A Phase Ib Study of Sorafenib (BAY 43-9006) in Patients with Kaposi Sarcoma.
Oral targeted agents are desirable for treatment of Kaposi sarcoma (KS); however, in patients with HIV, drug-drug interactions must be considered. In this study to treat KS, sorafenib was poorly tolerated at doses less than those approved by the U.S. Food and Drug Administration for hepatocellular carcinoma and other cancers, and showed only modest activity.Sorafenib's metabolism occurs via the CYP3A4 pathway, which is inhibited by ritonavir, a commonly used antiretroviral agent used by most patients in this study. Strong CYP3A4 inhibition by ritonavir may contribute to the observed sorafenib toxicity.Alternate antiretroviral agents without predicted interactions are preferred for co-administration in patients with HIV and cancers for which sorafenib is indicated.



We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity.



Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed.



Ten patients (nine HIV+) were enrolled: R1 (eight), NR1 (two). Median CD4+count (HIV+) was 500 cells/µL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUCTAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCTAUof the CYP3A4 metabolite sorafenib-N-oxide (3.8-fold decrease;p= .08) suggests other metabolites may be increased.



Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib.The Oncologist2017;22:505-e49.
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA uldrickts@mail.nih.gov.
Thomas S
TS
Uldrick
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
Priscila H
PH
Gonçalves
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
Kathleen M
KM
Wyvill
Clinical Pharmacology Program, National Cancer Institute, Bethesda, Maryland, USA.
Cody J
CJ
Peer
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
Wendy
W
Bernstein
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
Karen
K
Aleman
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
Mark N
MN
Polizzotto
Biostatistics and Data Management Section at the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
David
D
Venzon
Biostatistics and Data Management Section at the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Seth M
SM
Steinberg
Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Vickie
V
Marshall
Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Denise
D
Whitby
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
Richard F
RF
Little
Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA.
John J
JJ
Wright
Analytical Pharmacology Core, Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Michelle A
MA
Rudek
Clinical Pharmacology Program, National Cancer Institute, Bethesda, Maryland, USA.
William D
WD
Figg
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
Robert
R
Yarchoan
D000293:Adolescent; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics; D019438:Ritonavir / Q000008:administration & dosage* / Q000009:adverse effects; D012514:Sarcoma, Kaposi / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077157:Sorafenib; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000235:genetics
D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D040281:Vascular Endothelial Growth Factor Receptor-1; D019438:Ritonavir