Clinical Trials /

Dexamethasone in Refractory or First Relapsed Acute Myeloid Leukemia

NCT03765541

Description:

Recent preclinical and retrospective clinical data have suggested that dexamethasone might sensitize leukemic cells to chemotherapy-induced cell death and thus limit the risk of leukemic regrowth and relapse. Moreover, it has been experimentally shown that leukemic cells in acute myeloid leukemia patients who relapse become sensitive to glucocorticoids treatment highlighting a novel potential role for dexamethasone in relapsed or refractory acute myeloid leukemia (R/R). This study was designed to determine whether adding dexamethasone to standard salvage therapy in the treatment of relapsed/refractory acute myeloid leukemia in adult patients (intensive chemotherapy amsacrine-cytarabine or azacitidine according to investigator's willingness) results in a significant improvement of the overall survival.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Dexamethasone in Refractory or First Relapsed Acute Myeloid Leukemia
  • Official Title: Dexamethasone Plus Salvage Chemotherapy Versus Salvage Chemotherapy Alone in Patients With First Relapsed or Refractory Acute Myeloid Leukemia: a Randomized, Controlled, Open-label, Multicenter, Phase III Study

Clinical Trial IDs

  • ORG STUDY ID: RC31/17/0450
  • NCT ID: NCT03765541

Conditions

  • Relapsed or Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
DexamethasoneStandard salvage therapy + dexamethasone
AmsacrineStandard salvage therapy + dexamethasone
CytarabineStandard salvage therapy + dexamethasone
AzacitidineStandard salvage therapy + dexamethasone

Purpose

Recent preclinical and retrospective clinical data have suggested that dexamethasone might sensitize leukemic cells to chemotherapy-induced cell death and thus limit the risk of leukemic regrowth and relapse. Moreover, it has been experimentally shown that leukemic cells in acute myeloid leukemia patients who relapse become sensitive to glucocorticoids treatment highlighting a novel potential role for dexamethasone in relapsed or refractory acute myeloid leukemia (R/R). This study was designed to determine whether adding dexamethasone to standard salvage therapy in the treatment of relapsed/refractory acute myeloid leukemia in adult patients (intensive chemotherapy amsacrine-cytarabine or azacitidine according to investigator's willingness) results in a significant improvement of the overall survival.

Detailed Description

      The prognosis for patients with relapsed or refractory acute myeloid leukemia is poor ;
      median survival is less than 1 year. High-dose cytarabine monotherapy or cytarabine-based
      combination regimens are often used as salvage therapy with limited efficacy. A recent
      retrospective study has shown that the addition of dexamethasone to intensive chemotherapy
      was significantly associated with better disease-free and overall survival in hyperleukocytic
      acute myeloid leukemia patients. The gene signatures of some molecular subgroups of acute
      myeloid leukemia were highly enriched in genes responsive to dexamethasone, including acute
      myeloid leukemia with NPM1 mutations which were particularly sensitive to the antileukemic
      activity of dexamethasone both in vitro and in vivo. Moreover, three recent preclinical
      studies have shown that cytarabine-resistant or RUNX1-mutated acute myeloid leukemia cells
      acquired sensitivity to glucocorticoids. Therefore, dexamethasone might sensitize leukemic
      stem cells to chemotherapy-induced cell death and thus limit the risk of relapse.

      This study consists of a screening period, a treatment period, and a post-treatment follow-up
      period. Adult patients with relapsed/refractory acute myeloid leukemia are randomly assigned
      in a 1:1 ratio to receive either standard salvage therapy in combination with dexamethasone
      or standard salvage therapy alone. Standard salvage therapy is intensive chemotherapy
      (amsacrine-cytarabine) or azacitidine according to the investigator's willingness. For those
      patients with intensive chemotherapy amsacrine-cytarabine, the study treatment period
      includes 1 induction cycle and up to 3 consolidation cycles. For those patients with
      azacitidine, the study treatment period includes 3 cycles prior to the evaluation of the
      complete remission and thereafter lasts until progression. Of note, any patients in the study
      can undergo allogeneic hematopoietic stem cell transplantation providing his/her disease is
      controlled. After discontinuing the study treatment all patients must further carry out
      post-treatment follow-up visits every 3 months during the first and second year, and every 6
      months thereafter until death, withdrawal of consent, loss to follow-up, or the end of the
      study, whichever occurs first. The end of the study is planned 5 years after the
      randomization of the first patient. The primary endpoint is the overall survival.
    

Trial Arms

NameTypeDescriptionInterventions
Standard salvage therapy + dexamethasoneExperimentalIntensive chemotherapy amsacrine-cytarabine or azacitidine according to the investigator's willingness in combination with dexamethasone
  • Dexamethasone
  • Amsacrine
  • Cytarabine
  • Azacitidine
Standard salvage therapy aloneActive ComparatorIntensive chemotherapy amsacrine-cytarabine or azacitidine according to the investigator's willingness
  • Amsacrine
  • Cytarabine
  • Azacitidine

Eligibility Criteria

        Inclusion Criteria:

          1. At least 18 years of age or older

          2. Diagnosis of acute myeloid leukemia by World Health Organization classification

             First relapsed or refractory acute myeloid leukemia with at least 5% blasts by bone
             marrow biopsy or aspirate, or at least 1% blasts in peripheral blood, and meeting the
             following criteria:

             First relapsed acute myeloid leukemia :

               -  First relapse occurred at least 90 days to 24 months after the first complete
                  remission or complete remission with incomplete recovery

               -  The first complete remission or complete remission with incomplete recovery had
                  to result from no more than 2 cycles of cytotoxic chemotherapy. At least 1
                  induction cycle must have consisted of an anthracycline and cytarabine
                  combination with a reasonable schedule/dose of anthracycline in the judgment of
                  the investigator.

               -  The re-emergence of at least 5% leukemic blasts in bone marrow is not
                  attributable to other causes, regardless of new or recurrent dysplastic changes
                  or extramedullary disease, or the re-emergence of at least 1% blasts in the
                  peripheral blood is not attributable to other causes such as regenerating marrow.

             Refractory acute myeloid leukemia :

               -  Persistent acute myeloid leukemia was documented by bone marrow biopsy or
                  aspirate at least 28 days after day 1 of the first induction cycle of 1 or 2
                  cycles of cytotoxic chemotherapy.

               -  Re-emergence of at least 5% leukemic blasts in bone marrow or at least 1% blasts
                  in peripheral blood is not attributable to other causes such as regenerating
                  marrow, and was less than 90 days after the first complete remission or complete
                  remission with incomplete recovery.

               -  Prior induction therapy had to include no more than 2 cycles of cytotoxic
                  chemotherapy. At least 1 induction cycle must have consisted of an anthracycline
                  and cytarabine combination with a reasonable schedule/dose of anthracycline in
                  the judgment of the investigator.

          3. Eastern Cooperative Oncology Group performance status ≤ 2.

          4. Left ventricular ejection fraction ≥ 50% by echocardiogram or multi-gated acquisition
             scan ; only applicable for patients who will receive intensive chemotherapy.

          5. Serum creatinine ≤ 150 µmol/L and/or total bilirubin ≤ 1.5 × the upper limit of normal
             and/or, aspartate aminotransferase ≤ 2.5 × the upper limit of normal, and/or alanine
             aminotransferase ≤ 2.5 × the upper limit of normal (unless related to acute myeloid
             leukemia)

          6. Any clinically significant non-hematological toxicity after prior chemotherapy must be
             resolved or of grade 1 as per Common Terminology Criteria for Adverse Events version
             4.03.

          7. Women must be surgically or biologically sterile, or in post-menopause (amenorrheic
             for at least 12 months), or if of childbearing potential, must have a negative urine
             or serum pregnancy test within 14 days prior to the randomization and agree to use a
             highly effective method of contraception throughout the entire duration of the study
             treatment (including dose interruptions) and until 3 months after the last study
             treatment administration. Men must be surgically or biologically sterile, or agree to
             use a highly effective method of contraception throughout the entire duration of the
             study treatment (including dose interruptions) and until 6 months after the last study
             treatment administration.

          8. Registered to, or beneficiary of, social security insurance or equivalent.

          9. Signed written informed consent by both the patient and the investigator prior to
             perform any study-relayed procedure not part of normal medical care.

        Exclusion Criteria:

          1. Acute promyelocytic leukemia (M3 subtype of acute myeloid leukemia).

          2. More than 2 cycles of first line induction chemotherapy.

          3. Acute myeloid leukemia with Philadelphia chromosome or BCR-ABL1 or blast crisis stage
             of chronic myeloid leukemia.

          4. Known or suspected central nervous system leukemia.

          5. Undergoing allogeneic hematopoietic stem cell transplantation within 90 days prior to
             randomization, or being on immunosuppressive therapy for prophylaxis of
             graft-versus-host disease, or experiencing graft-versus-host disease within 2 weeks
             prior to randomization.

          6. Use of any experimental, cytotoxic, or targeted, anti-leukemic therapy within 14 days
             prior to randomization, with the exception of hydroxyurea.

          7. Formal contraindication to glucocorticoids.

          8. Non-acute myeloid leukemia-associated organic or psychiatric severe disease that
             contraindicates use of study treatment.

          9. Patient who may not be followed regularly in consultation because of psychological,
             family, social, or geographical reasons.

         10. History of uncontrolled other malignancy for at least two years, with the exception of
             basal cell carcinoma and in situ cervix carcinoma.

         11. Severe uncontrolled infection at time of inclusion.

         12. Positive serology for human immunodeficiency virus-1 or 2, and/or Human T-Cell
             lymphotropic viruses-1 or 2, and/or active viral infection with hepatitis B virus
             and/or hepatitis C virus.

         13. Pregnant (beta gonadotropic chorionic hormon positive) or breastfeeding woman.

         14. Incapable patient of age, under guardianship, curatorship or safeguard of justice.

         15. Patient under State Medical Assistance.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival
Time Frame:Up to 60 months
Safety Issue:
Description:Time from the date of randomization to the date of death from any cause

Secondary Outcome Measures

Measure:Response to therapy
Time Frame:Up to 60 months
Safety Issue:
Description:Best response of complete remission or complete remission with incomplete recovery as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
Measure:Minimal residual disease positivity
Time Frame:Up to 60 months
Safety Issue:
Description:Quantitative assessment by either quantitative polymerase chain reaction or multiparameter flow cytometry of any tumor cells greater than pre-specified sensitivity thresholds of detection
Measure:Number of patient who realize allogeneic hematopoietic stem cell transplantation
Time Frame:Up to 60 months
Safety Issue:
Description:Undergoing allogeneic hematopoietic stem cell transplantation
Measure:Duration of remission
Time Frame:Up to 60 months
Safety Issue:
Description:Time from the date of first complete remission or complete remission with incomplete recovery to the date of relapse, where complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
Measure:Relapse-free survival
Time Frame:Up to 60 months
Safety Issue:
Description:Time from the date of first complete remission or complete remission with incomplete recovery to the date of relapse or death from any cause, whichever occurs first, where complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
Measure:Event-free survival
Time Frame:Up to 60 months
Safety Issue:
Description:Time from the date of randomization to the date of treatment failure, or relapse from complete remission or complete remission with incomplete recovery, or death from any cause, whichever occurs first, where treatment failure, complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
Measure:Quality of life with leukemia questionnaire
Time Frame:At baseline, through complete remission, on Day 1 before dosing of each post-remission cycle, at 60 months
Safety Issue:
Description:Scoring of functional assessment of cancer therapy - Leukemia questionnaire
Measure:Adverse events
Time Frame:During 60 months
Safety Issue:
Description:Adverse events reported according to the descriptions and grading scale found in the version 4.03 of the National Cancer Institute - Common Terminology Criteria for Adverse Events

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University Hospital, Toulouse

Trial Keywords

  • dexamethasone
  • acute myeloid leukemia
  • relapse
  • refractory
  • azacitidine
  • amsacrine
  • cytarabine
  • randomized controlled trial

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