Chronic CED of TPT for Recurrent Malignant Glioma

NCT06666712 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: AAAV1710
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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 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).

Conditions

Brain Tumor, Recurrent; Malignant Glioma (WHO Grade III or IV); IDH1/IDH2 Mutation

Keywords

Brain Tumors; topotecan; Convection-Enhanced Delivery (CED); Glioma; IDH Mutation

Outcome Measures

Primary Outcomes (1)

• Safety, defined as dose at which all patients have had no greater than grade 2 adverse reactions

  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 examination, laboratory studies, radiographic studies, and adverse effects, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 out from Grade 1 (mild symptoms) to Grade 5 (death related to adverse event).

  Up to 29 days

Secondary Outcomes (3)

• Progression Free Survival (PFS), Overall Survival (OS)

  Up to 5 years

• Tumor Response to Treatment

  Up to 29 days of treatment, and 4-6 weeks post treatment period

• Clinical Toxicity Rate

  Up to 29 days

Study Arms (1)

Long-term CED of Topotecan

EXPERIMENTAL

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.

Drug: Topotecan

Interventions

Topotecan DRUG

Topotecan (TPT) is a chemotherapeutic agent that is a topoisomerase inhibitor. This intervention is uniquely distinguished through its administration using an externalized catheter and external microinfusion pump (Convection-Enhanced Delivery)

Also known as: TPT, Hycamtin

Long-term CED of Topotecan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Patients with recurrent malignant glioma, IDH-mutant, who have failed standard of care treatment are eligible.
• 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.
• Karnofsky performance score must be greater than or equal to 70.
• 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.
• Patients or appropriate legally authorized representatives must possess the ability to give Informed Consent.
• Patients must be willing to and medically capable of undergoing the surgical operation.
• Patients must be at least 18 years old.
• 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

You may not qualify if:

• Patients with diffuse subependymal or CSF disease.
• Patients with tumors involving the cerebellum or both cerebral hemispheres.
• Patients with an active infection requiring treatment or having an unexplained febrile illness.
• 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.
• Patients with systemic diseases which may be associated with unacceptable anesthetic/operative risk.
• Patients who have previously received systemic topotecan for their tumor.
• Patients who are not able to receive MRI or PET scans.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to topotecan, other topoisomerase inhibitors or gadolinium compounds.
• 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.
• 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.
• Women of childbearing potential who fail to demonstrate a negative pregnancy test 7 or fewer days from registration.
• Women who are breast-feeding.

Sponsors & Collaborators

• Jeffrey N. Bruce: lead

Study Sites (1)

Columbia University Irving Medical Center / NewYork-Presbyterian Hospital

New York, New York, 10032, United States

RECRUITING

Related Publications (6)

• Sonabend AM, Stuart RM, Yun J, Yanagihara T, Mohajed H, Dashnaw S, Bruce SS, Brown T, Romanov A, Sebastian M, Arias-Mendoza F, Bagiella E, Canoll P, Bruce JN. Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump. Neuro Oncol. 2011 Aug;13(8):886-93. doi: 10.1093/neuonc/nor051. Epub 2011 Jul 12.

  PMID: 21750007 BACKGROUND

• Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009 Feb 19;360(8):765-73. doi: 10.1056/NEJMoa0808710.

  PMID: 19228619 BACKGROUND

• Han S, Liu Y, Cai SJ, Qian M, Ding J, Larion M, Gilbert MR, Yang C. IDH mutation in glioma: molecular mechanisms and potential therapeutic targets. Br J Cancer. 2020 May;122(11):1580-1589. doi: 10.1038/s41416-020-0814-x. Epub 2020 Apr 15.

  PMID: 32291392 BACKGROUND

• Spinazzi EF, Argenziano MG, Upadhyayula PS, Banu MA, Neira JA, Higgins DMO, Wu PB, Pereira B, Mahajan A, Humala N, Al-Dalahmah O, Zhao W, Save AV, Gill BJA, Boyett DM, Marie T, Furnari JL, Sudhakar TD, Stopka SA, Regan MS, Catania V, Good L, Zacharoulis S, Behl M, Petridis P, Jambawalikar S, Mintz A, Lignelli A, Agar NYR, Sims PA, Welch MR, Lassman AB, Iwamoto FM, D'Amico RS, Grinband J, Canoll P, Bruce JN. Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial. Lancet Oncol. 2022 Nov;23(11):1409-1418. doi: 10.1016/S1470-2045(22)00599-X. Epub 2022 Oct 13.

  PMID: 36243020 BACKGROUND

• Bruce JN, Fine RL, Canoll P, Yun J, Kennedy BC, Rosenfeld SS, Sands SA, Surapaneni K, Lai R, Yanes CL, Bagiella E, DeLaPaz RL. Regression of recurrent malignant gliomas with convection-enhanced delivery of topotecan. Neurosurgery. 2011 Dec;69(6):1272-9; discussion 1279-80. doi: 10.1227/NEU.0b013e3182233e24.

  PMID: 21562434 BACKGROUND

• Bhowmik A, Khan R, Ghosh MK. Blood brain barrier: a challenge for effectual therapy of brain tumors. Biomed Res Int. 2015;2015:320941. doi: 10.1155/2015/320941. Epub 2015 Mar 19.

  PMID: 25866775 BACKGROUND

MeSH Terms

Conditions

Brain Neoplasms; Glioma; Lymphoma, Follicular

Interventions

Topotecan; 9 alpha,11 alpha,15 alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trienoic acid

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds

Study Officials

• Jeffrey Bruce, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jeffrey Bruce, MD

CONTACT

212-305-7346; jnb2@cumc.columbia.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neurological Surgery

Study Record Dates

• First Submitted: October 5, 2024
• First Posted: October 31, 2024
• Study Start: May 1, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2028
• Last Updated: April 15, 2026

Record last verified: 2026-04

Locations

US (1)