Phase Ib/2, Multicenter, Dose Escalation Study of DCR-MYC... | NCT02314052

Label	Type	Description	Intervention Names
DCR-MYC	Experimental	Patient groups (cohorts) will receive a single dose level of DCR-MYC; the dose level of DCR-MYC will be increased in subsequent cohorts	Drug: DCR-MYC

Name	Type	Description	Arm Group Labels	Other Names
DCR-MYC	Drug	Dosing: 2 hour IV infusion on Day 1 and 8 of each 21 day cycle. Starting dose: 0.125mg/kg/dose Number of cycles: until progression or unacceptable toxicity develops. PHASE 1b Dose escalation: 50% or 25% increase in subsequent cohorts depending upon toxicity until maximum tolerated dose (MTD) is identified. PHASE 2 Cohort expansion at the MTD: Additional patients to be treated at the highest dose tolerated to assess efficacy and further assess safety

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Phase 1b: Number of Patients With Adverse Events as a Measure of Safety and Tolerability	Part A: 3 patient cohorts with 50% dose increase between cohorts until study drug-related dose-limiting toxicity (DLT) during Cycle 1, then expand to 6 patients and move to Part B. Part B: 3 to 6 patient cohorts with 25% dose increase between cohorts until > 1 study drug-related DLT, then stop escalation. Expand MTD cohort to 12 patients; tumor biopsies to be performed in this Phase 1b MTD Biopsy Cohort (6 patients).	Cycle 1 (3 weeks), longer if DCR-MYC is continued; with 30 days follow-up after last dose
Phase 2: Patients With Adverse Events as a Measure of Safety and Tolerability	Up to 30 patients in the Phase 2 MTD Expansion Cohort (to be treated at the MTD identified in Phase 1b); further evaluation of safety and tolerability.	Cycle 1 (3 weeks), longer if DCR-MYC is continued; with 30 days follow-up after last dose
Phase 2: Preliminary Antitumor Activity	Up to 30 patients in the Phase 2 MTD Expansion Cohort (to be treated at the MTD identified in Phase 1b); evaluation for evidence of objective response or disease stabilization.	After Cycle 2 (6 weeks), then at 6 week intervals if DCR-MYC is continued

Secondary Outcomes

Measure	Description	Time Frame
Cmax (ng/mL) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8	Samples to be collected Week 1 (Day 1, 2, and 4) and Week 2 (Day 8 and 11). A summary of outcome measures reported here are noncompartmental PK parameters (Cmax, dose-normalized Cmax (Cmax_D), Tmax, AUClast, and dose-normalized AUClast (AUClast_D)) for both infusion days (Day 1 and Day 8).	Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male or female patients, > 18 years of age (in Singapore > 21 years or > 18 years with consent of guardian).
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.
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.
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.
Patients with underlying hepatic cirrhosis must have a current cirrhosis status of Child-Pugh Class A (i.e., score of 5-6) without encephalopathy.
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.
Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an anticipated life expectancy of ≥ 3 months.
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.
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):

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.
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.
Patients with mixed histology cholangiocarcinoma and HCC, or fibrolamellar variant HCC.
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
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
Patients with the following coagulation parameter abnormality at baseline:
- INR > 1.7 × ULN for the institution
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
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
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
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).
Patients with an estimated daily alcohol intake greater than 80 g/day.
Patients having undergone previous organ transplantation (e.g., liver transplantation) requiring immunosuppression; patients on long-term immunosuppressive therapy.
Patients with a known history of human immunodeficiency virus (HIV) seropositivity.
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.
Patients with inadequate recovery from an acute toxicity associated with any prior antineoplastic therapy.
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.
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)
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.
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.
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):

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.
Phase 2: greater than 1 prior systemic anti-cancer chemotherapy or targeted agent for HCC; prior loco-regional treatment, including TACE, is allowed.
Sorafenib therapy within 2 weeks prior to first study drug administration and during study.
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.
Loco-regional therapy including TACE or radioembolization within 6 weeks prior to first study drug administration and during study.
Radiotherapy within 4 weeks prior to first study drug administration and during study.
Therapy with sofosbuvir for HCV within 6 weeks prior to first study drug administration and during study.
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.
Systemic hormonal therapy within 2 weeks prior to first study drug administration and during study.
Any other investigational treatments during study. This includes participation in any medical device or therapeutic intervention clinical trial.
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.

Facility	Status	City	State	ZIP	Country	Contacts
Mayo Clinic		Scottsdale	Arizona	85259-5499	United States
Massachusetts General Hospital Cancer Center

ID	Title	Description
FG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
FG001

ID	Title	Description
BG000	DCR-MYC	Patient groups (cohorts) will receive a single dose level of DCR-MYC; the dose level of DCR-MYC will be increased in subsequent cohorts DCR-MYC: Dosing: 2 hour IV infusion on Day 1 and 8 of each 21 day cycle. Starting dose: 0.125mg/kg/dose Number of cycles: until progression or unacceptable toxicity develops. PHASE 1b Dose escalation: 50% or 25% increase in subsequent cohorts depending upon toxicity until maximum tolerated dose (MTD) is identified. PHASE 2 Cohort expansion at the MTD: Additional patients to be treated at the highest dose tolerated to assess efficacy and further assess safety

Units	Counts
Participants	BG00021

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Phase 1b: Number of Patients With Adverse Events as a Measure of Safety and Tolerability

Part A: 3 patient cohorts with 50% dose increase between cohorts until study drug-related dose-limiting toxicity (DLT) during Cycle 1, then expand to 6 patients and move to Part B.

Part B: 3 to 6 patient cohorts with 25% dose increase between cohorts until > 1 study drug-related DLT, then stop escalation.

Expand MTD cohort to 12 patients; tumor biopsies to be performed in this Phase 1b MTD Biopsy Cohort (6 patients).

Safety population

Posted

Count of Participants

Participants

Cycle 1 (3 weeks), longer if DCR-MYC is continued; with 30 days follow-up after last dose

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG003	Cohort 4	N = 3, received two, 2-hour infusions of 0.45 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG004	Cohort 5	N = 6, received two, 2-hour infusions of 0.68 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG005	Cohort 6	N = 3, received two, 2-hour infusions of 0.85 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.

Units	Counts
Participants	OG0003 OG0013 OG0023 OG003

Title

Denominators

Categories

Title	Measurements
	OG0003 OG0013 OG0023 OG003

Primary

Phase 2: Patients With Adverse Events as a Measure of Safety and Tolerability

Up to 30 patients in the Phase 2 MTD Expansion Cohort (to be treated at the MTD identified in Phase 1b); further evaluation of safety and tolerability.

N/A - Study terminated prior to Phase 2

Posted

Cycle 1 (3 weeks), longer if DCR-MYC is continued; with 30 days follow-up after last dose

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.

Primary

Phase 2: Preliminary Antitumor Activity

Up to 30 patients in the Phase 2 MTD Expansion Cohort (to be treated at the MTD identified in Phase 1b); evaluation for evidence of objective response or disease stabilization.

N/A - Study terminated prior to phase 2

Posted

After Cycle 2 (6 weeks), then at 6 week intervals if DCR-MYC is continued

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.

Secondary

Cmax (ng/mL) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8

Samples to be collected Week 1 (Day 1, 2, and 4) and Week 2 (Day 8 and 11). A summary of outcome measures reported here are noncompartmental PK parameters (Cmax, dose-normalized Cmax (Cmax_D), Tmax, AUClast, and dose-normalized AUClast (AUClast_D)) for both infusion days (Day 1 and Day 8).

Posted

Mean

Standard Deviation

ng/mL

Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.

Secondary

DCR-MYC Biological Activities (Phase 1b Only)

Collection of blood samples for cytokine measurements (Day 1, 2, and 4). No noteworthy increases were observed across dose groups or time for GM-CSF, IFNα, IFNɣ, or IL-1β. Changes that were observed for the other cytokines were not dose-dependent since they occurred sporadically and primarily in Cohorts 3 (0.3 mg/kg) and 4 (0.45 mg/kg). Pre-dose, 4 hours post-dose, and 24 hour post-dose results for TNF-α, IL-10, IL-6, IL-8, IL-1RA, and MCP-1 are summarized here.

Safety population

Posted

Mean

Standard Deviation

pg/mL

Cycle 1; Week 1

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3

Secondary

DCR-MYC Biological Activities (Phase 1b Only)

Tumor biopsies (2 total) to be performed in Phase 1b MTD expansion cohort only (6 patients). Patients will have biopsies performed prior to Cycle 1/Day 1 and on Cycle 2/Day 11.

Planned expansion into the MTD biopsy cohort and phase 2 portion of the study did not occur due to the sponsor's decision to prematurely end the study.

Posted

Cycle 1 and 2

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.

Secondary

Tmax (Hr) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8

Posted

Mean

Standard Deviation

Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.

Secondary

Cmax_D (kg*ng/mL/mg) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8

Posted

Mean

Standard Deviation

kg*ng/mL/mg

Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.

Secondary

AUClast_D (hr*kg*ng/mL/mg) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8

Posted

Mean

Standard Deviation

hr*kg*ng/mL/mg

Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.

Secondary

AUClast (hr*ng/mL) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8

Posted

Mean

Standard Deviation

hr*ng/mL

Week 1 Day 1 AND Week 2 Day 8 Cycle PK Sampling Points: 0 min, 1/4 through infusion, 1/2 through infusion, end of infusion, 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h, Day 4

ID	Title	Description
OG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.
OG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined five 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Cohort 1	N = 3, received two, 2-hour infusions of 0.125 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined 5 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.	2	3	1	3	3	3
EG001	Cohort 2	N = 3, received two, 2-hour infusions of 0.2 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined 5 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.	0	3	0	3	3	3
EG002	Cohort 3	N = 3, received two, 2-hour infusions of 0.3 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined 5 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.	3	3	0	3	3	3
EG003	Cohort 4	N = 3, received two, 2-hour infusions of 0.45 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined 5 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.	1	3	1	3	3	3
EG004	Cohort 5	N = 6, received two, 2-hour infusions of 0.68 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined 5 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.	3	6	2	6	6	6
EG005	Cohort 6	N = 3, received two, 2-hour infusions of 0.85 mg/kg DCR-MYC, once on Day 1 and once on Day 8 within a 21-day cycle. The protocol outlined 5 21-day cycles, each with dosing on days 1 and 8. The study was terminated prematurely and subjects were not treated after the termination date.	2	3	1	3	3	3

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Fatigue	General disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk EG0022 affected3 at risk EG0032 affected3 at risk EG0041 affected6 at risk EG0052 affected3 at risk
Oedema peripheral	General disorders	MedDRA (17.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Pyrexia	General disorders	MedDRA (17.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Chills	General disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Influenza-like illness	General disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Pain	General disorders	MedDRA (17.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Ascites	Gastrointestinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Abdominal distention	Gastrointestinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
AST increased	Investigations	MedDRA (17.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk EG0022 affected3 at risk EG003
ALT increased	Investigations	MedDRA (17.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Lipase increased	Investigations	MedDRA (17.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0012 affected3 at risk EG0020 affected3 at risk EG003
Blood bilirubin increased	Investigations	MedDRA (17.1)	Non-systematic Assessment	EG0001 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Blood creatinine increased	Investigations	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003
GGT increased	Investigations	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk EG0021 affected3 at risk EG003
Platelet count decreased	Investigations	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0010 affected3 at risk EG0020 affected3 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA (17.1)	Non-systematic Assessment	EG0002 affected3 at risk EG0010 affected3 at risk EG0021 affected3 at risk EG003
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk EG0022 affected3 at risk EG003
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 affected3 at risk EG0011 affected3 at risk EG0020 affected3 at risk EG003

ID	Term
D000230	Adenocarcinoma
D002277	Carcinoma
D009375	Neoplasms, Glandular and Epithelial
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D008113	Liver Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D004066	Digestive System Diseases
D008107	Liver Diseases

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Spinal cord compression/ Spinal Cord Compression Due To Pathologic Fracture Of T1	Nervous system disorders	MedDRA (17.1)	Non-systematic Assessment	EG0001 events1 affected3 at risk EG0010 events0 affected3 at risk EG0020 events0 affected3 at risk EG0030 events0 affected3 at risk
Oropharyngeal pain/ Sore Throat	Respiratory, thoracic and mediastinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0001 events1 affected3 at risk EG0010 events0 affected3 at risk EG0020 events0 affected3 at risk EG003
Dyspnoea/ Increased Dyspnea	Respiratory, thoracic and mediastinal disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected3 at risk EG0020 events0 affected3 at risk EG003
Influenza like illness/ Flu Like Symptom	General disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected3 at risk EG0020 events0 affected3 at risk EG003
Acute coronary syndrome/ Acute Coronary Syndrome	Cardiac disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected3 at risk EG0020 events0 affected3 at risk EG003
Cholangitis/ Cholangitis Due To Pd	Hepatobiliary disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected3 at risk EG0020 events0 affected3 at risk EG003
Metastases to bone/ Osteolytic Jaw Lesion Due To Progression Disease	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected3 at risk EG0020 events0 affected3 at risk EG003
Hypovolaemic shock/ Hypovolemic Hypoperfusion	Vascular disorders	MedDRA (17.1)	Non-systematic Assessment	EG0000 events0 affected3 at risk EG0010 events0 affected3 at risk EG0020 events0 affected3 at risk EG003