An interventional study of Sirolimus and Mitoxantrone in AML, sponsored by Sidney Kimmel Cancer Center at Thomas Jefferson University. Completed at 2 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-05-31.
Sponsored by Sidney Kimmel Cancer Center at Thomas Jefferson University · Not applicable, Interventional, and Treatment
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.
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.
Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following:
Exclusion Criteria:
Subjects taking the following are not eligible:
Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine)
Drug: Sirolimus · Drug: Mitoxantrone · Drug: Etoposide · Drug: Cytarabine
Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day.
Also known as: Rapamycin
Mitoxantrone 8mg/m2/day IV
Also known as: Mitozantrone, Novantrone
100 mg/m2/day IV
Also known as: Etoposide phosphate, VP-16, Etopophos
1000mg/m2/day IV every 24 hours for 5 days
Also known as: Cytosine arabinoside, Cytosar-U, Depocyt, ara-C
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.
Time frame: From pre- to post-treatment
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
Time frame: 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)
Time frame: 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
Time frame: Within one week of peripheral count recovery but no later than day 42
| Milestone | Sirolimus and MEC |
|---|---|
| Started | 36 |
| Completed | 36 |
| Not completed | 0 |
Percent change compared between response groups (responder vs nonresponder). This outcome measure only includes patients who survived to outcome assessment.
| percentage change in leukemic blasts | Sirolimus and MEC |
|---|---|
| Responders (17 pts) | 69 (42 to 98) |
| Nonresponders (10 pts) | -36 (-225 to 32) |
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
| participants | Sirolimus and MEC |
|---|---|
| Complete Response | 11 |
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)
| participants | Sirolimus and MEC |
|---|---|
| Complete Response in the Absence of Platelet Recovery | 2 |
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
| participants | Sirolimus and MEC |
|---|---|
| Partial Response | 3 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Sirolimus and MEC | — | 8/36 (22.2%) | 36/36 (100%) |
| Event | Sirolimus and MEC |
|---|---|
| InfectionGeneral disorders | 2/36 |
| Bone marrow cellularityGeneral disorders | 2/36 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 1/36 |
| Abdominal painGeneral disorders | 1/36 |
| Left ventricular systolic dysfunctionCardiac disorders | 1/36 |
| Prolonged QTc intervalGeneral disorders | 1/36 |
| SepsisGeneral disorders | 1/36 |
| Multi-organ failureGeneral disorders | 1/36 |
| Respiratory syncytial virusRespiratory, thoracic and mediastinal disorders | 1/36 |
| Event | Sirolimus and MEC |
|---|---|
| DiarrheaGastrointestinal disorders | 30/36 |
| FatigueGeneral disorders | 30/36 |
| NauseaGeneral disorders | 28/36 |
| EdemaSkin and subcutaneous tissue disorders | 28/36 |
| RashSkin and subcutaneous tissue disorders | 23/36 |
| Febrile neutropeniaBlood and lymphatic system disorders | 22/36 |
| CoughGeneral disorders | 21/36 |
| AnorexiaGeneral disorders | 21/36 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 19/36 |
| NeutropeniaBlood and lymphatic system disorders | 18/36 |
| Age, Continuous(years) | Sirolimus and MEC |
|---|---|
| Mean | 60.05 ± 11.84 |
| Age, Categorical(Participants) | Sirolimus and MEC |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 24 |
| >=65 years | 12 |
| Sex: Female, Male(Participants) | Sirolimus and MEC |
|---|---|
| Female | 16 |
| Male | 20 |
| Region of Enrollment(participants) | Sirolimus and MEC |
|---|---|
| United States | 36 |
This study is completed, as verified in May 2025. You cannot join it, but the record below documents what was studied.
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Sidney Kimmel Cancer Center at Thomas Jefferson University