Ignite Creation Date:
2024-05-05 @ 10:17 PM
Last Modification Date:
2024-10-26 @ 10:17 AM
Study NCT ID:
NCT01079286
Status:
COMPLETED
Last Update Posted:
2013-07-15
First Post:
2010-02-25
Brief Title:
Study of Nelfinavir and Temsirolimus in Patients With Advanced Cancers
Sponsor:
Academisch Medisch Centrum - Universiteit van Amsterdam AMC-UvA
Organization:
Academisch Medisch Centrum - Universiteit van Amsterdam AMC-UvA
Study Overview
Official Title:
Phase I Study of Nelfinavir in Combination With Temsirolimus in the Treatment of Patients With Advanced Cancers Including Second Line Renal Cell Cancer
Status:
COMPLETED
Status Verified Date:
2013-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
I-NET
Brief Summary:
In the present study the investigators want to explore the safety pharmacokinetics and activity of the combination of temsirolimus and nelfinavir both agents with PI3K AktmTOR inhibiting activity in patients with advanced malignanciesTemsirolimus has proven anti tumoral activity by mTOR inhibition Nelfinavir is a potential inhibitor of Akt Combining both agents might prevent upregulation of the P13k pathway and increase the anti-cancer activity of temsirolimus The strong CYP3A4 inhibition of nelfinavir and the dependence of temsirolimus on CYP3 A4 metabolism makes a dose finding study essential The investigators will also look at the prospective value of biomarkers of activity and the outcome of the treatment
Detailed Description:
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 PI3KAktmTOR 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 AktmTOR 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 mTORPI3kinase pathway by temsirolimus and nelfinavir is a promising strategy to treat cancer
Both temsirolimus and nelfinavir are agents with PI3K AktmTOR 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 mTORPI3kinase pathway by temsirolimus and nelfinavir is a promising strategy to treat cancer
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None