- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02314052
Phase Ib/2, Multicenter, Dose Escalation Study of DCR-MYC in Patients With Hepatocellular Carcinoma
Phase 1b/2, Multicenter, Dose Escalation Trial to Determine the Safety, Tolerance, Maximum Tolerated Dose and Recommended Phase 2 Dose of DCR-MYC, a Lipid Nanoparticle (LNP)-Formulated Small Inhibitory RNA (siRNA) Oligonucleotide Targeting MYC, in Patients With Hepatocellular Carcinoma (HCC)
Study Overview
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Seoul, Korea, Republic of, 138-736
- Asan Medical Center
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Singapore, Singapore, 169610
- National Cancer Centre Singapore
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Singapore, Singapore, 119228
- National University Hospital of Singapore
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Arizona
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Scottsdale, Arizona, United States, 85259-5499
- Mayo Clinic
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Massachusetts
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Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital Cancer Center
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Texas
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San Antonio, Texas, United States, 78229
- South Texas Accelerated Research Therapeutics, LLC
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: 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
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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 |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Phase 1b: Number of Patients With Adverse Events as a Measure of Safety and Tolerability
Time Frame: Cycle 1 (3 weeks), longer if DCR-MYC is continued; with 30 days follow-up after last dose
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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
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Phase 2: Patients With Adverse Events as a Measure of Safety and Tolerability
Time Frame: Cycle 1 (3 weeks), longer if DCR-MYC is continued; with 30 days follow-up after last dose
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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.
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Cycle 1 (3 weeks), longer if DCR-MYC is continued; with 30 days follow-up after last dose
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Phase 2: Preliminary Antitumor Activity
Time Frame: After Cycle 2 (6 weeks), then at 6 week intervals if DCR-MYC is continued
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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.
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After Cycle 2 (6 weeks), then at 6 week intervals if DCR-MYC is continued
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Cmax (ng/mL) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8
Time Frame: 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
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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).
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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
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DCR-MYC Biological Activities (Phase 1b Only)
Time Frame: Cycle 1; Week 1
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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.
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Cycle 1; Week 1
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DCR-MYC Biological Activities (Phase 1b Only)
Time Frame: Cycle 1 and 2
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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.
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Cycle 1 and 2
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Tmax (Hr) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8
Time Frame: 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
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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).
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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
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Cmax_D (kg*ng/mL/mg) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8
Time Frame: 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
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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).
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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
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AUClast_D (hr*kg*ng/mL/mg) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8
Time Frame: 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
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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).
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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
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AUClast (hr*ng/mL) - DCR-MYC Levels in Blood (Phase 1b Only): Dosing Day 1 and Day 8
Time Frame: 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
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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).
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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
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- DCR-MYC-102
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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