BaselineDay of Ad+V

SPD: 1955.7mm2

Day 14 SPD: 2595.7 mm2

Pseudoprogression

Week 16 SPD: 1658.4 mm2

Stable Disease

Week 40SPD: 1357.9 mm2

Stable Disease

Week 72SPD: 310.4 mm2

Partial Response

Week 96SPD: 303.2 mm2

Partial Response

Final Results of Controlled IL-12 Monotherapy in Adults with Grade III or IV GliomasE. Antonio Chiocca1, Rimas V. Lukas, MD2, John Yu, MD3, Bakhtiar Yamini, MD4, Nancy Ann Oberheim Bush, MD, PhD5, Christina Amidei PhD2, Jill Buck6,

Nathan Demars, MS6, Nira Hadar, PhD6, John Miao, MD6, Taylor Estupinan6, Yunxia Wang, PhD6, John W. Loewy PhD6 , Arnold B. Gelb, MD6, and Laurence Cooper, MD, PhD6

(1) Brigham and Women's Hospital, Boston, MA; (2) Northwestern Memorial Hospital, Chicago, IL; (3) Cedars-Sinai Medical Center, Los Angeles, CA;(4) University of Chicago. Chicago, IL; (5) University of California, San Francisco, CA; (6) Ziopharm Oncology, Inc, Boston, MA

Background: Interleukin-12 (IL-12), a master regulator of the immune system, results in anti-tumor responses in preclinical models, but safe use requires tightly controlled production. This phase 1 trial (NCT02026271) is the first to evaluate the safety and tolerability of Ad-RTS-hIL-12 (Ad) under transcriptional control with veledimex (V) in adults with grade III or IV gliomas.Methods: Multicenter, phase 1, open-label, 3 + 3 dose escalation study of Ad (a single intratumoral injection, 2 × 1011 viral particles, Day 0) with oral V dosing (Days 0 to 14) of 10, 20, 30, and 40 mg in subjects with rGBM.Results: 38 subjects were treated (resection group: V 10 mg (n=6); 20 mg (n=15); 30 mg (n=4); 40 mg (n=6); and, stereotactic group: V 20 mg, n=7). The adverse event profile of Ad+ V, was predictable and controllable, with the main adverse reactions (ARs) being mild to moderate. All ARs were manageable and reversible upon withholding V. We observed increased peak (mean ± SEM) serum recombinant IL-12 and downstream endogenous IFN-γ: V 10mg 21.4 ± 11.7 pg/mL and 14.6 ± 7.1 pg/mL; V 20 mg 25.8 ± 7.1 pg/mL and 57.0 ± 26.5 pg/mL; V 30 mg 65.7 ± 45.5 pg/mL and 60.7 ± 50.0 pg/mL; V 40mg 108.8 ±41.0 pg/mL and 167.5 ± 70.9 pg/mL, V 20mg (stereotactic) 25.1 ± 7.2 pg/mL and 69.8 ± 48.5 pg/mL, respectively. In the V 20 mg cohort, there was an increase in tumor-associated T cells (CD3+CD8+%) from pre-Ad (mean ± SEM) 0.6 ± 0.4 to biopsy (~5 mons) 6.3 ± 5.0 and production of IFN-γ 97.2 ± 85.3 pg/g (n=2). Median overall survival (mOS) in the V 20 mg cohort (resection, n=15) was 12.7 mons (mean follow-up, 13.1 mons). Subjects with unifocal disease (n=6) who received low-dose (≤ 20mg total) dexamethasone during active dosing (Days 0-14) had an mOS of 17.8 mons. Tumor response data will be presented.Conclusions: Results of Controlled IL-12 in rGBM are promising, with V-dependent and proportional increases in IL-12 and IFN-γ resulting in immune activation, with a favorable safety profile and encouraging survival. The 20 mg V dose is the recommended phase 2 dose. Controlled IL-12 is being evaluated in a monotherapy substudy (n=36, V 20 mg) and two combination studies with immune checkpoint inhibitors for rGBM. (Submitted February 2020)

Discussion and Conclusions

Subject Characteristics

Submitted Abstract

Safety Results1

Background on Controllable IL-121. Gene Switch Components: RheoSwitch Therapeutic System® (RTS®) technology includes VP16-RXR (co-activation partner, CAP) and Gal4-EcR (ligand-inducible transcription factor, LTF). Without ligand, LTF binds to the inducible promoter and does not form a stable complex with CAP.2. Inducible Promoter: Customizable (RTS) promoter to which basal transcription proteins are recruited and the target gene (IL-12) is transcribed. 3. Activator Ligand (veledimex): After oral administration, this ligand, an ecdysone analog, stabilizes a conformational change in the LTF leads to a stable, high-affinity interaction with CAP.

1Data collection and follow-up are ongoing: Data as of 24 Apr 20. 2Based on number of reported enhancing lesions. 3Based on number of enhancing and non-enhancing lesions.

Group 1 Group 2

Subject Characteristics1

Craniotomy Craniotomy Craniotomy Craniotomy Stereotactic

10 mg V (N=6)

20 mg V (N=15)

30 mg V (N=4)

40 mg V(N=6)

20 mg V (N=7)

Age, years (Mean, Range) 49 (29, 61) 46 (26, 68) 60 (43, 74) 48 (36, 58) 51 (28, 73)

Gender, N (%)Male Female

3 (50%)3 (50%)

10 (67%)5 (33%)

2 (50%)2 (50%)

4 (67%)2 (37%)

5 (71%)2 (29%)

Disease status at entry2

UnifocalMultifocal

5 (83%)1 (17%)

14 (93%)1 (7%)

3 (75%)1 (25%)

5 (83%)1 (17%)

6 (86%)1 (14%)

Number of Lesions at Entry3

123+

2 (33%)4 (67%)

0

13 (87%)1 (7%)1 (7%)

3 (75%)1 (25%)

0

5 (83%)1 (17%)

0

4 (57%)3 (43%)

0Number of recurrences

1st recurrence ≥2 recurrences

5 (83%)1 (17%)

14 (93%) 1 (7%)

3 (50%)1 (17%)

5 (83%)1 (17%)

6 (86%)1 (17%)

Prior Lines of Treatment (mean) 2.0 2.3 2.8 2.3 2.4

IDH Status, N (%)Wild-TypeMutatedTBD

5 (83%)1 (17%)

0

8 (53%)6 (40%)1 (7%)

2 (50%)0

2 (50%)

3 (50%)2 (33%)1 (17%)

2 (29%)0

5 (71%)Methylation Status, N (%)

Methylated Unmethylated TBD

1 (17%)2 (33%)2 (33%)

5 (33%)2 (13%)8 (53%)

2 (33%)0

2 (33%)

5 (83%)1 (17%)

0

3 (43%)3 (43%)1 (14%)

KPS at Screening, N (%)≥70 - 90≥ 90

3 3

9 6

3 1

2 4

3 4

Total Steroid Use, Days 0-14, Mean (Range) (mg) 61 (0, 102) 60 (0, 140) 87 (0-136) 45 (10-102) 51 (0, 163)

Concurrent steroid use≤20 mg dexamethasone total, Days 0-14>20 mg dexamethasone total, Days 0-14

2 (33%)

4 (67%)

6 (40%)

9 (60%)

1 (25%)

3 (75%)

1 (17%)

5 (83%)

4 (57%)

3 (43%)

Veledimex Dosing Compliance (%),

V qd (for 15 days) 79% 84% 63% 58% 90%

LFT: Liver Function Test; CRS: Cytokine Release Syndrome1Data collection and ongoing. 2Ziopharm Cytokine Release Syndrome Working Definition. SAEs reported in ≥5% subjects: CRS (13.2%); seizure (10.5%); thrombocytopenia, hyponatremia, and headache (7.9% each); and neutropenia, nausea, meningitis aseptic, and encephalopathy (5.3% each). Related SAEs reported in ≥5% of subjects: CRS (13.2%), thrombocytopenia (7.9%), and neutropenia (5.3%).

Unifocal,V Dose Cohort

Cumulative Steroids

(Days 0-14)

No. ofSubjects

No. of Subjects

Alive

Median Survival (95% CI)

(mos)

Mean Follow-up

(mos)

10, 30, 40 mg ≤20 mg 4 1 7.7 (3.8, ) 16.1>20 mg 9 0 8.1 (2.9, 9.8) 8.1

20 mg ≤20 mg 6 0 17.8 (14.6, ) 18.4>20 mg 8 0 6.0 (1.8, 12.7) 9.2

Survival of Group 1 with Unifocal Disease by Dose Cohort and Cumulative Steroid Dose

Evidence of Immune Mediated Anti-tumor Response by Serial MRI

• NCT02026271: Phase 1, single-arm, open-label, dose-escalation, multicenter study • Study enrollment and follow-up have been completed

Disposition of Patients:

• Results of Controlled IL-12 in rGBM are promising, with veledimex- dependent and proportional increases in IL-12 and IFN-γ, resulting in immune activation and eliciting a brisk cytotoxic T-cell response (i.e., making a “cold” tumor “hot”)

• Favorable safety profile: − Ad+V was safely administered and tolerable in both Craniotomy (Group 1) and Stereotactic subjects (Group 2)− 52 SAEs were reported in 21 subjects (55.3%) and 14 related SAEs were reported in 12 subjects (31.6%). There

have been no study treatment related deaths• 15 subjects treated at the V 20 mg dose level had encouraging survival with a median overall survival (mOS) of 12.7

months (mean follow-up of 13.1 months). Subjects (n=6, unifocal) who received low-dose (≤ 20-mg) steroid during veledimex dosing (Days 0-14, coinciding with administration of V) had a longer mOS of 17.8 months

• The V 20 mg dose is the recommended phase 2 dose as confirmed in the Expansion substudy focusing on veledimex 20 mg results (N=36; ASCO 2020 #2564)

• The V 10 mg dose level was studied to move forward with monotherapy in pediatric subjects (NCT03330197) and combination therapy with PD-1 inhibitors in adults with rGBM (ASCO 2020 #2510)

• In addition to this Main study and the Expansion substudy (NCT03679754) in monotherapy, evaluation of Controlled IL-12 is ongoing in two combination studies with immune checkpoint inhibitors for rGBM (NCT03636477, NCT04006119)

Group Veledimex No. of

Subjects

No. of Subjects

Alive

Median Survival (95% CI)(mos.)

Mean Follow-up

(mos.)

Group 1

20 mg 15 0 12.7 (4.1, 17.1) 13.110 mg, 30 mg, 40 mg 16 1 6.7 (3.8, 8.6) 9.1

10 mg 6 0 7.6 (1.8, ) 6.730 mg 4 0 3.4 (0.5, ) 3.140 mg 6 1 8.3 (3.9, ) 15.6

Group 2 20 mg 7 1 8.7 (1.3, 16.6) 9.7

Survival by Group and Veledimex Dose Cohort

Pharmacokinetic and Exposure Response With Increasing Veledimex DoseThere is a dose-dependent increase of veledimex concentrations in cerebrospinal fluid (CSF), tumor tissue, and plasma samples from subjects treated with veledimex among different dose cohorts

• On Day 0 veledimex was administered 3 ± 2 hours prior to surgical resection• LC-MS/MS assays for veledimex and its two major metabolites RG-116041 and RG-116043 • CSF samples collected during surgery, available from the V 20 mg and V 30 mg dose cohorts, were tested

for concentration of veledimex and its two major metabolites• Frozen tumor tissues were collected during surgery from 25 subjects and were analyzed for concentration

of veledimex and its two major metabolites • Plasma samples from 38 subjects were collected between 3 to 5 hours after veledimex dosing and were

analyzed for veledimex Cmax

Study Design

Glioblastoma subject 014 with MRI scans findings suggestive of progressive disease on imaging at Day 14 following Ad+V was subsequently shown to be pseudoprogression (PsP) with stable disease at Week 16 through 40, followed by a partial response starting at Week 72 continuing through Week 96, with monitoring on-going

• Subject 014, 51 year old male with 1 prior line of therapy• Unifocal disease at study entry, with 1 enhancing lesion• Administered 15 doses of veledimex 40 mg • Received dexamethasone 10mg cumulative dose during veledimex dosing• Subject has received no additional anti-cancer therapy following Ad+V

SPD: sum of products of bi-perpendicular diameters

CSF Veledimex Concentration Tumor Veledimex Concentration Plasma Veledimex Cmax

Ki-67

Baseline

Post-Treatment

H&E CD3 CD8 CD45RO

Histochemistry and Immunohistochemistry Show Increased Immune Cell Infiltrate

*Subject 037 IHC matched tumor samples were previously reported in Chiocca et al. (Sci Transl Med. 2019:11(505))

Two subjects* with matched baseline and posttreatment tumor biopsy samples from the V 20 mg cohort were studied by IHC. Representative images from Subject 039 show a cytotoxic T-cell infiltrate (increased CD3+, CD8+ and CD45RO+ cells ) making a “cold” tumor “hot”, and seemingly fewer tumor cells (H&E) having a decreased proliferation rate (Ki-67decreased) post-treatment vs. baseline

Adverse Events

Group 1 Group 2

Craniotomy Craniotomy Craniotomy Craniotomy Stereotactic

V 10 mg (N=6)

V 20 mg (N=15)

V 30 mg (N=4)

V 40 mg (N=6)

V 20 mg (N=7)

Related ≥ Grade 3 AEs in ≥ 5% of Subjects

Lymphopenia 1 (16.7) 2 (13.3) 1 (25.0) 2 (33.3) 1 (14.3)

Thrombocytopenia 0 2 (13.3) 0 0 0

Leukopenia 1 (16.7) 1 (6.7) 0 0 1 (14.3)

Neutropenia 1 (16.7) 1 (6.7) 0 0 1 (14.3)

AST/ALT increased 2 (33.3) 0 0 2 (33.3) 0

LFT increased 0 1 (6.7) 0 1 (16.7) 0

Headache 0 2 (13.3) 0 0 0

Meningitis Aseptic 0 1 (6.7) 0 0 0

Hyponatraemia 0 2 (13.3) 0 1 (16.7) 0

Amylase increased 0 1 (6.7) 0 0 0

Seizure 1 (16.7) 0 0 0 1 (14.3)

CRS 0 0 0 2 (3.3) 0

Confusional state 0 0 0 1 (16.7) 1 (14.3)

Delirium 0 0 0 0 1 (14.3)

Brain Oedema 0 0 1 (25.5) 0 0

Cerebral haemorrhage 0 0 1 (25.5) 0 0

Related Serious Adverse Events (SAEs)

CRS 0 2 (13.3) 1 (25.5) 2 (33.3) 0

Thrombocytopenia 0 2 (13.3) 0 1(16.7) 0

Neutropenia 0 1 (6.7) 0 0 1 (14.3)

Leukopenia 0 1 (6.7) 0 0 0

LFT increased 0 1 (6.7) 0 0 0

Meningitis Aseptic 0 1 (6.7) 0 0 0

Pyrexia 0 1 (6.7) 0 0 0

Nausea 0 2 (13.3) 0 0 0

Headache 0 1 (6.7) 0 0 0

Cerebral haemorrhage 0 0 1 (25.0) 0 0

Seizure 1 (16.7) 0 0 0 1 (14.3)

Delirium 0 0 0 0 1 (14.3)

Hyponatraemia 0 0 0 1 (16.7) 0

CRS2

Grade 2Grade 3

3 (50.0)0

8 (53.3)3 (20.0)

2 (50.0)1 (25.0)

2 (33.3)3 (50.0)

2 (28.6)1 (14.3)

10, 30, 40 mg V and ≤ 20 mg Dex20 mg V and ≤ 20 mg Dex

10, 30, 40 mg V and > 20 mg Dex20 mg V and > 20 mg Dex

ESP: Evaluable Safety Population (includes all subjects that received Ad-RTS-hIL-12 IT and at least one dose of veledimex)

GROUP 1 (N=46) GROUP 2 (N=9)

Cohort 40 mgConsent = 8Enrolled = 6

ESP = 6

Cohort 30mgConsent = 7Enrolled = 6

ESP = 4

Cohort 20mg Expansion

Consent = 14Enrolled = 9

ESP = 8

Cohort 10mgConsent = 6Enrolled = 6

ESP = 6

Cohort 20mgConsent = 11Enrolled = 7

ESP = 7

Cohort 1Consent = 9Enrolled = 8

ESP = 7

Subjects Screened (N=55)

Completed: Study = 2Dead = 5

Completed: Study = 1Dead = 5

Completed: Dead = 4

Withdrawn = 1Completed:

Dead = 7PD = 1

Completed: Dead = 6

Withdrawn = 1Completed:

Study = 1Dead = 5

PD/Hospice = 1

* Stereotactic

IHC MarkerSubject ID 039

Baseline1 Post-Tx1,2

CD3 <1% 11%

CD8 2% 7%

CD45RO <1% 14%

Ki-67 25% 19%1Percent positivity; 2Post-Tx: Post-treatment biopsy