PRIMARY OBJECTIVES:
I. Assess the proportion of chronic myelogenous leukemia (CML) patients on stable-dose
tyrosine kinase inhibitor (TKI) who convert to undetectable minimal residual disease (UMRD)
(molecular response [MR]^4.5) during or within 2 years of initiating pembrolizumab therapy.
SECONDARY OBJECTIVES:
I. Among patients who have converted to UMRD (MR^4.5), assess the proportion of CML patients
who maintain UMRD for 6 months and 12 months.
II. Among patients who have converted to UMRD (MR^4.5), assess the proportion of CML patients
who discontinue their TKI.
III. Among patients who have converted to UMRD (MR^4.5), assess the proportion of CML
patients who are UMRD and TKI-free at 2 years from first determined UMRD.
IV. Assess the proportion of CML patients who develop grade 3 or 4 immune related adverse
events related to pembrolizumab treatment during the first 2 years after registration (not
including grade 3 events that respond to corticosteroids and improve to grade 1 or less
within 4 weeks).
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and dasatinib,
imatinib mesylate, or nilotinib orally (PO) as clinically indicated per the treating
physician. Treatment repeats every 21 days for up to 18 courses in the absence of disease
progression or unacceptable toxicity. Patients with detectable MRD after course 18 continue
pembrolizumab and dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an
additional 18 courses in the absence of disease progression or unacceptable toxicity.
Patients with UMRD at any time before course 18 discontinue pembrolizumab after course 18 and
continue dasatinib, imatinib mesylate, or nilotinib every 21 days for up to an additional 18
courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for 6 years from
the date of registration.
Inclusion Criteria:
- PREREGISTRATION (STEP 0): Patient has pathologically-confirmed chronic phase-CML on a
first line TKI and must meet the following criteria:
- The patient has to be on first-line TKI therapy (the same TKI) for at least 2
years prior to pre-registration
- Has been in MMR (i.e. MR^3) but still have detectable BCR-ABL transcript by a
standard real-time quantitative polymerase chain reaction (RQ-PCR) assay with a
limit of detection (sensitivity) of 4.5 for at least 12 months from the first
documentation of the MMR
- Patient has not achieved MR^4.5 (complete molecular remission [CMR]) within the
time of initiation of TKI therapy and pre-registration
- PREREGISTRATION (STEP 0): Patient must be scheduled to undergo a standard of care bone
marrow biopsy within 7 days of step 0 registration
- PREREGISTRATION (STEP 0): Peripheral blood must be collected for submission to Fred
Hutchinson Cancer Research Center for central assessment of the establishment of
BCR/ABL status to confirm patient?s eligibility for registration to Step 1; Fred
Hutchinson will forward results within 1-2 business days of receipt of the peripheral
blood to the submitting institution
- REGISTRATION TO TREATMENT (STEP 1): Institution has received central BCR-ABL test
results confirming MRD positive status
- REGISTRATION TO TREATMENT (STEP 1): Patients have an Eastern Cooperative Oncology
Group (ECOG) performance status of 0-1
- REGISTRATION TO TREATMENT (STEP 1): No active hemolytic anemia requiring
immunosuppressive therapy or other pharmacologic treatment; patients who have a
positive Coombs test but no evidence of hemolysis are NOT excluded from participation
- REGISTRATION TO TREATMENT (STEP 1): No current use of corticosteroids; EXCEPTION: Low
doses of steroids (< 10 mg of prednisone or equivalent dose of other steroid) used for
treatment of non-hematologic medical condition (e.g. chronic adrenal insufficiency) is
permitted
- REGISTRATION TO TREATMENT (STEP 1): No other active primary malignancy (other than
non-melanomatous skin cancer or carcinoma in situ of the cervix) requiring treatment
or limiting expected survival to =< 2 years
- NOTE: If there is a history of prior malignancy, they must not be receiving other
specific treatment (other than hormonal therapy for their cancer)
- REGISTRATION TO TREATMENT (STEP 1): Women must not be pregnant or breastfeeding;
patients must also not expect to conceive or father children from the time of
registration, while on study treatment, and continue for 120 days after the last dose
of study treatment; all females of childbearing potential must have a negative urine
or serum pregnancy within 72 hours prior to receiving the first dose of pembrolizumab;
if the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required; a female of childbearing potential is any woman, regardless of
sexual orientation or whether they have undergone tubal ligation, who meets the
following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has
had menses at any time in the preceding 24 consecutive months)
- REGISTRATION TO TREATMENT (STEP 1): Women of childbearing potential and sexually
active males must use an accepted and effective method of contraception or to abstain
from sexual from time of registration, while on study treatment, and continue for 120
days after the last dose of study treatment
- REGISTRATION TO TREATMENT (STEP 1): Patients must have been on a stable dose of the
TKI for the last 3 months prior to pre-registration
- REGISTRATION TO TREATMENT (STEP 1): Patient may not be currently participating and
receiving study therapy or have 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
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have a diagnosis of
immunodeficiency or be receiving systemic steroid therapy or any other form of
immunosuppressive therapy within 7 days prior to the first dose of treatment
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have a known history of active TB
(Bacillus Tuberculosis)
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have a history of
hypersensitivity to pembrolizumab or any of its excipients
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have received a prior anti-cancer
monoclonal antibody (mAb) within 4 weeks prior to study registration or have not
recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents
administered more than 4 weeks earlier
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have had prior chemotherapy,
targeted small molecule therapy (aside from imatinib, dasatinib, or nilotinib), or
radiation therapy within 2 weeks prior to study registration; patients also must have
recovered from all adverse events due to a previously administered agent
- Note: Patients with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study
- REGISTRATION TO TREATMENT (STEP 1): Patients who have received major surgery must have
recovered adequately from the toxicity and/or complications from the intervention
prior to starting therapy
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have 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
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have 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 protocol
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 protocol treatment; this exception does not include carcinomatous meningitis
which is excluded regardless of clinical stability
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have 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
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have known history of, or any
evidence of active, non-infectious pneumonitis
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have an active infection
requiring systemic therapy
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have 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
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have known psychiatric or
substance abuse disorders that would interfere with cooperation with the requirements
of the trial
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have received prior therapy with
an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
- REGISTRATION TO TREATMENT (STEP 1): Patients who are Human Immunodeficiency Virus
(HIV) positive are eligible if they have undetectable HIV viral load and CD4+ T-cell
count ≥ 250/mm3.
- REGISTRATION TO TREATMENT (STEP 1): Patients with a known positive test for Hepatitis
C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection might be
enrolled if the viral load by PCR is undetectable with/without active treatment.
- REGISTRATION TO TREATMENT (STEP 1): Patients must not have known history of hepatitis
B (defined as Hepatitis B surface antigen [HBsAg] reactive).
- REGISTRATION TO TREATMENT (STEP 1): Patient must not have 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
- REGISTRATION TO TREATMENT (STEP 1): Absolute neutrophil count (ANC) >= 1,500 /mcL,
within 14 days prior to first dose of pembrolizumab
- REGISTRATION TO TREATMENT (STEP 1): Platelet count >= 100,000 /mcL, within 14 days
prior to first dose of pembrolizumab
- REGISTRATION TO TREATMENT (STEP 1): Hemoglobin (Hgb) >= 9 g/dL OR >= 5.6 mmol/L
without transfusion of erythropoietin (EPO) dependency, within 14 days prior to first
dose of pembrolizumab
- REGISTRATION TO TREATMENT (STEP 1): Serum creatinine =< 1.5 X upper limit of normal
(ULN) OR creatinine clearance (per institutional standards) >= 60 mL/min for patient
with creatinine levels > 1.5 X ULN, within 14 days prior to first dose of
pembrolizumab
- REGISTRATION TO TREATMENT (STEP 1): Serum total bilirubin =< 1.5 X ULN OR direct
bilirubin
=< ULN for subjects with total bilirubin levels > 1.5 X ULN, within 14 days prior to
first dose of pembrolizumab
- REGISTRATION TO TREATMENT (STEP 1): Aspartate aminotransferase (AST) (serum glutamic
oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic
pyruvic transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver
metastases, within 14 days prior to first dose of pembrolizumab
- REGISTRATION TO TREATMENT (STEP 1): Patients should not be receiving concomitant
strong CYP3A4 inducers or inhibitors ≤ 7 days prior to registration due to their
potential to effect the activity or pharmacokinetics of study agents and/or QT
interval prolongation toxicity. Should treatment with any of these agents be required,
consult with study chair.
- REGISTRATION TO TREATMENT (STEP 1): Patients should not have received prior allogeneic
transplant.
