DNA Vaccine Therapy in Treating Patients With Chronic Hepatitis C Virus Infection

PRIMARY OBJECTIVES:

I. To determine the safety profile of the HCV DNA vaccine, consisting of INO-8000 (HCV
antigen DNA) alone or co-administered with INO-9012 (interleukin [IL]-12 adjuvant DNA) (DNA
plasmid encoding interleukin-12 INO-9012).

II. To identify a dose of INO-9012 (IL-12 adjuvant DNA) for co-administration with INO-8000
(HCV antigen DNA) based on induction of HCV-specific interferon (IFN)-gamma production by
peripheral blood mononuclear cells at 26 weeks compared to baseline in HCV-infected
participants.

TRANSLATIONAL OBJECTIVES:

I. Determine the rate at which INO-8000 with different doses of INO-9012 induces a > 1 log
decrease (or undetectable) in HCV ribonucleic acid (RNA) level at weeks 14 and 26.

II. Determine the rate at which INO-8000 with different doses of INO-9012 induces an
end-of-treatment undetectable HCV RNA (end-of-treatment virologic response - EVR) at 26 weeks
and a sustained virologic response (SVR) at 36 weeks.

III. Determine the rate at which INO-8000 with different doses of INO-9012 induces other
parameters of cluster of differentiation (CD)8 and CD4 T lymphocyte responses as measured by
flow cytometry, and antibody responses to HCV antigen at weeks 14 and 26.

OUTLINE: This is a dose-escalation study of INO-9012.

Patients receive INO-8000 intramuscularly (IM) and DNA plasmid encoding interleukin-12
INO-9012 IM (dose levels 2-4) followed by electroporation (EP) at day 0 and at weeks 4, 12,
and 24.

After completion of study treatment, patients are followed up at weeks 48 and 76.

Inclusion Criteria:

- PRE-REGISTRATION INCLUSION CRITERIA

- Presence of active, chronic HCV infection confirmed by positive HCV RNA

- Willingness to use adequate contraception to avoid pregnancy or impregnation for the
duration of study participation; Note:

- The effects of INO-8000 with or without INO-9012 on the developing human fetus at
the recommended therapeutic dose are unknown; for this reason, women of
child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry
and for the duration of study participation

- For men and women who are not postmenopausal (i.e., >= 12 months of
non-therapy-induced amenorrhea, confirmed by follicle stimulating hormone [FSH],
if not on hormone replacement) or surgically sterile (vasectomy in males or
absence of ovaries and/or uterus in females), agreement to remain abstinent or
use highly effective or combined contraceptive methods that result in a failure
rate of < 1% per year during the treatment period and at least through week 12
after last dose

- Abstinence is only acceptable if it is in line with the preferred and usual
lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation,
symptothermal, or post-ovulation methods) and withdrawal are not acceptable
methods of contraception

- Examples of contraceptive methods with an expected failure rate of < 1% per year
include male sterilization and hormonal implants; alternatively, proper use of
combined oral or injected hormonal contraceptives and certain intrauterine
devices or two methods (e.g., two barrier methods such as a condom and a cervical
cap) may be combined to achieve a failure rate of < 1% per year (barrier methods
must always be supplemented with the use of a spermicide)

- Should a woman become pregnant or suspect she is pregnant while participating in
this study, she should inform her study physician immediately

- Should a female partner of a male study participant become pregnant while the
male participant is on study, the male participant should inform his study
physician immediately

- Willingness to avoid excessive use of alcohol during the study; note: excessive use is
defined as drinking >= 8 alcoholic drinks per week on average

- Willingness to provide blood samples for research tests specified in the protocol

- Ability to understand and willingness to sign a written informed consent document

- REGISTRATION INCLUSION CRITERIA

- Serum or plasma HCV RNA level >= 10,000 IU/mL

- Screening HCV genotype, demonstrating genotype 1

- Alpha feto protein (AFP) levels within normal institutional limits or judged to be not
clinically significant by the investigator; Exception: If deemed clinically
significant, then liver imaging must be available within previous 6 months (e.g.,
ultrasound, computed tomography [CT] scan, magnetic resonance imaging [MRI]) showing
no evidence of hepatocellular carcinoma

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Screening laboratory values (serum chemistry, hematology, prothrombin time
[PT](international normalized ratio [INR])/activated partial thromboplastin time
[APTT], and creatine phosphokinase [CPK]) obtained up to 45 days prior to
administration of first vaccine injection on day 0 within institutional normal range
or judged to be not clinically significant by principal investigator (PI) and medical
monitor

- 12-lead electrocardiogram (ECG) showing normal heart rhythm; note: if there are
abnormalities, then the abnormalities must be deemed of no clinical significance

Exclusion Criteria:

- PRE-REGISTRATION EXCLUSION CRITERIA

- Failure of previous HCV therapies

- Human immunodeficiency virus (HIV) infection

- Any previous treatment for HCV =< 6 months prior to registration

- Other uncontrolled immune-compromising illness

- Autoimmune disorders, transplant recipients, other immunosuppression including any
concurrent condition requiring the use of immunosuppressive/ immunomodulating agents;
Exception: eye drop-containing and infrequent inhaled corticosteroids are permissible;
topical corticosteroids are permissible at locations other than the administration
site (upper arm); Note: All systemic corticosteroids must be discontinued at least 4
weeks prior to randomization; inhaled corticosteroids must be discontinued >= 48 hours
prior to randomization and courses of more than 2 weeks are not permissible within 4
weeks of randomization

- Ongoing hepatitis B virus (HBV) infection

- Documented evidence of fibrosis or cirrhosis (Metavir 2, 3, and 4) and subjects with
significant extrahepatic manifestations of hepatitis C (such as cryoglobulinemia with
symptoms or evidence of end-organ manifestations, renal disease, type 2 diabetes, or
porphyria cutanea tarda

- Other known causes of significant liver disease including chronic or acute hepatitis
B, acute hepatitis A, hemochromatosis, or homozygote alpha-1 antitrypsin deficiency

- Active malignancy; exception: non-melanoma skin cancers cancer(s) for which diagnosis
and treatment was completed >= 3 years prior to pre-registration

- History of major organ transplantation with an existing functional graft

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- History of cardiac arrhythmia, controlled or uncontrolled, including ventricular and
supraventricular arrhythmia

- Pregnant or nursing women; Note: Pregnant women are excluded from this study because
INO-8000 has an unknown potential for teratogenic or abortifacient effects; because
there is an unknown but potential risk for adverse events in nursing infants secondary
to treatment of the mother with this DNA vaccine, breastfeeding should be discontinued
if the mother is treated with INO-8000

- Current diagnosis or history of cardiac pre-excitation syndromes (e.g.
Wolff-Parkinson-White)

- Metal implants on same limb as intended administration site

- Tattoos, scars, active lesions, or rashes =< 2 cm of the intended site of study
treatment

- Documentation of history of seizure within previous 5 years

- Pacemaker or other implanted device

- Any condition that, in the clinical judgement of the investigator, would place a
participant at unreasonably increased risk

- REGISTRATION EXCLUSION CRITERIA

- Receiving any other investigational agents =< 6 months prior to Registration

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to INO-8000 and INO-9012