PD-1 Inhibition in Advanced Myeloproliferative Neoplasms
Study Details
Study Description
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 |
|---|---|---|
| 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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Pembolizumab
|
Drug: Pembrolizumab
200 mg of Pembolizumab administered via intravenous infusion over 30 mins given every 3 weeks
Other Names:
|
Outcome Measures
Primary Outcome Measures
- European Leukemia Net -International Working Group (ELN-IWG) Criteria [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. Complete Remission - CR: Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF and Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥ 1 × 109/L and <UNL; Platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH Partial Remission (PR): Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥1 × 109/L and <UNL; platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH or Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF, and Hemoglobin ≥85 but <100 g/L and <UNL; neutrophil count ≥1 × 109/L and <UNL; plat
Secondary Outcome Measures
- Acute Myeloid Leukemia Response Criteria [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. Acute Myeloid Leukemia Response Assessment Criteria: Complete Response (CR) - The subject must be free of all symptoms related to leukemia and have an absolute neutrophil count of greater than 1 x 109/L, no need for red blood cell transfusion, platelet count greater than 100x 109/L, and normal marrow differential (<5% blasts) in a normo- or hypercellular marrow Complete Remission with Incomplete Hematologic Recovery (Cri) - As per CR but incomplete count recovery Partial Response - CR with 6-25% abnormal cells in the marrow or 50% decrease in bone marrow blasts
Eligibility Criteria
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 .
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Either not eligible or unwilling to proceed with hematopoietic stem cell transplantation (HSCT)
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Have a performance status of 0 or 1 on the ECOG Performance Scale.
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Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation.
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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.
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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.
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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.
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Has a known history of active TB (Bacillus Tuberculosis)
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Hypersensitivity to pembrolizumab or any of its excipients.
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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.
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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.
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Note: Subjects with = Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
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Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
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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.
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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.
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Has known history of, or any evidence of active, non-infectious pneumonitis.
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Has an active infection requiring systemic therapy.
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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.
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Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
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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.
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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)
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Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
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Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Harvard Medical School Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
| 2 | Montefiore Medical Center Division of Hematology, Department of Oncology | Bronx | New York | United States | 10467 |
| 3 | Icahn School of Medicine at Mount Sinai | New York | New York | United States | 10029 |
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
Study Documents (Full-Text)
More Information
Publications
None provided.- GCO 16-2350
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Pembolizumab |
|---|---|
| Arm/Group Description | 200 mg of Pembolizumab administered via intravenous infusion over 30 mins given every 3 weeks |
| Period Title: Overall Study | |
| STARTED | 10 |
| COMPLETED | 0 |
| NOT COMPLETED | 10 |
Baseline Characteristics
| Arm/Group Title | Pembolizumab |
|---|---|
| Arm/Group Description | 200 mg of Pembolizumab administered via intravenous infusion over 30 mins given every 3 weeks |
| Overall Participants | 10 |
| Age (years) [Mean (Full Range) ] | |
| Mean (Full Range) [years] |
70
|
| Sex: Female, Male (Count of Participants) | |
| Female |
5
50%
|
| Male |
5
50%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
1
10%
|
| White |
9
90%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
Outcome Measures
| Title | European Leukemia Net -International Working Group (ELN-IWG) Criteria |
|---|---|
| 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. Complete Remission - CR: Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF and Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥ 1 × 109/L and <UNL; Platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH Partial Remission (PR): Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥1 × 109/L and <UNL; platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH or Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF, and Hemoglobin ≥85 but <100 g/L and <UNL; neutrophil count ≥1 × 109/L and <UNL; plat |
| Time Frame | 18 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Pembolizumab |
|---|---|
| Arm/Group Description | 200 mg of Pembolizumab administered via intravenous infusion over 30 mins given every 3 weeks |
| Measure Participants | 10 |
| Count of Participants [Participants] |
0
0%
|
| Title | Acute Myeloid Leukemia Response Criteria |
|---|---|
| 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. Acute Myeloid Leukemia Response Assessment Criteria: Complete Response (CR) - The subject must be free of all symptoms related to leukemia and have an absolute neutrophil count of greater than 1 x 109/L, no need for red blood cell transfusion, platelet count greater than 100x 109/L, and normal marrow differential (<5% blasts) in a normo- or hypercellular marrow Complete Remission with Incomplete Hematologic Recovery (Cri) - As per CR but incomplete count recovery Partial Response - CR with 6-25% abnormal cells in the marrow or 50% decrease in bone marrow blasts |
| Time Frame | 18 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Pembolizumab |
|---|---|
| Arm/Group Description | 200 mg of Pembolizumab administered via intravenous infusion over 30 mins given every 3 weeks |
| Measure Participants | 10 |
| Count of Participants [Participants] |
0
0%
|
Adverse Events
| Time Frame | 18 weeks | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Pembolizumab | |
| Arm/Group Description | 200 mg of Pembolizumab administered via intravenous infusion over 30 mins given every 3 weeks | |
All Cause Mortality |
||
| Pembolizumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 1/10 (10%) | |
Serious Adverse Events |
||
| Pembolizumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/10 (30%) | |
| Cardiac disorders | ||
| Supraventricular Tachycardia | 1/10 (10%) | |
| Nervous system disorders | ||
| Weakness | 1/10 (10%) | |
| Reproductive system and breast disorders | ||
| High grade pleomorphic sarcoma of left breast. | 1/10 (10%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Pneumonia | 1/10 (10%) | |
| Respiraitory Failure | 1/10 (10%) | |
Other (Not Including Serious) Adverse Events |
||
| Pembolizumab | ||
| Affected / at Risk (%) | # Events | |
| Total | 10/10 (100%) | |
| Blood and lymphatic system disorders | ||
| Anemia | 9/10 (90%) | |
| Thrombocytopenia | 5/10 (50%) | |
| Leukopenia | 4/10 (40%) | |
| Lymphopenia | 5/10 (50%) | |
| WBC Decreeased | 4/10 (40%) | |
| Endocrine disorders | ||
| Hyperglycemia | 5/10 (50%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 3/10 (30%) | |
| Nausea | 3/10 (30%) | |
| Constipation | 2/10 (20%) | |
| Dyspepsia | 2/10 (20%) | |
| General disorders | ||
| Fatigue | 5/10 (50%) | |
| Fever | 3/10 (30%) | |
| Weight Loss | 2/10 (20%) | |
| Hepatobiliary disorders | ||
| AST Increased | 3/10 (30%) | |
| Hypoalbuminemia | 3/10 (30%) | |
| ALP Increased | 2/10 (20%) | |
| Nervous system disorders | ||
| Dizziness | 3/10 (30%) | |
| Headache | 4/10 (40%) | |
| Weakness | 3/10 (30%) | |
| Blurred Vision | 2/10 (20%) | |
| Renal and urinary disorders | ||
| Hyperuricemia | 4/10 (40%) | |
| Hypocalcaemia | 2/10 (20%) | |
| Hypernatremia | 2/10 (20%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 5/10 (50%) | |
| Dyspnea | 5/10 (50%) | |
| Chest Pain | 3/10 (30%) | |
| Productive Cough | 2/10 (20%) | |
| Sore Throat | 2/10 (20%) | |
| Upper Respiratory Infection | 2/10 (20%) | |
| Skin and subcutaneous tissue disorders | ||
| Rash | 2/10 (20%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Mikaela Dougherty |
|---|---|
| Organization | Icahn School of Medicine at Mount Sinai |
| Phone | 212-241-8839 |
| Mikaela.dougherty@mssm.edu |
- GCO 16-2350