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

Trial Summary

What is the purpose of this trial?

The primary goal of this study is to establish the safety of chronic Convection Enhanced Delivery (CED) of the chemotherapeutic drug Topotecan for patients with recurrent malignant glioma that harbors the Isocitrate Dehydrogenase mutation (IDH-mut). The secondary goal of the study is to study drug distribution and assess the tumor response to prolonged continuous CED of Topotecan. Convection Enhanced Delivery is a novel method of drug delivery that allows administration of a drug directly to the brain. In CED, a drug pump is placed under the skin in the chest or abdominal region. The pump is connected to a catheter that is tunneled underneath the skin to the brain. The tip of the catheter then infuses Topotecan directly onto the brain tumor. There will be a total of four treatment infusions over the course of 23-29 days, with a 5-7-day rest period between each infusion. Throughout this period, patients' health will be monitored through imaging, blood draws, and regular exams. At the end of the treatment period, the pump will be removed, followed by resection of the tumor. Patients will be followed for the duration of their lives. This is the investigator's second clinical trial studying CED of TPT in recurrent glioma. In the prior Phase 1b trial, chronic pulsatile CED safely and effectively delivered Topotecan to patients with IDH mutant recurrent Glioblastoma (WHO grade 4).

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 evidence supports the effectiveness of the drug Topotecan for brain cancer?

Topotecan has shown activity in various cancers, including ovarian and lung cancer, and is being studied for its potential in brain cancer treatment. It is often used in combination with other drugs and has demonstrated antitumor effects, although its effectiveness specifically for brain cancer is still under investigation. ^{1 2 3 4 5}

Is topotecan safe for use in humans?

Topotecan has been used in humans for various cancers, and its main side effects are related to blood cell counts, such as neutropenia (low white blood cells) and thrombocytopenia (low platelets). These side effects can be managed by adjusting the dose, especially in patients with prior extensive chemotherapy or radiation. ^{3 4 5 6 7}

What makes the drug Topotecan unique for treating brain cancer?

Topotecan is unique for treating brain cancer because it can cross the blood-brain barrier, which many drugs cannot do, and it enhances the effectiveness of radiation therapy by making tumor cells more sensitive to it. ^{1 3 4 8 9}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. Ireland 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. [2013]

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

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

3. Netherlands pubmed.ncbi.nlm.nih.gov

Open-label simultaneous radio-chemotherapy of glioblastoma multiforme with topotecan in adults. [2013]

4. Germany pubmed.ncbi.nlm.nih.gov

Acute toxicity and changes in quality of life during a combined radio-chemotherapy of glioblastomas with topotecan (Hycamtin). [2019]

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

Topotecan in combination chemotherapy. [2017]

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

Nursing considerations for managing topotecan-related hematologic side effects. [2013]

7. Greece pubmed.ncbi.nlm.nih.gov

Phase I study of weekly topotecan combined to concurrent external cranial irradiation in adults with glioblastoma multiforme of the brain. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

Phase I/II trial of simultaneous whole-brain irradiation and dose-escalating topotecan for brain metastases. [2013]

9. United States 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. [2013]