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Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy

NCT01869114

Description:

This phase II trial studies how well sirolimus and azacitidine works in treating patients with high-risk myelodysplastic syndrome or recurrent 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 azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Sirolimus and azacitidine may kill more cancer cells.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy
  • Official Title: A Phase II Study of Azacitidine and Sirolimus for the Treatment of High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia Refractory to or Not Eligible for Intensive Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: 12D.587
  • SECONDARY ID: 2012-50
  • NCT ID: NCT01869114

Conditions

  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • de Novo Myelodysplastic Syndromes
  • Myelodysplastic Syndrome With Isolated Del(5q)
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Sirolimusrapamycin, RapamuneHigh risk Myleodysplastic Syndrome (MDS)
Azacitidine5-azacytidine, VidazaHigh risk Myleodysplastic Syndrome (MDS)

Purpose

This phase II trial studies how well sirolimus and azacitidine works in treating patients with high-risk myelodysplastic syndrome or recurrent 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 azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Sirolimus and azacitidine may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To characterize the rate of response to azacitidine and sirolimus in adults with high-risk
      myelodysplastic syndrome (MDS), or relapsed or refractory acute myeloid leukemia (AML) or
      those unable or unwilling to tolerate high dose chemotherapy.

      SECONDARY OBJECTIVES:

      I. To determine the pharmacodynamic effect of sirolimus on inhibition of mammalian target of
      rapamycin (mTOR) signaling in adults with high-risk MDS, or relapsed or refractory AML or
      those unable or unwilling to tolerate high dose chemotherapy.

      II. To determine the safety and tolerability of sirolimus and azacitidine in adults with
      high-risk MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high
      dose chemotherapy.

      III. To determine the progression free survival and overall survival in adults with high-risk
      MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high dose
      chemotherapy.

      IV. To determine if the quality of life of patients is improved with the combination of
      azacitidine and sirolimus when compared to historical controls of azacitidine alone.

      OUTLINE:

      Patients receive sirolimus orally (PO) on days 1-10 or 1-12 and azacitidine intravenously
      (IV) on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of
      disease progression or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
High risk Myleodysplastic Syndrome (MDS)ExperimentalPatients receive sirolimus PO on days 1-10 or 1-12 and azacitidine IV on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
  • Sirolimus
  • Azacitidine
Acute Myeloid Leukemia (AML)ExperimentalPatients receive sirolimus PO on days 1-10 or 1-12 and azacitidine IV on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
  • Sirolimus
  • Azacitidine

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have a diagnosis of one of the following:

               -  MDS (Arm A): High-risk MDS defined as: >5% blasts in bone marrow and/or the
                  following cytogenetic categories: presence of inv(3)/t(3q)/del(3q), -7/del(7q),
                  complex cytogenetics (3 or more abnormalities)

               -  AML (Arm B): Relapsed/refractory/unable to tolerate conventional chemotherapy

               -  MDS or AML as above BUT with prior therapy with Azacitibine (Arm C): Patients who
                  meet criteria for either Arm A or Arm B but have been treated or are currently
                  treated with Azacitibine

          2. Patients must be ≥ 18 years old

          3. Patients must have an ECOG performance status of <= 2 (see Attachment 1).

          4. Patients must have a life expectancy of at least 4 weeks.

          5. Patients must be able to consume oral medication.

          6. Patients must have completed any radiotherapy four weeks prior to study entry, 0-2
             weeks for local palliative XRT (small port).

          7. Patients must have recovered from the toxic effects of any prior chemotherapy to <
             Grade 2 (except for alopecia).

          8. Required initial laboratory values: Creatinine≤ 2.0mg/dL; total or direct bilirubin ≤
             1.5mg/dL (if not due to the leukemia itself or known Gilbert's Syndrome);(as
             documented by treating physician) SGPT(ALT) ≤ 3xULN; glucose <200 mg/dL, negative
             pregnancy test for women of child-bearing potential.

          9. Patients must be able to sign consent and be willing and able to comply with scheduled
             visits, treatment plan and laboratory testing.

         10. Patients may have had a prior stem cell transplant (autologous or allogeneic), however
             they may not have active GvHD, nor be on any immunosuppression

        Exclusion Criteria:

          1. Patients must not be receiving any chemotherapy agents (except Hydroxyurea)

               -  Intrathecal ARA-C and intrathecal methotrexate are permissible (as they are not
                  systemic and only isolated to the central nervous system).

               -  Patients can not have received more than 3 prior lines of therapy for their
                  hematologic malignancy.

               -  Patients who meet all other study criteria but have either previously been
                  treated or are currently undergoing treatment with azacitibine shall be evaluated
                  in Arm C

          2. Patients must not be receiving growth factors.

          3. Patients with a current second malignancy requiring systemic therapy, other than
             non-melanoma skin cancers, are not eligible. If a patient has had a prior second
             malignancy that is not currently requiring active treatment, the patient will be
             considered eligible.

          4. Patients 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.

          5. Patients may not take any of the following medications while on study, but will be
             considered eligible if medication is discontinued 72 hrs prior to first dose of
             Sirolimus:

               -  Carbamazepine (e.g. Tegretol)

               -  Rifabutin (e.g. Mycobutin)

               -  Rifampin (e.g. Rifadin)

               -  Rifapentine (e.g. Priftin)

               -  St. John's Wort- may decrease effects of sirolimus by decreasing the amount of
                  sirolimus in the body

               -  Clarithromycin (e.g. Biaxin)

               -  Cyclosporin e.g. (Neoral or Sandimmune)

               -  Diltiazem (e.g. Cardizem)

               -  Erythromycin (e.g. Akne-Mycin, Ery-Tab)

               -  Itraconazole (e.g. Sporanox)

               -  Fluconazole (e.g. Diflucan)

               -  Ketoconazole (e.g. Nizoral)

               -  Telithromycin (e.g. Ketek)

               -  Verapamil (e.g. Calan SR, Isoptin, Verelan)

               -  Voriconazole (e.g. VFEND) - May increase the effects of sirolimus by increasing
                  the amount of this medicine in the body. Can take 72 hours after last dose of
                  Sirolimus

               -  Tacrolimus (e.g. Prograf) - May cause liver transplant rejection or serious side
                  effects in patients on sirolimus.

          6. Patients with known HIV positivity or AIDS-related illness are not eligible.

          7. Patients with other severe concurrent disease which in the judgment of the
             investigator would make the patient inappropriate for entry into this study are
             ineligible.

          8. Patients must not have received any investigational agents within 21days of study
             entry.

          9. Patients 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 rapamycin.
             Males or females of reproductive age may not participate unless they have agreed to
             use an effective contraceptive method.

         10. Patients 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. Patients with bacteremia must have documented negative blood
             cultures prior to study entry.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of response
Time Frame:Up to 5 years
Safety Issue:
Description:MDS: Patients meeting an erythroid response, a platelet response, or a neutrophil response will be considered responders. AML: Patients achieving a complete remission (CR), complete response in the absence of a total platelet recovery (CRp), or partial remission (PR) will be considered responders.

Secondary Outcome Measures

Measure:Toxicity referring to toxic events during the full course of treatment that are attributed as possibly, probably or definitely due to treatment, graded according to the National Institutes of Health (NIH) Common Toxicity Criteria (CTC) v. 4.0
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:The combination of these drugs will be deemed safe if the number of adverse events is no more that 10% greater than the additive number of events of azacitidine and sirolimus if administrated separately. This will be based upon data in the original phase 2 trials of azacitidine demonstrating an 8% toxic death rate and therefore be 18% of the total number enrolled (approx. 40 x18% = 7).
Measure:Pharmacokinetic assessment to assess levels of the drug in vivo
Time Frame:Day 4 of course 1
Safety Issue:
Description:Day 4 levels will be drawn prior to initiation of azacitidine to allow for a PK/PD correlation study
Measure:Inhibition of mTOR signaling by sirolimus measured by intracellular flow cytometry for phosphorylation of the downstream signaling target S6 ribosomal protein as a surrogate for mTOR activity
Time Frame:Up to day 4 before azacitidine administration
Safety Issue:
Description:Distributional characteristics are examined by: histograms, box plots and descriptive statistics (e.g., mean, median, standard deviation, range). Variability will be of particular interest. We will conduct within-patient comparison of baseline versus posts-treatment percentages by Student's paired t test. A nonparametric Wilcoxon signed ranks test will be employed if normality cannot be assumed or achieved by simple transformation.
Measure:Quality of life (QOL) assessed by the European Organization for Research and Treatment of Cancer (EORTC) QOL and the Mental Health Inventory (MHI)
Time Frame:Up to day 164
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sidney Kimmel Cancer Center at Thomas Jefferson University

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