Phase 1 Trials

The first-in-human phase 1 trial of voxtalisib enrolled 83 patients with advanced solid tumors who received the drug at doses ranging from 15 mg to 120 mg twice daily and 70 mg to 100 mg once daily.

Maximum-tolerated doses were 50 mg twice daily and 90 mg once daily. The best observed response was stable disease, which occurred in about half (48%) of patients. Twelve patients with stable disease were treated for 16 weeks or longer. The researchers observed a reduction in PI3K and mTORC1/mTORC2 pathway signaling in serial hair sheath cells, skin, and tumor samples.

The most common treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%).

An expansion cohort was created, which included 16 patients with relapsed/refractory lymphoma. Sixteen patients were given 50 mg voxtalisib twice daily.6 Among the 12 evaluable patients, there was 1 complete response and 2 partial responses. Among patients with mantle cell lymphoma who had a partial response, voxtalisib was associated with significant inhibition of PI3K/mTOR and extracellular signal-related kinase pathways.

Again, the most common treatment-related grade 3/4 adverse event was increased alanine aminotransferase (12.5%).

Another phase 1b trial combined voxtalisib with chemoimmunotherapy in patients with relapsed or refractory B-cell malignancies, including CLL.7 Patients were treated with voxtalisib 30 mg or 50 mg twice daily plus rituximab alone or rituximab plus bendamustine. The trial used a 3+3 dose-escalation design and found a recommended phase 2 dose of 50 mg twice daily.

Of 35 evaluable patients, 11.4% had a completed response and 37.1% had a partial response.

Four patients had 5 dose-limiting toxicities. The most common adverse events were nausea, fatigue, headache, and pyrexia. The most common grade 3 or worse events were neutropenia, thrombocytopenia, anemia, and febrile neutropenia.