Phase 1 pharmacokinetic study of MK-0646 (dalotuzumab), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in combination with cetuximab and irinotecan in Japanese patients with advanced colorectal cancer.
OBJECTIVE
The safety, tolerability, and pharmacokinetic (PK) interactions of MK-0646 in combination with cetuximab and irinotecan were investigated in Japanese patients with advanced colorectal cancer.


METHODS
Twenty patients were treated in the following study arms in combination with cetuximab and irinotecan: A [MK-0646 (10 mg/kg) weekly starting on Day 22], B [MK-0646 (15 mg/kg) on Day 8, followed by 7.5 mg/kg every 2 weeks], or C [MK-0646 (10 mg/kg) on Day 1 and weekly starting on Day 22]. Dose limiting toxicities (DLTs) were evaluated during a prespecified 4-week period in arms A and B. Full PK sampling was performed to evaluate the PK interactions.


RESULTS
One of the 6 evaluable patients in arm A developed a DLT (grade 3 hyperglycemia); no DLTs occurred in the 6 patients in arm B. Common treatment-related adverse events included leukopenia, neutropenia, dermatitis acneiform, paronychia, nausea, stomatitis, diarrhea, and decreased appetite. The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC0-168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase. The co-administration of MK-0646 with cetuximab and irinotecan did not affect the PK of cetuximab and irinotecan, but reduced the C max (from 16.8 to 13.0 ng/mL) and the AUC0-24h (by 13 %) of SN-38, the active metabolite of irinotecan.


CONCLUSIONS
The triple combination of MK-0646, cetuximab, and irinotecan was well tolerated in Japanese patients with advanced colorectal cancer. These results indicate a minimal potential for PK interactions between MK-0646 and cetuximab and between MK-0646 and irinotecan/SN-38.
National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, Japan. tdoi@east.ncc.go.jp
Toshihiko
T
Doi
Kei
K
Muro
Takayuki
T
Yoshino
Nozomu
N
Fuse
Takashi
T
Ura
Daisuke
D
Takahari
Hwa-Ping
HP
Feng
Takashi
T
Shimamoto
Kazuo
K
Noguchi
Atsushi
A
Ohtsu
D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017526:Receptor, IGF Type 1 / Q000276:immunology*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C569480:dalotuzumab; D000077146:Irinotecan; D017526:Receptor, IGF Type 1; D000068818:Cetuximab; D002166:Camptothecin