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Trial record 1 of 1 for:    NCT02858895
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Convection-Enhanced Delivery (CED) of MDNA55 in Adults With Recurrent or Progressive Glioblastoma

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ClinicalTrials.gov Identifier: NCT02858895
Recruitment Status : Recruiting
First Posted : August 8, 2016
Last Update Posted : January 4, 2018
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief 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).

Condition or disease Intervention/treatment Phase
Glioblastoma Grade IV Astrocytoma Glioblastoma Multiforme Grade IV Glioma Drug: MDNA55 Phase 2

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 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).


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 2016
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : July 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: MDNA55
Single infusion of MDNA55 at a fixed concentration of 3.0 μg/mL. Administration will employ convection enhanced delivery (CED).
Drug: MDNA55
Other Names:
  • IL4-PE
  • Interleukin-4 Pseudomonas Exotoxin
  • Interleukin-4 Pseudomonas Toxin
  • IL4 Pseudomonas Exotoxin
  • NBI-3001
  • cpIL4-PE


Outcome Measures

Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 12 months ]
    ORR, determined by independent central review (per modified RANO criteria)


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 12 months ]
    OS, time from treatment until death

  2. Progression Free Survival (PFS) [ Time Frame: 12 months ]
    PFS, time from treatment until disease progression (per modified RANO criteria) or death


Other Outcome Measures:
  1. Duration of response (DOR) [ Time Frame: 12 months ]
    DOR, time from first response until disease progression (per modified RANO criteria and as determined by an Independent Central Review) or death among those subjects achieving a complete response (CR) or partial response (PR) to treatment

  2. Duration of clinical benefit (DOCB) [ Time Frame: 12 months ]
    DOCB, time from first response until disease progression (per a modified RANO criteria and as determined an Independent Central Review) or death among those subjects achieving a complete response (CR), partial response (PR), or stable disease (SD)

  3. Serious adverse events (SAEs) [ Time Frame: 12 months ]
    Incidence of SAEs

  4. Treatment emergent adverse events (AEs) [ Time Frame: 12 months ]
    Incidence of Treatment-Emergent AEs

  5. Electrocardiogram (ECG) [ Time Frame: 0-2 days ]
    Incidence of clinically significant ECG findings

  6. Karnofsky Performance Score (KPS) [ Time Frame: 12 months ]
    Changes since baseline

  7. Pharmacokinetics (PK) of MDNA55 [ Time Frame: 14 days ]
    Blood samples will be collected to determine levels of MDNA55

  8. Anti-MDNA55 antibody [ Time Frame: 12 months ]
    Blood samples will be collected to determine anti-drug antibody titers

  9. Neutralizing antibody titer [ Time Frame: 12 months ]
    If elevated anti-MDNA55 titer is observed


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

    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
  5. 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
  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 < 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
    • adequate renal function:

      • creatinine not to exceed 1.5 X 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 (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
  13. 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; 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:

    • tumors that appear to wrap around ventricular structures (such as an "elbow" or "Lshape") 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
    • 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.
    • 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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02858895


Contacts
Contact: Patrick Ward 832-552-2660 pward@medicenna.com

Locations
United States, California
University of California San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Nurse Line    415-353-2652      
Principal Investigator: Nicholas Butowski, MD         
John Wayne Cancer Institute at Providence Saint John's Health Center Recruiting
Santa Monica, California, United States, 90404
Contact: Naj Boucher    310-582-7460    Najee.Boucher@providence.org   
Principal Investigator: Achal Achrol, MD         
United States, Florida
Boca Raton Regional Hospital Recruiting
Boca Raton, Florida, United States, 33486
Contact: Pilar Zuniga, MD    561-955-4800    pzuniga@brrh.com   
Principal Investigator: Frank Vrionis, MD         
United States, New York
Weill Cornell Medical Center - New York Presbyterian Recruiting
New York, New York, United States, 10022
Contact: Mary O'Hehir    212-746-7373    mao2037@med.cornell.edu   
Contact: Alyson Hignight    212-746-1788    alh2031@med.cornell.edu   
Principal Investigator: Mark Souweidane, MD         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Brain Tumor Center    919-684-5301      
Principal Investigator: Dina Randazzo, MD         
United States, Ohio
Cleveland Clinic Recruiting
Cleveland, Ohio, United States, 44195
Contact: Cathy Brewer, RN    216-444-7937    brewerc1@ccf.org   
Principal Investigator: Michael Vogelbaum, MD, PhD         
Ohio State University Recruiting
Columbus, Ohio, United States, 43210
Contact: Barb Kleiber    614-293-1815    Barbara.Kleiber@osumc.edu   
Principal Investigator: Russell Lonser, MD         
United States, Oregon
Oregon Health & Science University Not yet recruiting
Portland, Oregon, United States, 3
Contact: Amanda Cole, MS, ACRP    503-494-4988    coleam@ohsu.edu   
Principal Investigator: Seunggu Han, MD         
United States, Pennsylvania
Hospital of the University of Pennsylvania Not yet recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Scott Levy    215-662-6832    Scott.Levy@uphs.upenn.edu   
Principal Investigator: Steven Brem, MD         
United States, Texas
University of Texas Southwestern Cancer Center Recruiting
Dallas, Texas, United States, 75390
Contact: Rafael Leon    214-648-1929    Rafael.leon@utsouthwestern.edu   
Principal Investigator: Toral Patel, MD         
Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Epp Goodwin    210-450-5798    CTRC-ReferralCenter@uthscsa.edu   
Principal Investigator: Andrew Brenner, MD         
Poland
Mazovian Brodnowski Hospital Recruiting
Warsaw, Poland, 03-242
Contact: Karolina Karas    +48 600 953 994    k.karas.inc@gmail.com   
Principal Investigator: Miroslaw Zabek         
Sponsors and Collaborators
Medicenna Therapeutics, Inc.
More Information

Additional Information:
Responsible Party: Medicenna Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02858895     History of Changes
Other Study ID Numbers: MDNA55-05
First Posted: August 8, 2016    Key Record Dates
Last Update Posted: January 4, 2018
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Medicenna Therapeutics, Inc.:
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

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Interleukin-4
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antirheumatic Agents