Clinical Trials /

PD-1 Inhibition in Advanced Myeloproliferative Neoplasms

NCT03065400

Description:

The purpose of this study is to test the effectiveness of a drug called pembrolizumab in patients with Myeloproliferative Neoplasm (MPN); chronic phase (MF-CP), accelerated phase (MPN-AP), or blast phase (MF-BP). Myelofibrosis neoplasm (MPN) is a group of diseases of the bone marrow in which excessive cells are produced. Pembrolizumab also known as Keytruda is a drug that has recently been approved in the United Stated by the Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma and disease progression. Pembrolizumab is experimental in the treatment of MPN. The researchers want to find out what effects, good and /or bad it has on participants and the disease. Participants qualify to take part in this research study if have been diagnosed with a MPN blood disorder called myelofibrosis (MF). Accelerated (10-19% blasts in the blood or bone marrow) and blast phase (>20% blasts in the blood or bone marrow) MPN has been a difficult disease to treat. The term "blasts" refers to immature cells found in the bone marrow. They are not fully developed, and therefore, do not yet carry out any particular function within the body. Funds for conducting this research are provided by Merck and Company, the manufacturer of the study drug pembrolizumab.

Related Conditions:
  • Myelofibrosis Transformation in Essential Thrombocythemia
  • Myeloproliferative Neoplasm
  • Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase
  • Primary Myelofibrosis
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: PD-1 Inhibition in Advanced Myeloproliferative Neoplasms
  • Official Title: PD-1 Inhibition in Advanced Myeloproliferative Neoplasms

Clinical Trial IDs

  • ORG STUDY ID: GCO 16-2350
  • NCT ID: NCT03065400

Conditions

  • Chronic Phase Myelofibrosis
  • Primary Myelofibrosis
  • Post-essential Thrombocythemia Myelofibrosis
  • Polycythemia Vera

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaPembolizumab

Purpose

The purpose of this study is to test the effectiveness of a drug called pembrolizumab in patients with Myeloproliferative Neoplasm (MPN); chronic phase (MF-CP), accelerated phase (MPN-AP), or blast phase (MF-BP). Myelofibrosis neoplasm (MPN) is a group of diseases of the bone marrow in which excessive cells are produced. Pembrolizumab also known as Keytruda is a drug that has recently been approved in the United Stated by the Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma and disease progression. Pembrolizumab is experimental in the treatment of MPN. The researchers want to find out what effects, good and /or bad it has on participants and the disease. Participants qualify to take part in this research study if have been diagnosed with a MPN blood disorder called myelofibrosis (MF). Accelerated (10-19% blasts in the blood or bone marrow) and blast phase (>20% blasts in the blood or bone marrow) MPN has been a difficult disease to treat. The term "blasts" refers to immature cells found in the bone marrow. They are not fully developed, and therefore, do not yet carry out any particular function within the body. Funds for conducting this research are provided by Merck and Company, the manufacturer of the study drug pembrolizumab.

Detailed Description

      The researchers propose a Simon-two stage design for this study. The researchers will test
      pembrolizumab at the FDA approved dose (in head and neck cancer) of 200mg dose administered
      via intravenous infusion over 30 minutes given every 3 weeks. Nine patients will be enrolled
      in the first stage of the Simon-two stage design, and 15 in the second stage. A treatment
      cycle is 3 weeks and the core study period is 6 cycles. Response assessment by established
      consensus criteria will be used to assess response after 6 cycles in order to determine if
      the trial will progress to the second stage and for the purpose of determining the primary
      endpoint. In addition, allowed will be a maximum of ten patients with accelerated or blast
      phase disease (MPN-AP/BP) who are refractory or intolerant to conventional therapies such as
      decitabine, and in which hematopoietic stem cell transplant is not a therapeutic option
      (exploratory cohort), to enroll in the study as a separate exploratory cohort. These patients
      can be enrolled during stage 1 or 2 and will be analyzed separately from the primary cohort
      population.

      Exploratory biomarkers will be obtained from enrolled patients at baseline, cycle 3 and cycle
      7 and at 1 year of therapy. Patients that obtain at least a clinical improvement after 6
      cycles of therapy can continue receiving pembrolizumab until evidence of disease progression,
      unacceptable toxicity, and patient or physician decision for a maximum of 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
PembolizumabExperimental
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent/assent for the trial.

          -  Be ≥ 18 years of age on day of signing consent.

          -  Must have a diagnosis of chronic phase (CP) (defined as peripheral blood and bone
             marrow <10% blasts) primary myelofibrosis (PMF) or post essential thrombocythemia
             (post-ET) or polycythemia vera (post-PV) myelofibrosis by World Health Organization
             (WHO) criteria OR a diagnosis of a myeloproliferative neoplasm in accelerated/blast
             phase (MPN-AP/BP) defined as either a peripheral blood or bone marrow with =10% blasts
             .

          -  If the diagnosis is MF-CP, must have Dynamic International Prognostic Scoring System
             (DIPSS) intermediate-2/high risk disease and either be intolerant/resistant to
             ruxolitinib as determined by the treating investigator or ineligible for ruxolitinib
             therapy as determined by the treating investigator .

          -  If the diagnosis is MPN-AP/BP, must have progressive/resistant disease after treatment
             with a DNMT1 inhibitor therapy (azacytidine, decitabine) as determined by the treating
             investigator .

          -  Either not eligible or unwilling to proceed with hematopoietic stem cell
             transplantation (HSCT)

          -  Have a performance status of 0 or 1 on the ECOG Performance Scale.

          -  Demonstrate adequate organ function as defined in Table 1, all screening labs should
             be 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 (Reference
             Section 5.7.2). 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.

        Exclusion Criteria:

          -  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.

          -  Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or
             child) who is investigational site or sponsor staff directly involved with this trial,
             unless prospective IRB approval (by chair or designee) is given allowing exception to
             this criterion for a specific subject.

          -  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)

          -  Hypersensitivity to pembrolizumab or any of its excipients.

          -  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.

               1. Note: Subjects with = Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study.

               2. 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 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 (eg., 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.
             "Anti-CD137 or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody
             (including ipilimumab or any other antibody or drug specifically targeting T-cell
             co-stimulation or checkpoint pathways)

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 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:European Leukemia Net -International Working Group (ELN-IWG) criteria
Time Frame:18 weeks
Safety Issue:
Description:The proportion of treated MF-CP patients (primary cohort) that achieve at least a clinical improvement (CI, PR, CR) by combined European Leukemia Net -International Working Group (ELN-IWG) criteria after 6 cycles of pembrolizumab therapy.

Secondary Outcome Measures

Measure:Acute Myeloid Leukemia Response Criteria
Time Frame:18 weeks
Safety Issue:
Description:The proportion of treated MPN-AP/BP patients (exploratory cohort) that achieve at least a complete morphologic remission of the leukemic blasts (CR, Cri) by Acute Myeloid Leukemia Response Criteria within 6 cycles of pembrolizumab therapy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:John Mascarenhas

Trial Keywords

  • Myelofibrosis
  • Acute Leukemia

Last Updated

September 11, 2019