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Summary

for people ages 18 years and up (full criteria)
at San Francisco, California and other locations
study started
estimated completion:

Description

Summary

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. Eligible subjects will receive intratumoral infusion of MDNA55 administered via convection-enhanced delivery (CED).

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

Details

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 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. The study will be conducted at up to 12 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, 90, 120, 180, 240, and 360 days after CED infusion.

Subjects who complete the Day 360 study follow up visit without disease progression or discontinue early without disease progression will continue to be followed for disease status until progression where possible. After progression (on study or during post-study follow-up), subjects will continue to be followed for survival and post-study treatment(s) for GB and imaging for GB, where possible, until death (or termination of data collection by the Sponsor or withdrawal of consent by the subject).

Keywords

Glioblastoma Grade IV Astrocytoma Glioblastoma Multiforme Grade IV Glioma High grade glioma malignant glioma recurrent glioblastoma recurrent GBM recurrent GB glioblastoma (GB) glioblastoma multiforme (GBM) progressive glioblastoma Brain tumor Brain cancer immunotherapy targeted IL4R Glioma Astrocytoma Interleukin-4

Eligibility

You can join if…

Open to people ages 18 years and up

  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

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
  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. Women of child-bearing potential must have a negative beta-human chorionic gonadotropin pregnancy test documented within 14 days prior to treatment
  7. 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

  1. Requirements for organ and marrow function as follows:
  2. adequate bone marrow function:
  3. leukocytes > 2,000/μL
  4. absolute neutrophil count > 1,000/μL
  5. platelets > 100,000/μL
  6. adequate hepatic function:
  7. total bilirubin < 1.5 X institutional upper limit of normal (ULN)
  8. aspartate transaminase (AST) < 2.5 X institutional upper limit of normal(ULN)
  9. alanine transaminase (ALT) < 2.5 X institutional ULN
  10. adequate renal function:
  11. creatinine not to exceed 1.5 X institutional ULN OR
  12. creatinine clearance: ≥ 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN
  13. lymphocytes > 500/μL
  14. adequate coagulation function
  15. international normalized ratio (INR) < 1.4
  16. partial thromboplastin time (PTT) ≤ institutional ULN, unless receiving therapeutic low molecular weight heparin (corrected, if necessary, to exclude potential antibody effects)
  17. . 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
  18. . Subjects must be able and willing to undergo multiple brain MRI examinations
  19. . Subjects must be able and willing to comply with all study procedures
  20. . Any related toxicities following discontinuation of prior GB therapies must have resolved to CTCAE Grade 1 or lower prior to inclusion in this study

You CAN'T join if...

  1. Prior treatment with cytotoxic chemotherapy
  2. Temozolomide (standard induction and / or maintenance dosing) within the past 4 weeks prior to planned infusion
  3. "Metronomic" Temozolomide (low-dose, continuous administration) within the past 7 days prior to planned infusion
  4. Nitrosoureas within the past 6 weeks prior to planned infusion
  5. Treatment with any other cytotoxic agent within the past 4 weeks prior to planned infusion
  6. 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.
  7. 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
  8. Prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine implants) within the past 12 weeks prior to planned infusion
  9. Prior surgery (including stereotactic radiosurgery and biopsy procedures) within the past 4 weeks prior to planned infusion
  10. Ongoing Optune© therapy within 5 days of planned infusion
  11. Secondary GB (i.e., GB that progressed from low-grade diffuse astrocytoma or AA)
  12. Known mutation in either the isocitrate dehydrogenase 1 (IDH1) or the IDH2 gene.
  13. 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.
  14. . 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.
  15. . Tumor with a mass effect (e.g. 1-2 cm midline shift) causing clinically significant effects while on a stable corticosteroid dose
  16. . 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)
  17. . Tumor with geometric features that make them difficult to adequately cover the tumor volume with infusate by using CED catheters; these include the following:
  18. tumors that appear to wrap around ventricular structures (such as an "elbow" or"Lshape") where convection is likely to be compromised
  19. 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
  20. 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.
  21. 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)
  22. . Clinical symptoms that are thought by the Investigator to be caused by uncontrolled increased intracranial pressure, hemorrhage, or edema of the brain
  23. . Any condition that precludes the administration of anesthesia
  24. . Known to be human immunodeficiency virus positive
  25. . 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
  26. . 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
  27. . Known history of allergy to gadolinium contrast agents
  28. . 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
  29. . 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

Locations

  • University of California San Francisco accepting new patients
    San Francisco, California, 94143, United States
  • John Wayne Cancer Institute at Providence Saint John's Health Center accepting new patients
    Santa Monica, California, 90404, United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Medicenna Therapeutics, Inc.
Links
Sponsor website
ID
NCT02858895
Phase
Phase 2
Lead Scientist
Nicholas Butowski
Study Type
Interventional
Last Updated
February 13, 2018
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