Sirolimus, Idarubicin, and Cytarabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

February 2, 2023 updated by: Sidney Kimmel Cancer Center at Thomas Jefferson University

A Pilot, Pharmacodynamic Correlate Trial of Sirolimus in Combination With Chemotherapy (Idarubicin, Cytarabine) for the Treatment of Newly Diagnosed Acute Myelogenous Leukemia

This pilot clinical trial studies sirolimus, idarubicin, and cytarabine in treating patients with newly diagnosed acute myeloid leukemia. Sirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving sirolimus together with idarubicin and cytarabine may kill more cancer cells.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

1) To determine whether there is an association between baseline mammalian target of rapamycin (mTOR) activation paired with mTOR target inhibition post-treatment in leukemic blasts and clinical response in patients with newly diagnosed acute myeloid leukemia (AML) treated with sirolimus idarubicin/cytarabine.

SECONDARY OBJECTIVES:

  1. To estimate the response rate of sirolimus idarubicin/cytarabine in patients with newly diagnosed AML compared to historical data using idarubicin/cytarabine alone.
  2. To determine the ability of oral sirolimus to inhibit mTOR in leukemic blasts.
  3. To assess if mTOR pathway inhibition correlates with clinical response.
  4. To collect further information on the safety, tolerability, and efficacy of sirolimus in combination with idarubicin/cytarabine in patients with newly diagnosed AML.
  5. To describe the progression-free survival and overall survival (1 year, 2 year and 5 year) of patients treated with sirolimus idarubicin/cytarabine.

OUTLINE:

Patients receive sirolimus orally (PO) once daily (QD) on days 1-10, idarubicin intravenously (IV) over 3-5 minutes on days 4-6, and cytarabine IV continuously over 24 hours on days 4-10.

After completion of study treatment, patients are followed up every 3 months for 5 years.

Study Type

Interventional

Enrollment (Actual)

55

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
        • Thomas Jefferson University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Patients must have histologic evidence of newly diagnosed acute myeloid leukemia (non-M3 AML) as documented by the presence of >20% myeloid blasts in the bone marrow
  2. Subjects must be 18 years of age and <= 60
  3. Subjects must have an ECOG performance status of 2 or less. (see attachment 1).
  4. Subjects must have a life expectancy of at least 4 weeks.
  5. Subjects must be able to consume oral medication.
  6. Required initial laboratory values: Creatinine 2.0mg/dL; total or direct bilirubin 1.5mg/dL; SGPT(ALT) 3xULN (if not due to the leukemia itself); negative pregnancy test for women with child-bearing potential.
  7. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing.
  8. Subjects must have a left ventricular ejection fraction (LVEF) of >/= 45%.

Exclusion Criteria:

  1. Subjects with APL - FAB M3 (t(15;17)(q22;q21)[PML-RAR] are not eligible
  2. Subjects must not have received any chemotherapeutic agents for the AML (except Hydroxyurea). Intrathecal ARA-C and intrathecal methotrexate are permissible (as they are not systemic and only isolated to the central nervous system).
  3. Subjects must not be receiving growth factors, except for erythropoietin.
  4. Subjects with a "currently active" second malignancy, other than non-melanoma skin cancers are not eligible.
  5. Subjects with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible.

  6. Subjects taking the following are not eligible:

    1. Carbamazepine (e.g., Tegretol)
    2. Rifabutin (e.g., Mycobutin)
    3. Rifampin (e.g., Rifadin)
    4. Rifapentine (e.g., Priftin)
    5. St. John's wort
    6. Clarithromycin (e.g., Biaxin)
    7. Cyclosporine (e.g. Neoral or Sandimmune)
    8. Diltiazem (e.g., Cardizem)
    9. Erythromycin (e.g., Akne-Mycin, Ery-Tab)
    10. Itraconazole (e.g., Sporanox)
    11. Ketoconazole (e.g., Nizoral)
    12. Telithromycin (e.g., Ketek)
    13. Verapamil (e.g., Calan SR, Isoptin, Verelan)
    14. Voriconazole (e.g., VFEND)
    15. Tacrolimus (e.g. Prograf)
  7. 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.
  8. Subjects who require HIV protease inhibitors or those with AIDS-related illness
  9. Subjects with other severe concurrent disease which in the judgment of the investigator would make the patient inappropriate for entry into this study are ineligible.
  10. Subjects must not be pregnant or breastfeeding. Pregnancy tests must be obtained for all females of child-bearing potential. Pregnant or lactating patients are ineligible for this study due to the unknown human fetal or teratogenic toxicities of sirolimus. Males or females of reproductive age may not participate unless they have agreed to use an effective contraceptive method.
  11. Subjects who have uncontrolled infection are not eligible. Patients must have any active infections under control. Fungal disease must be stable for at least 2 weeks before study entry.
  12. Subjects with bacteremia must have documented negative blood cultures prior to study entry.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Treatment (sirolimus, idarubicin, cytarabine)
Patients receive sirolimus PO QD on days 1-10, idarubicin IV over 3-5 minutes on days 4-6, and cytarabine IV continuously over 24 hours on days 4-10.
Drug: Cytarabine
Given IV
Other Names:
  • Ara-C
  • Cytosar-U
  • cytosine arabinoside
  • Depocyt
  • Arabinofuranosyl Cytidine
Drug: Sirolimus
Given PO
Other Names:
  • Rapamune
  • rapamycin
Drug: Idarubicin
Given IV
Other Names:
  • Idamycin
  • Zavedos
  • 4-demethoxydaunorubicin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in measurement of mTOR activation paired with mTOR target inhibition
Time Frame: Baseline to day 4
The association between mTOR response and clinical response (complete or partial response) will be evaluated using the two-sided Fisher's exact test with alpha 0.05.
Baseline to day 4

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: 1 year, 2 years, 5 years
Will be evaluated using the Kaplan-Meier method stratified by mTOR response. Log rank test will be used to compare the overall survival in patients with and without mTOR response. Based on the estimated survival curves, the 1-year, 2-year, and 5-year survival rates will be computed with the corresponding 95% confidence intervals.
1 year, 2 years, 5 years
Progression free survival
Time Frame: 1 year, 2 years, 5 years
Based on the estimated survival curves, the 1-year, 2-year, and 5-year survival rates will be computed with the corresponding 95% confidence intervals.
1 year, 2 years, 5 years
Incidence of toxicities, graded according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) 4.0 guidelines
Time Frame: Up to 45 days
Safety data analysis is descriptive. All estimates of adverse events rates will be presented with corresponding confidence intervals using the exact method.
Up to 45 days
Response defined as patients achieving a complete remission (CR), complete response in absence of total platelet recovery (CRp), or partial remission (PR)
Time Frame: Up to 5 years
Proportions of complete response and partial response with be computed separately in patients with and without mTOR response and presented with corresponding exact binomial 95% confidence intervals.
Up to 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sidney Kimmel Cancer Center at Thomas Jefferson University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 15, 2013

Primary Completion (ACTUAL)

December 12, 2019

Study Completion (ACTUAL)

December 12, 2019

Study Registration Dates

First Submitted

March 25, 2013

First Submitted That Met QC Criteria

March 25, 2013

First Posted (ESTIMATE)

April 1, 2013

Study Record Updates

Last Update Posted (ACTUAL)

February 3, 2023

Last Update Submitted That Met QC Criteria

February 2, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 12D.588
  • 2012-55 (CCRRC)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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