convection-enhanced delivery (ced) of mdna55 in adults with … · 2019-11-25 ·...

TSX: MDNAOTCQB: MDNAF

Convection-Enhanced Delivery (CED) of MDNA55 in Adults with Recurrent Glioblastoma

Nicholas Butowski, MDProfessor, Neurological Surgery

Director, Translational Research, Neuro-OncologyHelen Diller Family Comprehensive Cancer Center

University of California San Francisco

Disclosure

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Research support from the following:Medicenna, Bayer, BMS, VBL, Tocagen, Ipsen, Celgene, Kiyatec, Oncoceutics, Istari, Amgen, Epicentrix, Orbus, Deciphera, Beigene

Consultant/Advisor role: Bayer, Medicenna, VBL, Tocagen, Nativis, Delmar, Boston Bio, Jazz Pharma.

Targeting the IL4 Receptor inCNS Cancers

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IL4R Interacts with Different Receptor Chains to Generate Different Types of IL4R Complexes

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IL4R Type-II

IL-4R⍺ IL-13R⍺1

• T Cells• NK Cells

• Solid Tumors• Fibroblasts• MDSCs• TAMsAdapted from Puri et al., 2009.

> 300 Patient Biopsies Analyzed1-7

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IL4 Receptor is Over-Expressed in Brain Tumors

Glioblastoma

76%Mixed Adult

Glioma

>83%Mixed Pediatric

Glioma

76%Pediatric DIPG

71%

Medulloblastoma

100%Adult Pituitary

Adenoma

100%Meningioma

77%Normal Brain

Tissue

0%1. Joshi BH, et. al. Cancer Res 2001;61:8058-8061.2. Puri RK, et. al., Cancer Res 1996;56:5631-5637. 3. Kawakami M, et. al., Cancer. 2004 Sep 1; 101(5):1036-42. 4. Berlow NE, et al. PLoS One. 2018 Apr 5; 13(4):e0193565.

5. Joshi BH, et. al. British J of Cancer (2002) 86, 285 –291.6. Chen L, et al. Neurosci Lett. 2007 Apr 24; 417 (1):30-5.7. Puri S, et. al., Cancer. 2005 May 15; 103(10):2132-42.

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IL4R Expression Predicts Poor Survival in GBM

Months from initial diagnosis

D'Alessandro G, et al. Cancers (Basel). 2019

p = 0.0100

Survival in Glioma Mouse Model

IL4R -/- (n=15); symptom-free survival = 90 days

IL4R +/+ (n=10); symptom-free survival = 55.5 days

Kohanbash G et al. Cancer Res 2013;73:6413-6423

Survival in GBM Patients

Perc

ent s

urvi

val

High IL4R gene expressionLow IL4R gene expression

Data Derived from TCGA GBM Database (https://tcga-data.nci.nih. gov/tcga/)

IL4R is Expressed in Cells of the Tumor Microenvironment (TME) – Tipping the Scale Towards a Pro-Tumor Response

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Adapted from Rothenberger NJ, et al. Int J of Mol Sci. 2018

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TME-Infiltrating MDSCs Express IL4R and Predict Poor Survival in GBM

MDSC gene signature (based on the combined positive expression of CD11b,

CD33, CD45, CD244, and CXCR2) negatively correlates with GBM patient

prognosis. Statistical significance of survival was based on log-rank analysis.

Otvos B et. al., (2016). Stem Cells 34:2026–2039Surface expression of IL-4Ra on tumor-infiltrating and splenic CD11b+/Gr-1+

MDSCs from GL26 tumor-bearing mice.

TME-MDSCs show 12-fold increase in IL-4R⍺expression compared to splenic myeloid cells

p < 0.001

Kamran N, et. al., (2017). Mol Ther 25:232-248

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MDNA55, A Powerful IL4R Targeted Molecular Trojan Horse

Ø MDNA55: Targets the IL4R expressed in CNS tumors but not healthy brain

Ø Localized Delivery: Bypasses Blood Brain Barrier (BBB)

Ø Highly Selective: Avoids collateral damage to healthy brain

Ø Disrupts the Tumor Microenvironment (TME): Targets IL4R positive MDSCs and disrupts Th2 bias

Ø Immunogenic Cell Death: Anti-tumor immunity is initiated and remains active after MDNA55 is cleared

Targeting DomainCircularly Permuted

Interleukin-4 (cpIL-4)

Lethal PayloadCatalytic domain of Pseudomonas Exotoxin A

ENDOCYTOSIS

FURIN PROTEASEADP RIBOSYLATION

Inhibit Protein Synthesis

CELL DEATH

NUCLEUS

(FDA approved in 2018, Moxetumomab pasudotox)

MDNA55 Treatment

Direct infusion into tumor

convection enhanceddelivery (CED)

75%

INOPERABLE rGBM

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Treatment Pathway for GBM

* Expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is responsible for resistance to Temodar used in GBM treatment.

DIAGNOSISADJUVANT TEMODARSURGERY

(85-90%) 55% of GBM Temodar-Resistant*

RADIOTHERAPY TEMODAR

RELAPSE

25%

OPERABLE rGBM

GBM IS UNIFORMLY FATAL – VIRTUALLY ALL TUMORS WILL RECUR (rGBM)

MDNA55 treatment can also provide benefit in newly diagnosed and

operable rGBM settings

Precise Drug Delivery of MDNA55Convection-Enhanced Delivery (CED)

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GBM Cells Invade Healthy Brain

courtesy of Dr Michael Vogelbaum

Tumor

Infiltrative Edge:Site of Relapse

High-flow Image Guided CED Improves Distribution

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Phase 2b MDNA55-05 TrialAn Open-Label Non-Randomized, Multi-Center Phase-2 Study of Convection-Enhanced Delivery (CED) of MDNA55 in Adults with Recurrent or Progressive Glioblastoma

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MDNA55-05 Phase 2b Study Design Summary

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Open-Label Single Arm Study in Recurrent GBM Patients (n=46) (NCT02858895)

DIAGNOSIS PLANNING TREATMENT FOLLOW UP

Brain Infusion System used in the MDNA55 Trial

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A

B

Marking access ports location

Drilling burr hole for cannula access ports

Key CED Parameters

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Parameters MDNA55 Subjects (n=46)

Drug Conc. 1.5 – 9 µg/mL

Vol of Infusion Based on tumor size (n=34); Fixed (60mL; n=12)

Tracer / conc. Gadolinium; 7mmol (then 2mmol*)

Flow rate Up to 50 µL/min/catheter

# Catheters / Placement 1 – 4 catheters / tumor region and peritumoral area

Real-Time Infusion Monitoring First 3 - 6 hours of infusion

Total Infusion Time Up to 48 hours

Catheter Trajectory Planning Brainlab iPlan® Flow Software

*Concentration of gadolinium was reduced to 2 mmol in later versions of the protocol due to FDA and EMA recommendation to minimize exposure in humans

MDNA55-05 Subjects (n=46)

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Summary of Drug Distribution Results

Vol of tumor, Vt *

(cm3)

Vol of infusion, Vi

(mL)

Time of infusion

(hrs)

Vol of distribution,

Vd (mL)Vd / Vi Vi / Vt

Median(range)

7.3(1.1 – 73.7)

30.0(12 – 66)

26.5(15.4 – 57.1)

51.2(1.7 – 175.3)

1.3(0.1 – 4.8)

4.2(0.4 – 17.9)

Mean (stdev)

10.8(± 12.0)

36.8(± 17.3)

29.1(± 8.7)

57.6(± 42.5)

1.6(± 1.0)

6.2(± 4.8)

* Volume of tumor determined using iPlan® Flow Software

Summary of Tumor Coverage Analysis

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Enhancing lesion

Enhancing lesion

+ 1cm Margin

Enhancing lesion

+ 2cm Margin

MDNA55-05 (n=46)

Median(range)

51.5%

(0 – 97.8)

54.0%

(5.4 – 95.2)

35.3%

(2.2 – 82.9)

Mean (stdev)

51.3%

(± 27.2)

47.5%

(± 25.7)

33.9%

(± 21.0)

NeoPHARM IL13 Ph3 Study (n=36 cases)

Mean (stdev)

NA 17.5%

(± 14.1)

21.0%

(± 14.0)

Sampson JH, J Neurosurg. 2010 Aug;113(2):301-9

Improved tumor coverage seen in MDNA55 trial compared to earlier CED trials

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Case 1 – High Vd/Vi Ratio and Tumor Coverage

Vt – 1.6 cm3

Vi – 15 mLVi/Vt ratio – 9.4 Vd of Gad – 72.8 cm3

Vd/Vi ratio – 4.8Tumor Coverage* – 90.7%

*Percent coverage was calculated based on the fraction of the target volumes covered by the determined gadolinium distribution at end of infusion.

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Case 2 – Moderately High Vd/Vi ratio and Tumor Coverage

Vt – 6.0 cm3

Vi – 20 mLVi/Vt ratio – 3.3Vd of Gad – 46.2 cm3



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Case 3 – Medium Vd/Vi Ratio and Tumor Coverage

Vt – 4.8 cm3

Vi – 20.0 mLVi/Vt ratio – 4.2Vd of Gad – 26.7 cm3



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Case 4 – Low Vd/Vi Ratio and Tumor Coverage

Vt – 13.1 cm3

Vi – 40.0 mLVi/Vt ratio – 3.1Vd of Gad – 32.9 cm3



0 5 10 15 20 25 300

50

100

Months From Start of MDNA55 Treatment

Perc

ent s

urvi

val

IL4RHigh (H-Score > 60); n=19IL4RLow (H-Score ≤ 60); n=11

IL4RHigh is Associated with Longer Survival Following MDNA55 Treatment

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Log-rankp-value = 0.0941

Group mOS(months)

Survival RatesOS-6 OS-12

IL4R High 15.2 89% 57%

IL4R Low 8.5 64% 27%

First 33 Subjects (30 evaluable for IL4R)

Patient Demographics are Similar Between IL4R High and Low Groups

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Baseline Characteristics IL4RHigh (N=19) IL4RLow (N=11)Sex

Male, n (%)Female, n (%)

10 (53%)9 (47%)

10 (91%)1 (9%)

AgeMedian (Range)Mean (StDev)

51 (35 – 77)55.3 (± 13.4)

59 (35 – 77)57 (± 12.6)

KPS, n (%) 70 and 8090 and 100

10 (53%)9 (47%)

5 (45%)6 (55%)

MGMT Status aPos (methylated)Neg (unmethylated)Unknown

9 (47%)9 (47%)1 (6%)

5 (45%)5 (45%)1 (10%)

Initial Dx to 1st relapse,months

Median (Range)Mean (StDev)

12.5 (4.7 – 37)15.2 (± 8.8)

11.9 (5.1 – 24.4)13.2 (± 6.9)

Initial Dx to start of MDNA55 Treatment, months

Median (Range)Mean (StDev)

17.4 (5.2 – 44.9)18.2 (± 10.0)

13 (5.8 – 33)15.8 (± 9.0)

Footnotes:a MGMT positive = promoter methylated (this group is likely to benefit from TMZ); MGMT negative = promoter unmethylated (this group is associated with resistance to TMZ)

Baseline Characteristics (cont.) IL4RHigh (N=19) IL4RLow (N=11)

Max Tumor Diameter, mmMedian (Range)Mean (StDev)

25.4 (9.8 – 41.5)25.1 (± 9.0)

34.5 (11.7– 42.3)29.2 (± 12.1)

Number of prior relapses, n (%):

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13 (68%)6 (32%)

9 (82%)2 (18%)

Prior Treatment, n (%)SurgeryTemozolomideRadiationExp Therapy

19 (100%)18 (95%)

19 (100%)2 (11%)

11 (100%)11 (100%)11 (100%)6 (55%)

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Drug Distribution Parameters are Similar Between IL4R High and Low Groups

Shown are the mean ratio of volume of distribution (Vd) to volume of infusion (Vi) (left graph) and mean ratio for volume of infusion (Vi) to volume of tumor (Vt) (right graph) for subjects expressing high levels of IL4R (IL4R High, n=19, black columns) and subjects with no/low IL4R expression (IL4R Low, n=11, gray columns) among the first 33 subjects treated with MDNA55 (30 of which were evaluable for IL4R).

IL4R High (n=19)

IL4R Low (n=11)

0.0

0.5

1.0

1.5

2.0

2.5

Vd /

Vi R

atio

Vd / Vi Ratiop-value = 0.4012

Mean = 1.9(SEM = 0.3)

Mean = 1.5(SEM = 0.3)

IL4R High (n=19)

IL4R Low (n=11)

0

2

4

6

8

10

Vi /

Vt R

atio

p-value = 0.6897

Mean = 8.1(SEM = 1.2)

Mean = 7.4(SEM = 1.4)

Vi / Vt Ratio

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Coverage of Tumor and Peritumoral Margin are Similar Between IL4R High and Low Groups

IL4R High (n=19)

IL4R Low (n=11)

0

20

40

60

80

100

% T

umor

Cov

erag

e

% Tumor Coveragep-value = 0.6074

Mean = 54.41(SEM = 6.1)

Mean = 59.8(SEM = 8.8)

IL4R High (n=19)

IL4R Low (n=11)

0

20

40

60

80

100

% T

umor

Cov

erag

e +

1cm

Mar

gin

% Tumor Coverage + 1cm Marginp-value = 0.7172

Mean = 56.1(SEM = 5.7)

Mean = 52.7(SEM = 7.2)

IL4R High (n=19)

IL4R Low (n=11)

0

20

40

60

80

100

% T

umor

Cov

erag

e +

2cm

Mar

gin

% Tumor Coverage + 2cm Marginp-value = 0.6885

Mean = 41.5(SEM = 4.8)

Mean = 38.3 (SEM = 6.0)

Mean % coverage of tumor (first graph), of tumor + 1cm margin (second graph), of tumor + 2cm margin (third graph) for subjects expressing high levels of IL4R (IL4RHigh, n=19, black columns) and subjects with no/low IL4R expression (IL4R Low, n=11, gray columns) among the first 33 subjects treated with MDNA55 (30 of which were evaluable for IL4R).

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Similar Rate of Toxicities Between Low and High Vi and Low and High Doses of MDNA55

TotalPatients(N=46)

Volume of Infusion Total MDNA55 Dose< 30 mL(N=22)

≥ 30 mL(N=24)

≤ 120(N=21)

> 120(N=25)

Subject with Related ≥ G3 AEs

and/or SAEs18 (39%) 8 (36%) 10 (42%) 8 (38%) 10 (40%)

• Drug-related AEs were primarily neurological/aggravation of pre-existing neurological deficits characteristic with GBM and had generally been manageable with standard measures.

• No deaths attributed to MDNA55 • No systemic toxicity• No clinically significant laboratory abnormalities• No evidence of a differential rate of neurological toxicities between doses of MDNA55 used

in the current study (up to 240 µg) and a range of higher doses explored in previous studies (up to 900 μg)

Compelling Efficacy of MDNA55 Compared to Approved Therapies for rGBM

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Therapy GBM Population (n)

mOS(months) OS-6 OS-12

MDNA55(First 33 subjects) (n=33) 11.9 82% 48%

MDNA55(First 33 subjects; IL4RHigh) (n=19) 15.2 89% 57%

Avastin1 (n=85) 9.2 75%* 22%*

Avastin2 (n=50) 8.0 62% 26%

Lomustine2 (n=46) 8.0 65% 30%

Lomustine3 (n=149) 8.6 NR 34%

Temozolomide4 (n=31) 5.6 45%* 30%*

Temozolomide5 (n=138) 5.4 46% 18%**Approximations based on Kaplan-Meier curve.

1 Friedman et al., J Clin Oncol. 2009 Oct 1;27(28):4733-40; 2 Taal et al., Lancet Oncol 2014 Aug;15(9):943-53; 3 Wick et al., N Engl J Med. 2017 Nov 16;377(20):1954-1963; 4 Kim et al., J Clin Neuroscience 22 (2015) 468–473, 2015; 5 Brada et al., Ann Oncol. 2001;12(2):259–266

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Summary

• Treatment options for patients with recurrent GBM are very limited and positive outcomes remain very rare.

• IL4R is frequently expressed in GBM and is associated with aggressive disease and poor survival outcomes.

• MDNA55 is an IL4R-targeted fusion toxin; administered by CED as a single treatment.• Co-infused GdDTPA enables real-time imaging and optimization of catheter placement.

• IL4RHigh subjects show promising survival following MDNA55 treatment.

Ø This does not seem to be a result of differences in drug distribution or patient demographics.

• Similar rate of toxicities seen between lower and higher Vi and MDNA55 doses.

• Safety events are consistent with nature of disease and therapy and have generally been manageable with standard measures.

• Precision delivery with targeted therapy such as MDNA55 by IL4R status may improve patient outcomes and help guide patient selection strategies for future clinical studies.

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Acknowledgements

Achal Achrol, MD &Santosh Kesari, MD, PhDPacific Neurosciences Institute and John Wayne Cancer Institute

Nicholas Butowski, MD &Krystof Bankiewicz, MD, PhD &Manish K. Aghi, MD, PhDJohn BringasUniversity of California San Francisco

Steven Brem, MDHospital of the University of Pennsylvania

Andrew Brenner, MD, PhD & John R. Floyd, MDCancer Therapy and Research Center at University of Texas at San Antonio

Seunggu Han, MDOregon Health & Science University

John Sampson, MD, PhD & Dina Randazzo, DODuke University School of Medicine

Michael Vogelbaum, MD, PhDCleveland Clinic

Frank Vrionis, MD, PhD &Sajeel Chowdhary, MDBoca Raton Regional Hospital

Miroslaw Zabek, MDMazovian Brodnowski Hospital

Eva Wembacher-Schroder, PhDBrainLab, Munich, Germany

…..And most of all, to the patients & their families

This study is partly supported by a grant from Cancer Prevention and Research

Institute of Texas (CPRIT)

convection-enhanced delivery (ced) of mdna55 in adults with … · 2019-11-25 ·...

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