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.

Abstract

PURPOSE:

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.

• Authors: Johanna C Bendell, Suzanne F Jones, Lowell Hart, David R Spigel, Cassie M Lane, Chris Earwood, Jeffrey R Infante, John Barton, Howard A Burris
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 1 Pg. 187-93 (Feb 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 25335932 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
• Imidazoles
• Protein Kinase Inhibitors
• Pyrazines
• Everolimus
• Receptor, IGF Type 1
• Sirolimus

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Colorectal Neoplasms (drug therapy)
• Everolimus
• Female
• Humans
• Imidazoles (administration & dosage, adverse effects)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Protein Kinase Inhibitors (administration & dosage, adverse effects)
• Pyrazines (administration & dosage, adverse effects)
• Receptor, IGF Type 1 (antagonists & inhibitors)
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives)