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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03969446
Recruitment Status : Not yet recruiting
First Posted : May 31, 2019
Last Update Posted : December 26, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Decitabine Biological: Pembrolizumab Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 54 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b Study of Pembrolizumab and Decitabine Combination Therapy in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
Estimated Study Start Date : February 1, 2020
Estimated Primary Completion Date : June 7, 2021
Estimated Study Completion Date : June 21, 2021


Arm Intervention/treatment
Experimental: Cohort I (pembrolizumab, decitabine)
Patients 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.
Drug: Decitabine
Given IV
Other Names:
  • 5-Aza-2'-deoxycytidine
  • Aza-TdC
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Experimental: Cohort II (pembrolizumab, decitabine)
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.
Drug: Decitabine
Given IV
Other Names:
  • 5-Aza-2'-deoxycytidine
  • Aza-TdC
  • Dacogen
  • Decitabine for Injection
  • Deoxyazacytidine
  • Dezocitidine

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 2 years ]
    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.

  2. Maximum-tolerated dose (MTD) [ Time Frame: Up to day 42 ]
    Will be based on the assessment of dose-limiting toxicities (DLTs) during cycle 1 and NCI CTCAE version 5.0. Standard 3+3 design rules will govern enrollment and dose de-escalation. In each arm, the dose level that produces =< 1/6 DLTs will be declared the MTD.

  3. Response to treatment [ Time Frame: Up to 2 years ]
    Will obtain preliminary estimates of complete remission (CR)+CR with incomplete hematologic recovery (CRi). Patients will have their response classified according to modified Cheson, 2006 criteria (myelodysplastic syndrome cohort) and Dohner et al., 2017 criteria (acute myeloid leukemia cohort). Rates and 95% Clopper-Pearson binomial confidence interval will be calculated for the complete remission rate (patients that have confirmed CR/CRi). Response rates will also be explored based on number/type of prior therapy(ies).


Secondary Outcome Measures :
  1. 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 ]
    Will be estimated using the product-limit method of Kaplan and Meier.

  2. Overall survival [ Time Frame: From date of first dose of study drug to date of death from any cause, assessed up to 2 years ]
    Will be estimated using the product-limit method of Kaplan and Meier.

  3. 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 ]
    Will be estimated using the product-limit method of Kaplan and Meier.

  4. Change in PD-1, PD-L1, and PD-L2 levels [ Time Frame: Baseline up to 2 years ]
  5. Change in T cell subset distribution [ Time Frame: Baseline up to 2 years ]
  6. Change in T cell receptor repertoire [ Time Frame: Baseline up to 2 years ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03969446


Locations
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United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
Contact: Guido Marcucci    626-256-4673 ext 62705    gmarcucci@coh.org   
Principal Investigator: Guido Marcucci         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Guido Marcucci City of Hope Medical Center

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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT03969446    
Other Study ID Numbers: 19107
NCI-2019-03153 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
19107 ( Other Identifier: City of Hope Medical Center )
First Posted: May 31, 2019    Key Record Dates
Last Update Posted: December 26, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Pembrolizumab
Decitabine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors