A phase Ib study of linsitinib (OSI-906), a dual inhibitor of IGF-1R and IR tyrosine kinase, in combination with everolimus as treatment for patients with refractory metastatic colorectal cancer.

OBJECTIVE

To determine the maximum tolerated dose (MTD) of the combination of linsitinib (OSI-906), a dual inhibitor of IGFR and IR tyrosine kinase activity, and everolimus as treatment for patients with refractory metastatic colorectal cancer (mCRC).

METHODS

Eligible adult patients with refractory mCRC, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate end-organ function received escalating doses of OSI-906 and everolimus in a 3 + 3 design. Treatment continued until disease progression or unacceptable toxicity, with response evaluations every 8 weeks.

RESULTS

Eighteen patients with metastatic CRC were treated. There were no dose-limiting toxicities (DLTs) in the first dose level (DL, OSI-906 50 mg BID; everolimus 5 mg QD). At DL2 (OSI-906 100 mg BID; everolimus 10 mg QD, n =6), three patients had DLTs considered related to everolimus (grade 3 mucositis, 2; grade 3 thrombocytopenia, 1). An amendment introduced DL2a (OSI-906 100 mg BID; everolimus 5 mg QD, n =5); DLTs were seen in two patients (one patient each: grade 3 thrombocytopenia with bleeding; inability to receive 75 % of doses due to neutropenia/thrombocytopenia). DL1 was the MTD; a total of 7 patients were treated at this dose. Common adverse events across all DLs included grade 1/2 fatigue (50 %) and anorexia (50 %). There were no objective responses to treatment; median time of study treatment was 7.6 weeks (range: 3.9-53 weeks).

CONCLUSIONS

The MTD of OSI-906 and everolimus was 50 mg BID and 5 mg QD, respectively. No indications of clinical activity were observed in refractory mCRC patients.