PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of the blinatumomab given in combination with
nivolumab alone, or in combination with both nivolumab and ipilimumab in subjects with
poor-risk, relapsed or refractory CD19+ pre-B cell acute lymphoblastic leukemia (ALL) or
CD19+ mixed phenotype acute leukemia (MPAL).
II. To determine the maximum tolerated dose (MTD) of the combination of blinatumomab plus
nivolumab, and blinatumomab plus both nivolumab and ipilimumab and to further confirm the
safety of the combination therapy in subjects with poor-risk, relapsed or refractory CD19+
pre-B cell ALL or CD19+ mixed phenotype acute leukemia (MPAL).
SECONDARY OBJECTIVES:
I. To observe and record anti-leukemia activity of blinatumomab and nivolumab, and
blinatumomab plus both nivolumab and ipilimumab, including the effects on minimal residual
disease (MRD).
II. To assess preliminary anti-leukemia activity in expansion cohorts of patients with
poor-risk, relapsed or refractory CD19+ precursor B-lymphoblastic leukemia, or CD19+ mixed
phenotype acute leukemia (MPAL).
EXPLORATORY OBJECTIVES:
I. To examine changes in absolute lymphocyte count and distribution of T cell subsets (CD4+,
CD8+, regulatory T cells [Tregs], effector T cells [Teffs]) and their differentiation status,
natural killer (NK) cells, and B cells before and post-blinatumomab, and immune checkpoint
inhibitor(s) therapy in both peripheral blood and the bone marrow microenvironment.
II. To explore changes in T cell co-signaling receptors expression in defined T cell
subpopulations and their canonic transcription factor expression in both peripheral blood and
bone marrow before and post-blinatumomab, and immune checkpoint inhibitor(s) therapy.
III. To examine changes in expression of co-signaling molecules on leukemia blasts
(CD10+/CD19+/CD34+) before and after treatment with blinatumomab and checkpoint inhibitors.
IV. To examine the serum levels of cytokines before and after treatment with blinatumomab and
checkpoint inhibitors, including the levels of sCTLA-4.
V. To perform immune profiling of T cell repertoire and characterize T cell transcriptional
signature before and after treatment.
OUTLINE: This is a dose-escalation study of blinatumomab.
Patients receive blinatumomab intravenously (IV) continuously on days 1-28. Treatment repeats
every 42 days for up to 5 cycles in the absence of disease progression or unacceptable
toxicity. Patients also receive nivolumab IV over 30 minutes on day 11 and then every 2 weeks
for up to year. Some patients also receive ipilimumab IV over 90 minutes on day 11 and then
every 6 weeks for up to 1 year.
After completion of study treatment, patients are followed up every 3 months for up to 2
years.
Inclusion Criteria:
- PRE-REGISTRATION ELIGIBILITY CRITERIA
- Patients must have suspected refractory or relapsed pre-B cell ALL or mixed phenotype
acute leukemia (MPAL), or if newly diagnosed, the patient must be 60 years of age or
older
- Bone marrow and/or peripheral blood specimens will be submitted for correlative
studies; patients who have a dry tap will still be eligible
- REGISTRATION ELIGIBILITY CRITERIA
- Patients must have histologically or cytologically confirmed by the local institution
CD19+ precursor B-acute lymphoblastic leukemia (pre-B cell ALL) OR CD19+ mixed
phenotype acute leukemia (MPAL): a) with relapse following or refractory to at least
one prior line of therapy if older than 21 years; b) in second or higher relapse or
refractory to at least two prior lines of therapy if 21 years old and younger (16-21);
c) or they must have a new diagnosis of pre-B cell ALL or CD19+ MPAL but are >= 60
years old and are either not a candidate for or do not wish to receive traditional
induction chemotherapy
- The evidence of CD19+ expression on leukemia cells must be confirmed by pathology
review of the bone marrow and/or peripheral blood specimens (flow cytometry and/or
immunohistochemistry) collected at the time of current relapse and prior to the
initiation of therapy
- Patients with Philadelphia chromosome (Ph) positive (+) pre-B cell ALL OR Ph+ MPAL
will be eligible if they have been refractory to or intolerant of treatment with at
least 1 second-generation or third-generation tyrosine kinase inhibitor (TKI)
- Patients who were treated with blinatumomab in the past will be allowed on the study
as long as they have persistent CD19 expression on leukemia cells and did not
experience unacceptable toxicities with prior blinatumomab administration; patients
who were treated with chimeric antigen receptor (CAR)-modified T cells targeting CD19
in the past will be allowed on the study as long as they have persistent CD19
expression on leukemia cells
- Patients with a history of allogeneic hematopoietic stem cell transplantation (HSCT)
will be eligible if they are more than 90 days removed from the date of stem cell
infusion, have no evidence of acute graft-versus-host disease (GVHD) or active chronic
(grade 2-4) GVHD, and are off of all transplant-related immunosuppression for at least
2 weeks
- Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status of 0-2
(Karnofsky >= 60%)
- Life expectancy of greater than 12 weeks
- Total bilirubin =< 2.0 mg/dL (except patients with Gilbert syndrome, who can have
total bilirubin < 3.0 mg/dL)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 x upper limit of normal (ULN)
- Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using
the Cockcroft-Gault formula)
- The effects of nivolumab, ipilimumab, and blinatumomab on the developing human fetus
are unknown; for this reason, women of child-bearing potential (WOCBP) and men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation; WOCBP
should use an adequate method to avoid pregnancy for 23 weeks after the last dose of
investigational drug; women of childbearing potential must have a negative serum or
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human
chorionic gonadotropin [HCG]) within 24 hours prior to the start of treatment on the
study; women must not be breastfeeding; men who are sexually active with WOCBP must
use any contraceptive method with a failure rate of less than 1% per year; men
receiving nivolumab +/- ipilimumab and blinatumomab and who are sexually active with
WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the
last dose of investigational product; women who are not of childbearing potential
(i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not
require contraception
- Note: Women of childbearing potential (WOCBP) is defined as any female who has
experienced menarche and who has not undergone surgical sterilization
(hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause
is defined clinically as 12 months of amenorrhea in a woman over 45 in the
absence of other biological or physiological causes; in addition, women under the
age of 55 must have a documented serum follicle stimulating hormone (FSH) level
less than 40 mIU/mL
- Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she (or the participating partner) should
inform the treating physician immediately
- Adequate pulmonary function as assessed by oxygen saturation >= 90% when ambulating
and not requiring supplemental oxygen
- Patients with a known history of testing positive for human immunodeficiency virus
(HIV) or known acquired immunodeficiency syndrome (AIDS) will be eligible if:
- They are generally healthy from an HIV perspective and on a stable
anti-retroviral regimen for > 6 months
- They have had no AIDS-defining conditions in the past 12 months other than
historically low CD4+ cell counts
- They have an undetectable viral load on standard assays
- Patients with a known history of hepatitis C (HCV) will be eligible if they have an
undetectable viral load; if the patient received treatment for HCV, then that
treatment must have been completed at least three weeks prior to enrollment
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have had chemotherapy or other systemic therapy or radiotherapy, or those
who have not recovered from adverse events due to prior administered agents as
follows: chemotherapy, radiotherapy or surgery =< 3 weeks prior to entering the study,
targeted therapy (e.g., TKI) =< 1 week prior to entering the study; autologous HSCT =<
6 weeks prior to entering the study; investigational drug or immunotherapy (e.g.
rituximab) =< 4 weeks prior to entering the study; prophylactic intrathecal
chemotherapy within one week of enrollment allowed; patients will be allowed to
receive cytoreduction with hydroxyurea, 6-mercaptopurine, corticosteroids
(dexamethasone, prednisone or similar) or cyclophosphamide provided that it is
discontinued at least 24 hours prior to the initiation of study treatment; pre-phase
treatment with dexamethasone 10 mg/m^2 (maximum total 24 mg per day) for up to 5 days
is required for patients with bone marrow blasts more than 50%, peripheral blood
blasts of 15,000/uL or higher, or elevated lactate dehydrogenase suggesting rapidly
progressing disease as per investigator's assessment; pre-phase treatment must be
stopped at least 24 hours prior to the initiation of blinatumomab
- Patients who are receiving any other investigational agents
- Patients should be excluded if they have had prior treatment with an anti-PD-1,
anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or immune checkpoint pathways
- Patients with active central nervous system leukemia are excluded from this clinical
trial because they may develop progressive neurologic dysfunction that would confound
the evaluation of neurologic and other adverse events; patients with a history of
central nervous system (CNS) leukemia but no active disease at the time of enrollment
are eligible; the absence of CNS disease must be confirmed by flow cytometric and
cytologic examination of the cerebrospinal fluid (CSF) within 7 days of study
enrollment
- Active leukemia in the testes or isolated extramedullary relapse; patients with a
history of treated leukemia in testes but no active disease at the time of enrollment
are eligible
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab, ipilimumab, or blinatumomab
- History of severe hypersensitivity reaction to any monoclonal antibody
- Uncontrolled intercurrent illness including, but not limited to, active, uncontrolled
infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac
arrhythmia; or psychiatric illness/social situations that would limit compliance with
study requirements; patients with infection under treatment and controlled with
antibiotics are eligible
- Pregnant women are excluded from this study because nivolumab and ipilimumab have the
potential for teratogenic or abortifacient effects; because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with nivolumab and ipilimumab, breastfeeding should be discontinued if the
mother is treated with nivolumab and ipilimumab; these potential risks may also apply
to blinatumomab
- History of any chronic hepatitis including alcoholic, non-alcoholic steatohepatitis
(NASH), drug related, autoimmune, chronic viral positive tests for hepatitis B virus
surface antigen (HBsAg), hepatitis B core antibody (anti-HBc) in the absence of
hepatitis B surface antibody (anti-HBs), or a positive hepatitis C (HCV) viral load;
these patients are excluded due to the risk for autoimmune hepatitis with immune
checkpoint inhibitors exacerbating their known liver disease as well as the unknown
risk for hepatitis B and/or C reactivation with blinatumomab and immune checkpoint
inhibitors
- Subjects with active autoimmune disease, a history of known or suspected autoimmune
disease or a history of a syndrome requiring systemic corticosteroids (> 10 mg daily
of prednisone equivalent) except for the treatment of malignancy with the exception
of:
- Isolated vitiligo
- Resolved childhood atopy
- History of a positive antinuclear antibody (ANA) titer without associated
symptoms or history of symptoms of an autoimmune disorder
- Controlled thyroid disorders
- Type I diabetes mellitus
- Psoriasis, Sjogren's syndrome, and arthropathies not requiring systemic treatment
- Autoimmune diseases: these include but are not limited to patients with a history
of immune related neurologic disease, multiple sclerosis, autoimmune
(demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic
autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue
diseases, scleroderma, autoimmune vasculitis, inflammatory bowel disease (IBD),
Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic
epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome
should be excluded because of the risk of recurrence or exacerbation of disease
- Patients should be excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration; inhaled or
topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease; patients are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption); physiologic replacement doses of systemic
corticosteroids are permitted, even if > 10 mg/day prednisone equivalents; a brief
course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for
treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction
caused by contact allergen), or as pre-phase treatment for cytoreduction; patients
will receive steroids with blinatumomab to reduce cytokine release syndrome (CRS) as
specified in the protocol
- Patients who have had evidence of active or acute diverticulitis, intra-abdominal
abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are
known risk factors for bowel perforation should be evaluated for the potential need
for additional treatment before coming on study
- Patients who have a history of clinically relevant CNS pathology such as epilepsy,
seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's
disease, cerebellar disease, psychosis, or other significant CNS abnormalities; a
history of treated CNS leukemia will be allowed if recent CNS studies confirm the
absence of active CNS disease at the time of study entry (screening)
- Patients with a known concurrent 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 carcinoma in
situ of the cervix
- Subjects with interstitial lung disease that is symptomatic or may interfere with the
detection or management of suspected drug-related pulmonary toxicity
