Randomized Phase II Trial of Chemoembolization and Sorafenib

NCT02908165 | Withdrawn Phase 2

• 1 other identifier: 1601017096
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The study will be a single-center, randomized Phase II study of conventional TACE in combination with sorafenib, given either continuously or sequentially, in patients with unresectable HCC. The primary variables will be tumor response (by MR Imaging) and plasma VEGF levels, prior to and after cTACE.

Conditions

Hepatocellular Carcinoma

Outcome Measures

Primary Outcomes (3)

• Tumor Response using Response Evaluation Criteria in Solid Tumors (RECIST)

  RECIST criteria for tumor response: * Complete response - complete disappearance of all target lesions * Partial response - at least 30% decrease in the sum of the longest diameter (LD) of the target lesions, taking as a reference the baseline sum LD. * Stable disease - all other cases. * Progressive disease - at least a 20% increase in the sum of the LD of the target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

  54 weeks

• Tumor Response using mREcist if applicable

  mRECIST criteria for tumor response: * Complete response -disappearance of any intratumoral arterial enhancement in all target lesions. * Partial response - at least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions. * Stable disease - Any cases that do not qualify for either partial response or progressive disease. * Progressive disease - An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started.

  54 weeks

• EASL criteria for tumor response

  * Complete response - Complete disappearance of all viable tumoral area and no new lesions. No new lesions may evolve during a 4 week period after initial documentation of response. * Partial response - Greater than 50% reduction in viable tumoral area of all measurable lesions via uptake of contrast. * Stable disease - All other cases. * Progressive disease - Greater than or equal to 25% increase in tumoral area of one or more measurable lesions or the appearance of new lesions.

  54 weeks

Secondary Outcomes (2)

• Laboratory Evaluations: Vascular endothelial growth factor (VEGF) Correlations

  baseline and 54 Weeks

• Overall survival (OS)

  54 weeks

Study Arms (2)

Group A- continuous schedule

EXPERIMENTAL

Subjects with HCC randomized to group A

Drug: conventional TACE in combination with sorafenib, administered on a continuous schedule

Group B- sequential schedule

ACTIVE COMPARATOR

Subjects with HCC randomized to group B

Drug: conventional TACE in combination with sorafenib, administered on a sequential schedule

Interventions

conventional TACE in combination with sorafenib, administered on a continuous schedule DRUG

Patients assigned to Group A will begin sorafenib on a continuous schedule starting at 400mg BID from Cycle 1 Day 1, one week prior to cTACE treatment on Cycle 1 Day 8. After week 6, cTACE will be provided on demand (as needed, up to 4 treatments total in the first 4 cycles) at week 2 in subsequent cycles, and sorafenib will continue to be administered. Patients will be allowed to undergo dose adjustments of sorafenib as long as it remains above the ¼ dose (400mg QOD).

Group A- continuous schedule

conventional TACE in combination with sorafenib, administered on a sequential schedule DRUG

Patients assigned to Group B will undergo cTACE up to 4 treatments within the first 4 cycles as needed prior to starting sorafenib. After it is determined that no further TACE treatment is necessary (via imaging and clinical assessment on follow-up), administration of sorafenib will begin on Day 1 of the following cycle. Dosing will begin at 400mg BID and maintained continuously provided no unmanageable toxicities develop, with follow-up assessments performed on week 6 of every 1-2 cycles as needed. Patients in Group B will also be allowed to undergo dose adjustments of sorafenib as long as it remains above the ¼ dose (400mg QOD).

Group B- sequential schedule

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Unresectable hepatocellular carcinoma with liver-predominant disease, or patients with hepatocellular carcinoma who refuse surgery. No more than 30% of the cohort should have macrovascular invasion and/or asymptomatic extrahepatic disease. Multifocal HCC is acceptable, no diffuse HCC with greater than 70% tumor burden.
• Patient is at least 18 years of age.
• ECOG performance status of 0-1.
• Child-Pugh class of A or B (up to 7).
• Adequate end-organ function as manifested by:
• Absolute neutrophil count of ≥ 1500/mm3 and platelets ≥ 50,000/mm3
• Creatinine ≤ 2.0 mg/dL
• AST, ALT \< 8X ULN
• Total bilirubin of ≤ 3 mg/dL
• Albumin \> 2.0 g/dL
• INR \< 2.0
• Leukocyte count \> 3000 cells/mm3
• Patients who have been treated with previous hepatic surgery, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), or cryoablation are eligible if target lesion(s) have not been treated and local therapy is completed at least 6 weeks prior to entry.
• Patients with HBV are eligible if controlled with medication. Patients with HCV must have completed treatment with sustained viral response before being eligible for study.
• Patients with asymptomatic HIV infection are not eligible.

You may not qualify if:

• Patients unable to swallow oral medications.
• Prior embolization, systemic, or radiation therapy for HCC (liver), or patients who have taken sorafenib for greater than 2 weeks. Patients randomized to the sequential arm who started taking sorafenib within 2 weeks of the planned TACE procedure will have to stop sorafenib for 2 weeks before undergoing TACE. This will prevent a possible confounding effect of sorafenib on patients randomized to the sequential arm.
• Tumor burden in the liver exceeding 70%.
• Complete occlusion of the main portal venous system. Partial or branch portal vein occlusion allowed if without reversal of flow.
• Ascites refractory to diuretic therapy (minimal or trace ascites on imaging is acceptable).
• Previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, and T1). Any cancer curatively treated more than 3 years prior to entry is permitted.
• Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry.
• History of bleeding within the past 4 weeks (unless deemed by PI as clinically insignificant, as for example, a brief episode of epistaxis).
• Any contraindication to doxorubicin or mitomycin-C administration.
• Evidence of severe or uncontrolled systemic diseases.
• Congestive cardiac failure greater than NYHA class 2 (Appendix E), myocardial infarction within 6 months, active coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, unstable angina, or laboratory or clinical finding that in the view of the principal investigator makes it undesirable for the patient to participate in the study.
• Any prior history of hypertensive crisis or hypertensive encephalopathy.
• History of stroke or transient ischemic attack within 6 months prior to study enrollment.
• Inadequately controlled hypertension (defined as systolic blood pressure of \> 150/100 mmHg on antihypertensive medications). Patients with treated hypertension are eligible. Patients noted to be hypertensive in our clinic, but with documented normal blood pressure in the office of their referring physician, close follow-up with their referring providers, and a plan for coordination between the referring physician and our team for management of blood pressure while on therapy, are eligible.
• Significant vascular disease (e.g. aortic aneurysm, aortic dissection, peripheral vascular disease).

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Smilow Cancer Center

New Haven, Connecticut, 06510, United States

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Jeff Geschwind

  Professor of Radiology and Biomedical Imaging

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2016
• First Posted: September 20, 2016
• Study Start: June 1, 2016
• Primary Completion: June 1, 2020
• Study Completion: June 1, 2020
• Last Updated: January 10, 2018

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)