Clinical Trials /

Azacitidine and Pembrolizumab in Treating Patients With Myelodysplastic Syndrome

NCT03094637

Description:

This phase II trial studies the side effects of azacitidine and pembrolizumab and to see how well they work in treating patients with myelodysplastic syndrome. Azacitidine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving azacitidine and pembrolizumab may work better at treating myelodysplastic syndrome.

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Azacitidine and Pembrolizumab in Treating Patients With Myelodysplastic Syndrome
  • Official Title: A Phase II Study of the Combination of Azacitidine and Pembrolizumab for Patients With MDS

Clinical Trial IDs

  • ORG STUDY ID: 2016-0343
  • SECONDARY ID: NCI-2018-01238
  • SECONDARY ID: 2016-0343
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03094637

Conditions

  • High Risk Myelodysplastic Syndrome
  • IPSS Risk Category Intermediate-1
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaTreatment (azacitidine, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (azacitidine, pembrolizumab)

Purpose

This phase II trial studies the side effects of azacitidine and pembrolizumab and to see how well they work in treating patients with myelodysplastic syndrome. Azacitidine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving azacitidine and pembrolizumab may work better at treating myelodysplastic syndrome.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the safety of the combination of azacitidine and MK3475 (pembrolizumab) in
      patients with higher risk myelodysplastic syndrome (MDS).

      II. To explore the clinical activity (response, survival effect) of the combination of
      azacitidine with MK-3475 in patients with higher risk MDS.

      EXPLORATORY OBJECTIVES:

      I. To study the biological effects of the combination of azacitidine and pembrolizumab in
      patients with MDS treated on this study.

      OUTLINE:

      Patients receive azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) on
      days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up within 30 days, every 12 weeks
      for 1 year, then annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (azacitidine, pembrolizumab)ExperimentalPatients receive azacitidine IV over 10-40 minutes or SC on days 1-7, and pembrolizumab IV over 30 minutes every 3 weeks. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Azacitidine
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Voluntary signed informed consent before performance of any study related procedure
             not part of normal medical care indicating that the patient is aware of the
             investigation and nature of this study in keeping with institutional policies and with
             the understanding that the consent may be withdrawn with the subject at any time
             without prejudice to future medical care

          -  Intermediate 1 (INT-1) or higher risk MDS defined by International Prognostic Scoring
             System (IPSS) criteria

          -  Patients can or cannot have receive prior therapy with hypomethylating agent but will
             be allocated to specific patient cohorts based on their prior exposure. Patients that
             had received prior hypomethylating agent therapy should have at least received 6
             cycles of therapy and not achieved any response or had progressed after any given
             number of cycles

          -  Eastern Cooperative Oncology Group (ECOG) performance of 0 to 2

          -  Male patients, even if surgically sterilized, should agree to practice effective
             barrier contraception for the entire study treatment period and through 120 days after
             the last dose of the study treatment or agree to completely abstain from heterosexual
             intercourse. Female patients who are postmenopausal for at least one year before the
             screening visit or are surgical sterile or if they are of child bearing potential must
             have a negative pregnancy test within 72 hours of treatment of the start date and
             agree to practice two effective methods of contraception forms at the same time from
             the time of signing the informed consent through 120 days of the last dose of the
             study treatment or agree to completely abstain from heterosexual intercourse

          -  Willingness and ability to comply with scheduled visits treatment plans, laboratory
             tests and other study procedures

          -  Serum creatinine or measured or calculated creatine clearance (glomerular filtration
             rate [GFR] can also be used in place of creatinine or creatinine clearance [CrcL]) =<
             2.0 x upper limit of normal (ULN) or >= 60 mL/min for subject with creatinine levels >
             1.5 x institutional ULN (performed within 10 days of treatment initiation). Creatinine
             clearance should be calculated per institutional standard

          -  Serum total bilirubin =< 2.0 x ULN (unless considered due to Gilbert's disease or
             leukemia disease) or direct bilirubin =< ULN for subjects with total bilirubin levels
             > 1.5 ULN (performed within 10 days of treatment initiation)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             ULN (unless considered due to Gilbert's disease or leukemia disease) or =< 5 x ULN for
             subjects with liver metastases (performed within 10 days of treatment initiation)

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication. Subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year

          -  Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy

          -  Patients must receive a minimum dose of azacitidine of 75mg/(m)(2) dose

        Exclusion Criteria:

          -  Significant medical psychiatric cognitive or other conditions that may compromise the
             patient ability to understand the patient information to give informed consent to
             comply with the study protocol or to complete the study

          -  Any severe or concurrent disease or condition including uncontrolled systemic
             infection, congestive heart failure, angina pectoris or cardiac arrhythmia and
             autoimmune processes that in the opinion of the investigator would make the patient
             inappropriate for study participation

          -  Patients with known hypersensitivity to 5-azacitdine or MK3475 or any of their
             excipients

          -  Prior history of stem cell transplantation

          -  For patients in the relapse or refractory cohort, any other therapy not being a
             hypomethylating agent after hypomethylating agents (HMA) failure or more than 4 months
             since completion of last cycle of hypomethylating agent. Please note that
             hypomethylating agent may include second generation compounds such as SGI-110, oral
             decitabine or oral azacitidine and will also include combinations with investigational
             agents

          -  Treatment with other investigational agents including chemotherapy, immunotherapy, or
             radiation therapy within a month prior to the start of this clinical trial

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
             baseline) from adverse events due to a previously administered agent. Note: Subjects
             with =< grade 2 neuropathy are an exception to this criterion and may qualify for the
             study. Note: If subject received major surgery, they must have recovered adequately
             from the toxicity and/or complications from the intervention prior to starting therapy

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment. This exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Has known history of, or any evidence of active, non-infectious pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Has received a live vaccine within 30 days of planned start of study therapy. Note:
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
             attenuated vaccines, and are not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) defined as complete response + partial response + hematological improvement
Time Frame:After course 6
Safety Issue:
Description:Will estimate the ORR for the experimental treatments, along with the 95% credible intervals. The association between ORR and patient's clinical characteristics will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

May 15, 2019