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Study of Convection-Enhanced, Image-Assisted Delivery of Liposomal-Irinotecan In Recurrent High Grade Glioma

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ClinicalTrials.gov Identifier: NCT02022644
Recruitment Status : Enrolling by invitation
First Posted : December 30, 2013
Last Update Posted : January 23, 2018
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Nicholas Butowski, University of California, San Francisco

Brief Summary:
This is a dose-toleration study designed to investigate and determine the maximum tolerated dose of nanoliposomal irinotecan in adults with recurrent high-grade glioma when administered directly into the tumor using a process called convection-enhanced delivery. (CED)

Condition or disease Intervention/treatment Phase
High Grade Glioma Drug: nanoliposomal irinotecan Phase 1

Detailed Description:

High grade gliomas (HGG) are the most common brain tumor in adults, with 15,000 new cases/year in the USA. Despite progress made using combination therapies including surgery, radiation and/or chemotherapy, the treatment of HGG remains challenging with a typical median survival of 6-12 months for patients with newly diagnosed glioblastoma multiforme (GB) and 24-36 months for patients with anaplastic astrocytoma. The time to tumor progression of patients with recurrent GBM is nine weeks and the median survival is 25 weeks, while for recurrent anaplastic astrocytomas (AA), the time to tumor progression is 13 weeks and the median survival is 47 weeks. More recently, single-agent Avastin has been seen to improve 6-month progression-free survival (PFS-6) to 42.6% as well as increase Median Overall Survival to 9.3 months in patients with recurrent GBM. However, chemotherapy treatment for malignant gliomas has limitations given the low activity of available antineoplastic agents, the emergence or de-novo presence of resistance to such agents, the sensitivity of the brain to irreversible damage from a therapeutic modality, and the compromised delivery of these agents to partially privileged intracranial sites. Effective agents with novel mechanisms of action need to be evaluated in HGG which account for these limitations.

With these limitations in mind, this study directs attention to two particularly appealing delivery modalities which may improve the efficacy of neuro-oncologic chemotherapeutic agents: liposomes (liposomal irinotecan) and convection enhanced delivery (CED). Liposomes are typically composed of double chain phospholipid amphiphiles (chemical compounds with combined hydrophilic and lipophilic properties) in combination with cholesterol, forming spheroidal bilayer membrane structures that encompass an aqueous internal domain. Based on structural/pharmacologic features, distinct liposome classes have been developed to package various therapeutic agents for the treatment of cancer. From the circulating bloodstream, liposomes are able to diffuse across the blood brain barrier (BBB) due to their lipophilic characteristics. An example is liposomal irinotecan which may reduce the toxicity of irinotecan to healthy tissues while maintaining or increasing its anti-tumor potency.

CED improves chemotherapeutic delivery to brain tumors intraparenchymally by utilizing bulk flow, or fluid convection, established as a result of a pressure gradient, rather than a concentration gradient. As such, CED offers markedly improved distribution of infused therapeutics within the central nervous system (CNS) compared to direct injection or via drug eluting polymers, both of which depend on diffusion for parenchymal distribution. Additionally, CED obviates the challenges of systemic agents crossing the blood brain barrier while minimizing systemic exposure and toxicity. Through the maintenance of a pressure gradient from the delivery cannula tip to the surrounding tissues, CED is able to distribute small and large molecules, including high molecular weight proteins, to clinically significant target volumes centimeters rather than millimeters in diameter. Although developed independently, work combining the two delivery options, liposomes and CED, is presently underway in an effort to improve treatment efficacy in the treatment of CNS malignancies. This clinical trial is a step in this direction with a prospective, single-arm, open-label trial that delivers liposomal-irinotecan and gadolinium (which provided real time imaging of delivery) by CED in patients with recurrent malignant glioma.

Added to this logic is support from a recent preclinical study at the University of California, San Francisco (UCSF) which compared routes of delivery for liposomal irinotecan (CED versus IV) and showed superior anti-tumor activity of CED administration in treating mice with intracranial glioblastoma xenografts. In total, such results indicate that liposomal formulation plus direct intratumoral administration of therapeutic are important for maximizing the anti-tumor effects of irinotecan and support the current clinical trial evaluation of this therapeutic plus CED route of administration combination.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Convection-Enhanced Delivery of Liposomal-Irinotecan Using Real-Time Imaging With Gadolinium In Patients With Recurrent High Grade Glioma
Study Start Date : February 2014
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : January 2019

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Group 1 - 20 mg
Tumor volume: 1-4 cm3, Infusion Volume: 1.0 ml, Irinotecan conc.: 20 mg/ml, Infusion Time: 2-3h
Drug: nanoliposomal irinotecan
Other Name: MM-398
Experimental: Group 2 - 40 mg
Tumor volume: 1-4 cm3, Infusion Volume: 1.0 ml, Irinotecan conc.: 40 mg/ml, Infusion Time: 2-3h
Drug: nanoliposomal irinotecan
Other Name: MM-398
Experimental: Group 3 - 60 mg
Tumor volume: 2-5 cm3, Infusion Volume: 1.5 ml, Irinotecan conc.: 40 mg/ml, Infusion Time: 3-4h
Drug: nanoliposomal irinotecan
Other Name: MM-398
Experimental: Group 4 - 80 mg
Tumor volume: 2-6 cm3, Infusion Volume: 2.0 ml, Irinotecan conc.: 40 mg/ml, Infusion Time: 3-4h
Drug: nanoliposomal irinotecan
Other Name: MM-398

Primary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: 30 Days post-dose ]
    Dose limiting toxicity (DLT) will be defined as any grade-3 or higher neurological toxicity felt to be attributable to the CED infusion of liposomal-irinotecan with gadolinium, as well as any systemic grade-3 or higher hematologic or non-hematologic toxicity (after maximal medical management of nausea/vomiting/diarrhea), over a period of 30 days after CED infusion.

Secondary Outcome Measures :
  1. Tumor Response Rate [ Time Frame: 12 Months ]
    To determine the objective tumor response rate, based upon MR imaging using RANO criteria, at 4 weeks post CED, then every 8 weeks thereafter for 12 months.

  2. Time to Progression (TTP) [ Time Frame: Until progression of disease up to 12 months from dosing. ]
    Estimated time to progression measured from the date of CED administration.

  3. Overall Survival (OS) [ Time Frame: Up to 12 months from time of dosing. ]

Other Outcome Measures:
  1. Pre-infusion modeling of the drug distribution vs. post-infusion imaging. [ Time Frame: Up to 48 hours pre-infusion and up to 48 hours post-infusion ]
  2. Ratio of the Volume of distribution (Vd) to volume infused (Vi) [ Time Frame: Up to 24 hours from time of dosing ]
  3. Effect of Nano CED on tumor histology [ Time Frame: Up to 12 months from date of surgery ]
    Assessed by comparing pre-treatment tumor samples to post-treatment tumor samples in patients who undergo subsequent repeat surgical procedures. (If applicable)

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients with radiographically proven recurrent, intracranial high grade glioma will be eligible for this protocol. Patients must have evidence of tumor progression as determined by the Revised Assessment in Neuro-Oncology RANO criteria following standard therapy.
  • High grade glioma includes glioblastoma multiforme (GBM), Gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma not otherwise specified. (NOS)
  • Magnetic resonance imaging (MRI) must be performed within 21 days prior to enrollment, and patients who are receiving steroids must be stable or decreasing for at least 5 days prior to imaging. If the steroid dose is increased between the date of imaging and enrollment, a new baseline MRI is required.
  • Patients must have completed only 1 prior course of radiation therapy and must have experienced an interval of greater than 12 weeks from the completion of radiation therapy to study entry.
  • Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a high grade glioma is made.
  • There is no limit as to the number of prior treatments but patients must have radiographic evidence of progressive disease
  • Recurrent tumor must be a solid, single, supratentorial, contrast-enhancing HGG which conforms to the following volume according to the relevant treatment group Group Tumor volume
  • 1 - 1-4 cm3
  • 2 - 1-4 cm3
  • 3 - 2-5 cm3
  • 4 - 2-6 cm3
  • All patients must sign an informed consent indicating that they are aware of the investigational nature of this study. Patients must be registered prior to treatment with study drug.
  • Patients must be> 18 years old, and with a life expectancy > 8 weeks
  • Patients with Karnofsky performance status of > 70.
  • At the time of registration: Patients must have recovered from the toxic effects of prior therapy: > 10 days from any noncytotoxic investigational agent, >28 days from prior cytotoxic therapy or Avastin, >14 days from vincristine, >42 days from nitrosoureas, >21 days from procarbazine administration, and >7 days for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count). Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.
  • requirements for organ and marrow function as follows:
  • Adequate bone marrow function:
  • leukocytes > 3,000/mcL
  • absolute neutrophil count > 1,500/mcL
  • platelets > 100,000/mcL
  • Adequate hepatic function:
  • total bilirubin within normal institutional limits
  • aspartate aminotransferase (AST) < 2.5 X institutional upper limit of normal
  • alanine aminotransferase (ALT) < 2.5 X institutional upper limit of normal
  • Adequate renal function:
  • creatinine within normal institutional limits OR
  • creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
  • The effects of nano liposomal irinotecan on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception: hormonal or barrier method of birth control; abstinence, etc. prior to study entry, for the duration of study participation, and for 6 months post drug administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Women of childbearing potential must have a negative beta-human chorionic gonadotropin (beta-HCG) pregnancy test documented within 14 days prior to treatment.
  • Patients with prior therapy that included interstitial brachytherapy, or Gliadel wafers must have confirmation of true progressive disease rather than radiation necrosis based upon either PET or Thallium scanning, MR spectroscopy or surgical documentation of disease
  • Patients must be able to have MRI brain imaging.
  • Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy
  • Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.
  • Patients must not have an active infection or serious intercurrent medical illness.
  • Patients must not be pregnant/breast feeding and must agree to practice adequate contraception.
  • HIV-positive patients on combination antiretroviral therapy are ineligible
  • Contrast-enhancing tumor which crosses the midline.
  • Multi-focal disease
  • Nonparenchymal tumor dissemination (e.g., subependymal or leptomeningeal)
  • History of hypersensitivity reactions to products containing irinotecan (irinotecan), topotecan or other topoisomerase inhibitors, gadolinium contrast agents or lipid products
  • Ongoing treatment with cytotoxic therapy
  • Patients may not be on an enzyme-inducing anti-epileptic drug (EIAED). If previously on an EIAED, patient must be off for at least 10 days prior to CED infusion.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02022644

United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
Sponsors and Collaborators
University of California, San Francisco
National Institutes of Health (NIH)
Principal Investigator: Nicholas Butowski, MD University of California, San Francisco
Study Director: Susan Chang, MD University of California, San Francisco

Responsible Party: Nicholas Butowski, Assistant Professor of Neurological Surgery; Director of Clinical Services, Division of Neuro-Oncology, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02022644     History of Changes
Other Study ID Numbers: Nano CED
13-12025 ( Other Identifier: University of California, San Francisco )
First Posted: December 30, 2013    Key Record Dates
Last Update Posted: January 23, 2018
Last Verified: January 2018

Additional relevant MeSH terms:
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action