Ignite Creation Date:
2024-05-05 @ 10:47 PM
Last Modification Date:
2024-10-26 @ 10:24 AM
Study NCT ID:
NCT01184898
Status:
COMPLETED
Last Update Posted:
2016-11-29
First Post:
2010-08-17
Brief Title:
Pilot Trial of SirolimusMEC in High Risk Acute Myelogenous Leukemia AML
Sponsor:
Sidney Kimmel Cancer Center at Thomas Jefferson University
Organization:
Thomas Jefferson University
Study Overview
Official Title:
A Pilot Pharmacodynamic Correlate Multi-Institutional Trial of Sirolimus in Combination With Chemotherapy Mitoxantrone Etoposide Cytarabine for the Treatment of High Risk Acute Myelogenous Leukemia
Status:
COMPLETED
Status Verified Date:
2016-10
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:
None
Brief Summary:
The purpose of this study is to evaluate the addition of Sirolimus rapamycin to standard chemotherapy for the treatment of patients with high risk acute myelogenous leukemia AML Cancer cells taken from the patients will be studied in the laboratory to see if rapamycin is affecting the mTOR pathway in the cells and if this effect is correlated with how well patients respond to the therapy
Detailed Description:
Recent improvements in our understanding of leukemia biology have led to the introduction of highly effective molecularly targeted therapies This is exemplified by the development of BCR-ABL tyrosine kinase inhibitors such as imatinib as monotherapy for chronic myeloid leukemia CML and in combination with chemotherapy for BCR-ABL acute lymphoblastic leukemia ALL Imatinib mesylate blocks the protein made by the BCR-ABL oncogene
The PI3K phosphatidylinositol 3-kinases signaling is critical to leukemia cell survival and can be targeted Growth and survival stimulating signal transduction pathways are abnormally and universally activated in AML Acute Myeloid Leukemia This signal cascade is thought to contribute to survival and growth in tumor cells via downstream effects upon target proteins AKTProtein kinase B and mammalian target of rapamycin mTOR a protein that helps control several cell functions
In AML we and others have shown that PI3K signaling is constitutively activated in over 85 of primary samples and that the small molecule PI3K inhibitor LY294002 is cytotoxic in vitro to virtually all samples tested As LY294002 is poorly suited for drug development we have concentrated upon other ways to inhibit signal transduction through this pathway Mammalian target of rapamycin mTOR emerged as a reasonable target due to the availability of clinically available highly specific inhibitors with favorable safety profiles Mammalian target of rapamycin mTOR plays a central but complex role in cancer cells metabolic regulation and survival This serinethreonine kinase coordinates several important cellular functions and its activity is modulated in response to amino acid glucose oxygen and ATP availability as well as extracellular growth factor ligation Mammalian target of rapamycin mTOR activity regulates protein translation nutrient and amino acid uptake mitochondrial respiration glycolysis cell size regulation cell cycle entry and progression ribosome biogenesis and autophagy Constitutive mammalian target of rapamycin mTOR activation is commonly seen in cancer cells and is thought to promote survival in the setting of a wide variety of cellular insults Importantly mTOR opening may cause chemotherapy resistance Although regulation of mTOR signaling in leukemia occurs through by several inputs mTOR activity in AML is thought to be primarily regulated by PI3K signaling through AKT via the agent tumor suppressor tuberous sclerosis complex TSC1 2 and its target rheb GTPase
Taken together mammalian target of rapamycin mTOR is a smart target for molecularly targeted therapy in AML due to its importance in the growth and survival of AML cells its necessity for AML cell survival in certain contexts and its probable role in chemotherapy resistance and relapse
The PI3K phosphatidylinositol 3-kinases signaling is critical to leukemia cell survival and can be targeted Growth and survival stimulating signal transduction pathways are abnormally and universally activated in AML Acute Myeloid Leukemia This signal cascade is thought to contribute to survival and growth in tumor cells via downstream effects upon target proteins AKTProtein kinase B and mammalian target of rapamycin mTOR a protein that helps control several cell functions
In AML we and others have shown that PI3K signaling is constitutively activated in over 85 of primary samples and that the small molecule PI3K inhibitor LY294002 is cytotoxic in vitro to virtually all samples tested As LY294002 is poorly suited for drug development we have concentrated upon other ways to inhibit signal transduction through this pathway Mammalian target of rapamycin mTOR emerged as a reasonable target due to the availability of clinically available highly specific inhibitors with favorable safety profiles Mammalian target of rapamycin mTOR plays a central but complex role in cancer cells metabolic regulation and survival This serinethreonine kinase coordinates several important cellular functions and its activity is modulated in response to amino acid glucose oxygen and ATP availability as well as extracellular growth factor ligation Mammalian target of rapamycin mTOR activity regulates protein translation nutrient and amino acid uptake mitochondrial respiration glycolysis cell size regulation cell cycle entry and progression ribosome biogenesis and autophagy Constitutive mammalian target of rapamycin mTOR activation is commonly seen in cancer cells and is thought to promote survival in the setting of a wide variety of cellular insults Importantly mTOR opening may cause chemotherapy resistance Although regulation of mTOR signaling in leukemia occurs through by several inputs mTOR activity in AML is thought to be primarily regulated by PI3K signaling through AKT via the agent tumor suppressor tuberous sclerosis complex TSC1 2 and its target rheb GTPase
Taken together mammalian target of rapamycin mTOR is a smart target for molecularly targeted therapy in AML due to its importance in the growth and survival of AML cells its necessity for AML cell survival in certain contexts and its probable role in chemotherapy resistance and relapse
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2009-42 | OTHER | CCRRC | None |