Study of Immunotoxin, MR1-1 (MR1-1)

March 18, 2015 updated by: Darell D. Bigner, MD, PhD

Phase I Study of Immunotoxin, MR1-1

Purpose of the study:

Primary Objective: Determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of MR1-1KDEL when delivered intracerebrally by convection-enhanced delivery (CED) in patients with supratentorial malignant brain tumors.

Secondary Objective: Document any radiographic responses associated with intracerebral CED of MR1-1KDEL.

Hypothesis: The investigators believe that MR1-1KDEL will be an effective anti-tumor agent for patients with supratentorial malignant brain tumors when delivered by CED.

Design & procedures: This protocol is designed primarily to determine the MTD and DLT of a novel, tumor-specific immunotoxin, MR1-1KDEL. MR1-1KDEL will be delivered intracerebrally by CED using 2 intracerebral catheters with at least one catheter placed within the enhancing portion of the tumor. 124I-labeled albumin will be co-infused with gadolinium and PET and MRI images will be obtained at the conclusion of the infusion to monitor volume of drug distribution and leakage into the CSF space.

Based on preclinical toxicity studies, the starting total drug dose will be 0.5μg (500ng) which represents 1/20th of the MTD in rats. The infusion flow rate will be fixed at 0.5 mL/h from each of two to four catheters. A total of 144 mLs of drug solution will be delivered over 72 hours. MR1-1KDEL dose escalation will be accomplished by increasing drug concentration allowing flow rate and infusion volume to remain unchanged. Drug dose will be doubled in successive cohorts so long as DLTs are not observed as follows: 25 ng/mL (2.4 μg)(starting dose); 50ng/mL (4.8μg); 100 ng/mL (9.6μg); 200ng/mL (19.2μg); 400 ng/mL (38.4μg); 800 ng/mL (76.8μg); and 1600 ng/mL (153.6μg). At least 3 patients will be enrolled in each cohort. All patients in a given cohort will be observed for at least two weeks following infusion of the study drug before patients in the next cohort are treated. If no patients in a given cohort experience a DLT, the dose will be escalated in the next cohort. If 1 out of 3 patients in a given cohort experience DLT, 3 additional patients will be entered in that cohort. If 2 patients develop a DLT in any cohort of 3 or 6 patients, the previous dose will be declared the MTD. Patients will be followed at 1, 3, 6, 9, 12 month intervals for toxicity and adverse events, radiographic response, and survival. Patients will be off study when progressive disease is documented.

Risk/benefit assessment: This is an experimental study and unforeseeable or unexpected risks may be involved.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

9

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Health System

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Residual, progressive, or recurrent supratentorial malignant brain tumor based on imaging studies with measurable disease (>0.5cm).
  • Patient will have completed some form of radiation therapy prior to toxin treatment.
  • Karnofsky Performance score >70.
  • The presence of the target antigen, EGFRvIII, must be identified on tumor tissue by immunohistochemistry.
  • Platelet count > 100 x 109/L; PTT and PT < 120% of normal range.
  • Creatinine < 120% of normal range.
  • Total bilirubin, SGOT, SGPT,alkaline phosphatase < 300% of normal range.

Exclusion Criteria:

  • Patients who are pregnant, breast-feeding, or unwilling to practice an effective method of birth control.
  • Patients with known potentially anaphylactic allergic reactions to iodine or gadolinium-DTPA.
  • Patients who cannot undergo MRI due to obesity or to having certain metal in their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, rods or plates).
  • Patients that have not recovered from the toxic effects of prior chemotherapy and/or radiation therapy.
  • Patients with an impending, life-threatening cerebral herniation syndrome.
  • Patients with subependymal or CSF disease.
  • Patients who are under the age of 18 years.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: MR1-1
All subjects are enrolled onto this arm. All subjects will receive MR1-1.
Biological: MR1-1
Based on preclinical toxicity studies, the starting total drug dose will be 0.5μg (500ng) which represents 1/20th of the MTD in rats. The infusion flow rate will be fixed at 0.5 mL/h from each of two catheters. A total of 96 mLs of drug solution will be delivered over 96 hours. MR1-1KDEL dose escalation will be accomplished by increasing drug concentration allowing flow rate and infusion volume to remain unchanged. Drug dose will be doubled in successive cohorts so long as DLTs are not observed as follows: 25 ng/mL (2.4 μg)(starting dose); 50ng/mL (4.8μg); 100 ng/mL (9.6μg); 200ng/mL (19.2μg); 400 ng/mL (38.4μg); 800 ng/mL (76.8μg); and 1600 ng/mL (153.6μg).
Other Names:
  • MR1-1KDEL

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Maximum tolerated dose and dose limiting toxicity
Time Frame: continual
continual

Secondary Outcome Measures

Outcome Measure
Time Frame
Disease Progression
Time Frame: continual
continual

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Darell D. Bigner, MD, PhD

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2006

Primary Completion (ACTUAL)

December 1, 2012

Study Completion (ACTUAL)

December 1, 2012

Study Registration Dates

First Submitted

November 6, 2009

First Submitted That Met QC Criteria

November 6, 2009

First Posted (ESTIMATE)

November 9, 2009

Study Record Updates

Last Update Posted (ESTIMATE)

March 20, 2015

Last Update Submitted That Met QC Criteria

March 18, 2015

Last Verified

March 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00011617
  • P50NS020023 (U.S. NIH Grant/Contract)

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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