UCSF BTC Clinical Trials

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

 

Summary

This clinical trial will evaluate the efficacy of MDNA55 in treating patients with recurrent glioblastoma. MDNA55 will be administered during a minimally invasive surgery, using convection-enhanced delivery, a technique that allows drugs to be delivered through a thin tube directly into the tumor tissue.

The drug being studied, MDNA55, is a genetically engineered protein that contains a targeting molecule linked to a cell-killing agent called PE. The targeting molecule is IL-4, a protein that binds to the IL-4 receptor, which is a protein that is abundant in cancer cells and other cells in the tumor microenvironment. Much higher levels of the IL-4 receptor protein are found on the surface of many cancer cells (including recurrent glioblastoma), than found on normal, healthy cells. MDNA55 was designed to take advantage of this observation, by creating a protein that binds to IL-4 receptors and thus delivers a cell-killing agent to tumor cells.

This Phase II clinical trial is specifically for patients with glioblastoma (first or second recurrence) that has recurred after treatments including surgery and radiation therapy, with or without chemotherapy.

 

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) 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 GB for biomarker analysis
  4. Subjects must have evidence of tumor recurrence/progression as determined by standard
  5. RANO criteria following standard therapy:
    1. Includes primary GB
    2. Screening MRI must be performed within 14 days prior to planned infusion, 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
  6. 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
  7. Karnofsky Performance Score (KPS) ≥ 70
  8. Women of child-bearing potential must have a negative beta-human chorionic gonadotropin pregnancy test documented within 14 days prior to treatment
  9. Women and men of child-bearing potential must agree to use adequate contraception:
    1. 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
  10. Requirements for organ and marrow function as follows:
    1. adequate bone marrow function:
      1. leukocytes > 2,000/μL
      2. absolute neutrophil count > 1,000/μL
      3. platelets > 100,000/μL
    2. adequate hepatic function:
      1. total bilirubin < 1.5 X institutional upper limit of normal (ULN)
      2. aspartate transaminase (AST) < 2.5 X institutional upper limit of normal (ULN)
      3. alanine transaminase (ALT) < 2.5 X institutional ULN
    3. adequate renal function:
      1. creatinine not to exceed 1.5 X institutional ULN OR
      2. creatinine clearance: ≥ 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN 
    4. lymphocytes > 500/μL
    5. adequate coagulation function
      1. international normalized ratio (INR) < 1.4
      2. partial thromboplastin time (PTT) ≤ institutional ULN, unless receiving therapeutic low molecular weight heparin (corrected, if necessary, to exclude potential antibody effects)
  11. 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
  12. Subjects must be able and willing to undergo multiple brain MRI examinations
  13. Subjects must be able and willing to comply with all study procedures
  14. Any related toxicities following discontinuation of prior GB therapies must have resolved to CTCAE Grade 1 or lower prior to inclusion in this study

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

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; Subjects with prior immunotherapy within 6 months of planned infusion must have confirmed evidence of tumor recurrence/progression as determined by iRANO or mRANO criteria.
  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. Multifocal or multicentric satellite tumors with enhancement observed outside a 4cm x 4cm area on a single plane (maximum area covered by infusate). Multifocal lesions are defined by >1 measurable enhancing lesion (1cm x 1cm perpendicular dimensions) separated by at least 1cm with confluent T2 hyperintensity between the lesions. Multicentric lesions are defined by >1 measurable enhancing lesion (1cm x 1cm perpendicular dimensions) separated by at least 1cm with normal brain between the lesions). Measurable enhancing tumors separated by at least 1cm with any enhancing components >4cm apart are excluded from the current study, as these regions will not be covered by the infusion.
  11. Tumor with a mass effect (e.g. 1-2 cm midline shift) causing clinically significant effects while on a stable corticosteroid dose
  12. 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)
  13. Tumor with geometric features that make them difficult to adequately cover the tumor volume with infusate by using CED catheters; these include the following:
    1. tumors that appear to wrap around ventricular structures (such as an "elbow" or "Lshape") where convection is likely to be compromised
    2. 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
    3. tumors determined by expert review not to be good candidates for convection (e.g. on grounds of consistency, location, geometry, relationship to surrounding structures, presence of cyst, etc.
    4. superficial tumors where direct infiltration of tumor into the cortical surface is apparent on MRI unless the distal margin of the enhancing tumor is ≥ 3cm from the cortical surface (Subjects with superficial tumors where separation of the tumor from the subdural space by a continuous layer of intact cortex is apparent on MRI remain eligible)
  14. Clinical symptoms that are thought by the Investigator to be caused by uncontrolled increased intracranial pressure, hemorrhage, or edema of the brain
  15. Any condition that precludes the administration of anesthesia
  16. Known to be human immunodeficiency virus positive
  17. On-going treatment with cytotoxic therapy; no additional antineoplastic therapies (including surgical modalities) are planned until there is confirmed evidence of tumor progression (as per modified RANO criteria) after administration of MDNA55
  18. 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
  19. Known history of allergy to gadolinium contrast agents
  20. 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
  21. Unwilling or unable to comply with the requirements of this protocol, including the presence of any condition (physical, mental, or social or geographical) that is likely to affect the subject's returning to the investigational site for follow-up visits including for imaging or other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the subject's enrollment incompatible with study objectives

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Investigator(s)

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