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

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma; Glioblastoma Multiforme; Grade IV Astrocytoma; Grade IV Glioma
• Intervention / Treatment: Drug: MDNA55

Detailed 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 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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • Santa Monica, California, United States, 90404
      • John Wayne Cancer Institute at Providence Saint John's Health Center
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Boca Raton Regional Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Hospital of the University of Pennsylvania
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio

Participation Criteria

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:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MDNA55; Single infusion of MDNA55 via convection enhanced delivery (CED).* *Subjects may be eligible to receive a second administration of MDNA55.	Drug: MDNA55; MDNA55 is an engineered circularly permuted interleukin-4 (cpIL-4) genetically fused to the catalytic domain of the pseudomonas exotoxin A (PE).; Other Names: IL4-PE; Interleukin-4 Pseudomonas Exotoxin; Interleukin-4 Pseudomonas Toxin; IL4 Pseudomonas Exotoxin; NBI-3001; cpIL4-PE

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Serious Adverse Events	Number of Subjects with Serious adverse events with Frequency >=5%	12 months
Treatment Emergent Adverse Events	Incidence of Treatment-Emergent adverse events	12 months
Level of MDNA55 in Peripheral Plasma	Systemic exposure to MDNA55 is not expected following intratumoral infusion and circulating MDNA55 has not been detected in previous clinical studies. To continue to evaluate the potential of systemic exposure, plasma collected at screening (baseline), within 1 hour following infusion end time, ~3 hours following completion of infusion and then (after the ~3 hour sample collection) every 6 hours ± 2 hours until 24 hours and at Day 14. PK data will be presented for the PK population in listing format by subject and sample collection time point. PK parameters would only be analyzed if MDNA55 levels above LLOQ (0.37 ng/mL) were detected.	14 days
ADA Titer / Neutralizing Antibody Analysis	Number of participants that were ADA Positive and had Neutralizing Antibody	12 months

Collaborators and Investigators

• Sponsor: Medicenna Therapeutics, Inc.

Publications and helpful links

General Publications

• Ellingson BM, Sampson J, Achrol AS, Aghi MK, Bankiewicz K, Wang C, Bexon M, Brem S, Brenner A, Chowdhary S, Floyd JR, Han S, Kesari S, Randazzo D, Vogelbaum MA, Vrionis F, Zabek M, Butowski N, Coello M, Merchant N, Merchant F. Modified RANO, Immunotherapy RANO, and Standard RANO Response to Convection-Enhanced Delivery of IL4R-Targeted Immunotoxin MDNA55 in Recurrent Glioblastoma. Clin Cancer Res. 2021 Jul 15;27(14):3916-3925. doi: 10.1158/1078-0432.CCR-21-0446. Epub 2021 Apr 16.

Helpful Links

• Sponsor website

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2017
• Primary Completion (Actual): September 12, 2019
• Study Completion (Actual): October 31, 2019

Study Registration Dates

• First Submitted: July 28, 2016
• First Submitted That Met QC Criteria: August 3, 2016
• First Posted (Estimate): August 8, 2016

Study Record Updates

• Last Update Posted (Actual): October 24, 2022
• Last Update Submitted That Met QC Criteria: October 18, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: immunotherapy; malignant glioma; Brain tumor; targeted; recurrent glioblastoma; High grade glioma; glioblastoma multiforme (GBM); Brain cancer; recurrent GBM; recurrent GB; glioblastoma (GB); progressive glioblastoma; IL4R
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma; Astrocytoma; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Adjuvants, Immunologic; Interleukin-4
• Other Study ID Numbers: MDNA55-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No