?

Jeffrey N. Bruce

Lead Sponsor

Trials

3

Recruited

30+

Published Research Related to This Trial

A treatment regimen combining thiotepa, topotecan, and carboplatin was administered to ten pediatric patients with recurrent central nervous system tumors, showing potential to consolidate remission in this challenging group.

Out of the ten patients, four are long-term survivors, particularly those with no evidence of disease at the time of stem cell rescue, suggesting that the extent of disease prior to treatment significantly influences outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa/topotecan/carboplatin with autologous stem cell rescue in recurrent/refractory/poor prognosis pediatric malignancies of the central nervous system. Gilheeney, SW., Khakoo, Y., Souweidane, M., et al.[2013]

In a phase I/II trial involving 47 patients with inoperable brain metastases, the maximum tolerated dose of topotecan given daily alongside whole-brain radiation therapy (WBRT) was determined to be 12 x 0.5 mg/m² for chemotherapy-naive patients, with significant hematologic toxicities observed in those with prior chemotherapy.

The treatment resulted in a 58% overall response rate, with a median survival of 5.1 months, indicating potential efficacy of topotecan in enhancing the effects of WBRT, warranting further investigation in a phase III trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial of simultaneous whole-brain irradiation and dose-escalating topotecan for brain metastases. Kocher, M., Eich, HT., Semrau, R., et al.[2013]

Topotecan has demonstrated effectiveness in treating various cancers, including metastatic ovarian cancer and recurrent small cell lung cancer, with response rates of 20% in ovarian cancer compared to 13% for paclitaxel, and a notable median survival of 5.4 months in SCLC patients.

The drug is generally well-tolerated, with myelosuppression being the main side effect, but serious complications are rare, making it a manageable option for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topotecan, an active new antineoplastic agent: review and current status. Carmichael, J., Ozols, RF.[2019]

Topotecan, a drug that targets topoisomerase I, has shown significant antitumor activity when combined with various chemotherapy agents like cisplatin and doxorubicin in both adult and pediatric patients with solid tumors.

The main side effect of these combination therapies is myelosuppression, particularly neutropenia, which limits the dosage; however, many early studies have reported major responses, indicating the potential effectiveness of these regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topotecan in combination chemotherapy. Rowinsky, EK., Kaufmann, SH.[2017]

Topotecan combined with either cisplatin or etoposide showed similar efficacy in treating untreated extensive disease small-cell lung cancer (ED SCLC), with response rates of 63.4% for the T/C group and 61.0% for the T/E group, indicating both combinations are effective treatment options.

While both regimens had similar overall deliverability, the T/C combination resulted in significantly higher rates of severe anemia (46.4%) compared to T/E (20%), suggesting that T/E may have a better safety profile regarding hematological toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised phase II study of the efficacy and safety of intravenous topotecan in combination with either cisplatin or etoposide in patients with untreated extensive disease small-cell lung cancer. Quoix, E., Breton, JL., Gervais, R., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7823846/

Convection Enhanced Delivery of Topotecan for Gliomas Convection enhanced delivery (CED) is a technique that uses a catheter placed directly into the brain parenchyma to infuse treatments using a pressure gradient.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03927274

Intratumorally-Administered Topotecan Using Convection ... The purpose of this study is to determine if treatment with Topotecan by an alternative method, delivering topotecan directly into brain tumors, is safe and ...

3. aacrjournals.org aacrjournals.org/cancerres/article/71/11/3963/657584/Convection-Enhanced-Delivery-of-Topotecan-into-a

Convection-Enhanced Delivery of Topotecan into a PDGF ... The findings of this study suggest that chemotherapy may prime later recurrence by decreasing recruitment of normal glial progenitor cells into a brain.

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-02808

Convection-Enhanced Delivery of Topotecan in Treating ... This early phase I trial studies how well convection-enhanced delivery of topotecan works in treating patients with World Health Organization (WHO) grade ...

5. thejns.org thejns.org/pediatrics/view/journals/j-neurosurg-pediatr/11/3/article-p289.xml

Convection-enhanced delivery of topotecan into diffuse ... Our previous studies showed that the blood-brain barrier to natural product drugs like topotecan was still partially intact in gliomas but not ...

6. novartis.com novartis.com/us-en/sites/novartis_us/files/hycamtin_caps.pdf

HYCAMTIN CAPSULES HYCAMTIN can cause severe myelosuppression. The following safety data are based on an integrated safety database from four trials in patients with lung ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2006/020671s014lbl.pdf

HYCAMTIN - accessdata.fda.gov HYCAMTIN (topotecan hydrochloride) is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT00553189

Safety Study of ABT-888 Plus Topotecan Hydrochloride to ... ABT-888 is an experimental drug that inhibits PARP and may help to increase the effectiveness of cancer treatments designed to damage DNA in cancer cells.

9. dailymed.nlm.nih.gov dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eeee060c-a9ec-423e-a374-8484009f8524

Label: HYCAMTIN- topotecan hydrochloride injection, powder ... HYCAMTIN can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts greater than or equal to 1,500/mm3 and ...

10. go.drugbank.com go.drugbank.com/drugs/DB01030

Topotecan: Uses, Interactions, Mechanism of Action Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other ...