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. An other 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 feasible
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.

- The primary objective is to determine the dose limiting toxicity and the
maximum tolerated dose and recommended dose of the combination of temsirolimus
weekly and nelfinavir orally BID to patients with advanced solid tumors.
- Secondary objective is to establish the effect of functional genetic
polymorphisms of drug metabolizing genes on the pharmacokinetics and
pharmacodynamics of temsirolimus and nelfinavir (pharmacogenetics).
- to establish the time to disease progression, toxicity profile
- To establish the relationship between pharmacokinetics, antitumor effect and
biomarker investigations of the treatment with temsirolimus and nelfinavir

This is a phase 1 non-randomized, single center trial.
The study is designed to define the maximum tolerated dose by dose escalation
of temsirolimus and nelfinavir. There will be dose escalation of temsirolimus
and nelfinavir.

Design (treatment schedule)
Day 1: patients will be treated with nelfinavir BID, orally. Blood samples will
be drawn for pharmacokinetics.
Day 4: patients will be treated with temsirolimus intravenously. Blood samples
will be drawn for pharmacokinetics.
Day 11: patients will be treated with combination of BID nelfinavir orally and
weekly temsirolimus intravenously.
Dose escalation will take place between cohorts in case the prior cohorts
tolerates the treatment well as defined in the protocol.

Treatment with BID nelfinavir orally
Treatment with weekly temsirolimus intravenously
Blood sampling

The burden for the patient may be the experience of side effects of the study
medication: nausea, vomiting, diarrhea, fatigue, anorexia, bone marrow
suppression, pneumonitis, dyslipidemia, skin reactions, increase in liver
enzymes. Patients will be checked regularly for development of these side
effects. Both temsirolimus and nelfinavir are known agents with an acceptable
toxicity profile.
Other burden for the patient will be the admission at the hospital for blood
samples and other investigations. To reduce the total time of admission the
investigations will be planned in a way that reduces the burden to a minimum.
Hospital admission will take place twice for the pharmacokinetic blood sampling
of a duration of 24 hours. In case the patient prefers to come to the hospital
twice within 24 hours then an overnight admission would not be necessary. Other
outpatient visits will take place following standard of care. Temsirolimus
treatment will take place on a weekly bases following standard procedures.
The benefit for the participant of this trial is the option to be treated for a
disease (advanced/metastatic malignancies) for which there is no standard
systemic anticancer treatment available.