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

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ClinicalTrials.gov Identifier: NCT02314052
Recruitment Status : Terminated (Sponsor decision)
First Posted : December 10, 2014
Results First Posted : September 3, 2018
Last Update Posted : September 3, 2018
Sponsor:
Information provided by (Responsible Party):
Dicerna Pharmaceuticals, Inc.

Brief Summary:
The purpose of this study is to assess the safety and tolerability of the investigational anticancer drug DCR-MYC. DCR-MYC is a novel synthetic double-stranded RNA in a stable lipid particle suspension that targets the oncogene MYC. MYC oncogene activation is important to the growth of many hematologic and solid tumor malignancies. In this study the Sponsor proposes to study DCR-MYC and its ability to inhibit MYC and thereby inhibit cancer cell growth.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: DCR-MYC Phase 1 Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : January 27, 2015
Actual Primary Completion Date : October 11, 2016
Actual Study Completion Date : October 11, 2016

Arm Intervention/treatment
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
Drug: 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





Primary Outcome Measures :
  1. 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 ]

    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).


  2. 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 ]
    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.

  3. Phase 2: Preliminary Antitumor Activity [ Time Frame: After Cycle 2 (6 weeks), then at 6 week intervals if DCR-MYC is continued ]
    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.


Secondary Outcome Measures :
  1. 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 ]
    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).

  2. DCR-MYC Biological Activities (Phase 1b Only) [ Time Frame: Cycle 1; Week 1 ]
    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.

  3. DCR-MYC Biological Activities (Phase 1b Only) [ Time Frame: Cycle 1 and 2 ]
    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.

  4. 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 ]
    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).

  5. 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 ]
    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).

  6. 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 ]
    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).

  7. 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 ]
    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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02314052


Locations
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United States, Arizona
Mayo Clinic
Scottsdale, Arizona, United States, 85259-5499
United States, Massachusetts
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States, 02114
United States, Texas
South Texas Accelerated Research Therapeutics, LLC
San Antonio, Texas, United States, 78229
Korea, Republic of
Asan Medical Center
Seoul, Korea, Republic of, 138-736
Singapore
National University Hospital of Singapore
Singapore, Singapore, 119228
National Cancer Centre Singapore
Singapore, Singapore, 169610
Sponsors and Collaborators
Dicerna Pharmaceuticals, Inc.

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Responsible Party: Dicerna Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02314052     History of Changes
Other Study ID Numbers: DCR-MYC-102
First Posted: December 10, 2014    Key Record Dates
Results First Posted: September 3, 2018
Last Update Posted: September 3, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases