Phase I, Multicenter, Dose Escalation Study of DCR-MYC in Patients With Solid Tumors, Multiple Myeloma, or Lymphoma

In this first-in human study, 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 either solid tumor malignancies, multiple myeloma, or non-Hodgkins lymphoma that have
not responded to previous treatment. 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 antitumor activity of DCR-MYC will be evaluated.

There will be 2 expansion cohorts at the maximum tolerated dose (MTD) (or highest safe dose
identified for further study which may be lower):

- Biopsy Cohort: 6 patients, tumor biopsies to be performed pre-dosing and Cycle 2/Day 11;
same assessments as dose escalation cohorts

- PNET Cohort: Up to 20 patients with pancreatic neuroendocrine tumors; same assessments
as dose escalation cohorts, however fewer PD (cytokine) assessments and no PK
assessments

Inclusion Criteria:

1. Male or female patients, > 18 years of age at the time of obtaining informed consent.

2. Patients with a documented solid tumor malignancy that is locally advanced or
metastatic; patients with documented multiple myeloma or non-Hodgkin's lymphoma.

3. Patients with a malignancy that is either refractory to standard therapy or for which
no standard therapy is available.

4. Patients with a malignancy that is currently not amenable to surgical intervention due
to either medical contraindications or non-resectability of the tumor.

5. Dose escalation portion of study: Patients with measurable or non-measurable disease
according to standard response criteria .

6. MTD Biopsy Cohort ONLY: Patients with measurable disease with primary or metastatic
tumor site(s) considered safely accessible for biopsy; patients must consent to
undergo 2 tumor biopsies.

7. MTD PNET Cohort ONLY: Patients with advanced (unresectable or metastatic),
histologically-confirmed low or intermediate grade PNET according to the World Health
Organization (WHO) 2010 classification. Patients with neuroendocrine tumors (e.g.,
gastrinoma, VIPoma) in whom a pancreatic or peripancreatic primary is strongly
suspected are also eligible. Patients must also have:

- A Ki-67 proliferation index < 20%

- Demonstrated radiological evidence of disease progression during or following the
last treatment regimen (based on CT, MRI, or Octreoscan®)

- Measurable disease according to RECIST v1.1 (determined by CT or MRI). Any
lesions which have been subjected to percutaneous therapies or radiotherapy
should not be considered measureable, unless the lesion has clearly progressed
(per RECIST v1.1) since the procedure.

- Received < 2 prior systemic treatments for PNET, at least one of which must have
been an FDA-approved targeted therapy for PNET (i.e., sunitinib [Sutent®] or
everolimus [Afinitor®]). Treatment with a somatostatin analog (SSA) will not be
considered as a systemic treatment for the purposes of eligibility.

8. Patients with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2,
and an anticipated life expectancy of ≥ 3 months.

9. 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.

10. 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 leukemia (any form) or myelodysplastic syndromes.

4. MTD PNET Cohort ONLY: Patients with poorly differentiated, high grade (grade 3)
neuroendocrine carcinoma, as well as patients with adenocarcinoid, goblet cell
carcinoid, or small cell carcinoma, or PNET patients with a Ki-67 proliferation index
> 20 %.

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

- Absolute neutrophil count < 1,500 per mm3

- Platelet count < 100,000 per mm3

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

- Total bilirubin > 1.5 × the ULN for the institution

- AST or ALT > 3 × the ULN for the institution (> 5 × if due to hepatic involvement
by tumor)

- Creatinine > 1.5 × ULN for the institution

7. Patients with any of the following coagulation parameter abnormalities at baseline:

- PT (INR) > 1.5 × ULN for the institution

- PTT > 1.5 × ULN for the institution

8. Patients with:

- Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism,
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

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 (e.g., 3rd degree heart block)

- Angina pectoris requiring therapy

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

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

- Uncontrolled hypertension (per the Investigator's discretion)

- Class III or IV cardiovascular disease according to the New York Heart
Association's 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.

11. Patients with a known history of human immunodeficiency virus or active infection with
hepatitis B virus or hepatitis C virus.

12. Patients with any other serious/active/uncontrolled infection, any infection requiring
parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to first
study drug administration.

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

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

15. 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.

16. 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.

17. Patients with the inability or with foreseeable incapacity, in the opinion of the
Investigator, to comply with the protocol requirements.

Exclusion Criteria-Treatments:

1. MTD PNET Cohort ONLY: Greater than 2 prior systemic treatments for the underlying
malignancy

2. Any antineoplastic agent for the primary malignancy (standard or experimental) within
4 weeks prior to first study drug administration with the exception of monoclonal
antibody therapy, nitrosoureas, and nitrogen mustard for the primary malignancy within
6 weeks prior to first study drug administration

3. Radiotherapy for the primary malignancy within 4 weeks prior to first study drug
administration and during study.

4. Herbal preparations or related over-the-counter preparations/supplements containing
herbal ingredients within 2 weeks prior to first study drug administration and during
study.

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

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

7. 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.