SOLID TUMORNCT02441543
Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus
An observational study of SOLID TUMOR, run by Istituto Clinico Humanitas at 1 site in Italy.
Trial summary
Preclinical studies and clinical observations have shown the Phosphoinositide 3-kinase (PI3K) /Protein kinase B (AKT) /mammalian (mechanistic) target of Rapamycin (known as the 'mTOR-pathway') signaling to be deregulated in several tumors. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- SOLID TUMOR
- How many people
- 45 participants
- Where
- 1 siteItaly
- Study dates
- Apr 2015to May 2018
- Phase
- Observational
- 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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Metastatic tumor patients treated with Everolimus
Who may be able to join
- Metastatic tumor cancer
- Treated with Everolimus
Who cannot join
- Non metastatic tumor
- Non previously treated with Everolimus
Trial locations and contacts
1 site in 1 country.
About this study
Preclinical studies and clinical observations have shown the Phosphoinositide 3-kinase (PI3K) /Protein kinase B (AKT) /mammalian (mechanistic) target of Rapamycin (known as the 'mTOR-pathway') signaling to be deregulated in several tumors.
Read the detailed description
Cancer is the second most-common cause of death in industrialized countries. Preclinical studies and clinical observations have shown the PI3K/AKT/mammalian (mechanistic) target of Rapamycin (known as the 'mTOR-pathway') signaling to be deregulated in several tumors.
The mTOR is evolutionary conserved Serine/Threonine protein kinase that senses and integrates signals from different environmental cues. It is a central regulator of cell growth, cell cycle progression, proliferation and metabolism. It has been found to form two distinct, multiprotein complexes based on the binding with different partners. In a complex with Regulatory-Associated Protein of mTOR (Raptor) mTOR forms mTORC1, whereas when bound to Rapamycin-Insensitive Companion of mTOR (Rictor) than the mTOR Complex 2 (mTORC2) is formed. Not only the structure of both mTOR complexes is different, but also they are characterized by distinct biological functions mediated by individual downstream targets. The mTORC1 promotes cap-dependent translation and elongation, increases Messenger RNA (mRNA) biogenesis as well as promotes ribosome biogenesis - via regulation of p70 ribosomal S6 kinase 1 (p70S6K) as well as the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4EBP-1). In addition mTORC1 promotes lipid synthesis via sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor-γ (PPARγ). The role of the mTORC2 is less defined. The best characterized, mTORC2 target is AKT, which regulates cell survival, metabolism and proliferation as well as differentiation in many primary and cancer cell types. Another direct targets of mTORC2 are the serum- and glucocorticoid-regulated kinase (SGK) controls cell survival and anabolism and protein kinase Cα (PKCα) involved in the control of cytoskeletal organization. Thus constitutive, oncogenic activation of mTOR signaling promotes protein and lipid synthesis needed for the increase in cell mass and it enhances surface transporters expression sustaining better uptake of glucose, amino acids and other nutrients sustaining cell growth and proliferation of transformed cells.
Since mTOR signalling pathway is critical for tumorigenesis, its inhibitors have been strongly wanted. As first approved by FDA in clinical setting was Rapamycin for its activity against transplant organ rejection and as a prophylactic agent in Graft-versus-Host disease after allogenic bone marrow transplantation. The immunosuppressive effects of Rapamycin were initially attributed to its ability to block the Interleukin 2 (IL-2) induced proliferation. However, later this was found not to be the case, and rather work through immunomodulation, in part due to the induction and expansion of T cells with regulatory phenotype. Moreover, in T cells mTORC1 modulates T helper cell differentiation towards Th1 and Th17 fate, while mTORC2 controls Th2 development. Also, Rapamycin is involved in immunostimulation of long-lived memory cluster of differentiation 8+ (CD8+) T cells. In addition to the Rapamycin effect on T cells, the drug exerts an inhibitory effect on the proliferation and function of other immune cells such as dendritic cells, B lymphocytes, Natural Killer cells (NK), neutrophiles and mast cells. Lastly, Rapamycin has been tested as a chemotherapy agent against cancer and it was shown to delay the growth and proliferation and to promote apoptosis of many cancer cell lines, and also to possess anti-angiogenic properties. During the past years different rapalogs have been synthesized among which is Everolimus (RAD001, Afinitor®) that is currently tested in clinical trials phase IV in patients with renal cell carcinoma (RCC) or advance large cell lung cancer with neuroendocrine differentiation as well as in the phase III of metastatic breast cancer. In addition, it is already approved in different tumors when the first-line treatment was ineffective. Even Everolimus seems to be very promising neoplastic agent, there is no clinical data about its effect on the immune competence of the patients. And it still remains unknown whether Everolimus exerts similar to Rapamycin effect on the modulation of the immune system when administrated into cancer patients.
- Conditions
- SOLID TUMOR
What is being measured
The primary outcome is the main question the study is designed to answer.
Sensitivity of mTORC1 and mTORC2
Evaluate the sensitivity of mTORC1 and mTORC2 to Everolimus in T and NK cells.Everolimus inhibits kinase activity of mTOR when bound to Raptor (mTORC1). Whether mTORC2 is sensitive to Everolimus will be elucidated.
Measured: 3 years
Secondary outcomes (2)
Determine the phenotype of T cells.
Determine the phenotype of T cells in patients with the use of mass cytometry and polychromatic flow cytometry. Everolimus alters the phenotype and dynamics of circulating T and NK cells.
Measured: 3 years
Evaluate the ability of T-cells
Evaluate the ability of T-cells from patients to differentiate into effector cells (anti-tumor and anti- viral in vitro responses. Everolimus potentiates anti-tumor and anti-viral immune responses and that will affect the differentiation of naive T cell precursors into memory cells
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 May 2015 (estimated)
- Study startApr 2015
- Primary completionApr 2018
- Study completionMay 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for SOLID TUMORStudies of the same condition, open and under way.
- More trials run by Istituto Clinico HumanitasThe 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 45 participants (actual)
Sponsor and investigators
- Lead sponsor
- Istituto Clinico Humanitas
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Enrico Lugli, Principal investigator, Istituto Clinico Humanitas
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02441543
- Sponsor's protocol ID
- ONC/OSS-01/2015
- Status last verified
- Sep 2022
- First submitted
- 28 Apr 2015
- Last updated
- 10 Sep 2022
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Publications
Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35. doi: 10.1038/nrm3025. Epub 2010 Dec 15.
PubMed 21157483Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005 Jun 15;105(12):4743-8. doi: 10.1182/blood-2004-10-3932. Epub 2005 Mar 3.
PubMed 15746082Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39-68. doi: 10.1146/annurev-immunol-020711-075024. Epub 2011 Nov 29.
PubMed 22136167Hasskarl J. Everolimus. Recent Results Cancer Res. 2014;201:373-92. doi: 10.1007/978-3-642-54490-3_23.
PubMed 24756805Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood. 2007 Apr 15;109(8):3509-12. doi: 10.1182/blood-2006-06-030833. Epub 2006 Dec 19.
PubMed 17179228Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaeth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012 Aug 1;30(22):2718-24. doi: 10.1200/JCO.2011.39.0708. Epub 2012 May 7.
PubMed 22565002Bendall SC, Simonds EF, Qiu P, Amir el-AD, Krutzik PO, Finck R, Bruggner RV, Melamed R, Trejo A, Ornatsky OI, Balderas RS, Plevritis SK, Sachs K, Pe'er D, Tanner SD, Nolan GP. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science. 2011 May 6;332(6030):687-96. doi: 10.1126/science.1198704.
PubMed 21551058Lugli E, Gattinoni L, Roberto A, Mavilio D, Price DA, Restifo NP, Roederer M. Identification, isolation and in vitro expansion of human and nonhuman primate T stem cell memory cells. Nat Protoc. 2013 Jan;8(1):33-42. doi: 10.1038/nprot.2012.143. Epub 2012 Dec 6.
PubMed 23222456Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. doi: 10.1002/cncr.25219.
PubMed 20549832Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E, Bondanza A, Bordignon C, Peccatori J, Ciceri F, Lupo-Stanghellini MT, Mavilio F, Mondino A, Bicciato S, Recchia A, Bonini C. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood. 2013 Jan 24;121(4):573-84. doi: 10.1182/blood-2012-05-431718. Epub 2012 Nov 15.
PubMed 23160470
Study at a glance
From the registry record, last updated by the sponsor on 10 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus
- ClinicalTrials.gov ID
- NCT02441543
- Acronym / sponsor ID
- ONC/OSS-01/2015
- Conditions
- SOLID TUMOR
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 45 participants (actual)
- Lead sponsor
- Istituto Clinico HumanitasUniversity, hospital or other
- Study start
- Apr 2015
- Primary completion
- Apr 2018 (actual)
- Study completion
- May 2018 (actual)
- First posted
- 12 May 2015 (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.
Preclinical studies and clinical observations have shown the Phosphoinositide 3-kinase (PI3K) /Protein kinase B (AKT) /mammalian (mechanistic) target of Rapamycin (known as the 'mTOR-pathway') signaling to be deregulated in several tumors.
Detailed description
Cancer is the second most-common cause of death in industrialized countries. Preclinical studies and clinical observations have shown the PI3K/AKT/mammalian (mechanistic) target of Rapamycin (known as the 'mTOR-pathway') signaling to be deregulated in several tumors.
The mTOR is evolutionary conserved Serine/Threonine protein kinase that senses and integrates signals from different environmental cues. It is a central regulator of cell growth, cell cycle progression, proliferation and metabolism. It has been found to form two distinct, multiprotein complexes based on the binding with different partners. In a complex with Regulatory-Associated Protein of mTOR (Raptor) mTOR forms mTORC1, whereas when bound to Rapamycin-Insensitive Companion of mTOR (Rictor) than the mTOR Complex 2 (mTORC2) is formed. Not only the structure of both mTOR complexes is different, but also they are characterized by distinct biological functions mediated by individual downstream targets. The mTORC1 promotes cap-dependent translation and elongation, increases Messenger RNA (mRNA) biogenesis as well as promotes ribosome biogenesis - via regulation of p70 ribosomal S6 kinase 1 (p70S6K) as well as the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4EBP-1). In addition mTORC1 promotes lipid synthesis via sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor-γ (PPARγ). The role of the mTORC2 is less defined. The best characterized, mTORC2 target is AKT, which regulates cell survival, metabolism and proliferation as well as differentiation in many primary and cancer cell types. Another direct targets of mTORC2 are the serum- and glucocorticoid-regulated kinase (SGK) controls cell survival and anabolism and protein kinase Cα (PKCα) involved in the control of cytoskeletal organization. Thus constitutive, oncogenic activation of mTOR signaling promotes protein and lipid synthesis needed for the increase in cell mass and it enhances surface transporters expression sustaining better uptake of glucose, amino acids and other nutrients sustaining cell growth and proliferation of transformed cells.
Since mTOR signalling pathway is critical for tumorigenesis, its inhibitors have been strongly wanted. As first approved by FDA in clinical setting was Rapamycin for its activity against transplant organ rejection and as a prophylactic agent in Graft-versus-Host disease after allogenic bone marrow transplantation. The immunosuppressive effects of Rapamycin were initially attributed to its ability to block the Interleukin 2 (IL-2) induced proliferation. However, later this was found not to be the case, and rather work through immunomodulation, in part due to the induction and expansion of T cells with regulatory phenotype. Moreover, in T cells mTORC1 modulates T helper cell differentiation towards Th1 and Th17 fate, while mTORC2 controls Th2 development. Also, Rapamycin is involved in immunostimulation of long-lived memory cluster of differentiation 8+ (CD8+) T cells. In addition to the Rapamycin effect on T cells, the drug exerts an inhibitory effect on the proliferation and function of other immune cells such as dendritic cells, B lymphocytes, Natural Killer cells (NK), neutrophiles and mast cells. Lastly, Rapamycin has been tested as a chemotherapy agent against cancer and it was shown to delay the growth and proliferation and to promote apoptosis of many cancer cell lines, and also to possess anti-angiogenic properties. During the past years different rapalogs have been synthesized among which is Everolimus (RAD001, Afinitor®) that is currently tested in clinical trials phase IV in patients with renal cell carcinoma (RCC) or advance large cell lung cancer with neuroendocrine differentiation as well as in the phase III of metastatic breast cancer. In addition, it is already approved in different tumors when the first-line treatment was ineffective. Even Everolimus seems to be very promising neoplastic agent, there is no clinical data about its effect on the immune competence of the patients. And it still remains unknown whether Everolimus exerts similar to Rapamycin effect on the modulation of the immune system when administrated into cancer patients.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Metastatic tumor patients treated with Everolimus
Key inclusion criteria (2 listed)
- Metastatic tumor cancer
- Treated with Everolimus
Key exclusion criteria (2 listed)
- Non metastatic tumor
- Non previously treated with Everolimus
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Sensitivity of mTORC1 and mTORC2
Time frame: 3 years
Evaluate the sensitivity of mTORC1 and mTORC2 to Everolimus in T and NK cells.Everolimus inhibits kinase activity of mTOR when bound to Raptor (mTORC1). Whether mTORC2 is sensitive to Everolimus will be elucidated.
2 secondary outcomes
Determine the phenotype of T cells.
Time frame: 3 years
Evaluate the ability of T-cells
Time frame: 3 years
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 10 Sep 2022.
- Background: PubMed 21157483Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35. doi: 10.1038/nrm3025. Epub 2010 Dec 15.
- Background: PubMed 15746082Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005 Jun 15;105(12):4743-8. doi: 10.1182/blood-2004-10-3932. Epub 2005 Mar 3.
- Background: PubMed 22136167Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39-68. doi: 10.1146/annurev-immunol-020711-075024. Epub 2011 Nov 29.
- Background: PubMed 24756805Hasskarl J. Everolimus. Recent Results Cancer Res. 2014;201:373-92. doi: 10.1007/978-3-642-54490-3_23.
- Background: PubMed 17179228Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, Giles FJ, Sabatini DM, Andreeff M, Konopleva M. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood. 2007 Apr 15;109(8):3509-12. doi: 10.1182/blood-2006-06-030833. Epub 2006 Dec 19.
- Background: PubMed 22565002Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaeth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012 Aug 1;30(22):2718-24. doi: 10.1200/JCO.2011.39.0708. Epub 2012 May 7.
- Background: PubMed 21551058Bendall SC, Simonds EF, Qiu P, Amir el-AD, Krutzik PO, Finck R, Bruggner RV, Melamed R, Trejo A, Ornatsky OI, Balderas RS, Plevritis SK, Sachs K, Pe'er D, Tanner SD, Nolan GP. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science. 2011 May 6;332(6030):687-96. doi: 10.1126/science.1198704.
- Background: PubMed 23222456Lugli E, Gattinoni L, Roberto A, Mavilio D, Price DA, Restifo NP, Roederer M. Identification, isolation and in vitro expansion of human and nonhuman primate T stem cell memory cells. Nat Protoc. 2013 Jan;8(1):33-42. doi: 10.1038/nprot.2012.143. Epub 2012 Dec 6.
- Background: PubMed 20549832Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A; RECORD-1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010 Sep 15;116(18):4256-65. doi: 10.1002/cncr.25219.
- Background: PubMed 23160470Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E, Bondanza A, Bordignon C, Peccatori J, Ciceri F, Lupo-Stanghellini MT, Mavilio F, Mondino A, Bicciato S, Recchia A, Bonini C. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood. 2013 Jan 24;121(4):573-84. doi: 10.1182/blood-2012-05-431718. Epub 2012 Nov 15.
- Individual participant dataSharing planned: Undecided
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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.
Enrico Lugli principal investigator
Istituto Clinico Humanitas
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of SOLID TUMOR, run by Istituto Clinico Humanitas at 1 site in Italy.
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 2 inclusion and 2 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 10 Sep 2022. 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 Italy. 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.
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?
Sensitivity of mTORC1 and mTORC2 (time frame: 3 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02441543, which also lists 10 linked publications.
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 10 Sep 2022.