Phase I Study of Nelfinavir in Combination With Temsirolimus in the Treatment of Patients With Advanced Cancers, Including Second Line Renal Cell Cancer
In the past decade, the characterization of human tumours at the molecular level has
considerably improved. This has led to the development of targeted therapeutics that inhibit
specific molecules and pathways involved in oncogenesis. One of the key pathways that is
dysregulated in cancer is the phosphatidylinositol 3'-kinase (PI3K)/Akt/mTOR pathway. This
pathway is important for cell growth and survival. In most cancer types this pathway is
over-activated leading to proliferation and survival of malignant cells. Inhibition of this
pathway is therefore of great therapeutic potential.
Both temsirolimus and nelfinavir are agents with PI3K /Akt/mTOR inhibiting activity. The
main active metabolite of temsirolimus is sirolimus that decreases mTOR activity. Inhibition
of mTOR activity results in G1 phase cell cycle arrest and subsequent inhibition of tumour
growth. Another effect is growth factor downregulation and inhibition of angiogenesis. In
addition, mTOR inhibition may exert its anti-tumour effect by inducing apoptosis.
Although inhibitors of mTOR demonstrated clinical activity in tumor types like, mantle cell
lymphoma, endometrial carcinoma, and neuro-endocrine tumors, most malignancies are resistant
by feedback PI3 kinase activation. Resent data suggest that this tumor escape mechanism can
be overcome by dual inhibition of mTOR and PI3 kinase.
Nelfinavir is a well known human immuno-deficiency protease inhibitor with PI3kinase
inhibiting activity, via inhibition of Akt, downstream the PI3kinase cascade. Nelfinavir is
able to inhibit Akt at concentrations that are achieved in HIV patients at standard
antiviral doses. Nelfinavir is therefore a feasable and generally well tolerated agent to be
used in combination with temsirolimus to overcome resistance of mTOR inhibition.
Simultaneous inhibition of mTOR/PI3kinase pathway by temsirolimus and nelfinavir is a
promising strategy to treat cancer.
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
PK Nelfinavir: D1, 11, 18, 25, 32 PK Temsirolimus: D4, 11, 18, 25,32
During the first 5 weeks of treatment
Heinz-Josef Klumpen, MD
Academic Medical Center, Amsterdam
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)