Phase 1 study combining alisertib with nab-paclitaxel in patients with advanced solid malignancies

Area of Science:

• Oncology
• Pharmacology
• Clinical Trials

Background:

• Aurora kinase A (AURKA) is crucial for mitotic progression.
• Paclitaxel disrupts mitotic spindle assembly by stabilizing microtubules.
• Combining an AURKA inhibitor (alisertib) with paclitaxel may offer synergistic effects in proliferative cancers.

Purpose of the Study:

• To evaluate the safety and maximum tolerated dose (MTD) of alisertib combined with nab-paclitaxel.
• To assess the preliminary efficacy of this combination in patients with refractory high-grade neuroendocrine tumors (NETs).

Main Methods:

• A two-part, Phase 1 clinical trial (NCT01677559) was conducted.
• Part A involved dose escalation using a 3+3 design to determine the MTD.
• Part B included dose expansion in patients with predominantly refractory high-grade NETs.

Main Results:

• The MTD was determined as alisertib 40 mg BID on D1-3 weekly and nab-paclitaxel 100 mg/m² weekly (3 weeks on, 1 week off).
• Neutropenia was the dose-limiting toxicity; fatigue, mucositis, and diarrhea were common side effects.
• Preliminary efficacy included partial responses and stable disease for extended periods in patients with high-grade NETs.

Conclusions:

• The combination of alisertib and nab-paclitaxel demonstrates a manageable side-effect profile.
• The regimen shows promising preliminary efficacy in high-grade neuroendocrine tumors.
• Further clinical evaluation of this combination is warranted.