Single center Phase 1 dose escalation trial of the combination of standard-of-care
blinatumomab plus Haplo-Mismatched Cellular Therapy (HMCT). HMCT refers to the infusion of
donor peripheral blood mononuclear cells collected via pheresis from a haploidentical family
member - the procedure is analogous to giving a donor lymphocyte infusion outside of the
setting of an allogeneic stem cell transplant; also known as 'microtransplantation'. The HMCT
is an unselected mix of lymphocytes and leukocytes, but the product dose escalation will be
done based on the T cell content.
Ten recipients are planned. Each subject will be administered one infusion of HMCT during the
first cycle of blinatumomab and two infusions during cycle two of blinatumomab; the CD3+ cell
dose of the HMCT infusion is governed by dose escalation / de-escalation following a Bayesian
This single center, phase 1 study will examine the safety, side effects, and effectiveness of
combining the investigational use of Haplo-Mismatched Cellular Therapy (HMCT) in combination
with blinatumomab. Investigators plan to give HMCT starting on day 15, after the initial CRS
caused by blinatumomab has resolved. The investigational treatment will start with 1% of the
typical HMCT dose (10e6 CD3+ cells/kg) and will employ a modified dose escalation design as
an additional safety measure. The primary end points will be DLT of the combination of
blinatumomab and HMCT.
- Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia. Patients with minimal residual
disease detected by NGS > 10e-6 or multiparameter flow cytometry > 10e-5 in blood or
bone marrow are eligible.
- Patients must belong to one of the following 'high risk' categories: (i) at least 2nd
relapse or refractory to at least one salvage therapy (ii) relapse after autologous
stem cell transplantation, (iii) any relapse in a patient with no immediate allogeneic
transplant option (such as advanced age, comorbidity, lack of identified donor, or
patient refusal) (iv) Patients with Ph+ ALL will be allowed on the trial at the
discretion of the treating physician if they are no longer candidates for further TKI
based therapy. Prior therapy with a minimum of 2 prior 2nd/3rd generation TKI is
required. (TKI therapy is not allowed while on trial).
- Patients with prior blinatumomab treatment are eligible if last treatment was at least
3 months prior to C1D1, patient's blasts are confirmed to express CD19, and patient
did not develop Grade 4 toxicities with prior blinatumomab therapy.
- Age ≥ 18 years.
- Patient has at least one medically fit first- or second-degree family member who is a
potential haploidentical donor. In addition, the prospective donor is willing to
voluntarily donate peripheral blood cells, and sign consent forms. For minors, consent
will be obtained from parent/guardian (assent from the minor is required).
- Patients must have adequate organ function as defined below (note there are no marrow
function criteria, cytopenias will not result in exclusion):
- Serum creatinine ≤ 2.0 x the upper limits of institutional normal (ULN)
- Total bilirubin ≤ 1.5x the upper limits of institutional normal, unless elevated
bilirubin is attributed to liver involvement of leukemia or Gilbert's disease.
- AST/ALT ≤ 2.5 x the upper limits of institutional normal (≤ 5 x ULN for patients
with suspected liver involvement of leukemia).
- ECOG performance status of 0, 1, or 2, and estimated survival of at least 3 months.
- Patients must be able to understand and agree to sign an IRB-approved informed consent
- The effects of treatment on the developing human fetus are unknown. For this reason,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control or complete abstinence) prior to study
entry, for the duration of study, and for two months after study participation. Should
a woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately.
- Written informed consent obtained from subject and ability for subject to comply with
the requirements of the study.
- Prior allogeneic stem cell transplant
- Prior treatment with fludarabine or cladribine within the last six months prior to
C1D1, or treatment with antithymocyte globulin (ATG) or alemtuzumab within the last 1
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
- Pregnant and/or lactating.
- Who have had non-biopsy surgery in the last 10 days.
- Who have active CNS disease. Patients with previously treated leptomeningeal disease
without evidence of remaining leukemia cells by spinal fluid will be eligible.
Intrathecal chemo may be given for prophylaxis for patients who previously had CNS
involvement but have now cleared the CSF, at the discretion of the treating physician.
Recommend to avoid IT chemotherapy for a few days before or after HMCT infusion.
- History or presence of clinically relevant CNS pathology such as epilepsy, childhood
or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia,
Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
(patients with minor prior stroke who are cognitively intact and capable of performing
all ADLs are permitted).
- Patients with known active autoimmune disorder.
- Known infection with HIV virus.
- Patients concurrently taking the following drugs are excluded: mycophenolate,
cyclosporine, prednisone > 20mg/day, or immunosuppressive agents (low dose maintenance
chemotherapy - POMP, hydroxyurea, low dose prednisone - is allowed until 24 hours
prior to starting blinatumomab).
- Patients known to have active hepatitis B or C (Hepatitis B positive patients are
allowed if they are on appropriate antiviral agents such as lamivudine).
- Subject likely to not be available to complete all protocol-required study visits or
procedures, including follow-up visits, and/or to comply with all required study
procedures to the best of the subject and Investigator's knowledge.
History or evidence of any other clinically significant disorder, condition or disease
(with the exception of those outlined above) that, in the opinion of the Investigator or
Amgen physician, if consulted, would pose a risk to subject safety or interfere with the
study evaluation, procedures or completion.