Biomarkers in Predicting Treatment Response to Sirolimus and Chemotherapy in Patients With High-Risk Acute Myeloid Leukemia

NCT02583893 | Completed Phase 2 Results DMC

• 4 other identifiers: 15D.3772013-087NCI-2015-01507JT 5530
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

This pilot phase II trial studies whether biomarkers (biological molecules) in bone marrow samples can predict treatment response to sirolimus and chemotherapy (mitoxantrone hydrochloride, etoposide, and cytarabine \[MEC\]) in patients with acute myeloid leukemia (AML) that is likely to come back or spread (high-risk). Sirolimus inhibits or blocks the pathway that causes cancer cells to grow. Adding sirolimus to standard chemotherapy may help improve patient response. Studying samples of bone marrow from patients treated with sirolimus in the laboratory may help doctors learn whether sirolimus reverses or turns off that pathway and whether changes in biomarker levels can predict how well patients will respond to treatment.

Conditions

Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Biochemical Response

  Defined by change in phosphorylated ribosomal protein S6 (pS6) positive blasts, measured as the % reduction in pS6 positive blasts from baseline to day 4. Biochemical response will be described by mean, median, standard deviation, range and coefficient of variation. The association between biochemical response and clinical response will be tested by Fisher's exact test.

  Baseline to day 4

• Clinical Response

  Clinical response was assessed at Day 45 using IWG criteria: Complete Remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), Partial Remission (PR), or No Response (NR). CR requires normalized blood counts and bone marrow blasts \<5%. CRp meets CR except platelet recovery; CRi meets CR except incomplete neutrophil/platelet recovery. PR is ≥50% reduction in marrow blasts to 5-25% with partial blood count improvement. NR indicates failure to meet these criteria. Tumor response per RECIST v1.0: CR = disappearance of all target lesions; PR = ≥30% decrease in sum of longest diameters; Overall Response = CR + PR. Progression = ≥20% increase in sum of longest diameters, measurable increase in non-target lesion, or new lesions.

  Day 45

Secondary Outcomes (3)

• Overall Response Rate (ORR) (Complete Response [CR], CR With Incomplete Platelet Recovery [CRp], or Partial Response)

  Day 45

• Relapse Free Survival (RFS)

  Time from study entry to first documented progression, death, or last contact, assessed up to 2 years

• Percentage of Participants by Risk Group

  Up to 2 years

Study Arms (1)

Sirolimus, MEC chemotherapy

EXPERIMENTAL

Patients undergo collection of bone marrow samples prior to sirolimus dosing on day 4 and within 1 week and no later than day 45 of hematologic recovery. Patients receive sirolimus PO on days 2-9 (loading dose on day 1 only), and standard MEC chemotherapy comprising mitoxantrone hydrochloride IV over 15 minutes, etoposide IV over 1 hour, and cytarabine IV over 1 hour every 24 hours on day 4-8.

Drug: Sirolimus; Drug: Mitoxantrone; Drug: Etoposide; Drug: Cytarabine

Interventions

Sirolimus DRUG

Given PO

Also known as: Rapamycin

Sirolimus, MEC chemotherapy

Mitoxantrone DRUG

Given IV

Also known as: Mitoxantrone hydrochloride, Novantrone

Sirolimus, MEC chemotherapy

Etoposide DRUG

Given IV

Also known as: Etoposide phosphate, VP-16, Etopophos

Sirolimus, MEC chemotherapy

Cytarabine DRUG

Given IV

Also known as: Cytosine arabinoside, Cytosar-U, Depocyt, ara-C

Sirolimus, MEC chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following:
• Primary refractory non-M3 AML
• Residual leukemia after a minimum of 2 prior courses of chemotherapy (Same or different)
• Evidence of leukemia recurrence after a nadir bone marrow biopsy demonstrates no evidence of residual leukemia.
• Evidence of leukemia after induction therapy which, in the opinion of the investigator, would be appropriate for reinduction with sirolimus/MEC therapy.
• Relapsed non-M3 AML
• Previously untreated non-M3 AML age \>60 with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) \[AML1-ETO\], inv16(p13;q22), or t(16;16)(p13;q22) \[CBFβ;MYH11\] by cytogenetics, FISH, or RT-PCR
• Previously untreated secondary AML (from antecedent hematologic malignancy or following therapy with radiation or chemotherapy for another disease) with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) \[AML1-ETO\], inv16(p13;q22), or t(16;16)(p13;q22) \[CBFβ;MYH11\] by cytogenetics, FISH, or RT-PCR
• Subjects must be ≥ 18 years of age.
• Subjects must have an ECOG performance status of 2 or less (see Appendix1).
• Subjects must have a life expectancy of at least 4 weeks.
• Subjects must be able to consume oral medication.
• Subjects must have recovered from the toxic effects of any prior chemotherapy to =\< Grade 1 (except alopecia).
• Required initial laboratory values:
• Creatinine ≤ 2.0mg/dL

You may not qualify if:

• Subjects with FAB M3 (t (15; 17) (q22; q21) \[PML-RARα\]) are not eligible.
• Subjects must not be receiving any chemotherapy agents (except Hydroxyurea).
• a) Intrathecal methotrexate and cytarabine are permissible.
• Subjects must not be receiving growth factors, except for erythropoietin.
• Subjects with a "currently active" second malignancy, other than non-melanoma skin cancers are not eligible.
• 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.
• Subjects taking the following are not eligible:
• Carbamazepine (e.g., Tegretol)
• Rifabutin (e.g., Mycobutin) or
• Rifampin (e.g., Rifadin)
• Rifapentine (e.g., Priftin)
• St. John's wort
• Clarithromycin (e.g., Biaxin)
• Cyclosporine (e.g. Neoral or Sandimmune)
• Diltiazem (e.g., Cardizem)

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University: lead

Study Sites (1)

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

Related Links

• Jefferson University Hospitals

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Sirolimus; Mitoxantrone; Etoposide; etoposide phosphate; Cytarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Quinones; Polycyclic Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Margaret Kasner
• Organization: Thomas Jefferson University

margaret.kasner@jefferson.edu

215-955-8874

Study Officials

• Margaret Kasner, MD

  Thomas Jefferson University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 8, 2015
• First Posted: October 22, 2015
• Study Start: October 7, 2015
• Primary Completion: April 17, 2023
• Study Completion: May 17, 2023
• Last Updated: May 29, 2026
• Results First Posted: May 29, 2026

Record last verified: 2026-05

Locations

US (1)