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

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.

INCLUSION CRITERIA:

1. Subjects must be ≥ 18 years old and have a life expectancy ≥ 12 weeks

2. Histologically proven, primary (de novo) GB that has recurred or progressed (first or
second recurrence, including this recurrence)

3. Confirmation that archived tissue is available from first diagnosis of GB for
biomarker analysis

4. 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

5. Karnofsky Performance Score (KPS) ≥ 70

6. Subjects must be able and willing to undergo multiple brain MRI examinations

7. Subjects must be able and willing to comply with all study procedures

8. 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:

1. Prior treatment with cytotoxic chemotherapy

1. Temozolomide (standard induction and / or maintenance dosing) within the past 4
weeks prior to planned infusion

2. "Metronomic" Temozolomide (low-dose, continuous administration) within the past 7
days prior to planned infusion

3. Nitrosoureas within the past 6 weeks prior to planned infusion

4. Treatment with any other cytotoxic agent within the past 4 weeks prior to planned
infusion

2. Prior investigational treatment within the past 4 weeks or prior immunotherapy or
antibody therapy within the past 4 weeks prior to planned infusion

3. 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

4. Prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine
implants) within the past 12 weeks prior to planned infusion

5. Prior surgery (including stereotactic radiosurgery and biopsy procedures) within the
past 4 weeks prior to planned infusion

6. Ongoing Optune© therapy within 5 days of planned infusion

7. Secondary GB (i.e., GB that progressed from low-grade diffuse astrocytoma or AA)

8. Known mutation in either the isocitrate dehydrogenase 1 (IDH1) or the IDH2 gene.

9. 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.

10. Tumor with a mass effect (e.g. 1-2 cm midline shift)

11. 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)

12. Tumor with geometric features that make them difficult to adequately cover the tumor
volume with infusate by using CED catheters

13. Clinical symptoms that are thought by the Investigator to be caused by uncontrolled
increased intracranial pressure, hemorrhage, or edema of the brain

14. Any condition that precludes the administration of anesthesia

15. Known to be human immunodeficiency virus positive

16. 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

17. Known history of allergy to gadolinium contrast agents

18. 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