Renal Cell CancerPhase 1I-NETNCT01079286
Study of Nelfinavir and Temsirolimus in Patients With Advanced Cancers
A Phase 1 study testing Nelfinavir and temsirolimus in people with Renal Cell Cancer and Cancer, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
Trial 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 /Akt/mTOR inhibiting activity, in patients with advanced malignancies.Temsirolimus has proven anti tumoral activity by mTOR inhibition. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Renal Cell Cancer, Cancer
- What is being tested?
- Nelfinavir and temsirolimus
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteNetherlands
- Study dates
- Jun 2009to Aug 2011
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 13Show fewer
- 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 < 150μmol/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 analysis
- 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 trial
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
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 /Akt/mTOR inhibiting activity, in patients with advanced malignancies.Temsirolimus 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.
Read the 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 (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.
- Conditions
- Renal Cell Cancer, Cancer
- Being tested
- Nelfinavir and temsirolimus
- Keywords
- mTOR inhibition, advanced malignancies, pharmacokinetics, Akt inhibition, Advanced malignancies, including metastatic renal cell cancer
- Medical subject headings
- Carcinoma, Renal Cell, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nelfinavir and temsirolimusDrug
Also called nelfinavir: viracept
Nelfinavir tablets of 250mg given twice daily in an escalating dosis schedule, Temsirolimus i.v. given weekly in an escalating dosis schedule
| Study group | Role | What they receive |
|---|---|---|
| nelfinavir and temsirolimus | Experimental | dose escalation Receives: Drug: Nelfinavir and temsirolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetics/pharmacodynamics
PK Nelfinavir: D1, 11, 18, 25, 32 PK Temsirolimus: D4, 11, 18, 25,32
Measured: During the first 5 weeks of treatment
Toxicity profile
Collection of clinical data according to CTC toxicity criteria
Measured: Day1 -Day90
Secondary outcomes (3)
Objective response to treatment
Progress-scans once every 9 weeks will be performed
Measured: Expected treatment duration: 2-12 months
Description and change of Biomarker analysis/Pharmacodynamics
Blood biomarker analysis will be performed of PBMCs and where possible of tumor biposies performed during treatment
Measured: Day 1, 18, 25
Pharmacogenetics
Full blood sample will be collected for pharmacogenetic analysis of important SNPs of drug disposition genes involved in the drug disposition of Nelfinivar and temsirolimus
Measured: day 1 of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Mar 2010 (estimated)
- Study startJun 2009
- Primary completionMay 2011
- Study completionAug 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Renal Cell CancerStudies of the same condition, open and under way.
- More trials run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Heinz-Josef Klumpen, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Investigators
- Heinz-Josef Klumpen, MD, Principal investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01079286
- Sponsor's protocol ID
- AMCmedonc09/039
- Acronym
- I-NET
- Status last verified
- Jul 2013
- First submitted
- 25 Feb 2010
- Last updated
- 15 Jul 2013
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 15 Jul 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01079286
- Acronym / sponsor ID
- I-NET / AMCmedonc09/039
- Conditions
- Renal Cell Cancer, Cancer
- Keywords
- mTOR inhibition, advanced malignancies, pharmacokinetics, Akt inhibition, Advanced malignancies, including metastatic renal cell cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Study start
- Jun 2009
- Primary completion
- May 2011 (actual)
- Study completion
- Aug 2011 (actual)
- First posted
- 3 Mar 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 /Akt/mTOR inhibiting activity, in patients with advanced malignancies.Temsirolimus 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 (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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| nelfinavir and temsirolimus | Experimental | Drug: Nelfinavir and temsirolimusdose escalation |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nelfinavir and temsirolimusAlso: nelfinavir: viraceptNelfinavir tablets of 250mg given twice daily in an escalating dosis schedule, Temsirolimus i.v. given weekly in an escalating dosis schedule | Drug | nelfinavir and temsirolimus |
Primary outcome
Pharmacokinetics/pharmacodynamics
Time frame: During the first 5 weeks of treatment
PK Nelfinavir: D1, 11, 18, 25, 32 PK Temsirolimus: D4, 11, 18, 25,32
Toxicity profile
Time frame: Day1 -Day90
Collection of clinical data according to CTC toxicity criteria
3 secondary outcomes
Objective response to treatment
Time frame: Expected treatment duration: 2-12 months
Description and change of Biomarker analysis/Pharmacodynamics
Time frame: Day 1, 18, 25
Pharmacogenetics
Time frame: day 1 of treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jul 2013.
Related trials for Renal Cell Cancer
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
Active, not recruitingPhase 3
A Study of Belzutifan (MK-6482) in Combination With Lenvatinib Versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011)
Carcinoma, Renal Cell
RecruitingPhase 2/3
Testing the Role of DNA Released From Tumor Cells Into the Blood in Guiding the Use of Immunotherapy After Surgical Removal of the Bladder, Kidney, Ureter, and Urethra for Urothelial Cancer Treatment, MODERN Study
Muscle Invasive Bladder Urothelial Carcinoma, Muscle Invasive Renal Pelvis Urothelial Carcinoma
Not yet recruitingPhase 2
Toripalimab and Lenvatinib With or Without SBRT Before Surgery for Non-Clear Cell Kidney Cancer
Nonmetastatic Locally Advanced Non-Clear Cell Renal Cell Carcinoma
Not yet recruitingPhase 1
A Study to Assess the Pharmacokinetics and Safety of Revumenib in Participants With Advanced Cancer and Hepatic or Renal Impairment
Relapsed/Refractory (R/R) Hematologic Malignancies, Acute Leukemia
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Heinz-Josef Klumpen, MD principal investigator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Nelfinavir and temsirolimus in people with Renal Cell Cancer and Cancer, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Jul 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacokinetics/pharmacodynamics (time frame: During the first 5 weeks of treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jul 2013.