Clinical trial NCT02022644: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: High Grade Glioma
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Ipsen
name: National Cancer Institute (NCI)
First posted: 2013-12-30
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single center, 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: PRIMARY OBJECTIVE:

I. To determine the safety and tolerability of liposomal-irinotecan with gadolinium given by intra tumoral real-time convection enhanced delivery in patients with recurrent high grade glioma (HGG).

SECONDARY OBJECTIVES:

I. To optimize the magnetic resonance image-guided intracranial injection procedure in patients with recurrent HGG by correlating the observed distribution of gadolinium to pre-treatment modeling of the drug distribution utilizing predictive imaging software.

EXPLORATORY OBJECTIVES:

I. To estimate the time to progression and overall survival measured from the date of CED.

II. To determine the objective tumor response rate, based upon MR imaging, every 8 weeks for first year and then every 12 weeks.

III. To evaluate the possible effect on tumor histology, as assessed by comparing pre-treatment tumor samples to post-treatment tumor samples in patients who undergo subsequent repeat surgical procedures for progression after being treated as part of this protocol.

IV. Pharmacokinetics measurements will also be taken at pre-dose, 1 day after the drug is administered, and 1 week post-op.

OUTLINE:

Participants will be enrolled in a 3+3 dose escalation model with a two cohort concentration escalation, enrolling at least 3 patients in each cohort which results in each total dose personalized for each participant as all participants will have different size and morphology of tumors requiring different volumes of study infusions ranging from 3 mL for smallest tumor to approximately 17 mL for largest tumor (4 cm). Enrollment into a subsequent cohort will not start until after 30 days after monitoring all patients in cohort prior. Participants will be followed for 12 months from CED procedure or until death or institution of alternate anti-neoplastic therapy for progressive recurrent HGG.

Eligibility criteria: Inclusion Criteria:

1. 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.

   1. 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)
   2. 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.
   3. 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.
2. Patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a high grade glioma is made.
3. There is no limit as to the number of prior treatments but patients must have radiographic evidence of progressive disease
4. Recurrent tumor must be a solid, single, supratentorial, contrast-enhancing HGG which have a tumor diameter no larger than 4cm or volume of 34cm3
5. All patients must sign an informed consent indicating that they are aware of the investigational nature of this study.

   a. Patients must be\> 18 years old, and with a life expectancy \> 8 weeks
6. Patients with Karnofsky performance status of \>= 70.
7. 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.
8. Requirements for organ and marrow function as follows:

   1. Adequate bone marrow function:

      * leukocytes \> 3,000/microliter (mcL)
      * absolute neutrophil count \> 1,500/mcL
      * platelets \> 100,000/mcL
   2. 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
   3. Adequate renal function:

      * creatinine within normal institutional limits OR
      * creatinine clearance \> 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal.
   4. Adequate coagulation function

      * International Normalized Ratio (INR) \< 2.0
      * partial thromboplastin time (PTT) \<= institution's upper limit of normal, unless receiving therapeutic low molecular weight heparin.
9. 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
10. Women of childbearing potential must have a negative beta-human chorionic gonadotropin (beta-HCG) pregnancy test documented within 14 days prior to treatment.
11. 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 Positron Emission Tomography (PET) or Thallium scanning, MR spectroscopy or surgical documentation of disease
12. Patients must be able to have MRI brain imaging.
13. UGT1A1 genotyping will be sent for testing at screening, but results do not have to be known before starting treatment

Exclusion Criteria:

1. 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
2. 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.
3. HIV-positive patients on combination antiretroviral therapy are ineligible.
4. Contrast-enhancing tumor which crosses the midline.
5. Multi-focal disease.
6. Nonparenchymal tumor dissemination (e.g., subependymal or leptomeningeal)
7. History of hypersensitivity reactions to products containing irinotecan (irinotecan), topotecan or other topoisomerase inhibitors, gadolinium contrast agents or lipid products.
8. Ongoing treatment with cytotoxic therapy.
9. 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.

Primary outcomes:
measure: Maximum tolerated dose
timeFrame: 30 days post-infusion
Secondary outcomes:
measure: Progression-Free Survival (PFS) at 6 months
timeFrame: Up to 6 months
measure: Progression-Free Survival (PFS)
timeFrame: Up to 10 years
measure: Overall Survival at 12 months
timeFrame: Up to 12 months
measure: Overall Survival (OS)
timeFrame: Up to 10 years
measure: Objective Tumor Response Rate
timeFrame: Up to 10 years
Other outcomes:
measure: Pre-infusion modeling of the drug distribution vs. post-infusion imaging.
timeFrame: Up to 48 hours pre-infusion and up to 48 hours post-infusion
measure: Ratio of the Volume of distribution (Vd) to volume infused (Vi)
timeFrame: Up to 24 hours from time of dosing
measure: Change in Tumor Histology
timeFrame: Up to 12 months from date of surgery
measure: Mean plasma levels of total Liposomal-irinotecan (MM-398, ONIVYDE)
timeFrame: Pre-infusion, 1 hour post-infusion, and approximately 1 week post-infusion
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Nicholas Butowski, MD
role: PRINCIPAL_INVESTIGATOR
References: