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IL13-PE38QQR

targeted fusion protein therapy

surgery

IL13-PE38QQR is an oncology drug product consisting of IL13 (interleukin-13) and PE38QQR (a bacteria toxin). IL13-PE38QQR is a protein that exhibits cell killing activity against a variety of IL13 receptor-positive tumor cell lines indicating that it may show a therapeutic benefit. In reciprocal competition experiments, the interaction between IL13-PE38QQR and the IL13 receptors was shown to be highly specific for human glioma cells.

Prior to treatment, patients will have physical and neurologic exams, MRI to measure the extent of tumor, tumor biopsy, and screening laboratory tests. On Day 1, one or two catheters will be inserted directly into the tumor, after which a CT scan will be used to confirm placement. Each patient will receive one IL13-PE38QQR infusion, and the tumor will be surgically removed on approximately Day 15. In the first group of patients, IL13-PE38QQR will be infused directly into the tumor for 4 days. Depending on effectiveness or side effects of the study drug, the duration will be increased stepwise to a maximum of 7 days in subsequent groups of patients. Once duration of infusion has been determined, the dose of IL13-PE38QQR will be increased stepwise (in separate groups of patients), depending on effectiveness or side effects of the study drug. The activity of the drug against the tumor cells will be judged by examining the removed tumor tissue. Patients will have neurologic exams and MRI scans immediately after the resection and every eight weeks until disease progression is observed.

OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of IL13-PE38QQR delivered by continuous infusion via 1 or 2 intratumoral catheters into recurrent or progressive malignant glioma.

II. To determine: the pathologic effect of intratumoral IL13-PE38QQR infusion determined at Day 15 resection; the neuroradiographic characteristics of convection-enhanced drug delivery; serum levels of study drug and detect the appearance of antibody to study drug.

III. To determine the proportion of patients surviving at 6 months after continuous intratumoral IL13-PE38QQR infusion at the MTD, followed by Day 15 resection, of recurrent or progressive malignant glioma.

IV. To determine: the proportion of patients remaining disease free at 6 months; the time to progression and overall survival of patients with recurrent or progressive malignant glioma after infusion of IL13-PE38QQR at the selected dose followed by resection; the pathologic response rate of recurrent or progressive malignant glioma to IL13-PE38QQR delivered by continuous intratumoral infusion at the MTD; any additional toxicities of IL13-PE38QQR administered by stereotaxic catheters into recurrent or progressive malignant glioma at the MTD; the neuroradiographic characteristics of convection-enhanced drug delivery; serum levels of study drug and detect the appearance of antibody to study drug.

PROTOCOL OUTLINE: Patients with recurrent or progressive supratentorial malignant glioma who are considered appropriate for re-operation will be eligible for either phase of the study. Each patient will have tumor biopsy at study entry, followed by continuous intratumoral infusion of IL13-PE38QQR via 1 or 2 intratumoral catheters, placed within the enhancing portion of the tumor. Infusion rate will be held constant at 540 mL/hr (total). Toxicity will be assessed by clinical neurologic examination and laboratory values. Resection will be performed on Day 15 (6-13 days after end of infusion). Pathologic evidence of tumor necrosis will be assessed. Follow-up assessments will include neurologic examinations and MRI scans. No other anti-tumor treatment will be administered for at least 60 days after resection (except for progressive disease). Patients will be observed until death.

Phase I: The infusion duration will be escalated first in cohorts of 3-6 patients from 51.8 mL (4 days) to a maximum of 90.7 mL (7 days), to identify a MTD based on infusion duration.

Once duration is determined, IL13-PE38QQR concentration will be escalated in cohorts of 3-6 patients from 90.7 mg to a maximum of 362.8 mg (assuming 7-day infusion) to identify a MTD based on concentration.

Phase II: Patients will be treated at a selected dose no higher than the MTD to estimate the proportion of patients surviving at 6 months, time to progression and survival, and pathologic response rate.

PROJECTED ACCRUAL: In Phase I, 12-48 patients, up to 6 centers in Europe, Israel and North America. In Phase II, up to 35 efficacy evaluable patients, up to 6 centers.

Pre-operative IL13-PE38QQR in Patients With Recurrent or Progressive Malignant Glioma

Pre-operative IL13-PE38QQR Infusion in Patients With Recurrent or Progressive Supratentorial Malignant Glioma: A Phase I/II Study

INSYS Therapeutics Inc

Jon Weingart, MD

IL13-PE38QQR is an oncology drug product consisting of IL13 (interleukin-13) and PE38QQR (a bacteria toxin). IL3-PE38QQR is a protein that exhibits cell killing activity against a variety of IL13 receptor-positive tumor cell lines indicating that it may show a therapeutic benefit. In reciprocal competition experiments, the interaction between IL13-PE38QQR and the IL13 receptors was shown to be highly specific for human glioma cells.

IL13-PE38QQR will be infused in two courses of 96 hours each, eight weeks apart, directly into the malignant brain tumors of patients to determine the dose of drug these patients can tolerate. After that, the selected dose will be studied to give an estimate of the response rate, response duration, time to response, and survival after infusing that dose of IL13-PE38QQR into the recurrent malignant glioma.

OBJECTIVES:

I. Determine the toxicities and maximum tolerated dose of IL13-PE38QQR delivered by continuous infusion into malignant glioma over 96 hours, in two courses eight weeks apart.

II. Estimate the response rate, response duration, time to response, and survival after interstitial infusion of IL13-PE38QQR into recurrent malignant glioma.

III. Describe the toxicities of interstitial infusion of IL13-PE38QQR at the selected dose.

PROTOCOL OUTLINE: Patients are expected to receive two IL13-PE38QQR infusions at 8-week intervals. For each course, drug will be infused through each of two catheters; infusion rate will be held constant during a 96-hour infusion.

In Phase I, the dose of IL13-PE38QQR will be increased by increasing the IL13-PE38QQR concentration in stepwise fashion, while holding infusion volume and duration constant. Three patients will be treated at each dose level until the maximum tolerated dose (MTD) is reached, and an additional three patients are treated at that level. In Phase II, patients will be treated at the selected MTD.

PROJECTED ACCRUAL: In Phase I, up to 30 patients will be treated. In Phase II, up to 35 patients will be treated.

Interstitial Infusion of IL13-PE38QQR Cytotoxin in Recurrent Malignant Glioma

Interstitial Infusion of IL13-PE38QQR Cytotoxin in Recurrent Malignant Glioma: Phase I/II Study

IL13-PE38QQR is an oncology drug product consisting of IL13 (interleukin-13) and PE38QQR (a bacteria toxin). IL3-PE38QQR is a protein that exhibits cell killing activity against a variety of IL13 receptor-positive tumor cell lines indicating that it may show a therapeutic benefit. In reciprocal competition experiments, the interaction between IL13-PE38QQR and the IL13 receptors was shown to be highly specific for human glioma cells.

Patients will receive IL13-PE38QQR via a catheter placed directly into the brain tumor. Tumor recurrence will be confirmed by biopsy. The next day, patients will start a continuous 48-hour infusion of IL13-PE38QQR into the tumor. The dose (concentration) will be increased in the pre-resection infusion until the endpoint is reached (histologic evidence of tumor cytotoxicity or a maximum tolerated dose). Tumor resection will be planned for one week after biopsy, plus or minus 1 day. A histologically-effective concentration (HEC) will be determined using pathologic observations. At the end of resection, three catheters will be placed in brain tissue next to the resection site and assessed within 24 hours using MRI. On the second day after surgery, IL13-PE38QQR infusion will begin and will continue for 4 days. The lowest pre-resection IL13-PE38QQR concentration will be used as the starting dose for post-resection infusions. After an HEC or maximum tolerated dose (MTD) is determined, the pre-resection infusion will no longer be administered. Subsequent patients will have tumor resection and placement of three peri-tumoral catheters at study entry. IL13-PE38QQR will be infused starting on the second day after surgery and continuing for 4 days. Escalation of the post-resection IL13-PE38QQR concentration will be continued until the previously-defined HEC or MTD is reached, after which duration of the post-resection infusion will be increased in one day increments for up to 6 days. If a post-resection MTD is obtained, there will be no increase in duration of infusion. In the final stage of the study, catheters will be placed 2 days after tumor resection, and a 4-day IL13-PE38QQR infusion will begin the day after catheter placement. Patients will be observed clinically and radiographically for toxicity and duration of tumor control.

OBJECTIVES:

I. Determine the concentration of IL13-PE38QQR that produces histologic evidence of toxicity to tumor, and the corresponding drug toxicity, following a 2-day continuous infusion into recurrent malignant glioma prior to surgical resection.

II. Determine the toxicity of IL13-PE38QQR administered as a 4-day continuous infusion via catheters into brain adjacent to tumor resection site, after surgical resection, at concentrations up to the selected concentration.

III. Determine the toxicity of increasing duration of continuous infusion of IL13- PE38QQR via catheters into brain adjacent to tumor resection site, after surgical resection, at the selected concentration.

IV. Determine the feasibility and safety of IL13-PE38QQR administration following post-operative placement of stereotaxic catheters 2 days after tumor resection, utilizing a post-operative imaging study for planning of catheter placement. A 4-day continuous infusion at the MTD is planned.

V. Describe the time to progression and survival of patients treated with IL13-PE38QQR.

PROTOCOL OUTLINE: This study is designed to determine two dose levels. The first is defined as the histologically effective concentration (HEC) when the agent is administered prior to tumor resection. The second is defined using safety and tolerability of study drug administered after tumor resection at doses up to the HEC. Safety and tolerability of increasing duration of infusion after tumor resection will then be assessed.

Patient cohorts will be treated at escalating pre-resection dose-levels until a stopping criterion for the pre-surgery dose is met, holding the post-resection dose constant at the starting level. Stopping criteria for dose escalation of the pre-surgery infusion are determination of the HEC or the maximum tolerated dose (MTD).

Subsequent cohorts will be treated only post-operatively at escalating dose levels until a stopping criterion for the post-surgery dose is met. Stopping criteria for dose escalation of the post-surgery infusion are reaching the HEC determined for the pre-operative infusion or determination of the MTD. After the HEC is reached, subsequent cohorts will be treated with post-operative infusions of increasing duration at the HEC until the maximum duration defined in the study is reached or an MTD is defined. (If an MTD has already detected, duration will not be escalated.)

After the stage of the study evaluating escalation of infusion duration has completed, the study will expand to evaluate post-operative placement of catheters after tumor resection. This stage of the study will assess the feasibility and safety of stereotaxic placement of catheters 2 days after tumor resection using a post-operative imaging study for planning. Patients will receive a 96 hour post-resection infusion at the MTD.

Cohorts of at least three patients will be entered at each dose level. Each cohort will be observed for at least thirty days after completion of administration of study drug to allow for observation of toxicity before the next cohort is enrolled.

PROJECTED ACCRUAL: Depends on number of dose-levels, estimated at 25-50 patients.

Histologic Effect/Safety of Pre/Post-Operative IL13-PE38QQR in Recurrent Resectable Supratentorial Malignant Glioma Patients

Phase I Study to Assess the Histologic Effect and Safety of Pre-Operative and Post-Operative Infusions of IL13-PE38QQR Cytotoxin in Patients With Recurrent Resectable Supratentorial Malignant Glioma

Nervous System Diseases

Brain Neoplasms

Central Nervous System Neoplasms

Oligodendroglioma

Anaplastic Oligodendroglioma

All Drugs and Chemicals

Immunotoxins

The experimental anti-cancer drug IL13-PE38QQR, which is being developed for the treatment of malignant brain tumors, is composed of parts of two proteins: the immune system cytokine IL13 and a toxin from the bacterium Pseudomonas aeruginosa. The IL13 part of the drug binds to another protein, the IL13 receptor, when this receptor is displayed on the outside surface of cells. Cells with drug bound to the IL13 receptor take up the drug, and the toxin part of the drug then kills those cells. Since brain tumor cells display the IL13 receptor, they are potential targets that may be killed by this drug. This is a pilot study to visualize the distribution of IL13-PE38QQR infused into and around brain tumor tissue before and after surgical removal of the tumor in adult patients with recurrent malignant glioma.

Stored tumor tissue will be tested for presence of the receptor protein, which is required for study entry. Eligible patients will then undergo biopsy to confirm the diagnosis of recurrent malignant glioma. IL13-PE38QQR will be infused for 96 hours into and around tumor tissue through catheters that have been placed surgically. For the first 48 hours the drug will be mixed with a radioactive tracer, so that the distribution of the drug can be followed by a type of scanning called SPECT. Surgery to remove the tumor will be performed approximately 15 days after the end of the infusion. Catheters will again be placed surgically, and IL13-PE38QQR will be infused a second time for 96 hours. Radioactive tracer will be included in the infusion for the first 48 hours. For both infusions, SPECT scans will be taken at 6, 24, and 48 hours after the start of infusion. MRI scans will be taken within 90 minutes of the 24 and 48 hour SPECT scans. Patients will be followed closely with further scans and laboratory tests until completion of the study approximately 58 days after completion of the second infusion.

OBJECTIVES:

* Assess the distribution of IL13-PE38QQR following continuous infusion via catheter(s) into recurrent malignant glioma prior to surgical resection and a continuous infusion via catheter(s) into brain tissue adjacent to tumor resection site after surgical resection. 123I-HSA tracer will be used as a surrogate for study drug distribution.
* Determine the toxicities associated with administration of IL13-PE38QQR as described above.
* Assess the effect on distribution of IL13-PE38QQR of varying the catheter type (up to 3) and flow rate per catheter, keeping the total flow rates constant, for the pre- and post-resection infusions.

OUTLINE: This is a pilot study to assess the distribution of IL13-PE38QQR delivered by intratumoral infusion prior to surgical resection and by interstitial infusion into tissue surrounding the resection site (peritumoral) after surgical resection. Prior to resection, catheters will be placed in the region of the solid contrast-enhancing tumor component. The volume of infusion, the duration of infusion, and the concentration of IL13-PE38QQR in the infusate will be fixed. For the post-resection infusion, catheters will be placed peritumorally into areas at greatest risk for residual or infiltrating tumor. The post-resection volume of infusion, the duration of infusion, and the concentration of IL13-PE38QQR in the infusate will be fixed. For the first 48 hours of each infusion, IL13-PE38QQR will be prepared with 123I-HSA tracer as the surrogate for distribution of study drug. The type and number of catheters utilized to deliver the pre- and post-surgery infusions will vary. To maintain a fixed total volume of infusate over 96 hours, the rate of infusion will vary depending upon the number of catheters utilized. Up to three different catheter types will be tested. However, only the same, single type of catheter will be utilized for the pre- and post-resection infusions for a given patient.

To allow assessment of the distribution of the infused material, the first 48 hours of both the pre- and post-resection infusions will utilize 123I-HSA in the infusate. For the last 48 hours of both infusions, the 123I-HSA will be replaced by non-labeled HSA. The distribution of the 123I-HSA tracer will be measured by Single-Photon Emission Computed Tomography (SPECT) scanning.

PROJECTED ACCRUAL: Up to 18 patients will be enrolled at a single site.

Imaging Study of the Distribution of IL13-PE38QQR Infused Before and After Surgery in Adult Patients With Recurrent Malignant Glioma

Pilot Imaging Study to Assess the Distribution of IL13-PE38QQR Cytotoxin Infusions in Patients With Recurrent, Resectable, Supratentorial Malignant Glioma

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pre-operative IL13-PE38QQR in Patients With Recurrent or Progressive Malignant Glioma	NCT00041587	Malignant Gliom... Glioblastoma Mu... Anaplastic Astr... Mixed Oligoastr...	IL13-PE38QQR targeted fusion... surgery	18 Years -	INSYS Therapeutics Inc
Interstitial Infusion of IL13-PE38QQR Cytotoxin in Recurrent Malignant Glioma	NCT00024570	Malignant Gliom... Glioblastoma Mu... Anaplastic Astr... Mixed Oligoastr...	IL13-PE38QQR targeted fusion... surgery	18 Years -	INSYS Therapeutics Inc
Histologic Effect/Safety of Pre/Post-Operative IL13-PE38QQR in Recurrent Resectable Supratentorial Malignant Glioma Patients	NCT00024557	Malignant Gliom... Glioblastoma Mu... Anaplastic Astr... Mixed Oligoastr... Malignant Astro...	IL13-PE38QQR targeted fusion... surgery	18 Years -	INSYS Therapeutics Inc
Imaging Study of the Distribution of IL13-PE38QQR Infused Before and After Surgery in Adult Patients With Recurrent Malignant Glioma	NCT00064779	Malignant Gliom... Glioblastoma Mu... Anaplastic Astr... Anaplastic Olig... Mixed Oligoastr...	IL13-PE38QQR targeted fusion... surgery	18 Years -	INSYS Therapeutics Inc
Interstitial Infusion of IL13-PE38QQR Cytotoxin in Recurrent Malignant Glioma	NCT00024570	Malignant Gliom... Glioblastoma Mu... Anaplastic Astr... Mixed Oligoastr...	IL13-PE38QQR targeted fusion... surgery	18 Years -	INSYS Therapeutics Inc
Imaging Study of the Distribution of IL13-PE38QQR Infused Before and After Surgery in Adult Patients With Recurrent Malignant Glioma	NCT00064779	Malignant Gliom... Glioblastoma Mu... Anaplastic Astr... Anaplastic Olig... Mixed Oligoastr...	IL13-PE38QQR targeted fusion... surgery	18 Years -	INSYS Therapeutics Inc

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