Patient case: 84-year-old male with glioblastoma; genetic feature: CDK6

Clinical trial: Convection-Enhanced Delivery (CED) of MDNA55 in Adults With Glioblastoma at First Recurrence or Progression

Summary: This is a single-arm, open-label, multicenter study in approximately 43 adults with primary (de novo) Glioblastoma that has recurred or progressed after failure of first-line therapy [according to Response Assessment in Neuro-Oncology (RANO) criteria]. Eligible subjects will receive intratumoral infusion of MDNA55 administered via convection-enhanced delivery (CED).

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 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) Glioblastoma that has recurred or progressed after failure of standard first-line therapy (according to RANO criteria). 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. ≥ 18 years old, have access to archival tissue from first diagnosis of Glioblastoma and have a life expectancy ≥ 12 weeks
  2. Histologically proven, primary (de novo) Glioblastoma that has recurred or progressed after only 1 standard treatment regimen including surgery and radiotherapy with or without chemotherapy (according to local practice; Stupp protocol, Stupp et al., 2005)
  3. Subjects must have evidence of first tumor recurrence/progression as determined by standard RANO criteria:
  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
  4. Recurrent tumor must be a solid, supratentorial, contrast-enhancing Glioblastoma no smaller than 1 cm and no larger than 4 cm in diameter as assessed by the Imaging Core Laboratory based on MRI taken within 14 days prior to catheter placement
  5. If temozolomide was received as part of first line therapy, subjects must have recovered from the toxic effects of temozolomide and be at least 23 days from last dose prior to start of CED infusion
  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:
  -  adequate bone marrow function: leukocytes > 2,000/μL; absolute neutrophil count > 1,000/μL; platelets > 100,000/μL
  -  adequate hepatic function: total bilirubin within normal institutional limits; aspartate transaminase (AST) < 2.5 X institutional upper limit of normal (ULN); alanine transaminase (ALT) < 2.5 X institutional ULN
  -  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
  -  lymphocytes > 500/μL
  -  adequate coagulation function: international normalized ratio (INR) < 1.4; partial thromboplastin time (PTT) ≤ institutional ULN, unless receiving therapeutic low molecular weight heparin
  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. Any prior therapy for Glioblastoma other than that which is considered standard of care for primary Glioblastoma, including but not limited to the following:
  -  more than one line of adjuvant temozolomide; temozolomide treatment must have been completed at least 23 days prior to CED infusion
  -  prior treatment with another investigational drug
  -  prior treatment with bevacizumab (Avastin) or other vascular-endothelial growth factor (VEGF) inhibitors or VEGF-receptor signaling inhibitors
  -  prior treatment with nitrosoureas
  -  prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine implants)
  2. Secondary Glioblastoma (i.e., Glioblastoma that progressed from low-grade diffuse astrocytoma or AA)
  3. Unable to provide archival tissue from first diagnosis of Glioblastoma
  4. Tumor in the brain stem (not including fluid-attenuated inversion recovery [FLAIR] changes), an infratentorial tumor, or multifocal satellite tumors
  5. Tumor with a clinically significant mass effect (> 5 mm midline shift) while on a stable corticosteroid dose
  6. Subjects with tumors that are completely liquefied (> 95% cyst) in which convection would not be possible
  7. 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 that the catheter tips may be positioned > 1.0 cm of a ventricle or such that a large angle (such as an "elbow" or "L- shape") in the tumor shape is present and 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 exceeds 1 cm thickness are excluded
  8. Clinical symptoms that are thought by the Investigator to be caused by uncontrolled increased intracranial pressure, hemorrhage, or edema of the brain
  9. Significant heart disease that precludes the administration of anesthesia
  10. Known to be human immunodeficiency virus positive
  11. On-going treatment with cytotoxic therapy; no additional antineoplastic therapies are planned until there is evidence of tumor progression after administration of the study drug
  12. 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
  13. Known history of allergy to gadolinium contrast agents
  14. 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
  15. Unwilling or unable to comply with the requirements of the 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

Relevance to patient case: not relevant