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

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ClinicalTrials.gov Identifier: NCT02583893
Recruitment Status : Recruiting
First Posted : October 22, 2015
Last Update Posted : December 8, 2020
Sponsor:
Information provided by (Responsible Party):
Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )

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.

Condition or disease Intervention/treatment Phase
Recurrent Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Untreated Adult Acute Myeloid Leukemia Drug: Sirolimus Drug: Mitoxantrone Drug: Etoposide Drug: Cytarabine Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To test the association between biochemical response and clinical response.

SECONDARY OBJECTIVES:

I. To estimate complete response rate of sirolimus MEC in patients with high risk AML.

II. To estimate progression free survival in this patient population. III. To collect further information on the safety, tolerability, and efficacy of sirolimus in combination with MEC in patients with relapsed or refractory myeloid malignancies.

OUTLINE:

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 orally (PO) on days 2-9 (loading dose on day 1 only), and standard MEC chemotherapy comprising mitoxantrone hydrochloride intravenously (IV) over 15 minutes, etoposide IV over 1 hour, and cytarabine IV over 1 hour every 24 hours on day 4-8.

After completion of study treatment, patients are followed up every 3 months for 2 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 65 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Biomarker Validation Study to Establish Whether Serial Flow Cytometric Measurements Predict Clinical Response to Sirolimus and MEC (Mitoxantrone Etoposide Cytarabine) Treatment in Patients With High-Risk Acute Myelogenous Leukemia
Actual Study Start Date : October 7, 2015
Estimated Primary Completion Date : October 8, 2021
Estimated Study Completion Date : January 2022


Arm Intervention/treatment
Experimental: Sirolimus, MEC chemotherapy
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
Given PO
Other Name: Rapamycin

Drug: Mitoxantrone
Given IV
Other Names:
  • Mitoxantrone hydrochloride
  • Novantrone

Drug: Etoposide
Given IV
Other Names:
  • Etoposide phosphate
  • VP-16
  • Etopophos

Drug: Cytarabine
Given IV
Other Names:
  • Cytosine arabinoside
  • Cytosar-U
  • Depocyt
  • ara-C




Primary Outcome Measures :
  1. Biochemical response [ Time Frame: Baseline to day 4 ]
    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.

  2. Clinical response [ Time Frame: Day 45 ]
    Based on hematologic recovery/day 45 marrow assessed according to International Working Group (IWG) criteria. The association between biochemical response and clinical response will be tested by Fisher's exact test.

  3. Incidence of adverse events [ Time Frame: Up to day 45 ]
    Recorded and graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Worse toxicity grades observed during treatment will be described. Toxicities will be graded and tabled.


Secondary Outcome Measures :
  1. Overall response rate (ORR) (complete response [CR], CR with incomplete platelet recovery [CRp], or partial response) [ Time Frame: Day 45 ]
    Fraction of patients who achieve CR, CRp, or PR will be assessed. ORR and 95% exact confidence interval will be computed for all patients and for sensitive and resistant subgroups.

  2. Relapse free survival (RFS) [ Time Frame: Time from study entry to first documented progression, death, or last contact, assessed up to 2 years ]
    RFS will be estimated by the Kaplan-Meier method. A landmark analysis of RFS by clinical response (CR+CRp, CRi, PR or no response [NR]) will be computed from day 45 marrow assessment. Median values and 95% confidence intervals will be calculated.

  3. Overall survival (OS) [ Time Frame: Time from study entry to death or last contact, assessed up to 2 years ]
    OS will be estimated by the Kaplan-Meier method. A landmark analysis of RFS by clinical response (CR+CRp, CRi, PR or NR) will be computed from day 45 marrow assessment. Median values and 95% confidence intervals will be calculated.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following:

    1. 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.
    2. Relapsed non-M3 AML
    3. 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
    4. 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
  2. Subjects must be ≥ 18 years of age.
  3. Subjects must have an ECOG performance status of 2 or less (see Appendix1).
  4. Subjects must have a life expectancy of at least 4 weeks.
  5. Subjects must be able to consume oral medication.
  6. Subjects must have recovered from the toxic effects of any prior chemotherapy to =< Grade 1 (except alopecia).
  7. Required initial laboratory values:

    1. Creatinine ≤ 2.0mg/dL
    2. total or direct bilirubin ≤ 1.5mg/dL; SGPT (ALT) ≤ 3xULN
    3. negative pregnancy test for women with child-bearing potential.
  8. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing.
  9. Subjects must have a left ventricular ejection fraction (LVEF) of ≥ 45%.

Exclusion Criteria:

  1. Subjects with FAB M3 (t (15; 17) (q22; q21) [PML-RARα]) are not eligible.
  2. Subjects must not be receiving any chemotherapy agents (except Hydroxyurea).

    a) Intrathecal methotrexate and cytarabine are permissible.

  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) or
    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) Subjects taking fluconozole, voriconizole, itraconazole, posaconazole, and ketokonazole within 72 hours of study drug starting are not eligible. Reinstitution of fluconozole, voriconizole, itraconazole, posaconazole, ketokonazole and diltiazem is permissible 72 hours after the last dose of sirolimus.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02583893


Contacts
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Contact: Neil Palmisiano, MD 215-955-8874
Contact: Clinical Trials Office 215-955-1661

Locations
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United States, Pennsylvania
Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Neil Palmisiano, MD    215-955-8874      
Contact: Clinical Trials Office    215-955-1661      
Principal Investigator: Neil Palmisiano, MD         
Sub-Investigator: Neal Flomenberg, MD         
Sub-Investigator: Joanne Filicko-O'Hara, MD         
Sub-Investigator: Manish Sharma, MD         
Sub-Investigator: John Wagner, MD         
Sub-Investigator: Matthew Carabasi, MD         
Sub-Investigator: S. Onder Alpdogan, MD         
Sub-Investigator: Mark Weiss, MD         
Sub-Investigator: Ubaldo Martinez Outschoorn, MD         
Sub-Investigator: Thomas Klumpp, MD         
Sub-Investigator: Michael Ramirez, MD         
Sub-Investigator: Sameh Gaballa, MD         
Sponsors and Collaborators
Sidney Kimmel Cancer Center at Thomas Jefferson University
Investigators
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Principal Investigator: Neil Palmisiano, MD Thomas Jefferson University
Additional Information:
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Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University
ClinicalTrials.gov Identifier: NCT02583893    
Other Study ID Numbers: 15D.377
2013-087 ( Other Identifier: PRC )
NCI-2015-01507 ( Other Identifier: NCI Trial ID )
First Posted: October 22, 2015    Key Record Dates
Last Update Posted: December 8, 2020
Last Verified: December 2020
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Sirolimus
Etoposide
Mitoxantrone
Etoposide phosphate
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Antibiotics, Antineoplastic
Antifungal Agents
Analgesics
Sensory System Agents
Peripheral Nervous System Agents