Pembrolizumab in Treating Patients with Relapsed Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome after Donor Stem Cell Transplant
- Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS) in confirmed relapse based on bone marrow examination after allogeneic HCT; biopsy confirmed myeloid sarcoma or extramedullary AML may also be considered
- Confirmation of ‘measurable disease’ by blast % will be defined as a marrow blast percentage of > 5% by morphologic assessment on bone marrow examination; this criteria does not apply to myeloid sarcoma which must also show measurable lesion by computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)/CT or photograph (i.e. Leukemia cutis); if marrow blasts of =< 5% blasts are enumerated the patient may be eligible only if there is clear (probable or definite) flow cytometric, cytogenetic or molecular aberrations (e.g. FLT3-ITD, NPM1, etc.) documenting relapse of the leukemia associated clone defined prior to HCT
- Patient may not have received definitive salvage therapy for their post-transplant relapse; use of hydroxyurea is permitted
- Be willing and able to provide written informed consent/assent for the trial
- Be willing to provide tissue from bone marrow biopsies
- Have a performance status of 0, to 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale; for purposes of HCT, this will correspond to a Karnofsky performance status of >= 80%
- Must have been off immunosuppressive therapy for >= 7 days before receiving first dose of pembrolizumab
- Serum creatinine =<1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]), performed within 10 days of treatment initiation * Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 X ULN 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 glutamic pyruvic transaminase [SGPT]) =< 5 X ULN for subjects, performed within 10 days of treatment initiation
- International normalized ratio (INR) or prothrombin time (PT) =<1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants, performed within 10 days of treatment initiation
- Activated partial thromboplastin time (aPTT) =<1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants, performed within 10 days of treatment initiation
- Must have an absolute blast count (ABC) of < 15 K/ul in the peripheral blood prior to initiating study treatment, performed within 10 days of treatment initiation; use of hydroxyurea to control blast counts prior to initiating study treatment is acceptable
- 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 must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Male subjects of childbearing potential must 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 * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Has had relapse prior to primary neutrophil engraftment or =< 21 days post HCT
- Has received cytotoxic chemotherapy for post-transplant relapse prior to study entry
- Rapidly progressive relapse requiring urgent chemotherapy as determined by treating physician
- Is currently participating and receiving study therapy of an investigational agent and received study therapy within 2 weeks of the first dose of treatment; this 2 week washout period would not apply to investigational food ingredients
- Has a diagnosis of active GvHD (>= grade I); patients with prior active GvHD that is quiescent (grade 0) at time of entry may be considered
- Receiving systemic steroid therapy of > 10 mg prednisone daily or equivalent * Note: ** Corticosteroid use on study after cycle 1 for management of adverse events, serious adverse events, and events of clinical interest, as a premedication for IV contrast allergies/reactions, or if considered necessary for a subject’s welfare is allowed ** Subjects who receive daily steroid replacement therapy are an exception; daily prednisone at doses of 5 to 7.5 mg is an example of replacement therapy ** Equivalent hydrocortisone doses are also permitted if administered as replacement therapy
- Has been on immunosuppressant therapy within 7 days prior to the first dose of pembrolizumab
- Has received granulocyte-macrophage colony-stimulating factor (GM-CSF) within 14 days of first dose of pembrolizumab
- Has a known history of active tuberculosis (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 * 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 (secondary) 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 or suspected active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with suspected central nervous system (CNS) disease should have lumbar puncture performed to exclude this possibility; 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis
- 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 virus 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
I. To establish the safety of delivering single agent pembrolizumab +/- chemotherapy to patients with relapse of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic transplantation.
II. To determine the overall response rate (ORR) to single agent pembrolizumab +/- chemotherapy in patients with relapsed ALL, AML or MDS after allogeneic transplantation.
III. To describe the incidence of graft versus (vs.) host disease (GvHD) and/or other clinically significant immune mediated toxicities after pembrolizumab +/- chemotherapy.
I. Estimate the one-year overall and disease-free survival in patients administered pembrolizumab for relapse after hematopoietic cell transplant (HCT).
I. Determine the immunologic correlates of response to checkpoint blockade in patients with hematologic malignancies who have relapsed after allogeneic transplantation via assessment of PD1-PDL1 axis with a well-defined focus on T and natural killer (NK) cell phenotypes, functions and leukemia specific responses.
II. Determine the antigenic peptide repertoire of relapsed MDS and AML by whole exome sequencing (WES), bioinformatically nominate the most immunogenic antigens from the WES analyses and then functionally validate the top predicted peptides in silico and in vitro.
III. Determine if PD-L1 expression at relapse serves as a biomarker for response to pembrolizumab in hematologic malignancies as has been reported in solid malignancies.
IV. Identify responsive and resistant malignant clones and assess kinetics and depth of response to treatment with ultrasensitive mutation detection (droplet digital PCR [ddPCR] and single-molecule/real-time sequencing [SMRT]).
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients who are tolerating therapy without drug related adverse events and have disease in partial response (PR) or complete response (CR) may continue to receive pembrolizumab on day 1. Treatment repeats every 3 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 8 weeks for 90 days or 1 year after initiation of study treatment, whichever occurs first.
Trial Phase Phase I
Trial Type Treatment
University of Michigan Comprehensive Cancer Center
John Martin Magenau
- Primary ID UMCC 2017.056
- Secondary IDs NCI-2017-02016
- Clinicaltrials.gov ID NCT03286114