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Interleukin-4

Adjuvants, Immunologic

Immunologic Factors

Single infusion of MDNA55 via convection enhanced delivery (CED).\*

\*Subjects may be eligible to receive a second administration of MDNA55.

MDNA55 is an engineered circularly permuted interleukin-4 (cpIL-4) genetically fused to the catalytic domain of the pseudomonas exotoxin A (PE).

MDNA55

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 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.

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

An Open-Label Non-Randomized, Multi-Center Phase-2 Study of Convection-Enhanced Delivery (CED) of MDNA55 in Adults With Recurrent or Progressive Glioblastoma

Number of Subjects with Serious adverse events with Frequency \>=5%

Incidence of Treatment-Emergent adverse events

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.

Number of participants that were ADA Positive and had Neutralizing Antibody

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.

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

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

Medicenna Therapeutics, Inc.

All patients were included in the in the ITT / Safety Population (N=47) for "MDNA55 (Overall)"; there is one patient that underwent catheter placement but did not receive the study drug; the infusion did not proceed due to catheter misplacement. Therefore, this participant is not included in the individual MDNA55 infusion arms (N=46)

Single infusion of MDNA55 administered via Convection Enhanced Delivery (CED) Dose conc. range 1.5 to 9.0 mcg/mL; total dose range 18 to 240 mcg

MDNA55 (Overall)

Single infusion of MDNA55 administered via Convection Enhanced Delivery (CED) Dose conc. 1.5 mcg/mL

MDNA55 (1.5 mcg/mL)

Single infusion of MDNA55 administered via Convection Enhanced Delivery (CED) Dose conc. 3.0 mcg/mL

MDNA55 (3.0 mcg/mL)

Single infusion of MDNA55 administered via Convection Enhanced Delivery (CED) Dose conc. 6.0 mcg/mL

MDNA55 (6.0 mcg/mL)

Single infusion of MDNA55 administered via Convection Enhanced Delivery (CED) Dose conc. 9.0 mcg/mL

MDNA55 (9.0 mcg/mL)

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)

Age (years)

Age, Customized

Sex: Female, Male

American Indian or Alaska Native

Asian

Black or African American

Native Hawaiian or Other Pacific Islander

White

Other

Race/Ethnicity, Customized

Ethnicity

Karnofsky Performance Score (KPS)

o6-methylguanine-DNA-methyltransferase (MGMT) Status

Steroid Use

Biopsy

Diagnostic method of Glioblastoma

Initial Surgery - Total Resection

Initial Surgery - Partial Resection

Initial Surgery - Other

Additional Surgery - Resection

Additional Surgery - Debulking

Additional Surgery - Other

Radiotherapy

Temozolomide

Other Chemotherapy

Investigational

Prior Glioblastoma treatment

Initial diagnosis to 1st relapse

Max tumor diameter at initial diagnosis

1st relapse

2nd relapse

Number of prior relapse

Tumor volume at baseline

Maximum tumor diameter at baseline

Lymphocyte Count

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.

Rosemina Merchant - Chief Development Officer

All subjects enrolled, received any amount of study drug

MDNA55 (ITT Analysis)

In support of the primary efficacy analysis, evaluation of the primary endpoint was also conducted on the PP population.

MDNA55 (PP Analysis)

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.

Overall Survival (OS)

Single infusion of MDNA55 via convection enhanced delivery (CED).\*

\*Subjects may be eligible to receive a second administration of MDNA55.

MDNA55: MDNA55 is an engineered circularly permuted interleukin-4 (cpIL-4) genetically fused to the catalytic domain of the pseudomonas exotoxin A (PE).

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.

Objective Response Rate (ORR)

Progression Free Survival (PFS)

Single infusion of MDNA55 via convection enhanced delivery (CED).

MDNA55: MDNA55 is an engineered circularly permuted interleukin-4 (cpIL-4) genetically fused to the catalytic domain of the pseudomonas exotoxin A (PE).

Number of Subjects With Serious Adverse Events

Treatment Emergent Adverse Events

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

Level of MDNA55 in Peripheral Plasma

ADA positive

Neutralizing Antibody (NAb)

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.

ADA Titer / Neutralizing Antibody Analysis

Subjects received a single infusion of MDNA55 (via convection enhanced delivery) at concentrations ranging from 1.5 to 9.0 μg/mL. Total dose administered did not exceed 240 μg (the established maximum tolerated dose \[MTD\]).

Overall Study

Bevacizumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Participants will receive N-803 1 mg subcutaneously (SC), PD-L1 t-haNK (\~2 × 10\^9 cells/infusion) intravenously (IV), and Bevacizumab (10 mg/kg IV) combination therapy during 28-day cycles on days 1 and 15 of each cycle. Maximum treatment period is 76 weeks, 19 cycles.

Participants will receive 10mg/kg of Bevacizumab intravenously (IV) on Day 1 and Day 15 of each repeated cycle of treatment.

Participants will receive PD-L1 t-haNK (\~2 × 109 cells/infusion) intravenously (IV) on Day 1 and Day 15 of each repeated cycle of treatment.

PD-L1 t-haNK

Participants will receive 1mg subcutaneously (SC) on Day 1 and Day 15 of each repeated cycle of treatment.

N-803

Aubrey Gonzalez

Jayson Garmizo

This is a phase 2 open-label study to evaluate the safety and efficacy of N-803 and PD-L1 t-haNK when combined with Bevacizumab in subjects with recurrent or progressive GBM.

Participants will receive N-803 subcutaneously (SC), PD-L1 t-haNK intravenously (IV), and Bevacizumab IV combination therapy.

Treatment for all enrolled participants will consist of repeated cycles of 28 days for a maximum treatment period of 76 weeks (19 cycles). Treatment will be administered on days 1 and day 15 of each cycle. Treatment will be discontinued if the participant reports unacceptable toxicity (not corrected with dose reduction), withdraws consent, if the Investigator feels it is no longer in the participant's best interest to continue treatment, or the participant has confirmed progressive disease by iRANO, unless the participant is potentially deriving benefit per Investigator's assessment. Participants will be followed for collection of survival status every 12 weeks (± 2 weeks) for the first 2 years, then yearly thereafter.

N-803 and PD-L1 t-haNK Combined With Bevacizumab for Recurrent or Progressive Glioblastoma

Open-label Phase 2 Study of N-803 and PD-L1 t-haNK Combined With Bevacizumab in Subjects With Recurrent or Progressive Glioblastoma

TEAEs and SAEs graded using the NCI CTCAE v5.0

Standard blood chemistry panel made up of 14 separate chemistry measurements so can detect a range of abnormalities in blood sugar, nutrient balance, and liver and kidney health. Each clinical site will use their local laboratory upper limit of normal (ULN) range. The treating investigator will assess each result composing the CMP and determine if each result is within expected normal range or outside of the expected normal range.

Blood test checking the levels for White Blood Cell, Red Blood Cell, Platelets, Hemoglobin, Hematocrit, Basophils, Eosinophils, Lymphocytes, Monocytes and Neutrophils per unit volume. Each clinical site will use their local laboratory upper limit of normal (ULN) range. The treating investigator will assess each component of the Hematology panel and determine if each result is within expected normal range or outside of the expected normal range.

Checking the appearance, concentration and content of urine for any abnormalities. Each clinical site will use their local laboratory upper normal limit (UNL) range. The treating investigator will assess each component of the urinalysis and determine if each result is within expected normal range or outside of the expected normal range.

Perform 12-lead ECG as safety monitoring measurement. The parameters to be assessed for each one are the following: QT Interval, QTc Interval, QTcB Interval, QTcF Interval, PR Interval, QRS Duration and RR Interval with the unit in msec.

Temperature measured in either Fahrenheit or Celsius and for any abnormalities. Each site will assess to determine if temperature is within expected normal range or outside of the expected normal range.

Heart rate measured in beats/minute. Each site will assess to determine if heart rate is within expected normal range or outside of the expected normal range.

Respiratory rate measured in breaths/minute. Each site will assess to determine if respiratory rate is within expected normal range or outside of the expected normal range.

Blood pressure measured in Systolic and Diastolic mmHg. Each site will assess to determine if blood pressure is within expected normal range or outside of the expected normal range.

A pulse oximeter measures oxygen saturation as a percentage. Determines the ratio of the current levels of oxygenated hemoglobin to deoxygenated hemoglobin. Each site will assess to determine if oxygen saturation is within expected normal range or outside of the expected normal range.

Using a 10-point immune effector cell encephalopathy \[ICE\] score for the grading of ICANS. A score of 10 represents no impairment, 7-9 score is grade 1 ICANS, 3-6 score is grade 2 ICANS, 0-2 score is grade 3 ICANS and finally grade 4 ICANs is where cannot perform assessment of tasks.

The safety cytokine levels are TNF-α and IL-6

Profile of each participant PK profile of N-803 from their serum sample

Profile of each participant PK profile of PD-L1 t-haNK from their serum sample

Detection of N-803 in each participant ADA serum blood samples

Detection of PD-L1 t-haNK in each participant ADA serum blood samples

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Convection-Enhanced Delivery (CED) of MDNA55 in Adults With Recurrent or Progressive Glioblastoma	NCT02858895	Glioblastoma Grade IV Astroc... Glioblastoma Mu... Grade IV Glioma	MDNA55	18 Years -	Medicenna Therapeutics, Inc.
Convection-Enhanced Delivery (CED) of MDNA55 in Adults With Recurrent or Progressive Glioblastoma	NCT02858895	Glioblastoma Grade IV Astroc... Glioblastoma Mu... Grade IV Glioma	MDNA55	18 Years -	Medicenna Therapeutics, Inc.
N-803 and PD-L1 t-haNK Combined With Bevacizumab for Recurrent or Progressive Glioblastoma	NCT06061809	Glioblastoma	Bevacizumab PD-L1 t-haNK N-803	18 Years -	ImmunityBio, Inc.

Spots Global Cancer Trial Database for progressive glioblastoma