Glioblastoma, Glioblastoma Multiforme, Grade IV Astrocytoma, Grade IV Glioma
Conditions
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
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.
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 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 and efficacy will be performed monthly for the first 6 months and bimonthly thereafter for approximately 1 year after study drug administrations. Subjects will continued to be followed for survival and post-study treatment(s) of GB after study completion or withdrawal.
Interventions
DRUGMDNA55
MDNA55 is an engineered circularly permuted interleukin-4 (cpIL-4) genetically fused to the catalytic domain of the pseudomonas exotoxin A (PE).
Sponsors
Medicenna Therapeutics, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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) 3. Confirmation that archived tissue is available from first diagnosis of GB for biomarker analysis 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. Subjects must be able and willing to undergo multiple brain MRI examinations 7. Subjects must be able and willing to comply with all study procedures 8. 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 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. Tumor with a mass effect (e.g. 1-2 cm midline shift) 11. 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) 12. Tumor with geometric features that make them difficult to adequately cover the tumor volume with infusate by using CED catheters 13. Clinical symptoms that are thought by the Investigator to be caused by uncontrolled increased intracranial pressure, hemorrhage, or edema of the brain 14. Any condition that precludes the administration of anesthesia 15. Known to be human immunodeficiency virus positive 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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From start of treatment until date of death from any cause. Subjects who were not known to have died at the time of the analysis were to be censored at the date of last contact. | Primary endpoint analysis was based on the ITT population. The null hypothesis was mOS of 8.0 months, based on a clinically-weighted average of published studies of FDA-approved therapies versus the alternative hypothesis of 11.5 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 12 months | ORR, determined by independent central review (per RANO-based criteria) Complete Response - Disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. Partial Response - ≥50% decrease in sum of products of perpendicular diameters or ≥65% decrease in total volume of all measurable enhancing lesions compared with baseline, sustained for at least 4 weeks Progressive Disease - At least two sequential scans separated by at ≥4 weeks both exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume of enhancing lesions. Stable Disease - Does not qualify for CR, PR, or PD as defined above |
| Progression Free Survival (PFS) | 12 months | PFS, time from treatment until disease progression (per RANO-based criteria) or death Progressive Disease per RANO - At least two sequential scans separated by at ≥4 weeks both exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume of enhancing lesions |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Serious Adverse Events | 12 months | Number of Subjects with Serious adverse events with Frequency \>=5% |
| ADA Titer / Neutralizing Antibody Analysis | 12 months | Number of participants that were ADA Positive and had Neutralizing Antibody |
| Treatment Emergent Adverse Events | 12 months | Incidence of Treatment-Emergent adverse events |
| Level of MDNA55 in Peripheral Plasma | 14 days | Systemic exposure to MDNA55 is not expected following intratumoral infusion and circulating MDNA55 has not been detected in previous clinical studies. To continue to evaluate the potential of systemic exposure, plasma collected at screening (baseline), within 1 hour following infusion end time, \ 3 hours following completion of infusion and then (after the \ 3 hour sample collection) every 6 hours ± 2 hours until 24 hours and at Day 14. PK data will be presented for the PK population in listing format by subject and sample collection time point. PK parameters would only be analyzed if MDNA55 levels above LLOQ (0.37 ng/mL) were detected. |
Countries
United States
Participant flow
Pre-assignment details
Pre-treatment catheter trajectory planning performed to place up to 4 catheters, depending upon the tumor size.
Participants by arm
| Arm | Count |
|---|---|
| MDNA55 Subjects received a single infusion of MDNA55 (via convection enhanced delivery) at concentrations ranging from 1.5 to 9.0 μg/mL and volumes ranging from 12 to 66 mL (total dose between 18 to 240 mcg) | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 2 |
| Overall Study | did not receive drug due to catheters misplaced | 1 |
| Overall Study | Disease progression | 31 |
| Overall Study | hospice, | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | MDNA55 |
|---|---|
| Age, Customized Age (years) | 56.7 years STANDARD_DEVIATION 11.82 |
| Diagnostic method of Glioblastoma Biopsy | 30 participants |
| Diagnostic method of Glioblastoma CT | 4 participants |
| Diagnostic method of Glioblastoma MRI | 32 participants |
| Ethnicity Hispanic or Latino | 3 Participants |
| Ethnicity Not Hispanic or Latino | 44 Participants |
| Initial diagnosis to 1st relapse | 12.98 months STANDARD_DEVIATION 7.673 |
| Karnofsky Performance Score (KPS) 100 (normal, no complaints, no signs of disease) | 5 Participants |
| Karnofsky Performance Score (KPS) 70 (caring for self, not capable of normal activity or work) | 3 Participants |
| Karnofsky Performance Score (KPS) 80 (normal activity with some difficulty, some symptoms or signs) | 20 Participants |
| Karnofsky Performance Score (KPS) 90 (capable of normal activity, few symptoms or signs of disease) | 19 Participants |
| Lymphocyte Count | 0.991 10^9 cells/L STANDARD_DEVIATION 0.3839 |
| Maximum tumor diameter at baseline | 3.160 cm STANDARD_DEVIATION 1.1736 |
| Max tumor diameter at initial diagnosis | 3.331 cm STANDARD_DEVIATION 1.431 |
| Number of prior relapse 1st relapse | 37 Participants |
| Number of prior relapse 2nd relapse | 10 Participants |
| o6-methylguanine-DNA-methyltransferase (MGMT) Status Methylated | 18 Participants |
| o6-methylguanine-DNA-methyltransferase (MGMT) Status Not Available | 5 Participants |
| o6-methylguanine-DNA-methyltransferase (MGMT) Status Unmethylated | 24 Participants |
| Prior Glioblastoma treatment Additional Surgery - Debulking | 6 participants |
| Prior Glioblastoma treatment Additional Surgery - Other | 4 participants |
| Prior Glioblastoma treatment Additional Surgery - Resection | 10 participants |
| Prior Glioblastoma treatment Initial Surgery - Other | 6 participants |
| Prior Glioblastoma treatment Initial Surgery - Partial Resection | 4 participants |
| Prior Glioblastoma treatment Initial Surgery - Total Resection | 37 participants |
| Prior Glioblastoma treatment Investigational | 13 participants |
| Prior Glioblastoma treatment Other | 7 participants |
| Prior Glioblastoma treatment Other Chemotherapy | 5 participants |
| Prior Glioblastoma treatment Radiotherapy | 46 participants |
| Prior Glioblastoma treatment Temozolomide | 46 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Race/Ethnicity, Customized White | 41 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 30 Participants |
| Steroid Use Missing | 1 Participants |
| Steroid Use No | 13 Participants |
| Steroid Use Not applicable | 14 Participants |
| Steroid Use Yes | 19 Participants |
| Tumor volume at baseline | 10.543 cm^3 STANDARD_DEVIATION 11.0621 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 36 / 47 | 16 / 18 | 8 / 9 | 3 / 6 | 8 / 13 |
| other Total, other adverse events | 46 / 47 | 18 / 18 | 9 / 9 | 6 / 6 | 13 / 13 |
| serious Total, serious adverse events | 24 / 47 | 7 / 18 | 4 / 9 | 3 / 6 | 9 / 13 |
Outcome results
Primary
Overall Survival (OS)
Primary endpoint analysis was based on the ITT population. The null hypothesis was mOS of 8.0 months, based on a clinically-weighted average of published studies of FDA-approved therapies versus the alternative hypothesis of 11.5 months.
Time frame: From start of treatment until date of death from any cause. Subjects who were not known to have died at the time of the analysis were to be censored at the date of last contact.
Population: Primary endpoint analysis was based on the ITT population. The null hypothesis was mOS of 8.0 months, based on a clinically-weighted average of published studies of FDA-approved therapies.~ITT/Safety population: all subjects who signed an informed consent form and received any amount of study drug.~Per-Protocol Population: all subjects in the ITT Population who had no major protocol violation during the study.~Primary efficacy analysis was not performed for individual dose concentrations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MDNA55 (ITT Analysis) | Overall Survival (OS) | 10.2 months |
| MDNA55 (PP Analysis) | Overall Survival (OS) | 11.64 months |
Secondary
Objective Response Rate (ORR)
ORR, determined by independent central review (per RANO-based criteria) Complete Response - Disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. Partial Response - ≥50% decrease in sum of products of perpendicular diameters or ≥65% decrease in total volume of all measurable enhancing lesions compared with baseline, sustained for at least 4 weeks Progressive Disease - At least two sequential scans separated by at ≥4 weeks both exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume of enhancing lesions. Stable Disease - Does not qualify for CR, PR, or PD as defined above
Time frame: 12 months
Population: Modified Intent-to-Treat Population (mITT): mITT population was used for secondary response analyses and consisted of all subjects who received any amount of study drug, had adequate imaging (at least 1 post-treatment scan), and had sufficient clinical data for ORR analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MDNA55 (ITT Analysis) | Objective Response Rate (ORR) | 1 Participants |
Secondary
Progression Free Survival (PFS)
PFS, time from treatment until disease progression (per RANO-based criteria) or death Progressive Disease per RANO - At least two sequential scans separated by at ≥4 weeks both exhibiting ≥25% increase in sum of products of perpendicular diameters or ≥40% increase in total volume of enhancing lesions
Time frame: 12 months
Population: Modified Intent-to-Treat Population (mITT): mITT population was used for secondary response analyses and consisted of all subjects who received any amount of study drug, had adequate imaging (at least 1 post-treatment scan), and had sufficient clinical data for ORR analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MDNA55 (ITT Analysis) | Progression Free Survival (PFS) | 3.61 months |
Other Pre-specified
ADA Titer / Neutralizing Antibody Analysis
Number of participants that were ADA Positive and had Neutralizing Antibody
Time frame: 12 months
Population: Anti-Drug-Antibody (ADA) Population: ADA population included all subjects who received any dose of study drug and had a pre-treatment baseline blood sample and at least one post-treatment blood sample available for determination of ADA. Neutralizing antibody (NAb) titers were assessed in the ADA population as appropriate and applicable.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MDNA55 (ITT Analysis) | ADA Titer / Neutralizing Antibody Analysis | ADA positive | 19 Participants |
| MDNA55 (ITT Analysis) | ADA Titer / Neutralizing Antibody Analysis | Neutralizing Antibody (NAb) | 16 Participants |
Other Pre-specified
Level of MDNA55 in Peripheral Plasma
Systemic exposure to MDNA55 is not expected following intratumoral infusion and circulating MDNA55 has not been detected in previous clinical studies. To continue to evaluate the potential of systemic exposure, plasma collected at screening (baseline), within 1 hour following infusion end time, \ 3 hours following completion of infusion and then (after the \ 3 hour sample collection) every 6 hours ± 2 hours until 24 hours and at Day 14. PK data will be presented for the PK population in listing format by subject and sample collection time point. PK parameters would only be analyzed if MDNA55 levels above LLOQ (0.37 ng/mL) were detected.
Time frame: 14 days
Population: Pharmacokinetic (PK) Population: Subjects who received the highest concentrations (6 μg/mL and 9 μg/mL) were analysed first. If all results were shown to be below lower limit of quantitation (LLOQ) of 0.37 ng/mL, consistent with historical data showing no evidence of systemic exposure with MDNA55, then no further subjects were to be analyzed. All subjects analyzed had levels of MDNA55 that were below lower limit of quantitation (LLOQ) of 0.37 ng/mL
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MDNA55 (ITT Analysis) | Level of MDNA55 in Peripheral Plasma | NA ng/mL |
Other Pre-specified
Number of Subjects With Serious Adverse Events
Number of Subjects with Serious adverse events with Frequency \>=5%
Time frame: 12 months
Population: Intent-to-Treat and Safety: ITT and Safety populations were identical and consisted of all subjects who signed an informed consent form and received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MDNA55 (ITT Analysis) | Number of Subjects With Serious Adverse Events | 24 Participants |
Other Pre-specified
Treatment Emergent Adverse Events
Incidence of Treatment-Emergent adverse events
Time frame: 12 months
Population: Intent-to-Treat and Safety: ITT and Safety populations were identical and consisted of all subjects who signed an informed consent form and received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MDNA55 (ITT Analysis) | Treatment Emergent Adverse Events | 46 Participants |