Phase Ib/2, Multicenter, Dose Escalation Study of DCR-MYC in Patients With Hepatocellular Carcinoma

In this second study in humans, DCR-MYC will be administered by 2 hour intravenous (IV)
infusion, once weekly for 2 weeks followed by a rest week (3 weeks = 1 cycle), to patients
with hepatocellular carcinoma who are either sorafenib-refractory, sorafenib-intolerant
despite dose reduction and best supportive care, or for whom neither sorafenib nor other
suitable therapy is available. During the Phase 1b portion of the study, the highest safe
dose of DCR-MYC that can be administered will be identified. In addition, the pharmacokinetic
(PK) profile, potential pharmacodynamic (PD) effects, as well as the preliminary antitumor
activity of DCR-MYC will be evaluated. During the Phase 2 portion of the study, up to 30
patients will be treated at the MTD identified in Phase 1b in order to further evaluate
safety and tolerability, as well as assess the antitumor activity, of DCR-MYC.

Inclusion Criteria:

1. Male or female patients, > 18 years of age (in Singapore > 21 years or > 18 years with
consent of guardian).

2. Patients with documented (histologically- or cytologically-proven) HCC, with at least
1 measureable lesion > 10 mm (excluding bone metastases). If the measurable lesion(s)
is in the liver, it either should not have been treated previously with loco-regional
therapy, or there must be demonstrated progression of the lesion following previous
loco-regional therapy.

3. Patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC not amenable to
surgical intervention due to either medical contraindications or non-resectability of
the tumor.

4. Patients who are either refractory to or intolerant of sorafenib despite dose
reduction and best supportive care, or patients who do not have access to sorafenib or
other suitable therapy for HCC.

5. Patients with underlying hepatic cirrhosis must have a current cirrhosis status of
Child-Pugh Class A (i.e., score of 5-6) without encephalopathy.

6. Phase 1b MTD Biopsy Cohort: Patients with primary or metastatic tumor site(s)
considered safely accessible for biopsy and consenting to undergo pre- and post-dosing
tumor biopsies.

7. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
1, and an anticipated life expectancy of ≥ 3 months.

8. Patients, both male and female, who are either not of childbearing potential or who
agree to use a medically effective method of contraception during the study and for 3
months after the last dose of study drug.

9. Patients with the ability to understand and give written informed consent for
participation in this trial, including all evaluations and procedures as specified by
this protocol.

Exclusion Criteria (Patients):

1. Women who are pregnant or lactating; women of child-bearing potential (WOCBP), and
fertile men with a WOCBP-partner not using and not willing to use a medically
effective method of contraception.

2. Patients with known central nervous system (CNS) or leptomeningeal metastases not
controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS
involvement for which treatment is required.

3. Patients with mixed histology cholangiocarcinoma and HCC, or fibrolamellar variant
HCC.

4. Patients with any of the following hematologic abnormalities at baseline:

- Hemoglobin < 8.5 g/dL

- Absolute neutrophil count < 1,500 per mm3

- Platelet count < 75,000 per mm

5. Patients with any of the following serum chemistry abnormalities at baseline:

- Total bilirubin > 1.5 × the upper limit of normal (ULN) for the institution

- AST or ALT > 5 × the ULN for the institution

- Serum creatinine > 1.5 × the ULN for the institution

6. Patients with the following coagulation parameter abnormality at baseline:

- INR > 1.7 × ULN for the institution

7. Patients with:

- A history of deep vein thrombosis (DVT) or pulmonary embolism (PE), within 6
months prior to first study drug administration; patients receiving systemic
anti-coagulation for prophylactic or therapeutic reasons

- Active uncontrolled bleeding or a known bleeding diathesis

8. Patients with:

- Esophageal or gastric variceal bleeding within 2 months prior to first study drug
administration; patients with a history of variceal bleeding between 2 and 12
months prior to first study drug administration should have undergone adequate
treatment and be considered clinically stable in the opinion of the investigator

- A history of symptomatic ascites requiring paracentesis within the past 3 months
or any encephalopathy requiring hospitalization or medication within the past 3
months

- Portal-caval shunts

9. Patients with a significant cardiovascular disease or condition, including:

- Congestive heart failure currently requiring therapy

- Need for antiarrhythmic medical therapy for a ventricular arrhythmia

- Severe conduction disturbance (i.e., 3rd degree heart block)

- Angina pectoris requiring therapy

- Known left ventricular ejection fraction (LVEF) < 50% by MUGA or echocardiogram

- QTc interval > 450 msec in males, or > 470 msec in females

- Uncontrolled systemic hypertension (per the Investigator's discretion)

- Class III or IV cardiovascular disease according to the New York Heart
Association (NYHA) Functional Criteria

- Myocardial infarction within 6 months prior to first study drug administration

10. Patients with a known or suspected hypersensitivity to any of the components of lipid
nanoparticle-formulated DCR-MYC; patients with a known sensitivity to cremophor (found
with paclitaxel and other formulations).

11. Patients with an estimated daily alcohol intake greater than 80 g/day.

12. Patients having undergone previous organ transplantation (e.g., liver transplantation)
requiring immunosuppression; patients on long-term immunosuppressive therapy.

13. Patients with a known history of human immunodeficiency virus (HIV) seropositivity.

14. Patients with any other serious/active/uncontrolled infection, with the exception of
chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection; any
infection requiring parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks
prior to first study drug administration.

15. Patients with inadequate recovery from an acute toxicity associated with any prior
antineoplastic therapy.

16. Patients with inadequate recovery from any previous surgical procedure, or patients
having undergone any major surgical procedure within 4 weeks prior to first study drug
administration.

17. Patients with an active second malignancy or history of another malignancy within the
last 3 years, with the exception of:

- Treated, non-melanoma skin cancers

- Treated CIS of the breast or cervix

- Controlled, superficial carcinoma of the bladder

- T1a or b carcinoma of the prostate treated according to local standard of care,
with prostate specific antigen (PSA) within normal limits (wnl)

18. Patients with any other life-threatening illness, significant organ system
dysfunction, or clinically significant laboratory abnormality, which, in the opinion
of the Investigator, would either compromise the patient's safety or interfere with
evaluation of the safety of the study drug.

19. Patients with a psychiatric disorder or altered mental status that would preclude
understanding of the informed consent process and/or completion of the necessary
study-related evaluations.

20. Patients with the inability or with foreseeable incapacity, in the opinion of the
Investigator, to comply with the protocol requirements, including the ability to
attend all visits and undergo all assessments.

Exclusion Criteria (Treatments):

1. Phase 1b: Greater than 3 prior systemic anti-cancer chemotherapies or targeted agents
for HCC; prior loco-regional treatment, including transcatheter arterial
chemo-embolization (TACE), is allowed.

2. Phase 2: greater than 1 prior systemic anti-cancer chemotherapy or targeted agent for
HCC; prior loco-regional treatment, including TACE, is allowed.

3. Sorafenib therapy within 2 weeks prior to first study drug administration and during
study.

4. Any other antineoplastic agent (standard or experimental) within 4 weeks; monoclonal
antibody therapy, nitrosoureas, and nitrogen mustard within 6 weeks prior to first
study drug administration and during study.

5. Loco-regional therapy including TACE or radioembolization within 6 weeks prior to
first study drug administration and during study.

6. Radiotherapy within 4 weeks prior to first study drug administration and during study.

7. Therapy with sofosbuvir for HCV within 6 weeks prior to first study drug
administration and during study.

8. Herbal preparations, or related non-prescription preparations/supplements containing
herbal ingredients, aimed at treating the underlying malignancy within 2 weeks prior
to first study drug administration and during study.

9. Systemic hormonal therapy within 2 weeks prior to first study drug administration and
during study.

10. Any other investigational treatments during study. This includes participation in any
medical device or therapeutic intervention clinical trial.

11. Prophylactic use of hematopoietic growth factors within 1 week prior to first study
drug administration and during Cycle 1 of study; thereafter prophylactic use of growth
factors is allowed as clinically indicated.