GDC-0575 — a checkpoint kinase 1 inhibitor — may be administered safely alone or in combination with gemcitabine among patients with advanced or metastatic solid tumors who have failed or for whom standard therapies are unavailable, according to a study published in the Annals of Oncology.1

Checkpoint kinase 1 inhibitors may increase the effectiveness of chemotherapy by increasing cell death and mitotic catastrophe. Previous models showed that GDG-0575 may shrink tumors and delay tumor growth.

For this phase 1 dose-escalation study (ClinicalTrials.gov Identifier: NCT01564251), 21 patients received GDC-0575 15 to 90 mg alone once daily on 3 consecutive days a week for 3 weeks (group 1), and 81 patients received gemcitabine 1000 mg/m2 (group 2a) or 500 mg/m2 (group 2b) followed by GDC-0575 45 or 80 mg, respectively. Seventy percent of study patients were women and had a median age of 70 years.

Of the 81 patients who received gemcitabine plus GDC-0575, 4 patients had confirmed partial responses, 3 of which occurred in patients with TP53-positive tumors.

No pharmacokinetic drug-drug interactions were observed between gemcitabine and GDC-0575, and the maximum concentration of GDC-0575 occurred within 2 hours of administration. The half-life was approximately 23 hours.

The most frequently observed adverse events of any grade were neutropenia, anemia, nausea, fatigue, and thrombocytopenia.

The authors concluded that “strategies such as that pursued in this trial that combine lower dose intensity chemotherapy with greater [checkpoint inhibition] may be more successful in creating a broader therapeutic index by impacting additional [checkpoint kinase 1] functions and exploiting multiple cancer vulnerabilities, including exacerbation of replication stress.”

Reference

  1. Italiano A, Infante JR, Shapiro GI, et al. Phase I study of the checkpoint kinase inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors. Ann Oncol. 2018 February 23. doi: 10.1093/annonc/mdy076 [Epub ahead of print]