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Phase I Study of Nelfinavir in Combination With Temsirolimus in the Treatment of Patients With Advanced Cancers, Including Second Line Renal Cell Cancer

Phase 1
18 Years
Not Enrolling
Renal Cell Cancer, Cancer

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Trial Information

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.

Inclusion Criteria:

- Patients with histological or cytological confirmed malignancies

- ECOG / WHO performance status of 0-2

- Age 18 years

- Life expectancy of at least 3 months

- Minimal acceptable safety laboratory values defined as

- WBC 3.0 x 109 /L

- Platelet count 100 x 109 /L

- Hepatic function as defined by serum bilirubin 1.5 x ULN, ALT or AST 2.5 x ULN, in
case of liver metastases 5 x ULN

- Renal function as defined by creatinine < 150╬╝mol/L

- Able and willing to give written informed consent according to ICH/GCP, and
national/local regulations.

- Able to swallow and retain oral medication

- Able and willing to undergo blood sampling for pharmacokinetic and pharmacogenetic

- Absence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule;
those conditions should be discussed with the patient before registration in the

Exclusion Criteria:

- Patients with known alcoholism, drug addiction and/or psychotic disorders in the
history that are not suitable for adequate follow up

- Women who are pregnant or breast feeding

- Women of childbearing potential who refuse to use a reliable contraceptive method
throughout the study

- Serious concomitant systemic disorder that would compromise the safety of the
patient, at the discretion of the investigator

- Any other medical condition that would interfere with study procedures and/or
decrease safety of the protocol treatment

- Concomitant use of strong CYP3A4 inhibitors, CYP3A4 inducers or CYP substrates

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

PK Nelfinavir: D1, 11, 18, 25, 32 PK Temsirolimus: D4, 11, 18, 25,32

Outcome Time Frame:

During the first 5 weeks of treatment

Safety Issue:


Principal Investigator

Heinz-Josef Klumpen, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Academic Medical Center, Amsterdam


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

June 2009

Completion Date:

August 2011

Related Keywords:

  • Renal Cell Cancer
  • Cancer
  • mTOR inhibition
  • advanced malignancies
  • pharmacokinetics
  • Akt inhibition
  • Advanced malignancies, including metastatic renal cell cancer
  • Carcinoma, Renal Cell