AMLNCT01184898
Pilot Trial of Sirolimus/MEC in High Risk Acute Myelogenous Leukemia (AML)
A study testing Sirolimus, Mitoxantrone and Etoposide in people with AML, run by Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University at 2 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- AML
- What is being tested?
- Sirolimus, Mitoxantrone and Etoposide
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 2 sitesUnited States
- Study dates
- Jul 2010to Feb 2016
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 must have histologic evidence of high risk acute myeloid leukemia defined as one of the following:
- Primary refractory non-M3 AML (i) Residual leukemia after a minimum of 2 prior courses of chemotherapy (Same or different) (ii) Evidence of leukemia after a nadir bone marrow biopsy demonstrates no evidence of residual leukemia.
- Relapsed non-M3 AML
- Any non-M3 AML age >60 with no evidence of favorable karyotype (stratum 2 ONLY), defined by presence of t(8;21)(q22;q22) [AML1-ETO], inv16(p13;q22), or t(16;16)(p13;q22) [CBF;MYH11] by cytogenetics, FISH, or RT-PCR
- Secondary AML (from antecedent hematologic malignancy or following therapy with radiation or chemotherapy for another disease) with no evidence of favorable karyotype (stratum 2 ONLY), defined by presence of t(8;21)(q22;q22) [AML1-ETO], inv16(p13;q22), or t(16;16)(p13;q22) [CBF;MYH11] by cytogenetics, FISH, or RT-PCR
- Age > or = 18
- ECOG = 0 or 1
Who cannot join
- Subjects with FAB M3 (t(15;17)(q22;q21)[PML-RAR]) are not eligible
- Subjects taking the following are not eligible:
- Carbamazepine (e.g., Tegretol)
- Rifabutin (e.g., Mycobutin) or
- Rifampin (e.g., Rifadin)
- Rifapentine (e.g., Priftin)
Show all 20Show fewer
- St. John's wort
- Clarithromycin (e.g., Biaxin)
- Cyclosporine (e.g. Neoral or Sandimmune)
- Diltiazem (e.g., Cardizem)
- Erythromycin (e.g., Akne-Mycin, Ery-Tab)
- Itraconazole (e.g., Sporanox)
- Ketoconazole (e.g., Nizoral)
- Telithromycin (e.g., Ketek)
- Verapamil (e.g., Calan SR, Isoptin, Verelan)
- Voriconazole (e.g., VFEND)
- Tacrolimus (e.g. Prograf)
- Subjects taking fluconazole, voriconazole, itraconazole, posaconazole, and ketoconazole within 72 hours of study entry are not eligible. Reinstitution of fluconazole, voriconazole, itraconazole, posaconazole, ketoconazole and diltiazem is permissible 72 hours after the last dose of sirolimus.
- Subjects must not be receiving any chemotherapy agents (except Hydroxyurea). Intrathecal methotrexate and cytarabine are permissible
- Subjects must not be receiving growth factors, except for erythropoietin
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Thomas Jefferson University
Philadelphia, Pennsylvania, 19107
About this study
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
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.
Read the 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 AKT/Protein 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 serine/threonine 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.
- Conditions
- AML
- Being tested
- Sirolimus, Mitoxantrone, Etoposide, Cytarabine
- Keywords
- AML, mTOR, rapamycin
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SirolimusDrug
Also called Rapamycin
Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day.
MitoxantroneDrug
Also called Mitozantrone, Novantrone
Mitoxantrone 8mg/m2/day IV
EtoposideDrug
Also called Etoposide phosphate, VP-16, Etopophos
100 mg/m2/day IV
CytarabineDrug
Also called Cytosine arabinoside, Cytosar-U, Depocyt, ara-C
1000mg/m2/day IV every 24 hours for 5 days
| Study group | Role | What they receive |
|---|---|---|
| Sirolimus and MEC | Experimental | Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) Receives: Drug: Sirolimus; Drug: Mitoxantrone; Drug: Etoposide; Drug: Cytarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Association Between the Magnitude of mTOR Target Inhibition Post-treatment in Leukemic Blasts and Clinical Response in Patients With High Risk AML Treated With Sirolimus MEC
Percent change compared between response groups (responder vs nonresponder).
This outcome measure only includes patients who survived to outcome assessment.
Measured: From pre- to post-treatment
Secondary outcomes (3)
Complete Response
Complete response is defined as:
- Peripheral Blood Counts -Neutrophil count >1 x 109/L.
- Platelet count ≥ 100 x 109/L.
- Reduced hemoglobin concentration or hematocrit has no bearing on remission status.
- Leukemic blasts must not be present in the peripheral blood.
- Cellularity of bone marrow biopsy must be > 20% with maturation of all cell lines with < 5% blasts and no Auer rods.
- Extramedullary leukemia, such as CNS or soft tissue involvement, must not be present
Measured: Within one week of peripheral count recovery but no later than day 42
Complete Response in the Absence of Platelet Recovery
Complete response in the absence of platelet recovery is defined as:
- Bone marrow (<5% blasts) with adequate bone marrow cellularity, no evidence of circulating blasts or extramedullary disease and normalization of peripheral blood counts except for platelets (neutrophil count =1,000/µL)
Measured: Within one week of peripheral count recovery but no later than day 42
Partial Response
Partial response is defined as:
- Requires that all of the criteria for complete remission be satisfied except that the bone marrow may contain ≥ 5% blasts but < 25% blasts.
- A marrow with <5% blasts that contain Auer rods will also be considered a PR
Measured: Within one week of peripheral count recovery but no later than day 42
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Aug 2010 (estimated)
- Study startJul 2010
- Primary completionJan 2012
- Study completionFeb 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for AMLStudies of the same condition, open and under way.
- 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 N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University
- Sponsor type
- University, hospital or other
- Collaborators
- University of Pennsylvania
- Responsible party
- Sponsor
- Investigators
- Margaret Kasner, MD, Principal investigator, Thomas Jefferson University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01184898
- Sponsor's protocol ID
- 10D.21
- Other IDs
- 2009-42, JT 1520
- Status last verified
- May 2025
- First submitted
- 17 Aug 2010
- Last updated
- 31 May 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 31 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01184898
- Acronym / sponsor ID
- 10D.21
- Conditions
- AML
- Keywords
- AML, mTOR, rapamycin
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson UniversityUniversity, hospital or other
- Collaborators
- University of Pennsylvania
- Study start
- Jul 2010
- Primary completion
- Jan 2012 (actual)
- Study completion
- Feb 2016 (actual)
- First posted
- 19 Aug 2010 (estimated)
- Results
- Posted 27 Aug 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 AKT/Protein 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 serine/threonine 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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Sirolimus and MEC | Experimental | Drug: Sirolimus, Drug: Mitoxantrone, Drug: Etoposide, Drug: CytarabineSirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following:
- Age > or = 18
- ECOG = 0 or 1
Key exclusion criteria (20 listed)
- Subjects with FAB M3 (t(15;17)(q22;q21)[PML-RAR]) are not eligible
- Subjects taking the following are not eligible:
- Subjects taking fluconazole, voriconazole, itraconazole, posaconazole, and ketoconazole within 72 hours of study entry are not eligible. Reinstitution of fluconazole, voriconazole, itraconazole, posaconazole, ketoconazole and diltiazem is permissible 72 hours after the last dose of sirolimus.
- Subjects must not be receiving any chemotherapy agents (except Hydroxyurea). Intrathecal methotrexate and cytarabine are permissible
- Subjects must not be receiving growth factors, except for erythropoietin
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 |
|---|---|---|
| SirolimusAlso: RapamycinSirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day. | Drug | Sirolimus and MEC |
| MitoxantroneAlso: Mitozantrone, NovantroneMitoxantrone 8mg/m2/day IV | Drug | Sirolimus and MEC |
| EtoposideAlso: Etoposide phosphate, VP-16, Etopophos100 mg/m2/day IV | Drug | Sirolimus and MEC |
| CytarabineAlso: Cytosine arabinoside, Cytosar-U, Depocyt, ara-C1000mg/m2/day IV every 24 hours for 5 days | Drug | Sirolimus and MEC |
Primary outcome
Association Between the Magnitude of mTOR Target Inhibition Post-treatment in Leukemic Blasts and Clinical Response in Patients With High Risk AML Treated With Sirolimus MEC
Time frame: From pre- to post-treatment
Percent change compared between response groups (responder vs nonresponder). This outcome measure only includes patients who survived to outcome assessment.
3 secondary outcomes
Complete Response
Time frame: Within one week of peripheral count recovery but no later than day 42
Complete Response in the Absence of Platelet Recovery
Time frame: Within one week of peripheral count recovery but no later than day 42
Partial Response
Time frame: Within one week of peripheral count recovery but no later than day 42
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 May 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer CenterLink provided by the sponsor.
- Thomas Jefferson University HospitalsLink provided by the sponsor.
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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.
Margaret Kasner, MD principal investigator
Thomas Jefferson University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Sirolimus, Mitoxantrone and Etoposide in people with AML, run by Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University at 2 sites in United States.
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 7 inclusion and 20 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 31 May 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. 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?
Yes. Results are posted in the registry (first posted 27 Aug 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Association Between the Magnitude of mTOR Target Inhibition Post-treatment in Leukemic Blasts and Clinical Response in Patients With High Risk AML Treated With Sirolimus MEC (time frame: From pre- to post-treatment). 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 31 May 2025.