Use of KW-2189, a DNA Minor Groove-Binding Agent, in Patients with Hepatocellular Carcinoma: A North Central Cancer Trea
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Use of KW-2189, a DNA Minor Groove-Binding Agent, in Patients with Hepatocellular Carcinoma: A North Central Cancer Treatment Group (NCCTG) Phase II Clinical Trial Steven R. Alberts & Vera J. Suman & Henry C. Pitot & John K. Camoriano & Joseph Rubin
Published online: 3 January 2008 # Humana Press Inc. 2007
Abstract Background Hepatocellular carcinoma (HCC) is a common cancer in certain portions of the world. Currently no effective therapies exist for patients with advanced or metastatic HCC. KW-2189, a DNA minor groove-binding agent, has shown promising activity against HCC in preclinical evaluations. Methods A phase II study was conducted to evaluate the activity of KW-2189 in patients with histologic or cytologic confirmed advanced or metastatic HCC who had no prior systemic therapy. Patients received KW-2189 at a dose of 0.5 mg/m2 administered on day 1 of a 6-week cycle. The primary endpoint of the trial was objective regression. Other endpoints included toxicity, disease-free survival, and overall survival. Results Due to hematologic toxicity the dose of KW-2189 was reduced to 0.375 mg/m2 after 11 patients had been enrolled into the trial. Due to continued significant hematologic toxicity in the next five patients enrolled at the lower dose the trial was closed to accrual. Two responses were seen in patients enrolled at the higher dose, including one sustained CR. Conclusion KW-2189 showed evidence of anti-tumor activity in HCC. However, because of significant and prolonged hematologic toxicity, when given as a single
S. R. Alberts (*) : V. J. Suman : H. C. Pitot : J. Rubin Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected] J. K. Camoriano Scottsdale CCOP, Scottsdale, AZ 85259-5404, USA
dose every 6 weeks, further development of this drug in HCC is not possible. Further exploration of DNA minor groove-binding agents in the treatment of HCC appears warranted. Keywords hepatocellular carcinoma . metastatic . chemotherapy . DNA minor-groove binding agent . clinical trial
Introduction The majority of patients presenting with hepatocellular carcinoma (HCC) will have advanced disease at the time of presentation with only 10–30% having potentially resectable disease. [1] Few effective options are available for the treatment of unresectable disease. Chemotherapy, in particular, has been of limited benefit for patients with unresectable or metastatic HCC. [2] As such there is a need for new agents with activity in HCC. The duocarmycins (DUMs) are a new group of antitumor antibiotics produced by Streptomyces. [3–6] The DUM’s antitumor activity occurs through a sequencespecific covalent binding to the minor groove of DNA, which in turn leads to DNA fragmentation. [7, 8] This DNA binding activity appears to be similar to that seen with other minor groove-binding agents including CC-1065 and its analogues. [9] While a variety of DUMs have been described, their use has been limited by their instability in aqueous solutions and in serum. KW-2189 is a semisynthetic
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