Doxorubicin-eluting LC Bead M1 for Patients With Hepatocellular Carcinoma (DEBDOX)

Doxorubicin-eluting LC Bead M1 for Patients With Hepatocellular Carcinoma (DEBDOX)

The purpose of this study is to determine the feasibility and safety of using small beads (70-150 micron in place of 100-300 micron) to deliver chemotherapy into the liver to treat patients with hepatocellular carcinoma (HCC). The beads (LC-Bead M1) will be loaded with doxorubicin (DEBDOX-M1), and used to administer transarterial chemoembolization (TACE) DEBDOX, loaded with doxorubicin, is a device that utilizes tiny beads (70-150 microns) to deliver chemotherapy agents into liver tumor(s) via the hepatic artery. This device allows for continuous release of doxorubicin into the liver tumor tissue(s) causing necrosis of the targeted tumor(s). The potential advantages of the smaller beads are deeper penetration into the tumor bed, while avoiding premature proximal occlusion of vessels feeding the tumor, and more consistent dosing. Response to therapy will be evaluated monthly by clinic visits and blood tests (to include assessment of liver function and tumor markers) and by imaging (usually MRIs) every 1-2 months. Patients will be on study for 6 months after which they will be exited from the study and followed for survival. Once exited from the study they will continue to be eligible to receive the smaller beads (DEBDOX), should it be recommended.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Device: DEBDOX

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA:

1. The patient has preserved liver function (Child-Pugh A-B class) without significant liver decompensation.
2. The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at study entry.
3. The patient is age 18 years or older.
4. The patient has a life expectancy of > 12 weeks.
5. The patient has measurable or evaluable disease that will be directly treated with intrahepatic therapy (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1).

6. The patient has adequate hematologic function as defined by the following criteria:

   • An absolute neutrophil count (ANC) ≥ 1500/micro L,
   • Hemoglobin ≥ 9.5 g/dL, and a
   • Platelet count ≥ 50,000/micro L.

7. The patient has adequate hepatic function, as defined by the following criteria:

   • Total bilirubin </= 3.0 mg/dL
   • Aspartate transaminase (AST) and alanine transaminase (ALT) </= 8 x the upper limit of normal (ULN).

8. The patient has adequate renal function, as defined by the following criteria:

   • Serum creatinine </= 2.0 x the institutional ULN
9. The patient has a baseline international normalized ratio (INR) < 1.5.
10. The patient, if a woman of childbearing potential, has a negative pregnancy test.
11. The patient is able to give written informed consent.
12. The patient is willing and able to comply with study procedures, scheduled visits, and treatment plans.
13. Patients with early stage HCC may be included in the protocol to receive DEBDOX-M1 prior to resection

EXCLUSION CRITERIA:

1. The patient has a history of another primary cancer (ie, a primary cancer not associated with the patient's current liver tumor), with the exception of (a) curatively resected nonmelanomatous skin cancer; (b) curatively treated cervical carcinoma in situ; or (c) other primary solid tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years prior to enrollment (date of informed consent).
2. The patient is receiving concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, chemoembolization, targeted therapy, or an investigational agent.
3. The patient has extrahepatic, metastatic, symptomatic HCC. Enlarged reactive lymph nodes, or indeterminate lesions, such as lung nodules are acceptable.
4. The patient's tumor has replaced >70% of the liver volume.
5. The patient has clinically significant ascites. Trace ascites on imaging is acceptable.
6. Marco-shunting noted on the hepatic angiogram.
7. The patient has untreatable bleeding diathesis.
8. The patient has complete main portal vein thrombosis with reversal of flow.
9. The patient has a left ventricle ejection fraction of less than 45%.
10. The patient has evidence of clinically significant peripheral vascular disease.

11. The patient has clinically significant or symptomatic extrahepatic disease, for example, an uncontrolled inter-current illness including, but not limited to:

    • Ongoing or active infection requiring parenteral antibiotics
    • Symptomatic congestive heart failure (class II to IV of the New York Heart Association classification for heart disease)
    • Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months
    • Uncontrolled hypertension (systolic blood pressure > 150 mmHg, diastolic blood pressure > 90 mmHg, found on 2 consecutive measurements separated by a 1-week period despite adequate medical support)
    • Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [NCI-CTCAE Grade 3] or asymptomatic sustained ventricular tachycardia)
    • Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements
12. There is evidence of substance abuse or medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of study results.
13. The patient is pregnant or breast-feeding.
14. The patient is allergic to contrast media that cannot be readily prevented with premedication or managed.
15. The patient has extra-hepatic, metastatic, and symptomatic HCC.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: DEBDOX

Device: DEBDOX; DEBDOX, loaded with doxorubicin, is a device that utilizes beads in place of lipiodol to deliver the chemotherapy into the liver tumor. The device allows for continuous elution of doxorubicin into the liver tumor tissue. The advantages of this method of delivery in comparison to conventional TACE are that the beads are able to deliver a greater volume and concentration of the drugs to the tumor because of their unique ability to elute the drug over a period of several days. As a result of this unique delivery, systemic toxicity is significantly reduced. The potential advantages of the smaller beads are deeper penetration into the tumor bed, while avoiding premature proximal occlusion of vessels feeding the tumor, and more consistent dosing. These properties translate into greater potency of therapy and potentially improved patient survival.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Success of DEBDOX-M1 Procedure as a Measure of Feasibility	Feasibility is defined as achieving an acceptable level of technical success in the use of DEBDOX-M1 beads treating hepatic lesions in patients with hepatocellular carcinoma.	6 months
Collection of Adverse Events Related to Study Device as a Measure of Safety	For safety, all toxicities assessed as being at least possibly related will be analyzed by descriptive statistics to show type, grade (NCI Common Toxicity Criteria v.4 toxicity criteria), frequency and time from DEBDOX-M1TACE.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy - Tumor Response by EASL	Efficacy as assessed by radiographic tumor response using EASL amendment at baseline and at 1 month imaging following TACE treatments. Complete Response (CR): Achieving 100% tumor necrosis of lesions targeted by DEBDOX-M1. Baseline degree of tumor enhancement used as a reference. Partial Response (PR): Demonstrating greater than 50% tumor necrosis in lesions targeted by DEBDOX-M1. Stable Disease (SD): Not meeting requirements for CR or PR and not demonstrating evidence of progression of lesions targeted by DEBDOX-M1. Progressive Disease (PD): Reappearance of or increased tumor enhancement greater than 25% in lesions previously targeted by DEBDOX-M1.	1 month
Efficacy - Tumor Response by qEASL	Efficacy as assessed by radiographic tumor response using qEASL at baseline and at 1-month imaging following TACE treatments. Complete Response (CR): Disappearance of any intratumoral arterial enhancement in all target lesions. Partial Response (PR): At least a 65% decrease in the sum of enhancing tissue volume of the lesions. Stable Disease (SD): Any cases that do not qualify for complete response, partial response, or progressive disease. Progressive Disease (PD): an increase of at least 73% in the sum of enhancing tissue volume of the lesions.	1 month
Efficacy - Tumor Response by mRECIST	Efficacy as assessed by radiographic tumor response using modified RECIST (mRECIST) criteria at baseline and at 1-month imaging following TACE treatments. Complete Response (CR): Disappearance of any intratumoral arterial enhancement in all target lesions Partial Response (PR): At least 30% decrease in the sum of diameters of viable target lesions, taking as reference the baseline sum of the diameters of target lesions Progressive Disease (PD): At least 20% increase in the sum of diameters of viable target lesions, taking as reference the smallest sum of diameters of viable target lesions since treatment started Stable Disease (SD): Any cases that do not qualify for either PR or PD.	1 month
Efficacy - Number of Patients Downstaged or Bridged to Surgical Interventions	The number of patients who underwent a liver transplantation following treatment on this protocol.	6 months
AFP Tumor Marker Pre- and Post-treatment	The change in alpha-fetoprotein tumor marker levels pre- and post-treatment with one DEBDOX-M1 TACE procedure.	1 month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Endpoint - Pharmacokinetic (PK) Profile of Doxorubicin and Doxorubicinol Post DEBDOX-M1 TACE	PK analysis of doxorubicin and its metabolite doxorubicinol post DEBDOX-M1 in the first 10 patients enrolled on protocol including peak plasma concentration (Cmax). Time points assessed in protocol were pre-dose, and then 5min, 20min, 40min, 1hr, 2hr, and 24hr post administration of 50-100mg doxorubicin.	24 hours
Exploratory Endpoint - Total Drug Exposure Over Time (AUC) of Doxorubicin and Doxorubicinol Post TACE	Total drug exposure over time (AUC) of doxorubicin and its metabolite doxorubicinol post DEBDOX in the first 10 patients enrolled on protocol. Time points assessed in protocol were pre-dose, and then 5min, 20min, 40min, 1hr, 2hr, and 24hr post administration of 50-100mg doxorubicin..	24 hours
Exploratory Endpoint - Tmax of Doxorubicin and Doxorubicinol Post DEBDOX-M1 TACE	Time taken to reach maximum concentration (Tmax) of doxorubicin and its metabolite doxorubicinol post DEBDOX-M1 in the first 10 patients enrolled on protocol. Time points assessed in protocol were pre-dose, and then 5min, 20min, 40min, 1hr, 2hr, and 24hr post administration of 50-100mg doxorubicin..	24 hours

Collaborators and Investigators

• Sponsor: Yale University
• Investigators: Principal Investigator: Jeff Geschwind, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): August 11, 2015
• Study Completion (Actual): November 18, 2016

Study Registration Dates

• First Submitted: November 21, 2013
• First Submitted That Met QC Criteria: December 5, 2013
• First Posted (Estimate): December 11, 2013

Study Record Updates

• Last Update Posted (Actual): August 11, 2017
• Last Update Submitted That Met QC Criteria: July 12, 2017
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: HCC
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: J1306; NA_00077927 (Other Identifier: JHMIRB)