The Very Busy Field of Clinical Trials for Hepatobiliary Cancers


The portfolio of hepatobiliary cancer clinical trials at Memorial Sloan Kettering is dynamic and includes first-line and beyond first-line therapies, combined modality therapies, as well as an organ dysfunction program. (1) Collaborating investigators are drawn from across disciplines.

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a complex and challenging malignancy. Historically, for patients with advanced HCC, the median overall survival was about 6.5 months.  During the modern era of rapid technological development, advances in systemic therapy for HCC remained slow, while advances in surgery, transplant, and loco-regional therapies were much more rapid and began to offer curative potential for patients diagnosed at early stages.

Nonetheless, today, approximately 50 percent of the patients who undergo resection as well as a much higher percentage of the patients who receive local ablative therapy will ultimately need systemic therapy.

Over the last decade, encouraging results of systemic therapy in patients with advanced HCC have been reported. Sorafenib, a synthetic compound targeting growth signaling (via blocking RAF kinase) and angiogenesis (via inhibition of VEGFR-2/PDGFR-beta signaling), has been shown in two randomized clinical trials to lead to increased survival times in patients with advanced HCC.

Specifically, the SHARP trial, a phase III, double-blind study of sorafenib in patients with advanced HCC and Child-Pugh A cirrhosis and without prior therapy, demonstrated a significant improvement in median overall survival: 10.7 months in the sorafenib group versus 7.9 months in the placebo group (HR 0.69, p < 0.001). (2)  As a result, sorafenib has become the standard of care therapy for patients with advanced HCC.

With the US Food and Drug Administration approval in 2007 of sorafenib for unresectable HCC, the mythology that advanced HCC is untreatable began to dissipate and research efforts into systemic therapy were renewed.  The focus of these efforts was on identifying a more potent anti-angiogenic approach as the increased survival seen with sorafenib was attributed to its anti-angiogenic activity, although the mechanism was not well understood.

Three phase III randomized studies have compared sorafenib to three different anti-angiogenics (sunitinib, brivanib, and linifanib) that were thought to be more precise or more potent, and none of these trials demonstrated an improvement beyond that offered by sorafenib.3  Based on such results, the approximately 10-month median overall survival shown for sorafenib might be viewed as a ceiling for single-agent anti-angiogenic therapy.

Commensurate efforts have focused on combining different biologic therapies.  Predicated on a proposed synergy between anti-angiogenics and tyrosine kinase inhibitors, a phase II study evaluating the combination of bevacizumab (monoclonal antibody that binds circulating VEGF-A ligand) plus erlotinib (tyrosine kinase inhibitor that inhibits phosphorylation of the intracellular domain of EGFR) showed promising results: a median overall survival of 13.7 months. (4)

A randomized phase II study evaluating bevacizumab plus erlotinib versus sorafenib alone (NCT00881751(5) is under way. The presumed similar combination of sorafenib plus erlotinib was studied in a randomized phase III trial with disappointing results: the combined therapy did not show superiority to sorafenib single-agent therapy. (6)

Based on hypotheses that support a synergy between sorafenib and the anthracycline antibiotic doxorubicin, an exploratory comparison analysis was made as part of a randomized phase II study evaluating doxorubicin plus sorafenib versus single-agent doxorubicin. The analysis showed an increase in median overall survival: 13.7 months in the doxorubicin plus sorafenib group versus 6.5 months in the doxorubicin group.(7) 

To further evaluate the proposed synergy, a phase III study is currently under way evaluating the combination of doxorubicin plus sorafenib versus sorafenib alone (NCT01015833(8) (MSK IRB#11-039). This trial is the first phase III HCC study that is sponsored by the National Cancer Institute. It is endorsed by all cooperative groups and is led by the Alliance for Clinical Trials in Oncology and Memorial Sloan Kettering Cancer Center.

The recognition that HGF (hepatocyte growth factor) and c-met (a proto-oncogene) are important targets, and the development of c-met inhibitors (e.g., cabozantinib and tivantinib), together provide another means to bypass the alleged anti-angiogenic ceiling. Early data suggest that an enriched c-met population may have greater benefit from these agents.(9),(10)

These data also suggest that a better understanding of molecular differences in the heterogeneous biology of hepatocellular carcinoma may be needed to improve outcomes of systemic therapy in HCC.  Two new studies evaluating c-met inhibitors in advanced HCC patients are opening at Memorial Sloan Kettering: a phase III study evaluating cabozantinib versus placebo in the second-line (prior treatment with sorafenib) setting (NCT01908426(11) (MSK IRB #13-151) (12), and  a phase 1b study evaluating the monoclonal antibody onartuzumab as a single agent versus combined with sorafenib (NCT01897038(13) (MSK IRB #13-155).

Research into combining systemic therapy with local therapies continues to evolve. The STORM study (NCT00692770(14), a phase III, randomized, international study evaluating sorafenib as an adjuvant therapy for HCC after surgical resection or local ablation is now closed to accrual, but the results have not yet been reported. Although combining systemic sorafenib with transarterial chemoembolization (doxorubicin-eluting beads) was shown to be safe, it was not shown to be effective and thus is not recommended. (15)

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Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar hepatocellular carcinoma (FLL-HCC) is a very rare form of primary liver cancer that affects mainly young adults and remains poorly understood. (16) Memorial Sloan Kettering has joined efforts with Dana-Farber Cancer Institute, Brigham and Women’s Cancer Center, Massachusetts General Hospital Cancer Center, Johns Hopkins University, and the University of California San Francisco to establish the Fibrolamellar Hepatocellular Carcinoma Consortium.  This collaborative initiative was developed to improve FLL-HCC treatment options.

To date, there is no effective standard treatment for patients with unresectable FLL-HCC. Based on preclinical and other data, the consortium has launched a multi-institutional, phase II study evaluating everolimus (an mTOR inhibitor) and leuprolide plus letrozole (two estrogen deprivation therapies). Patients with unresectable disease are assigned randomly to three experimental arms: A) everolimus, B) leuprolide + letrozole, and C) everolimus +leuprolide + letrozole.  In either arm A or B, if the cancer continues to progress, patients may have the option to receive all three drugs together (NCT01642186)17 (MSK IRB #11-211) (18).

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Biliary Tumors

In previous years, there was a debate regarding a standard of care systemic therapy for advanced biliary cancers. Recently, results of a randomized study demonstrated significantly improved median overall survival in patients treated with cisplatin plus gemcitabine (11.7 months) versus single-agent gemcitabine (8.1 months) (HR 0.64, p<0.001). (19)

Today, the combination of gemcitabine plus cisplatin is the standard systemic therapy for advanced biliary cancer. However, there is still a need to improve outcomes in patients with biliary tumors. To determine whether the addition of MEK162 (inhibitor of MEK1/2 protein kinases) to standard therapy is beneficial, we have a recently opened a phase I/II study of combined gemcitabine, cisplatin, and MEK162 therapy for advanced bile duct and gallbladder carcinomas (NCT01828034(20) (MSK IRB #13-004) (21).

Finally, one more important component of our research program is the use of hepatic arterial infusion (HAI) therapy. In an initial study evaluating HAI-floxuridine therapy, a 53.8 percent response rate was shown in the subgroup of intrahepatic cholangiocarcinoma patients, with encouraging overall survival. (22) A current study is looking at the addition of gemcitabine plus oxaliplatin therapy to HAI-floxuridine therapy (NCT01862315(23) (MSK IRB #13-066) (24) for patients with liver-confined cholangiocarcinoma.

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  1. Miller G, Socci ND, Dhall D, et al. Genome wide analysis and clinical correlation of chromosomal and transcriptional mutations in cancers of the biliary tract. J Exp Clin Cancer Res. 2009; 28:62.
  2. Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90.
  3. Abou-Alfa GK, Venook AP. The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached? Lancet Oncol. 2013 Jun;14(7):e283-8.
  4. Kaseb AO, Garrett-Mayer E, Morris JS, et al. Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial. Oncology. 2012;82(2):67-74.
  5. Bevacizumab and Erlotinib or Sorafenib as First-Line Therapy in Treating Patients With Advanced Liver Cancer
  6. Zhu AX, Rosmorduc O, Evans J, et al. SEARCH: A phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with hepatocellular carcinoma (HCC). Ann Oncol. 2012;23 (suppl 9): LBA2. 
  7. Abou-Alfa GK, Johnson P, Knox JJ, et al.  Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial.  JAMA. 2010 Nov 17;304(19):2154-60.
  8. Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic Liver Cancer
  9. Verslype C, Cohn AL, Kelley RK, et al. Activity of cabozantinib (XL184) in hepatocellular carcinoma:  results from a randomized phase II discontinuation study.  J Clin Oncol. 2012;30 (suppl); abstr 4007.
  10. Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013 Jan;14(1):55-63.
  11. Study of Cabozantinib (XL184) vs Placebo in Subjects With Hepatocellular Carcinoma Who Have Received Prior Sorafenib (CELESTIAL)
  12. A Phase III Study of Cabozantinib versus Placebo in Patients with Liver Cancer Who Received Previous Therapy with Sorafenib
  13. A Study of Onartuzumab as Single Agent and in Combination With Sorafenib in Patients With Advanced Hepatocellular Carcinoma
  14. Sorafenib as Adjuvant Treatment in the Prevention Of Recurrence of Hepatocellular Carcinoma (STORM)
  15. Lencioni R, Llovet JM, Han G, et al.  Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II, randomized, double-blind SPACE trial. J Clin Oncol. 2012; 30 (suppl 4); abstr LBA154.
  16. Ang CS, Kelley RK, Choti MA, et al. Clinicopathologic characteristics and survival outcomes of patients with fibrolamellar carcinoma: data from the fibrolamellar carcinoma consortium. Gastrointest Cancer Res. 2013 Jan;6(1):3-9.
  17. Study of (1) Everolimus, (2) Estrogen Deprivation Therapy (EDT) With Leuprolide + Letrozole and (3) Everolimus + EDT in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLL-HCC)
  18. A Phase II Study of Everolimus, Leuprolide/Letrozole, and Everolimus/Leuprolide/Letrozole in Patients with Inoperable Fibrolamellar Hepatocellular Carcinoma
  19. Valle J, Wasan H, Palmer DH, et al.  ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81.
  20. First Line Gemcitabine, Cisplatin and MEK162 in Advanced Biliary Tract Carcinoma
  21. A Phase I/II Study of Gemcitabine, Cisplatin, and MEK162 as Initial Treatment for Advanced Bile Duct or Gallbladder Cancer
  22. Jarnagin WR, Schwartz LH, Gultekin DH, et al. Regional chemotherapy for unresectable primary liver cancer: results of a phase II clinical trial and assessment of DCE-MRI as a biomarker of survival. Ann Oncol. 2009 Sep;20(9):1589-95.
  23. Hepatic Arterial Infusion (HAI) With Floxuridine (FUDR) and Dexamethasone (Dex) Combined With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma (ICC)
  24. A Phase II Study of Hepatic Arterial Infusion with Floxuridine and Dexamethasone plus Systemic Gemcitabine and Oxaliplatin in Patients with Inoperable Intrahepatic Cholangiocarcinoma