| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the objective response rate (ORR) per a modified RANO criteria
following an intra- and peritumoral infusion CED of MDNA55 using CED
relative to pre-operative planning MRI (baseline) |
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| E.2.2 | Secondary objectives of the trial |
To assess the safety of MDNA55 following CED in adult subjects with GB at first recurrence following standard therapy.
To assess overall survival (OS) in these subjects
To assess progression-free survival (PFS; using iRANO criteria) in these subjects |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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:
a) Includes primary GB
b) 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
c) More than 12 weeks must have elapsed since the completion of radiation therapy at the time of study entry, unless the majority of the new enhancement is outside of the radiation field (for example, beyond the high-dose region or 80% isodose line)
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:
o leukocytes > 2,000/μL
o absolute neutrophil count > 1,000/μL
o platelets > 100,000/μL
• adequate hepatic function:
o total bilirubin < 1.5 X institutional upper limit of normal (ULN)
o aspartate transaminase (AST) < 2.5 X institutional upper limit of normal (ULN)
o alanine transaminase (ALT) < 2.5 X institutional ULN
• adequate renal function:
o creatinine not to exceed 1.5 X institutional ULN
OR
o creatinine clearance: ≥ 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN
• lymphocytes > 500/μL
• adequate coagulation function
o international normalized ratio (INR) < 1.4
o 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
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| E.4 | Principal exclusion criteria |
1) Prior treatment with cytotoxic chemotherapy
a) Temozolomide (standard induction and / or maintenance dosing) within the past 4 weeks prior to planned infusion
b) “Metronomic” Temozolomide (low-dose, continuous administration) within the past 7 days prior to planned infusion
c) Nitrosoureas within the past 6 weeks prior to planned infusion
d) 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 of infusion
6) Ongoing Optune© therapy within 5 days of planned initiation of 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 drug infusion). 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 cm midline shift)
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; 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 the study drug
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 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 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR as determined by an independent central review (Imaging Core Lab) according to modified RANO criteria, as assessed by gadolinium-enhanced MRI approximately 30, 60, 90, 120, 180, 240, and 360 days post-CED infusion relative to pre-treatment baseline MRI (acquired for treatment planning prior to catheter placement). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assessment by gadolinium-enhanced MRI approximately 30, 60, 90, 120, 180, 240, and 360 days post-CED infusion relative to pre-treatment baseline MRI |
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| E.5.2 | Secondary end point(s) |
1.OS, defined as the time from treatment until death.
2.PFS, defined as the time from treatment until disease progression (per modified RANO criteria and as determined by an independent central review) or death. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After progression (on study or during follow-up), subjects will continue to be followed for survival and post-study treatment for GB until death (or termination of data collection by the Sponsor or withdrawal of consent by the subject). |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial months | 21 |
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