- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02022644
Study of Convection-Enhanced, Image-Assisted Delivery of Liposomal-Irinotecan In Recurrent High Grade Glioma
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 Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
California
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San Francisco, California, United States, 94143
- University of California, San Francisco
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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.
a. 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/microliter (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 m^2 for patients with creatinine levels above institutional normal.
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.
- 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 Positron Emission Tomography (PET) or Thallium scanning, MR spectroscopy or surgical documentation of disease
- Patients must be able to have MRI brain imaging.
- UGT1A1 genotyping will be sent for testing at screening, but results do not have to be known before starting treatment
Exclusion Criteria:
- 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.
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Group 1 - 20 mg
Tumor diameter: 1 cm, Tumor volume: ~0.5cm3, Infusion Volume: 2-3 ml, Irinotecan conc.: 20 mg/ml, Infusion time: 6-24 hours, no more than 48
|
The drug named here (nanoliposomal irinotecan) will be used in varying amounts, based on tumor volume.
Other Names:
|
Experimental: Group 2 - 40 mg
Tumor diameter: 2 cm,Tumor volume: ~4.1cm3, Infusion Volume: 3-4 ml, Irinotecan conc.: 40 mg/ml, Infusion Time: 6-24 hours, no more than 48
|
The drug named here (nanoliposomal irinotecan) will be used in varying amounts, based on tumor volume.
Other Names:
|
Experimental: Group 3 - 140 mg
Tumor diameter: 3 cm, Tumor volume: ~14cm3, Infusion Volume: 6-7 ml, Irinotecan conc.: 140 mg/ml, Infusion Time: 6-24 hours, no more than 48
|
The drug named here (nanoliposomal irinotecan) will be used in varying amounts, based on tumor volume.
Other Names:
|
Experimental: Group 4 - 340 mg
Tumor diameter: 4 cm, Tumor volume: ~34cm3, Infusion Volume: ≤17 ml, Irinotecan conc.: 340 mg/ml, Infusion Time: 6-24 hours, no more than 48
|
The drug named here (nanoliposomal irinotecan) will be used in varying amounts, based on tumor volume.
Other Names:
|
Experimental: Group 5 - 40 mg
Tumor diameter: 1 cm, Tumor volume: ~0.5cm3, Infusion Volume: 2-3 ml, Irinotecan conc.: 40 mg/ml, Infusion Time: 6-24 hours, no more than 48
|
The drug named here (nanoliposomal irinotecan) will be used in varying amounts, based on tumor volume.
Other Names:
|
Experimental: Group 6 - 80 mg
Tumor diameter: 2 cm, Tumor volume: ~4.1cm3, Infusion Volume: 3-4 ml, Irinotecan conc.: 80 mg/ml, Infusion Time: 6-24 hours, no more than 48
|
The drug named here (nanoliposomal irinotecan) will be used in varying amounts, based on tumor volume.
Other Names:
|
Experimental: Group 7 - 280 mg
Tumor diameter: 3 cm, Tumor volume: ~14cm3, Infusion Volume: 6-7 ml, Irinotecan conc.: 280 mg/ml, Infusion Time: 6-24 hours, no more than 48
|
The drug named here (nanoliposomal irinotecan) will be used in varying amounts, based on tumor volume.
Other Names:
|
Experimental: Group 8 - 680 mg
Tumor diameter: 4 cm, Tumor volume: ~34cm3, Infusion Volume: ≤17 ml, Irinotecan conc.: 680 mg/ml, Infusion Time: 6-24 hours, no more than 48
|
The drug named here (nanoliposomal irinotecan) will be used in varying amounts, based on tumor volume.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum tolerated dose
Time Frame: 30 days post-infusion
|
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.
|
30 days post-infusion
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Progression-Free Survival (PFS) at 6 months
Time Frame: Up to 6 months
|
Number of patients not having objective progression or death at 6 months after the time from date of study enrollment estimated from the PFS distribution.
For patients who are not known to have died or progressed as of the data-inclusion cut-off date, PFS time will be censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systematic anticancer therapy.
PFS will be summarized using Kaplan Meier methods and displayed graphically.
The median event time and two-sided 95% confidence interval for the median will be reported.
|
Up to 6 months
|
Progression-Free Survival (PFS)
Time Frame: Up to 10 years
|
The time from the date of study enrollment to the date of first observation of objective progression or death from any cause, whichever occurs first.
For patients who are not known to have died or progressed as of the data-inclusion cut-off date, PFS time will be censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systematic anticancer therapy.
PFS will be summarized using Kaplan Meier methods and displayed graphically.
The median event time and two-sided 95% confidence interval for the median will be reported.
|
Up to 10 years
|
Overall Survival at 12 months
Time Frame: Up to 12 months
|
The time from the date of study enrollment to the date of death from any cause.
For patients who are not known to have died as of the 12 month cut-off date, survival time will be censored at the date of the last known survival status of participant prior to the date of any subsequent systematic anticancer therapy.
OS will be summarized using Kaplan Meier methods and displayed graphically.
The median event time and two-sided 95% confidence interval for the median will be reported.
|
Up to 12 months
|
Overall Survival (OS)
Time Frame: Up to 10 years
|
The time from the date of study enrollment to the date of death from any cause.
For patients who are not known to have died as of the data-inclusion cut-off date, survival time will be censored at the date of the last known survival status of participant prior to the date of any subsequent systematic anticancer therapy.
OS will be summarized using Kaplan Meier methods and displayed graphically.
The median event time and two-sided 95% confidence interval for the median will be reported.
|
Up to 10 years
|
Objective Tumor Response Rate
Time Frame: Up to 10 years
|
Overall response rate (ORR) is the proportion of patients who achieved a complete response (CR) or partial response (PR) out of all randomly assigned patients.
Based on Response assessment in neuro-oncology criteria (RANO), a responder is defined by radiographic and clinical criteria.
Complete response or PR will be first assessed by radiographic changes as determined by an improvement of the bi-dimensional evaluation of the tumor size.
In addition, changes in neurologic function and steroid use will be considered to determine stable disease (SD).
The objective response rate (ORR) will be summarized with the corresponding exact two-sided 95% confidence interval calculated using a method based on the F distribution
|
Up to 10 years
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
Pre-operative MRIs will be compared to post-operative MRIs to determine the location and pattern of infusate spread.
|
Up to 48 hours pre-infusion and up to 48 hours post-infusion
|
Ratio of the Volume of distribution (Vd) to volume infused (Vi)
Time Frame: Up to 24 hours from time of dosing
|
The volume of distribution of study infusion will be compared to the total volume infused.
An average Vd/Vi will be established for each flow rate, and mean distribution volume lengths, widths, and positions with respect to the infusion cannula tip will be generated as a function of infusion volume (Vi)
|
Up to 24 hours from time of dosing
|
Change in 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)
|
Up to 12 months from date of surgery
|
Mean plasma levels of total Liposomal-irinotecan (MM-398, ONIVYDE)
Time Frame: Pre-infusion, 1 hour post-infusion, and approximately 1 week post-infusion
|
Pharmacokinetic testing will be performed on plasma levels of total Liposomal-irinotecan (MM-398, ONIVYDE) will be measured at 0 (pre-infusion), approximately 1-hour after infusion, and approximately 1-week following the end of irinotecan infusion into the brain.
|
Pre-infusion, 1 hour post-infusion, and approximately 1 week post-infusion
|
Collaborators and Investigators
Investigators
- Principal Investigator: Nicholas Butowski, MD, University of California, San Francisco
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms, Glandular and Epithelial
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Glioma
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Topoisomerase Inhibitors
- Topoisomerase I Inhibitors
- Irinotecan
Other Study ID Numbers
- Nano CED
- 13-12025 (Other Identifier: University of California, San Francisco)
- 5R21CA186140-02 (U.S. NIH Grant/Contract)
- NCI-2017-01304 (Registry Identifier: NCI Clinical Trials Reporting Program (CTRP))
- 13108 (Other Identifier: University of California, San Francisco)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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