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

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.

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
have a tumor diameter no larger than 4cm or volume of 34cm3

- 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.