A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors.
OBJECTIVE
Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination.


METHODS
Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity.


RESULTS
Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months.


CONCLUSIONS
The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.
Duke University Medical Center, Seeley G. Mudd Bldg, 10 Bryan Searle Drive, Box 3052, Durham, NC 27710, USA.
Gordana
G
Vlahovic
Kellen L
KL
Meadows
Hope E
HE
Uronis
Michael A
MA
Morse
Gerard C
GC
Blobe
Richard F
RF
Riedel
S Yousuf
SY
Zafar
Angeles
A
Alvarez-Secord
Jon
J
Gockerman
Alexander N
AN
Starodub
Neal E
NE
Ready
Elizabeth L
EL
Anderson
Johanna C
JC
Bendell
Herbert I
HI
Hurwitz
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068338:Everolimus; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D006996:Hypocalcemia / Q000139:chemically induced; D007008:Hypokalemia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D000077544:Panitumumab; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016896:Treatment Outcome; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000077544:Panitumumab; D000068338:Everolimus; D020123:Sirolimus