Regulated intratumoral expression of IL -12 as a basis for ... · 12/12/2013 · 1. The Switch...
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Regulated intratumoral expression of IL-12 as a basis for combination therapy in melanoma John J. Nemunaitis 1 , Gerald P. Linette 2 , Omid Hamid 3 , Sanjiv S. Agarwala 4 , Alexander Starodub 5 , Lei Sun 6 , Francois Lebel 6 , John A. Barrett 6 , Jonathan Lewis 6 1 Mary Crowley Cancer Research Center, Dallas Tx 2 Washington University, Saint Louis, MO 3 The Angeles Clinic and Research Institute, Los Angeles, CA 4 Saint Luke's University Health System, Bethlehem, PA 5 Indiana University Health Goshen Center for Cancer Care; IN 6 ZIOPHARM Oncology Inc., Boston, MA
Transcript of Regulated intratumoral expression of IL -12 as a basis for ... · 12/12/2013 · 1. The Switch...
Regulated intratumoral expression of IL-12 as a basis for combination therapy in melanoma
John J. Nemunaitis1 , Gerald P. Linette2, Omid Hamid3, Sanjiv S. Agarwala4, Alexander Starodub5, Lei Sun6, Francois Lebel6, John A. Barrett6, Jonathan Lewis6
1 Mary Crowley Cancer Research Center, Dallas Tx
2 Washington University, Saint Louis, MO 3 The Angeles Clinic and Research Institute, Los Angeles, CA 4 Saint Luke's University Health System, Bethlehem, PA
5 Indiana University Health Goshen Center for Cancer Care; IN 6 ZIOPHARM Oncology Inc., Boston, MA
1. The Switch Components: The RTS® gene program includes 2 receptor protein fusions: VP16-RXR and Gal4-EcR. They form unstable and unproductive heterodimers in the absence of any ligand.
2. The Inducible Promoter: A customizable promoter to which basal transcription proteins are recruited and the target gene is transcribed.
3. The Activator Ligand (veledimex): An ecdysone analog, diacylhydrazine-based small molecule functions as an activator. In the presence of the ligand, the protein heterodimer changes to a stable conformation and binds to the inducible promoter.
EcR
RXR
VP16
Gal4 Basal Transcription
Proteins
Activator Ligand
RXR VP16 Gal4 EcR Inducible Gene Program Inducible Gene Program
RheoSwitch Therapeutic System® (RTS®) is a 3-component transcriptional regulator
Inducible Gene Regulation: RheoSwitch Therapeutic System®
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200
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300
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400
IL-1
2 (p
g/m
g pr
otei
n)
0.00.51.01.52.02.53.03.54.0
Tumor and Serum IL-12 Levels
Vehicle Ad+150 mg/m2
AL
Ad+75 mg/m2
AL
Ad+30 mg/m2
AL
Ad+15 mg/m2
AL
AL Alone
Vehicle Ad+150 mg/m2
AL
Ad+75 mg/m2
AL
Ad+30 mg/m2
AL
Ad+15 mg/m2
AL
AL Alone
Tumor Serum
Ad - Ad-RTS-mIL-12 AL - veledimex
Ad-RTS-mIL-12 + Veledimex Induces Systemic Immune-Mediated Anti-tumor Effect in B16 Melanoma Model
Days Post Tumor Cell Inoculation
*Arrows indicate administration of Ad-RTS-mIL-12 IT. N= 10-12/group AL - veledimex
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5
10
15
20
25
10 12 14 16 18 20 22
Tum
or V
olum
e V/
V0
Time (Days)
Right Tumor Treated
- 12
0
5
10
15
20
25
10 12 14 16 18 20 22 Time (Days)
Left Tumor Untreated
Control
AL 680 mg/m2
Ad-RTS-mIL-12
Ad-RTS-mIL-12 + AL 680 mg/m2
• Phase 1/ 2 subjects with unresectable stage III/IV melanoma, n=13 (Phase 1) + n= 8 (Phase 2, ongoing)
• Intratumoral injection of Ad-RTS-hIL-12 on Day 1 of each cycle
• Oral administration of veledimex to activate gene expression of hIL-12
Primary Objective Evaluate the safety and tolerability of intratumoral injections of Ad-RTS-hIL-12 in combination with veledimex
Secondary Objective Inform the selection of a veledimex dose and regimen for further study in combination with Ad-RTS-hIL-12
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Study Design
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Demographics and Prior Therapies
Phase 1 (n=13) Phase 2 (n=8)
Gender (n)
Female 6 2
Male 7 6
Age (years)
Median (range) 70 (34 to 94) 59 (22 to 90)
Number of Prior Therapies
Median (range) 7 (4-12) 3.5 (2-15)
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10000
100000
1000000Tu
mor
mR
NA
(mR
NA/
1e6
vp)
100 mg160 mg
~
Off
On
Off
Veledimex Tightly and Precisely Controls the Expression of IL-12β mRNA in the Tumor
Baseline Maximum D1-D7
7 Days Post-treatment
Veledimex Dose
n=7
Safety1
≥ Grade 3 related TEAEs (>5%)* AST elevation 19% Hypotension 14% Hyponatremia 9% Leukopenia 9% Pyrexia 9%
Related SAEs (7 subjects)* Pyrexia (n=2), Hypotension (n=2), Mental Status Changes (n=2), Pancytopenia, Dehydration, Failure to Thrive, Febrile Neutropenia, Cytokine Release Syndrome, Neutropenia, Delirium, Anemia, Encephalopathy * All reverse on discontinuation of Veledimex
113Nov13 Datacut
9
Evaluable Patients (N = 16)
Response CR 0
PR 0
SD 4
PD 4
uPD 8
Overall Response Rate mRECIST – Phase 1/ 2 All Evaluable Patients
uPD = unconfirmed progressive disease
For All Evaluable Patients: • 11 of 16 had a response of stable disease or better on a per
lesion basis • 4 of 16 did not complete Cycle 1
Multi-effector/ multigenic synthetic plasmid: Mesenchymal Stem Cells
pRTS-hIFNα
pRTS-hIL-12
pRTS-CTLA-4 DCY
pRTS-hIFNα−hIL-12
pRTS-hIFNα−CTLA-4 DCY
pRTS-hIL-12-CTLA-4 DCY
pRTS-hIFNα−hIL-12-CTLA-4 DCY
IP1
IP3 IP2
IP4
IP1 IP3 IP2
IP3 IP2 IP4
IP1 IP3 IP2 IP4
IP1 IP4
IFNα IL-12B IL-12A CTLA-4 DCY
IFNα
IL-12B IL-12A
CTLA-4 DCY
IFNα IL-12B IL-12A
IFNα CTLA-4 DCY
IL-12B IL-12A CTLA-4 DCY
SP-RTS
SP-RTS
SP-RTS
SP-RTS
SP-RTS
SP-RTS
SP-RTS
Conclusions • RTS® technology enables precise and controlled expression of
IL-12 DNA. This facilitates exact control of dose and schedule • Ad-RTS-hIL-12 + veledimex is biologically active as measured
by on mechanism and on target toxicity, and response in injected and non-injected lesions
• All related AEs and SAEs reverse upon discontinuation of veledimex
• Discontinuation of veledimex in Cycle 1 resulted in 6 patients receiving incomplete cycle 1 dosing
• Clinical development is ongoing, refining dose, schedule and combination
