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.

• MDNA55 (Drug), also known as IL4-PE, Interleukin-4 Pseudomonas Exotoxin, Interleukin-4 Pseudomonas Toxin, IL4 Pseudomonas Exotoxin, NBI-3001, cpIL4-PE: MDNA55 is an engineered circularly permuted interleukin-4 (cpIL-4) genetically fused to the catalytic domain of the pseudomonas exotoxin A (PE).

Primary outcomes

• Overall Survival (OS) [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.]: 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.

Secondary outcomes

• Objective Response Rate (ORR) [12 months]: 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
• Progression Free Survival (PFS) [12 months]: 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

Other outcomes

• Number of Subjects With Serious Adverse Events [12 months]: Number of Subjects with Serious adverse events with Frequency >=5%
• Treatment Emergent Adverse Events [12 months]: Incidence of Treatment-Emergent adverse events
• Level of MDNA55 in Peripheral Plasma [14 days]: 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.
• ADA Titer / Neutralizing Antibody Analysis [12 months]: Number of participants that were ADA Positive and had Neutralizing Antibody

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Overall Survival (OS) (Primary), Median, months: MDNA55 (ITT Analysis) 10.2 (8.39 to 12.75); MDNA55 (PP Analysis) 11.64 (8.62 to 15.02)
• Objective Response Rate (ORR) (Secondary), Count of participants, Participants: MDNA55 1
• Progression Free Survival (PFS) (Secondary), Median, months: MDNA55 3.61 (2.79 to 5.08)
• Number of Subjects With Serious Adverse Events (Other pre specified), Count of participants, Participants: MDNA55 24
• Treatment Emergent Adverse Events (Other pre specified), Count of participants, Participants: MDNA55 46
• Level of MDNA55 in Peripheral Plasma (Other pre specified), Median, ng/mL: MDNA55 NA +/- NA
• ADA Titer / Neutralizing Antibody Analysis (Other pre specified), Count of participants, Participants: MDNA55 19

Adverse events

Time frame: AEs were collected from catheter placement through 12 months post treatment or early withdrawal and followed until resolution, stabilization, data cut-off, or death. For subjects that withdraw from the study, SAEs that occur within 30 days of the date of discontinuation collected.

Serious adverse events by term

Other adverse events by term

2 more terms not shown.

• Results publication: Sampson JH, Singh Achrol A, Aghi MK, Bankiewicz K, Bexon M, Brem S, Brenner A, Chandhasin C, Chowdhary S, Coello M, Ellingson BM, Floyd JR, Han S, Kesari S, Mardor Y, Merchant F, Merchant N, Randazzo D, Vogelbaum M, Vrionis F, Wembacher-Schroeder E, Zabek M, Butowski N. Targeting the IL4 receptor with MDNA55 in patients with recurrent glioblastoma: Results of a phase IIb trial. Neuro Oncol. 2023 Jun 2;25(6):1085-1097. doi: 10.1093/neuonc/noac285. PMID 36640127
• Results publication: 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. PMID 33863808

• Study Protocol (PDF, 2019-07-19)
• Statistical Analysis Plan (PDF, 2019-10-23)