Clinical Trials /

Testing Nivolumab in Combination With Decitabine and Venetoclax in Patients With Newly Diagnosed TP53 Gene Mutated Acute Myeloid Leukemia

NCT04277442

Description:

This trial studies the side effects of nivolumab in combination with decitabine and venetoclax and to see how well they work in treating patients with TP53-mutated acute myeloid leukemia. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as decitabine and venetoclax, 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. This study is being done to find out whether giving nivolumab, decitabine, and venetoclax is better or worse than the usual approach for TP53-mutated acute myeloid leukemia.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing Nivolumab in Combination With Decitabine and Venetoclax in Patients With Newly Diagnosed TP53 Gene Mutated Acute Myeloid Leukemia
  • Official Title: A Pilot Study of Nivolumab in Combination With Decitabine and Venetoclax in TP53-Mutated Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-01125
  • SECONDARY ID: NCI-2020-01125
  • SECONDARY ID: OSU 19305
  • SECONDARY ID: 10317
  • SECONDARY ID: 10317
  • SECONDARY ID: UM1CA186712
  • NCT ID: NCT04277442

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Decitabine5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineTreatment (nivolumab, decitabine, venetoclax)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, decitabine, venetoclax)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (nivolumab, decitabine, venetoclax)

Purpose

This trial studies the side effects of nivolumab in combination with decitabine and venetoclax and to see how well they work in treating patients with TP53-mutated acute myeloid leukemia. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as decitabine and venetoclax, 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. This study is being done to find out whether giving nivolumab, decitabine, and venetoclax is better or worse than the usual approach for TP53-mutated acute myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To obtain preliminary data regarding the safety and tolerability of decitabine and
      venetoclax in combination with nivolumab when given for frontline therapy in TP53 mutated
      acute myeloid leukemia (AML) patients.

      II. To obtain preliminary data regarding the rate of complete remission (CR), complete
      remission with incomplete hematological recovery (CRh), and complete remission with
      incomplete count recovery (CRi) in TP53 mutated AML who are treated with decitabine and
      venetoclax in combination with nivolumab for frontline therapy.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. II. To obtain preliminary data regarding
      progression free survival (PFS) for TP53 mutated AML patients receiving combination therapy.

      III. To obtain preliminary data regarding the overall survival (OS) for TP53 mutated patients
      receiving this combination therapy.

      IV. To obtain preliminary data regarding minimal residual disease through monitoring TP53
      mutational burden prior and throughout treatment.

      V. To obtain preliminary data regarding the frequency of graft versus host disease (GVHD)
      including veno-occlusive disease (VOD) in patients who subsequently receive allogeneic
      transplantation after this combination therapy.

      OUTLINE:

      INDUCTION: Patients receive nivolumab intravenously (IV) over 30 minutes on day 15 of cycle 1
      and days 1 and 15 of subsequent cycles, decitabine IV over 60 minutes on days 1-10 of
      induction cycle 1 (and cycles 2 and 3 if needed), and venetoclax orally (PO) once daily (QD)
      on days 1-21. Treatment repeats every 28 days for up to 3 cycles in the absence of disease
      progression or unacceptable toxicity.

      MAINTENANCE: Patients who achieve a CR or CRi receive nivolumab IV over 30 minutes on days 1
      and 15, decitabine IV over 60 minutes on days 1-5, and venetoclax PO QD on days 1-21. Cycles
      repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, decitabine, venetoclax)ExperimentalINDUCTION: Patients receive nivolumab IV over 30 minutes on day 15 of cycle 1 and days 1 and 15 of subsequent cycles, decitabine IV over 60 minutes on days 1-10 of induction cycle 1 (and cycles 2 and 3 if needed), and venetoclax PO QD on days 1-21. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients who achieve a CR or CRi receive nivolumab IV over 30 minutes on days 1 and 15, decitabine IV over 60 minutes on days 1-5, and venetoclax PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Decitabine
  • Nivolumab
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed acute myeloid leukemia
             (AML)

          -  Presence of TP53 mutation at diagnosis

          -  Newly diagnosed, untreated AML

          -  Patients who received prior hypomethylating therapy for a prior myelodysplastic
             syndrome (MDS) diagnosis are allowed

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), (except for
             patients with Gilbert's disease)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 5 x institutional ULN

          -  Glomerular filtration rate (GFR) > 40 mL/min/1.73 m^2

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association functional classification. To be
             eligible for this trial, patients should be class 2B or better. A baseline troponin
             should be within normal limits and baseline oxygen saturation should be greater than
             or equal to 92%. A baseline electrocardiogram (ECG) should be normal, or with stable
             changes if patient has chronic ECG changes

          -  Active infection is permitted if the infection is under control

          -  White blood count (WBC) must be =< 25,000 at time of day 1 of study treatment.
             Cytoreduction with Hydrea and leukapheresis is allowed

          -  Risks from venetoclax and nivolumab to the developing human fetus cannot be ruled out.
             For this reason and because decitabine is 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 and for the duration
             of study participation. Should a woman become pregnant or suspect she is pregnant
             while she or her partner is participating in this study, she should inform her
             treating physician immediately. Contraception use should be continued 6 months after
             the completion of all study treatments for women of child bearing potential. Men
             treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of study participation, and 7 months after
             completion of decitabine, venetoclax, or nivolumab administration

          -  Ability to understand and the willingness to sign a written informed consent document.
             Patients with impaired decision-making are allowed to participate as long as the
             patient has a legally authorized representative (LAR) or caregiver

        Exclusion Criteria:

          -  Patients with history of prior allogeneic transplantation. This is due to this being a
             pilot study with a limited number of patients

          -  Patients with known autoimmune disease. Patients with active autoimmune disease or
             history of autoimmune disease that might recur, which may affect vital organ function
             or require immune suppressive treatment including systemic corticosteroids, should be
             excluded. These include but are not limited to patients with a history of immune
             related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy,
             Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as
             systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma,
             inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients
             with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or
             phospholipid syndrome should be excluded because of the risk of recurrence or
             exacerbation of disease. Patients with vitiligo, endocrine deficiencies including
             thyroiditis managed with replacement hormones including physiologic corticosteroids
             are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's
             syndrome and psoriasis controlled with topical medication and patients with positive
             serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be
             evaluated for the presence of target organ involvement and potential need for systemic
             treatment but should otherwise be eligible

          -  Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
             residual hypothyroidism due to autoimmune condition only requiring hormone
             replacement, psoriasis not requiring systemic treatment, or conditions not expected to
             recur in the absence of an external trigger (precipitating event)

          -  Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids (> 10 mg daily prednisone equivalents) or other
             immunosuppressive medications within 14 days of study drug administration. Inhaled or
             topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents
             are permitted in the absence of active autoimmune disease. Patients are permitted to
             use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
             (with minimal systemic absorption). Physiologic replacement doses of systemic
             corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents. A brief
             course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
             treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
             caused by contact allergen) is permitted

          -  Patients with hyperleukocytosis requiring immediate cytoreductive chemotherapy (WBC >=
             100,000 with symptoms of leukostasis)

          -  Isolated extramedullary leukemia of central nervous system (CNS) involvement with
             leukemia

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1) with the exception of alopecia

          -  Patients who are receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to decitabine, venetoclax, or nivolumab

          -  Patients with uncontrolled intercurrent illness

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because fetal risk has been demonstrated
             with decitabine with the potential for teratogenic or abortifacient effects. Because
             there is an unknown but potential risk for adverse events in nursing infants secondary
             to treatment of the mother with decitabine, breastfeeding should be discontinued if
             the mother is treated with decitabine. These potential risks may also apply to other
             agents used in this 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
Time Frame:Up to end of cycle 3 (each cycle is 28 days)
Safety Issue:
Description:Toxicity will be graded and reported according to the revised National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Secondary Outcome Measures

Measure:Anti-tumor activity
Time Frame:Up to 3 years
Safety Issue:
Description:Patients will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. Data that are collected serially over time will be explored graphically using box plots and/or individual time plots as well as analytically with either repeated measures analysis of variance or Friedman's nonparametric test.
Measure:Progression-free survival
Time Frame:Up to 3 years
Safety Issue:
Description:95% confidence intervals will be given.
Measure:Overall survival
Time Frame:Up to 3 years
Safety Issue:
Description:95% confidence intervals will be given.
Measure:Minimal residual disease (MRD)
Time Frame:Up to 3 years
Safety Issue:
Description:Will assess MRD by measuring the TP53 mutational burden with variant allele frequency before and after response is achieved to see if there is a change. Will also evaluate its association with MRD status at each time point using chi-square test of independence.
Measure:T cell response
Time Frame:Up to 3 years
Safety Issue:
Description:Will study the T cell response against both tumor associated antigen and tumor specific antigen. Analyses of the data will be primarily descriptive in nature given the relatively small sample size.
Measure:Deoxyribonucleic acid (DNA) methylation
Time Frame:Up to 3 years
Safety Issue:
Description:Will study the level of global DNA methylation as well as methylation levels of specific genes involved in immune checkpoint, such as PD-L1, PD-L2, PD-1 and CTLA4. Analyses of the data will be primarily descriptive in nature given the relatively small sample size.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 2, 2020