Chronic CED of TPT for Recurrent Malignant Glioma

Phase 1

Not yet recruiting

• Conditions: Brain Tumor, Recurrent; Malignant Glioma (WHO Grade III or IV); IDH1/IDH2 Mutation
• Interventions: Drug: Topotecan

• Registration Number: NCT06666712
• Lead Sponsor: Jeffrey N. Bruce

Brief Summary

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 conti...

Detailed Description

Malignant gliomas are among the most pernicious of human tumors. They are locally invasive and universally recurrent, often recurring within two centimeters of the original resection cavity. Although numerous chemotherapeutic drugs demonstrate significant anti-tumor activity in preclinical studies, their efficacy in clinical trials has been dismal; systemic ...

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Status Verified: 2024-10
• Study First Submitted: 2024-10-05
• Study First Submitted QC: 2024-10-29
• Last Update Submitted: 2024-10-29
• Study First Posted: 2024-10-31
• Last Update Posted: 2024-10-31
• Study Start: 2025-10-04
• Primary Completion: 2028-01
• Study Completion: 2028-06

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 6

Inclusion Criteria

1. Patients must have recurrent malignant glioma with a history of WHO grade 3-4 IDH-mutant status and evidence of radiographic progression and suspicion of histopathological recurrence. Stereotactic biopsies will be performed to assess the presence of active tumor by frozen section prior to initiating treatment. Patients with a history of WHO grade 2 recurrent glioma, IDH-Mutant, who now demonstrate high-grade features of IDH-mutant WHO grade 3-4 will also be included.

2. Patients with recurrent malignant glioma, IDH-mutant, who have failed standard of care treatment are eligible.

3. An MRI scan must be obtained within 30 days of enrollment and must demonstrate an enhancing mass without significant mass effect. Tumors must be less than 32 cc in total volume as assessed by the principal investigator based on pre-enrollment MRI. The lesion must be stereotactically accessible.

4. Karnofsky performance score must be greater than or equal to 70.

5. Men and women of childbearing potential must practice birth control. Women of childbearing potential must have a urine pregnancy test within 7 days of study entry. In accordance with topotecan administration guidelines, women must practice birth control for at least 1 month following chemotherapy infusion. Men must practice birth control for at least four months following termination of chemotherapy infusion.

6. Patients or appropriate legally authorized representatives must possess the ability to give Informed Consent.

7. Patients must be willing to and medically capable of undergoing the surgical operation.

8. Patients must be at least 18 years old.

9. Patients must not have known abnormal organ and marrow function as defined below 14 days or fewer from registration:

   • Leukocytes: ≥3,000/mcL
   • Absolute neutrophil count : ≥1,500/mcL
   • Platelets: ≥100,000/mcL
   • Total bilirubin: within normal institutional limits
   • AST(SGOT)/ALT(SGPT): ≤2.5 × institutional upper limit of normal
   • Creatinine: within normal institutional limits OR
   • Creatinine clearance: ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

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Exclusion Criteria

1. Patients with diffuse subependymal or CSF disease.
2. Patients with tumors involving the cerebellum or both cerebral hemispheres.
3. Patients with an active infection requiring treatment or having an unexplained febrile illness.
4. Patients who are known HIV, Hepatitis B or Hepatitis C positive. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Topotecan. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. HIV, Hepatitis B and Hepatitis C testing is not required for patients not known to have these infections.
5. Patients with systemic diseases which may be associated with unacceptable anesthetic/operative risk.
6. Patients who have previously received systemic topotecan for their tumor.
7. Patients who are not able to receive MRI or PET scans.
8. History of allergic reactions attributed to compounds of similar chemical or biologic composition to topotecan, other topoisomerase inhibitors or gadolinium compounds.
9. Patients who are currently receiving treatment with agents that are metabolized solely through cytochrome P450 (CYP) 3A4/5 (CYP3A4/5) and have a narrow therapeutic index or are strong CYP2C8 inhibitors. Patients who are receiving treatment with agents that carry a risk for QT prolongation and are CYP3A substrates are also ineligible. Caution should be used in patients taking other CYP2C8 - or CYP3A4/5-interacting agents as they may increase the serum concentrations of topotecan. If previously on such agents, the patient must discontinue them for at least two weeks prior to study treatment.
10. Patients with uncontrolled intercurrent illness including, but not limited to, ongoing active infection, systemic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
11. Women of childbearing potential who fail to demonstrate a negative pregnancy test 7 or fewer days from registration.
12. Women who are breast-feeding.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Long-term CED of Topotecan	Topotecan	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.

Primary Outcome Measures

Name	Time	Method
Safety, defined as dose at which all patients have had no greater than grade 2 adverse reactions	Up to 29 days	The primary outcome of the study is to measure the safety of prolonged CED of Topotecan in patients with recurrent IDH-mutant malignant glioma. Safety is defined as the dose at which all patients have had no greater than grade 2 adverse reactions possibly, probably, or definitely related to CED of Topotecan as measured through physical and neurologic examina...

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS), Overall Survival (OS)	Up to 5 years	Progression Free Survival is defined as the duration of time from start of Topotecan treatment to time of progression or death from any cause, whichever occurs first. Overall survival is defined as the duration of time from the start of Topotecan treatment to death from any cause. Patients will be contacted every 3-6 months, up to 5 years, by phone until dea...
Tumor Response to Treatment	Up to 29 days of treatment, and 4-6 weeks post treatment period	The response of the tumor to TPT treatment will be measured radiographically with MRI periodically throughout the 23-29 day treatment period and on follow up 4-6 weeks after treatment, per the international criteria proposed by the updated Response Assessment in Neuro-oncology (RANO) guidelines.
Clinical Toxicity Rate	Up to 29 days	This is defined by the number of serious adverse events occuring, which is projected to be ≤ 5% at 23-29 days. A clinical toxicity rate that exceeds 20% will be considered unacceptable for this procedure.

Trial Locations

Locations (1)

Columbia University Irving Medical Center / NewYork-Presbyterian Hospital; 🇺🇸 New York, New York, United States