Single Agent Decitabine in TP53 Mutated Relapsed/Refractory Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia; Acute Myeloid Leukemia, Relapsed, Adult
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Decitabine; Bone marrow biopsy/aspirate; Peripheral blood draw; Skin biopsy; Buccal swab
Intervention description: After 2 cycles, patients with progressive disease or relapse (a clear progression with at least >20% bone marrow blasts and an increase of at least 50% from prior biopsy) should be removed from protocol and proceed to salvage treatment according to center preference
Transplant eligible patients who achieve CR, CRc, or CRi, after 3 cycles with a suitable donor will proceed to conditioning regimen and transplant
Transplant eligible patients with PR after 3 cycles may be removed from protocol and proceed to salvage treatment according to center preference
Transplant eligible patients with a suitable donor who achieve mLFS, CR, CRc, or CRi, may proceed to transplant after at 3 cycles
Transplant ineligible patients with (CR, CRc or CRi, PR) will continue on maintenance doses
Transplant ineligible patient with SD after cycle 4 may be removed from protocol and proceed to alternative treatment or continue on protocol according to treating physician's preference.; Baseline, Cycle 1 Day 10, Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, and Progression or relapse
Biopsy/aspirate on Cycle 1 Day 10 is for participants enrolled at Washington University only
Biopsy/aspirate on Cycle 2 Day 28 is at the discretion of the treating physician; -Baseline, Cycle 1 Day 10, Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, and Progression/Relapse; Optional but if refuse skin biopsy then participant can provided buccal swab
There is no required time frame for this sample - it may have been collected months or even years prior to the first dose of decitabine
If WBC at time of enrollment is >30,000/µl, skin biopsy should be collected at the time of C1D28 bone marrow biopsy or thereafter; -Baseline (if skin biopsy declined) and Cycle 2 Day 28
Intervention MeSH terms: Decitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      In this study, the investigators seek to determine whether decitabine therapy can improve
      outcomes, specifically overall survival this selected subset of acute myeloid leukemia (AML)
      patients with the poorest prognosis based on refractoriness to induction treatment and high
      risk genetic mutations.
    

Eligibility criteria:

        Inclusion Criteria:

          -  TP53 mutant AML. The presence of a TP53 mutation should be determined by Genoptix (or
             institutional preferred equivalent assay). Detection of a TP53 mutation at the time of
             initial diagnosis is sufficient for enrollment at the time of relapsed/refractory
             disease. Detection of a TP53 mutation in either the peripheral blood or bone marrow is
             adequate for enrollment. Alternatively, patients who have not had TP53 mutation
             analysis performed, but who have > 20% TP53 positive cells by immunohistochemistry
             detected on a bone marrow aspirate may also be enrolled,29 provided that mutation
             analysis is requested at the time of enrollment.

          -  Relapsed/refractory AML following 7+3 (or similar cytarabine containing induction
             chemotherapy for AML) disease detected by one of the following methods:

               -  bone marrow blasts > 5%, or

               -  Hematologics flow cytometry assay (threshold > 0.5%) (alternative equivalent
                  assay may be substituted), or

               -  Persistent cytogenetic abnormality (e.g. del5, del17p, etc), by FISH or
                  conventional karotyping, or

               -  Persistent TP53 mutation (at least 5 variant reads with at least 50x coverage)
                  determined by Genoptix (or institutional preferred equivalent assay).

          -  Patients with > 10% blasts on a day +14 bone marrow biopsy following 7+3 may either be
             enrolled or may be treated with a course of standard re-induction (e.g. 5+2 or
             similar) and then re-evaluated for response. Eligible patients will meet any of the
             above criteria on a subsequent biopsy.

          -  Bone marrow and organ function as defined below:

               -  Peripheral white blood cell count < 50,000/mcl (patients may receive hydroxyurea
                  as necessary for cytoreduction),

               -  Total bilirubin < 1.5 x upper limit of normal,

               -  AST and ALT < 2.5 x upper limit of normal,

               -  Serum creatinine < 2.0 x upper limit of normal, and,

          -  At least 18 years of age.

          -  Women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control, abstinence) prior to study entry and for
             the duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while participating in this study, she must inform her treating physician
             immediately

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable

          -  Performance status ≤ 3

        Exclusion Criteria:

          -  Prior treatment with either decitabine or azacitidine or an investigational agent

          -  Acute promyelocytic leukemia with PML-RARA or t(15;17).

          -  History of HIV, Hepatitis B, or Hepatitis C infection.

          -  Concurrent illness including, but not limited to, ongoing uncontrolled infection,
             symptomatic NYHA class 3 or 4 congestive heart failure, unstable angina pectoris, or
             cardiac arrhythmia.

          -  Radiation therapy within 14 days of enrollment.

          -  Chemotherapy administration in the 7 days preceding enrollment with the exception of
             hydroxyurea, which can be continued until Cycle 2. A washout period for oral tyrosine
             kinase inhibitors (e.g. Jakafi, etc) is not required, although tyrosine kinase
             inhibitors therapy must be discontinued prior to enrollment.

          -  Malignancies (other than AML) requiring active therapy or diagnosed within the last
             year, with the exception of non-melanoma skin cancer which can be treated or in situ
             malignancies (such as cervical, breast, prostate, etc.)

          -  Currently receiving any other investigational agents.

          -  Known central nervous system (CNS) leukemia or testicular involvement of leukemia

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to decitabine or other agents used in the study.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             urine pregnancy test within 7 days of study entry.