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PD-1 Inhibition in Advanced Myeloproliferative Neoplasms

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ClinicalTrials.gov Identifier: NCT03065400
Recruitment Status : Recruiting
First Posted : February 27, 2017
Last Update Posted : March 5, 2018
Sponsor:
Collaborators:
Massachusetts General Hospital
Montefiore Medical Center
Information provided by (Responsible Party):
John Mascarenhas, Icahn School of Medicine at Mount Sinai

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Chronic Phase Myelofibrosis Primary Myelofibrosis Post-essential Thrombocythemia Myelofibrosis Polycythemia Vera Drug: Pembrolizumab Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PD-1 Inhibition in Advanced Myeloproliferative Neoplasms
Actual Study Start Date : June 14, 2017
Estimated Primary Completion Date : April 30, 2019
Estimated Study Completion Date : April 30, 2020


Arm Intervention/treatment
Experimental: Pembolizumab Drug: Pembrolizumab
200 mg of Pembolizumab administered via intravenous infusion over 30 mins given every 3 weeks
Other Name: Keytruda




Primary Outcome Measures :
  1. European Leukemia Net -International Working Group (ELN-IWG) criteria [ Time Frame: 18 weeks ]
    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 :
  1. Acute Myeloid Leukemia Response Criteria [ Time Frame: 18 weeks ]
    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.



Information from the National Library of Medicine

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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:

  • 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.

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): NCT03065400


Contacts
Contact: John Mascarenhas, MD 212-241-3417 john.mascarenhas@mssm.edu
Contact: Lonette Sandy 212-241-4546 Lonette.Sandy@mssm.edu

Locations
United States, Massachusetts
Harvard Medical School Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Gabriela Hobbs, MD    617-643-1754    ghobbs@partners.edu   
Principal Investigator: Gabriela Hobbs, MD         
United States, New York
Montefiore Medical Center Division of Hematology, Department of Oncology Not yet recruiting
Bronx, New York, United States, 10467
Contact: Swati Goel, MD    718-920-4137    swgoel@montefiore.org   
Principal Investigator: Swait Goel, MD         
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Principal Investigator: John Mascarenhas, MD         
Sponsors and Collaborators
John Mascarenhas
Massachusetts General Hospital
Montefiore Medical Center
Investigators
Study Chair: John Mascarenhas, MD Icahn School of Medicine at Mount Sinai
Study Chair: Gabriela Hobbs, MD Harvard Medical School Massachussets General Hospital

Responsible Party: John Mascarenhas, Associate Professor, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT03065400     History of Changes
Other Study ID Numbers: GCO 16-2350
First Posted: February 27, 2017    Key Record Dates
Last Update Posted: March 5, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by John Mascarenhas, Icahn School of Medicine at Mount Sinai:
Myelofibrosis
Acute Leukemia

Additional relevant MeSH terms:
Neoplasms
Primary Myelofibrosis
Polycythemia
Myeloproliferative Disorders
Polycythemia Vera
Thrombocytosis
Thrombocythemia, Essential
Bone Marrow Diseases
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
Pembrolizumab
Antineoplastic Agents