Clinical Trials /

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

NCT02022644

Description:

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)

Related Conditions:
  • Anaplastic Oligoastrocytoma
  • Anaplastic Oligodendroglioma
  • Astrocytoma
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: Nano CED
  • SECONDARY ID: 13-12025
  • NCT ID: NCT02022644

Conditions

  • High Grade Glioma

Interventions

DrugSynonymsArms
nanoliposomal irinotecanMM-398Group 1 - 20 mg

Purpose

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)

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.
    

Trial Arms

NameTypeDescriptionInterventions
Group 1 - 20 mgExperimentalTumor volume: 1-4 cm3, Infusion Volume: 1.0 ml, Irinotecan conc.: 20 mg/ml, Infusion Time: 2-3h
  • nanoliposomal irinotecan
Group 2 - 40 mgExperimentalTumor volume: 1-4 cm3, Infusion Volume: 1.0 ml, Irinotecan conc.: 40 mg/ml, Infusion Time: 2-3h
  • nanoliposomal irinotecan
Group 3 - 60 mgExperimentalTumor volume: 2-5 cm3, Infusion Volume: 1.5 ml, Irinotecan conc.: 40 mg/ml, Infusion Time: 3-4h
  • nanoliposomal irinotecan
Group 4 - 80 mgExperimentalTumor volume: 2-6 cm3, Infusion Volume: 2.0 ml, Irinotecan conc.: 40 mg/ml, Infusion Time: 3-4h
  • nanoliposomal irinotecan

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose
Time Frame:30 Days post-dose
Safety Issue:
Description: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

Measure:Tumor Response Rate
Time Frame:12 Months
Safety Issue:
Description: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.
Measure:Time to Progression (TTP)
Time Frame:Until progression of disease up to 12 months from dosing.
Safety Issue:
Description:Estimated time to progression measured from the date of CED administration.
Measure:Overall Survival (OS)
Time Frame:Up to 12 months from time of dosing.
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Enrolling by invitation
Lead Sponsor:University of California, San Francisco

Last Updated

August 15, 2016