Clinical trial NCT01618253: Radiation Therapy With Sorafenib for TACE-Resistant Hepatocellular Carcinoma
Official title: Phase I Study of Radiation Therapy With Concurrent Sorafenib for Hepatocellular Carcinoma Not Responding to Transarterial Chemoembolization
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Hepatocellular Carcinoma
Hepatocellular Cancer
Hepatoma
Liver Cancer
Keywords: Transarterial Chemoembolization
TACE
Sorafenib Tosylate
Sorafenib
Nexavar
External Beam Radiation Therapy
Radiation Therapy
Radiotherapy
Radiation
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
First posted: 2012-06-13
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: To determine the maximum tolerated radiation dose with concurrent sorafenib for unresectable hepatocellular carcinoma that has not responded to transarterial chemoembolization.

Detailed description: In patients with unresectable hepatocellular carcinoma (HCC), transarterial chemoembolization (TACE) is first line therapy. Non-responders to TACE (i.e. stable or progressive disease) represent a poor prognosis population with limited options. Sorafenib is indicated for first line salvage therapy, however it only improves survival 2-3 months and just has a 2-3% response rate. Thus, sorafenib is merely a cytostatic agent that delays progression and does not cytoreduce disease.

Radiation therapy (RT) is a non-invasive treatment that can cytoreduce HCC with minimal morbidity using modern techniques. A meta-analysis and multiple retrospective series suggest TACE + RT improve survival when compared to TACE alone. Higher RT doses are similarly associated with increased survival due to improved local control. Paradoxically, some series suggest that RT can induce vascular endothelial growth factor (VEGF) expression which may stimulate HCC.

Pre-clinical data suggest that combining RT with concurrent sorafenib (a VEGF inhibitor) improves tumor control. However, clinical data is limited to case reports and safety has not been well characterized. Prior to determining if this combination can improve control of HCC in this poor prognosis population, the optimal radiation dose with concurrent sorafenib must be determined by a phase I dose escalation trial.

Eligibility criteria: Inclusion Criteria:

* Radiographic or histologic diagnosis of hepatocellular carcinoma (HCC).
* Maximum of 3 HCC lesions within the liver.
* No evidence of lymphadenopathy or metastatic disease per either CT or PET.
* Prior transarterial chemo-embolization (TACE) at least 28 days prior to initiation of protocol therapy.
* Evidence of either progressive disease or stable disease following TACE.
* Child Pugh Class A (score 5-6) or B (score 7).
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 (or Karnofsky ≥70%).
* Normal organ and marrow function (platelets \>60,000/mc; hemoglobin ≥8.5 g/dL; international normalized ratio (INR) ≤2.3; albumin ≥2.8 g/dL; total bilirubin ≤3 mg/dL; aspartate aminotransferase (AST) / alanine aminotransferase (ALT) \<5x upper limit of normal; creatinine ≤1.5x upper limit of normal).
* Negative human immunodeficiency virus serology.
* Negative pregnancy test for women of child bearing age.
* Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

* Less than 800 cc of normal liver.
* Child Pugh Class B (score 8-9) or C (score 10-15).
* Acute/active hepatitis B infection.
* Prior systemic chemotherapy or abdominal radiation therapy.
* Portal venous (main, primary right, or primary left trunks) or inferior vena cava thrombosis.
* Prior malignancy within 5 years of enrollment except for non-melanoma skin cancer.
* Prior history of myocardial infarction, cerebrovascular accident, or esophageal variceal bleed in the last 6 months.
* Pre-existing heart failure with either a clinical classification of New York Heart Association Class III or IV or cardiac ejection fraction of \<45%.
* Systolic blood pressure \> 160 mmHg or diastolic pressure \> 100 mmHg despite optimal medical management.
* Pulmonary hemorrhage or other serious bleeding event (grade 2+) within 4 weeks initiation of protocol therapy.
* Prior history of scleroderma or active systemic lupus erythematosus.

Primary outcomes:
measure: Maximum Tolerated Dose
timeFrame: From date of enrollment until 3 months after completion of treatment.
Secondary outcomes:
measure: Radiographic Response
timeFrame: 1 & 3 months post-treatment.
measure: Patterns of Failure
timeFrame: From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.
measure: Progression Free Survival
timeFrame: From date of enrollment until the date of first documented progression, last known folow-up, or date of death from any cause, whichever came first, assessed up to 10 years.
measure: Overall Survival
timeFrame: From date of enrollment until the date of last known folow-up or date of death from any cause, whichever came first, assessed up to 10 years.
measure: Health Related Quality of Life
timeFrame: 1, 2, & 3 months post-treatment.
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Froedtert Memorial Lutheran Hospital
state: Wisconsin
Study officials:
affiliation: Medical College of Wisconsin
name: Beth A. Erickson-Wittmann, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chung YL, Jian JJ, Cheng SH, Tsai SY, Chuang VP, Soong T, Lin YM, Horng CF. Sublethal irradiation induces vascular endothelial growth factor and promotes growth of hepatoma cells: implications for radiotherapy of hepatocellular carcinoma. Clin Cancer Res. 2006 May 1;12(9):2706-15. doi: 10.1158/1078-0432.CCR-05-2721.
citation: Plastaras JP, Kim SH, Liu YY, Dicker DT, Dorsey JF, McDonough J, Cerniglia G, Rajendran RR, Gupta A, Rustgi AK, Diehl JA, Smith CD, Flaherty KT, El-Deiry WS. Cell cycle dependent and schedule-dependent antitumor effects of sorafenib combined with radiation. Cancer Res. 2007 Oct 1;67(19):9443-54. doi: 10.1158/0008-5472.CAN-07-1473.
citation: Ren ZG, Zhao JD, Gu K, Chen Z, Lin JH, Xu ZY, Hu WG, Zhou ZH, Liu LM, Jiang GL. Three-dimensional conformal radiation therapy and intensity-modulated radiation therapy combined with transcatheter arterial chemoembolization for locally advanced hepatocellular carcinoma: an irradiation dose escalation study. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):496-502. doi: 10.1016/j.ijrobp.2009.10.070. Epub 2010 Apr 24.