A Phase I Trial of Nelfinavir (Viracept) in Adults With Solid Tumors

Background:

• The PI3K/Akt/mTOR pathway is an important target in cancer because it promotes chemotherapeutic resistance and confers a poor prognosis for many types of cancers.
• Several inhibitors of the pathway are being developed as cancer therapeutics. However, the process of de novo drug development takes years, and is often curtailed due to diminished activity and/or unforeseen toxicities in clinical trials.
• One approach to expedite the development of new cancer therapies is to test drugs that are already approved for other indications.
• Our group has shown that nelfinavir, an orally available FDA-approved HIV-1 protease inhibitor used to treat HIV/AIDS, can inhibit endogenous Akt and growth factor receptor induced Akt activity in cancer cells.
• Importantly, nelfinavir demonstrates dose-dependent cytotoxicity in every cell line in the NCI 60 cell line panel at plasma concentrations attainable in human plasma, is profoundly effective in cancer cell lines that have been selected to become resistant to standard therapies, and inhibits tumor growth in-vivo.

Objectives:

• Because an MTD with nelfinavir has not been observed in prior phase I studies with HIV patients, the objectives of the Phase I design will be:
• To establish the MTD and dose limiting toxicity for this drug in patients with solid Tumors.
• To correlate nelfinavir pharmacokinetics with baseline activity of CYP3A4 as assessed by measuring midazolam clearance.
• To preliminarily explore the biological and clinical effects through a series of correlative studies involving analysis of blood and tissue across patients throughout the study.

Eligibility:

-Adults with solid tumors who are refractory to, or have relapsed after receiving, standard front-line chemotherapies are eligible.

Design:

• Patients will receive nelfinavir beginning at the FDA-approved dose for HIV patients (1250 mg po bid).
• Dose escalations will occur for 6 dose levels i.e. cohorts, or until the MTD is reached.
• Up to 45 patients are expected to be enrolled.
• Staging CT scans will be performed every two cycles.