Clinical Trials /

Pembrolizumab and Decitabine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome That Is Newly-Diagnosed, Recurrent, or Refractory

NCT03969446

Description:

This phase Ib trial studies the side effects and best dose of pembrolizumab and how well it works in combination with decitabine in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is newly-diagnosed, has come back, or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as pembrolizumab, 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, 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 trial may help doctors find the best dose of pembrolizumab that can be safely given in combination with decitabine, and to determine what side effects are seen with this treatment.

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

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Decitabine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome That Is Newly-Diagnosed, Recurrent, or Refractory
  • Official Title: Phase 1b Study of Pembrolizumab and Decitabine Combination Therapy in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: 19107
  • SECONDARY ID: NCI-2019-03153
  • SECONDARY ID: 19107
  • NCT ID: NCT03969446

Conditions

  • Acute Myeloid Leukemia
  • High Risk Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Recurrent High Risk Myelodysplastic Syndrome
  • Refractory Acute Myeloid Leukemia
  • Refractory High Risk Myelodysplastic Syndrome
  • Secondary Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Decitabine5-Aza-2'-deoxycytidine, Aza-TdC, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineCohort I (pembrolizumab, decitabine)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Cohort I (pembrolizumab, decitabine)

Purpose

This phase Ib trial studies the side effects and best dose of pembrolizumab and how well it works in combination with decitabine in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is newly-diagnosed, has come back, or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as pembrolizumab, 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, 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 trial may help doctors find the best dose of pembrolizumab that can be safely given in combination with decitabine, and to determine what side effects are seen with this treatment.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Assess the safety and tolerability of pembrolizumab in combination with decitabine, by
      evaluation of toxicities including: type, frequency, severity, attribution, time course and
      duration.

      II. Determine the maximum tolerated dose(s)/schedule (MTD) and phase 2 recommended dose(s)/
      schedule (RP2D) of the combination for acute myeloid leukemia (AML) and high-risk
      myelodysplastic syndrome (MDS).

      III. Obtain preliminary estimate of complete remission (CR/CR with incomplete hematologic
      recovery [CRi]) rate.

      SECONDARY OBJECTIVES:

      I. Obtain estimates of remission duration and survival probabilities (overall and
      progression-free) at 2 years.

      II. Explore the possible association between pre-treatment PD-1, PD-L1, and PD-L2 and
      clinical response.

      III. Evaluate change in PD-1, PD-L1, PD-L2 levels as a result of the combination therapy.

      IV. Explore the possible association between specific T cell subsets (e.g. CD4 T regulatory
      cells, T naive, effector and memory cells), other immunological correlatives (e.g. T-cell
      receptor [TCR] repertoire analysis) including post-treatment changes, and clinical response
      to combination therapy.

      OUTLINE: Patients are assigned to 1 of 2 cohorts.

      COHORT I: Patients with AML receive pembrolizumab intravenously (IV) over 30 minutes on days
      1 and 22 and decitabine IV over 1 hour on days 1-10. Patients who achieve a CR receive
      decitabine on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from
      start of therapy, whichever comes first, in the absence of disease progression or
      unacceptable toxicity.

      COHORT II: Patients with MDS receive pembrolizumab IV over 30 minutes on days 1 and 22 and
      decitabine over 1 hour on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1
      year from start of therapy, whichever comes first, in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days, then every 3 and 6
      months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort I (pembrolizumab, decitabine)ExperimentalPatients with AML receive pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine IV over 1 hour on days 1-10. Patients who achieve a CR receive decitabine on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.
  • Decitabine
  • Pembrolizumab
Cohort II (pembrolizumab, decitabine)ExperimentalPatients with MDS receive pembrolizumab IV over 30 minutes on days 1 and 22 and decitabine over 1 hour on days 1-5. Treatment repeats every 42 days for up to 8 cycles or 1 year from start of therapy, whichever comes first, in the absence of disease progression or unacceptable toxicity.
  • Decitabine
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Documented informed consent of the participant and/or legally authorized
             representative

          -  Agreement to allow the use of archival blood samples and marrow from diagnostic tumor
             biopsies. If unavailable, exceptions may be granted with study principal investigator
             (PI) approval

          -  Eastern Cooperative Oncology Group (ECOG) status of 0-1

          -  Histologically confirmed AML or MDS with the following characteristics

          -  Patients diagnosed with AML by World Health Organization (WHO) classification, meeting
             one of following criteria:

               -  Age 60 or older, newly diagnosed, untreated, who are unwilling to undergo or not
                  candidates for conventional induction chemotherapy with cytarabine/anthracyclines

               -  Age 60 or older with relapsed or refractory disease

               -  Adult patients < 60 with previously untreated high-risk disease (complex
                  karyotype, inv(3) or t(3;3), t(6;9), monosomal karyotype, therapy-related and
                  secondary disease) that are unwilling to undergo or not candidates for
                  conventional induction chemotherapy with cytarabine/anthracyclines and/or
                  allogeneic stem cell transplantation

               -  Adult patients < 60 with refractory/relapsed AML who are otherwise not candidates
                  for allogeneic stem cell transplantation

               -  Patients with extramedullary disease who meet one of the above criteria may be
                  included

          -  Patients with a diagnosis of MDS as per WHO Classification that meets one of the
             following treatment history criteria

               -  Newly diagnosed high-risk MDS (International Prognostic Scoring System [IPSS]:
                  intermediate 2 and high risk)

               -  Refractory to or relapsed after previous therapies

               -  Human leukocyte antigen (HLA)-DR15-positive MDS that has failed immunosuppressive
                  therapies

          -  Must have a life expectancy of >= 3 months

          -  Fully recovered (=< grade 1) from the acute toxic effects (except alopecia) of prior
             anti-cancer therapy

          -  Cannot be a candidate for allogeneic hematopoietic cell transplantation (alloHCT)
             within 90 days of starting treatment on the protocol and should be off pembrolizumab
             for at least 30 days to become eligible for alloHCT post-protocol therapy

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless has Gilbert?s disease)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN or =<
             5 x ULN

          -  Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault
             formula

          -  International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN

          -  Left ventricular ejection fraction (LVEF) >= 50%

          -  Corrected QT (QTc) =< 480 ms, Note: electrocardiogram (ECG) to be performed within 14
             days prior to day 1 of protocol therapy

          -  Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo,
             hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative),
             and syphilis (rapid plasma reagin [RPR]) (within 28 days prior to day 1 of protocol
             therapy)

               -  If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed

          -  Meets other institutional and federal requirements for infectious disease titer
             requirements

               -  Note: Infectious disease testing to be performed within 28 days prior to day 1 of
                  protocol therapy

          -  Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

          -  Agreement by males and females of childbearing potential to use an effective birth
             control method of low user dependency or abstain from heterosexual activity from 4
             weeks prior to first dose of treatment throughout the study treatment period and 3
             (males) to 4 (females) months from the last dose of treatment

               -  Childbearing potential is defined as not being surgically sterilized (men and
                  women) or have not been free from menses for > 1 year (women only)

          -  Also, male subjects should refrain from sperm donation from the start of treatment
             throughout the study treatment period and for 6 months following the last dose of
             treatment

        Exclusion Criteria:

          -  Previous allogeneic cell transplantation for at least 1 year (yr) prior, have no
             history of graft versus host disease (GVHD) and been off all immunosuppression for at
             least 3 months

          -  Previous treatment with pembrolizumab

          -  Systemic steroid therapy or any other form of immunosuppressive medication

          -  Received a live-virus vaccination within 30 days of planned treatment start

          -  Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD
             ligand-1 (PD-L1) or PD ligand-2 (PD-L2) agent or an antibody targeting other
             immuno-regulatory receptors or mechanisms

          -  Prior therapy with an anti-CD137, anti-CTLA-4 antibody (including ipilimumab),
             denosumab or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways

          -  Current or planned use of other investigational agents, or concurrent biological,
             chemotherapy, or radiation therapy during the study treatment period, or within 4
             weeks prior to day 1 of protocol therapy

          -  Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery
             within 4 weeks prior to day 1 of protocol therapy

          -  Concurrent use of corticosteroids (exception: nasal or topical corticosteroids or
             physiologic levels for steroid replacement are allowed)

          -  Concurrent use of granulocyte-macrophage colony-stimulating factor (GMCSF) or
             granulocyte colony stimulating factor (GCSF), or within 7 days prior to start of study
             treatment

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to study agent

          -  Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)

          -  Active central nervous system (CNS) disease

          -  History of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Active autoimmune disease that has required systemic treatment in the past 2 years
             (replacement therapies for hormone deficiencies are allowed)

          -  Uncontrolled active infection requiring therapy

          -  Seronegative for HIV Ag/Ab combo, HCV, active HBV (surface antigen negative), and
             syphilis (RPR).

               -  If positive, hepatitis C RNA quantitation must be performed

          -  Known history of active TB (Bacillus tuberculosis)

          -  History of deep venous thrombosis (DVT) or pulmonary embolism

          -  Symptomatic ascites or pleural effusion

          -  Clinically significant uncontrolled illness

          -  Females only: Pregnant or breastfeeding

          -  Any other condition that would, in the investigator?s judgment, contraindicate the
             patient?s participation in the clinical study due to safety concerns with clinical
             study procedures

          -  Prospective participants who, in the opinion of the investigator, may not be able to
             comply with all study procedures (including compliance issues related to
             feasibility/logistics)
      
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 2 years
Safety Issue:
Description:Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.

Secondary Outcome Measures

Measure:Response duration
Time Frame:From date of first documented response (CR + CRi) to documented disease relapse or death whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier.
Measure:Overall survival
Time Frame:From date of first dose of study drug to date of death from any cause, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier.
Measure:Progression-free survival
Time Frame:From date of first dose of study drug to first documented disease relapse/progression or death from any cause, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the product-limit method of Kaplan and Meier.
Measure:Change in PD-1, PD-L1, and PD-L2 levels
Time Frame:Baseline up to 2 years
Safety Issue:
Description:
Measure:Change in T cell subset distribution
Time Frame:Baseline up to 2 years
Safety Issue:
Description:
Measure:Change in T cell receptor repertoire
Time Frame:Baseline up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:City of Hope Medical Center

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