Clinical Trials /

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

NCT02858895

Description:

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: MDNA55-05
  • NCT ID: NCT02858895

Conditions

  • Glioblastoma
  • Grade IV Astrocytoma
  • Glioblastoma Multiforme
  • Grade IV Glioma

Interventions

DrugSynonymsArms
MDNA55IL4-PE, Interleukin-4 Pseudomonas Exotoxin, Interleukin-4 Pseudomonas Toxin, IL4 Pseudomonas Exotoxin, NBI-3001, cpIL4-PEMDNA55

Purpose

This is a single-arm, open-label, multicenter study in approximately 43 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).

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) 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
MDNA55ExperimentalSingle infusion of MDNA55 at a fixed concentration of 1.5 μg/mL. Administration will employ convection enhanced delivery (CED).
  • MDNA55

Eligibility Criteria

        Inclusion Criteria:

          1. Male or Female ≥ 18 years old and have a life expectancy ≥ 12 weeks

          2. Histologically proven, primary (de novo) Glioblastoma 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 Glioblastoma
             for biomarker analysis

          4. Subjects must have evidence of tumor recurrence/progression as determined by standard
             RANO criteria following standard therapy:

               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

          5. Recurrent tumor must be a solid, supratentorial, contrast-enhancing Glioblastoma no
             smaller than 1 cm x 1 cm (largest perpendicular dimensions) and no larger than 4 cm
             maximum in a single diameter based on MRI taken within 14 days prior to catheter
             placement

          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:

               1. adequate bone marrow function: leukocytes > 2,000/µL; absolute neutrophil count
                  > 1,000/µL; platelets > 100,000/μL

               2. adequate hepatic function: total bilirubin < 1.5 X institutional upper limit of
                  normal (ULN); aspartate transaminase (AST) < 2.5 X institutional upper limit of
                  normal (ULN); alanine transaminase (ALT) < 2.5 X institutional ULN

               3. 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;

               4. lymphocytes > 500/μL

               5. adequate coagulation function: international normalized ratio (INR) < 1.4;
                  partial thromboplastin time (PTT) ≤ institutional ULN, unless receiving
                  therapeutic low molecular weight heparin (corrected, if necessary, to exclude
                  potential antibody effects)

         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. Prior treatment with cytotoxic chemotherapy (e.g. temozolomide) within the past 4
             weeks (6 weeks for nitrosoureas) prior to planned CED infusion

          2. Prior investigational treatment within the past 4 weeks or prior immunotherapy or
             antibody therapy within the past 4 weeks prior to planned CED 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 CED infusion

          4. Prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine
             implants)

          5. Ongoing Optune© therapy within 5 days of planned initiation of CED infusion

          6. Secondary Glioblastoma (i.e., Glioblastoma that progressed from low-grade diffuse
             astrocytoma or AA) and/ or known mutation in the isocitrate dehydrogenase 1 (IDH1) or
             IDH2 gene.

          7. Unable to provide archival tissue from first diagnosis of Glioblastoma

          8. 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) or multifocal or multicentric satellite tumors.

          9. Tumor with a mass effect (e.g. 1-2 cm midline shift) causing clinically significant
             effects while on a stable corticosteroid dose

         10. Subjects with tumors for which the preponderance of tissue is not that in which
             convection would be possible (e.g. preponderance of cystic component)

         11. 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 as an "elbow" or
                  "L- shape") where 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 is below 1 cm thickness are excluded

         12. Clinical symptoms that are thought by the Investigator to be caused by uncontrolled
             increased intracranial pressure, hemorrhage, or edema of the brain

         13. Any condition that precludes the administration of anesthesia

         14. Known to be human immunodeficiency virus positive

         15. On-going treatment with cytotoxic therapy; no additional antineoplastic therapies are
             planned until there is confirmed evidence of tumor progression after administration
             of the study drug

         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 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

         19. Unwilling or unable to comply with the requirements of this 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:12 months
Safety Issue:
Description:ORR, determined by independent central review (per modified RANO criteria)

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:12 months
Safety Issue:
Description:OS, time from treatment until death
Measure:Progression Free Survival (PFS)
Time Frame:12 months
Safety Issue:
Description:PFS, time from treatment until disease progression (per modified RANO criteria) or death

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Medicenna Therapeutics, Inc.

Trial Keywords

  • 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

Last Updated

June 9, 2017