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

Study ID
STU 102016-025

Study Sites

  • Clements University Hospital

Contact
Rafael Leon
214/648-1929
Rafael.Leon@UTSouthwestern.edu

Principal Investigator
Toral Patel, M.D.

Official Title

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

Brief Overview

This is a single-arm, open-label, multicenter study in approximately 43 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. Eligible subjects will receive intratumoral infusion of MDNA55 administered via convection-enhanced delivery (CED).

Description

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 target, IL4R, is an ideal but under-exploited target for the development of cancer therapeutics, as it is frequently and intensely expressed on a wide variety of human carcinomas. Expression levels of IL4R are low on the surface of healthy and normal cells, but increase several-fold on cancer cells. A majority of cancer biopsy and autopsy samples from adult and pediatric brain tumors, including recurrent glioblastoma biopsies, have been shown to over-express the IL4R. Cells that do not express the IL4R biomarker do not bind to MDNA55 and are, therefore, not subject to PE-mediated effects.
This is a single-arm, open-label, multicenter study in approximately 43 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. 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 will be performed 14 days after CED infusion. Thereafter, efficacy and safety assessments will be performed at 30, 60, 120, 180, 270, and 360 days after CED infusion. Subjects who discontinue before the Day 360 visit will undergo all the procedures scheduled for the Day 360 visit at the time of discontinuation.

Eligibility

Inclusion Criteria:
1. Male or Female ≥ 18 years old and have a life expectancy ≥ 12 weeks
2. Histologically proven, primary (de novo) Glioblastoma that has recurred or progressed (first or second recurrence, including this recurrence) after treatment(s) including surgery and radiotherapy with or without chemotherapy (according to local practice; Stupp protocol, Stupp et al., 2005) and following discontinuation of any previous standard or investigational lines of therapy
3. Confirmation that archived tissue is available from first diagnosis of Glioblastoma for biomarker analysis
4. Subjects must have evidence of tumor recurrence/progression as determined by standard RANO criteria following standard therapy:
1. Includes primary Glioblastoma
2. Screening MRI must be performed within 14 days prior to enrollment, and subjects receiving steroids must be on a stable, or decreasing dose for at least 5 days prior to imaging
3. More than 12 weeks must have elapsed since the completion of radiation therapy at the time of study entry
5. Recurrent tumor must be a solid, supratentorial, contrast-enhancing Glioblastoma no smaller than 1 cm x 1 cm (largest perpendicular dimensions) and no larger than 4 cm maximum in a single diameter based on MRI taken within 14 days prior to catheter placement
6. Karnofsky Performance Score (KPS) ≥ 70
7. Women of child-bearing potential must have a negative beta-human chorionic gonadotropin pregnancy test documented within 14 days prior to treatment
8. Women and men of child-bearing potential must agree to use adequate contraception: hormonal or barrier method of birth control; abstinence, etc. 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
9. Requirements for organ and marrow function as follows:
1. adequate bone marrow function: leukocytes > 2,000/µL; absolute neutrophil count > 1,000/µL; platelets > 100,000/μL
2. adequate hepatic function: total bilirubin < 1.5 X institutional upper limit of normal (ULN); aspartate transaminase (AST) < 2.5 X institutional upper limit of normal (ULN); alanine transaminase (ALT) < 2.5 X institutional ULN
3. adequate renal function: creatinine not to exceed 1.5 × institutional ULN; OR creatinine clearance: ≥ 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN;
4. lymphocytes > 500/μL
5. adequate coagulation function: international normalized ratio (INR) < 1.4; partial thromboplastin time (PTT) ≤ institutional ULN, unless receiving therapeutic low molecular weight heparin (corrected, if necessary, to exclude potential antibody effects)
10. Able to read, understand, and sign the informed consent document before undergoing any study-specific procedures or have a legal representative willing to do so; subjects must be registered prior to treatment with study drug
11. Subjects must be able and willing to undergo multiple brain MRI examinations
12. Subjects must be able and willing to comply with all study procedures
Exclusion Criteria:
1. Prior treatment with cytotoxic chemotherapy (e.g. temozolomide) within the past 4 weeks (6 weeks for nitrosoureas) prior to planned CED infusion
2. Prior investigational treatment within the past 4 weeks or prior immunotherapy or antibody therapy within the past 4 weeks prior to planned CED 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 CED infusion
4. Prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine implants)
5. Ongoing Optune© therapy within 5 days of planned initiation of CED infusion
6. Secondary Glioblastoma (i.e., Glioblastoma that progressed from low-grade diffuse astrocytoma or AA) and/ or known mutation in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene.
7. Unable to provide archival tissue from first diagnosis of Glioblastoma
8. 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) or multifocal or multicentric satellite tumors.
9. Tumor with a mass effect (e.g. 1-2 cm midline shift) causing clinically significant effects while on a stable corticosteroid dose
10. Subjects with tumors for which the preponderance of tissue is not that in which convection would be possible (e.g. preponderance of cystic component)
11. Tumor with geometric features that make them difficult to adequately cover the tumor volume with infusate by using CED catheters; these tumors include the following:
- tumors that appear to wrap around ventricular structures (such as an "elbow" or "L- shape") where convection is likely to be compromised
- tumors in which post-surgical enhancement in T1 images in the margins around a resection cavity may be confused with recurring tumor; subjects in whom this enhancement is below 1 cm thickness are excluded
12. Clinical symptoms that are thought by the Investigator to be caused by uncontrolled increased intracranial pressure, hemorrhage, or edema of the brain
13. Any condition that precludes the administration of anesthesia
14. Known to be human immunodeficiency virus positive
15. On-going treatment with cytotoxic therapy; no additional antineoplastic therapies are planned until there is confirmed evidence of tumor progression after administration of the study drug
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 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
19. Unwilling or unable to comply with the requirements of this protocol, including the presence of any condition (physical, mental, or social) that is likely to affect the subject's returning for follow-up visits or other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the subject's enrollment incompatible with study objectives