Clinical Trials /

Salsalate, Venetoclax, and Decitabine or Azacitidine for the Treatment of Acute Myeloid Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease

NCT04146038

Description:

This phase II trial studies the side effects of salsalate when added to venetoclax and decitabine or azacitidine in treating patients with acute myeloid leukemia or myelodysplasia/myeloproliferative disease that has spread to other places in the body (advanced). Drugs used in chemotherapy, such as salsalate, venetoclax, decitabine, and azacitidine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Related Conditions:
  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic Syndromes
  • Myeloproliferative Neoplasm
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Salsalate, Venetoclax, and Decitabine or Azacitidine for the Treatment of Acute Myeloid Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease
  • Official Title: Salsalate + Venetoclax/Decitabine for Patients With Acute Myelogenous Leukemia or Advanced Myelodysplasia/Myeloproliferative Disease

Clinical Trial IDs

  • ORG STUDY ID: 021905
  • SECONDARY ID: NCI-2019-07031
  • SECONDARY ID: Pro2019001209
  • SECONDARY ID: 021905
  • SECONDARY ID: P30CA072720
  • NCT ID: NCT04146038

Conditions

  • Acute Myeloid Leukemia
  • Chronic Myelomonocytic Leukemia
  • Myeloblasts 10 Percent or More of Bone Marrow Nucleated Cells
  • Myelodysplastic Syndrome
  • Myeloproliferative Neoplasm
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia
  • Secondary Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (salsalate, decitabine, azacitidine, venetoclax)
Decitabine5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (salsalate, decitabine, azacitidine, venetoclax)
SalsalateDisalcid, Mono-Gesic, o-Salicylsalicylic Acid, Salflex, Salicylsalicylic Acid, SalsitabTreatment (salsalate, decitabine, azacitidine, venetoclax)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (salsalate, decitabine, azacitidine, venetoclax)

Purpose

This phase II trial studies the side effects of salsalate when added to venetoclax and decitabine or azacitidine in treating patients with acute myeloid leukemia or myelodysplasia/myeloproliferative disease that has spread to other places in the body (advanced). Drugs used in chemotherapy, such as salsalate, venetoclax, decitabine, and azacitidine work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Determine the tolerability of the addition of standard dose salsalate to the standard
      treatment combination of venetoclax + hypomethylating agent (HMA) (decitabine or azacitidine
      [5-azacytidine]).

      SECONDARY OBJECTIVES:

      I. Determine the remission rate and, when feasible, perform exploratory studies of:

      Ia. Patterns of mutation clearance. Ib. Distribution of cells with low and high reactive
      oxygen species (ROS) content at various points during therapy.

      OUTLINE:

      CYCLE 1: Patients receive salsalate orally (PO) twice daily (BID) until completion of cycle
      1. 24-48 hours later or concurrent with salsalate, patients begin to receive decitabine
      intravenously (IV) for 10 days or azacitidine IV for 7 days. Starting 24 hour after
      salsalate, patients also receive venetoclax PO continuously until completion of cycle 1.

      CYCLE 2: Patients receive decitabine IV for 5 days or azacitidine IV for 7 days, salsalate PO
      BID, and venetoclax PO continuously.

      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (salsalate, decitabine, azacitidine, venetoclax)ExperimentalCYCLE 1: Patients receive salsalate PO BID until completion of cycle 1. 24-48 hours later or concurrent with salsalate, patients begin to receive decitabine IV for 10 days or azacitidine IV for 7 days. Starting 24 hour after salsalate, patients also receive venetoclax PO continuously until completion of cycle 1. CYCLE 2: Patients receive decitabine IV for 5 days or azacitidine IV for 7 days, salsalate PO BID, and venetoclax PO continuously. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Decitabine
  • Salsalate
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically proven acute myelogenous leukemia (AML) or advanced myeloid malignancy
             [myelodysplasia; chronic myelomonocytic leukemia (CMML); or chronic myeloproliferative
             disease (MPD) each with >= 10% myeloblasts in blood or bone marrow]

          -  For patients with de novo AML: must not be a candidate for standard induction therapy
             based upon age, co-morbidities, patient choice, high risk features known to have poor
             outcomes with standard induction therapy (ELN high risk disease by cytogenetics,
             deoxyribonucleic acid [DNA] mutation profile or TP53 mutation)

          -  Patients with advanced myelodysplastic syndrome (MDS), secondary AML,
             relapsed/refractory AML, prior hypomethylating agent are eligible

          -  Patients must give informed consent

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =<
             2

          -  Total bilirubin < 2 x upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             < 2.5 X institutional ULN

          -  Creatinine < 2 mg/dL

        Exclusion Criteria:

          -  White blood cell (WBC) uncontrolled (> 15,000/uL) despite hydroxyurea or cytarabine x
             3 days. Known central nervous system (CNS) AML

          -  Serious concomitant systemic disorders (including active infections) that would
             compromise the safety of the patient or compromise the patient?s ability to complete
             the study, at the discretion of the investigator. Pregnant patients are excluded

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to Salsalate or other agents used in the study. Examples include aspirin

          -  The effects of venetoclax and decitabine or 5-azacytidine on the developing human
             fetus at the recommended therapeutic dose are unknown. For this reason and because
             therapeutic agents used in this trial are known to be teratogenic, women of
             child-bearing potential and men must agree to use adequate contraception (hormonal or
             barrier method of birth control; abstinence) prior to study entry, for the duration of
             study participation and for 24 weeks after. Should a woman become pregnant or suspect
             she is pregnant while participating in this study, she should inform her treating
             physician immediately

          -  Patients with immune deficiency are at increased risk of lethal infections when
             treated with marrow-suppressive therapy, therefore, known human immunodeficiency virus
             (HIV)-positive patients receiving combination anti-retroviral therapy are excluded
             from the study because of possible pharmacokinetic interactions with treatment
             medications or other agents administered during the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events of salicylate + venetoclax + decitabine
Time Frame:During the first 2 cycles (56 days), up to 3 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Response rates
Time Frame:During the first 2 cycles (56 days), up to 3 years
Safety Issue:
Description:Wwill correspond response rates with the pattern of survival of low oxygen reactive species cells. The administration of drugs will be timed to determine if there is a measurable added effect of salicylate on the oxidative state of cells when used in combination with venetoclax + decitabine. Next generation sequencing will determine also if there is a correspondence of remission with patterns of mutation clearance and/or effects of treatment on the oxidative state of the leukemia cells.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Rutgers, The State University of New Jersey

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