Convection-Enhanced Delivery (CED) of MDNA55 in Adults With Recurrent or Progressive Glioblastoma

Study Overview
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Brief Summary
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This is a single-arm, open-label, multicenter study in approximately 52 adults with primary (de novo) GB that has recurred or progressed (first or second recurrence, including this recurrence) after treatment(s) including surgery and radiotherapy with or without chemotherapy and following discontinuation of any previous standard or investigational lines of therapy.

Detailed Description
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The study drug, MDNA55, is a fusion protein comprising a genetically engineered Interleukin-4 (IL-4) linked to a modified version of the Pseudomonas aeruginosa exotoxin A (PE). MDNA55 binds to the IL-4 receptor (IL4R), over-expressed by cancer cells and non-malignant immunosuppressive cells of the tumor microenvironment (TME), and delivers a potent cell-killing agent, PE. The study will be conducted at up to 10 clinical sites following institutional review board approval and completed informed consent. Subjects that meet the study eligibility criteria will undergo surgery associated with study drug administration. MDNA55 will be administered locally by convection-enhanced delivery (CED). Post-treatment follow-up assessment of safety and efficacy will be performed monthly for the first 6 months and bimonthly thereafter for approximately 1 year after study drug administrations. Subjects will continued to be followed for survival and post-study treatment(s) of GB after study completion or withdrawal.

Official Title
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An Open-Label Non-Randomized, Multi-Center Phase-2 Study of Convection-Enhanced Delivery (CED) of MDNA55 in Adults With Recurrent or Progressive Glioblastoma

Conditions
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Glioblastoma, Grade IV Astrocytoma, Glioblastoma Multiforme, Grade IV Glioma

Intervention / Treatment
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* Drug: MDNA55


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Subjects must be ≥ 18 years old and have a life expectancy ≥ 12 weeks Histologically proven, primary (de novo) GB that has recurred or progressed (first or second recurrence, including this recurrence) Confirmation that archived tissue is available from first diagnosis of GB for biomarker analysis Recurrent tumor must be supratentorial, contrast-enhancing GB no smaller than 1 cm x 1 cm (largest perpendicular dimensions) and no larger than 4 cm maximum in a single direction based on MRI taken within 14 days prior to catheter placement Karnofsky Performance Score (KPS) ≥ 70 Subjects must be able and willing to undergo multiple brain MRI examinations Subjects must be able and willing to comply with all study procedures Any related toxicities following discontinuation of prior GB therapies must have resolved to CTCAE Grade 1 or lower prior to inclusion in this study EXCLUSION CRITERIA: Prior treatment with cytotoxic chemotherapy Temozolomide (standard induction and / or maintenance dosing) within the past 4 weeks prior to planned infusion Metronomic Temozolomide (low-dose, continuous administration) within the past 7 days prior to planned infusion Nitrosoureas within the past 6 weeks prior to planned infusion Treatment with any other cytotoxic agent within the past 4 weeks prior to planned infusion Prior investigational treatment within the past 4 weeks or prior immunotherapy or antibody therapy within the past 4 weeks prior to planned infusion Prior treatment with bevacizumab (Avastin) or other vascular-endothelial growth factor (VEGF) inhibitors or VEGF-receptor signaling inhibitors within the past 4 weeks prior to planned infusion Prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine implants) within the past 12 weeks prior to planned infusion Prior surgery (including stereotactic radiosurgery and biopsy procedures) within the past 4 weeks prior to planned infusion Ongoing Optune© therapy within 5 days of planned infusion Secondary GB (i.e., GB that progressed from low-grade diffuse astrocytoma or AA) Known mutation in either the isocitrate dehydrogenase 1 (IDH1) or the IDH2 gene. Tumor in the brainstem (not including fluid-attenuated inversion recovery [FLAIR] changes), an infratentorial tumor, diagnosis of gliomatosis cerebri (highly infiltrative T2 hyperintense tumor with ill-defined margins encompassing at least three lobes of the brain. Tumor with a mass effect (e.g. 1-2 cm midline shift) Subjects with tumors for which the preponderance of tissue is not of the type in which convection would be possible (e.g. preponderance of cystic component) Tumor with geometric features that make them difficult to adequately cover the tumor volume with infusate by using CED catheters Clinical symptoms that are thought by the Investigator to be caused by uncontrolled increased intracranial pressure, hemorrhage, or edema of the brain Any condition that precludes the administration of anesthesia Known to be human immunodeficiency virus positive Concurrent or a history of any significant medical illnesses that in the Investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the subject's ability to tolerate the study drug therapy and/or put the subject at additional risk or interfere with the interpretation of the results of this trial Known history of allergy to gadolinium contrast agents Presence of another type of malignancy requiring treatment within < 3 years prior to the screening visit, except for adequately treated carcinoma in-situ of the cervix, prostate cancer not actively treated, and basal or squamous cell carcinoma of the skin

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MDNA55<br>Single infusion of MDNA55 via convection enhanced delivery (CED).* *Subjects may be eligible to receive a second administration of MDNA55. | Drug: MDNA55<br>* MDNA55 is an engineered circularly permuted interleukin-4 (cpIL-4) genetically fused to the catalytic domain of the pseudomonas exotoxin A (PE).<br>* Other names: cpIL4-PE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Primary endpoint analysis was based on the ITT population. The null hypothesis was mOS of 8.0 months, based on a clinically-weighted average of published studies of FDA-approved therapies versus the alternative hypothesis of 11.5 months. | From start of treatment until date of death from any cause. Subjects who were not known to have died at the time of the analysis were to be censored at the date of last contact. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR, determined by independent central review (per RANO-based criteria) Complete Response - Disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. Partial Response - ≥50% decrease in sum of products of perpendicular diameters or ≥65% decrease in total volume of all measurable enhancing lesions compared with baseline, sustained for at least 4 weeks Progressive Disease - At least two sequential scans separated by at ≥4 weeks both exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume of enhancing lesions. Stable Disease - Does not qualify for CR, PR, or PD as defined above | 12 months | 
| Progression Free Survival (PFS) | PFS, time from treatment until disease progression (per RANO-based criteria) or death Progressive Disease per RANO - At least two sequential scans separated by at ≥4 weeks both exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume of enhancing lesions | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain cancer, Brain tumor, High grade glioma, malignant glioma, recurrent glioblastoma, recurrent GBM, recurrent GB, glioblastoma (GB), glioblastoma multiforme (GBM), progressive glioblastoma, immunotherapy, targeted, IL4R