Overview
This is a pilot study; patients will receive 131-I apamistamab prior to CAR T-cell infusion in order to determine the maximum tolerated dose of 131-I apamistamab is exceeded at 75 mCi, and if so, to assess the safety of a step-down dose of 50 mCi.
Eligibility
Patients with B-ALL or DLBCL (or subtypes thereof) who have relapsed or refractory disease
will be eligible. Refractory disease is defined by failure to achieve at least a partial
response or disease progression within 6 months of the last therapy. Patients who initially
respond but subsequently demonstrate disease progression are considered to have relapsed
disease
Participant Inclusion Criteria:
- To be eligible for leukapheresis, patients must have a CD19+ B-cell malignancy with
relapsed or refractory disease, defined below. To be eligible for 131-I apamistamab
conditioning and treatment with 19-28z CAR T-cells, patients must additionally have
detectable evidence of residual malignancy at the time of assessment prior to CAR T-cell
infusion (as defined below), regardless of therapy administered following leukapheresis.
a. Patients with diffuse large B-cell lymphoma (de novo or DLBCL transformed from an
indolent lymphoma (follicular lymphoma, chronic lymphocytic leukemia [Richter syndrome]) or
high-grade B-cell lymphoma (HGBL): ("DLBCL patients") i. Defined as relapsed or refractory
DLBCL or high-grade B-cell lymphoma (HGBL) following 2 or more prior chemoimmunotherapy
regimens (with at least one course including an anthracycline and CD20-directed therapy)
following diagnosis of de novo DLBCL/HGBL or DLBCL arising from indolent lymphoma, and
requiring further treatment. Exception: patients with Richter syndrome (DLBCL arising from
CLL/small lymphocytic lymphoma) are eligible following 1 or more prior chemoimmunotherapy
regimens (with at least one course including an anthracycline and CD20-directed therapy)
and do not require a second course of chemoimmunotherapy to be eligible.
ii. Patients must have at least one FDG-avid (PET-avid) measurable lesion iii. Biopsy
confirmation of relapsed of refractory DLBCL is required iv. For patients who have received
treatment for confirmed relapsed or refractory disease otherwise meeting criteria
a.i.-a.iii. as above, within 6 weeks of study enrollment, active disease does not need to
be re-confirmed or present immediately prior to Screening A for the patient to be eligible
for leukapheresis. However, detectable evidence of residual malignancy must be present at
Screening B in order for the patient to be eligible for 131-I apamistamab and CAR T-cell
therapy.
b. Patients with B-cell acute lymphoblastic leukemia or B lymphoblastic lymphoma (ALL) or
chronic myeloid leukemia (CML) in lymphoid blast crisis: ("B-ALL patients") i. Patients
with Philadelphia chromosome-negative B-cell ALL must have been refractory to at least 1
line of multi-agent chemotherapy or relapsed following at least 1 prior multiagent systemic
chemotherapy regimen that included induction and consolidation therapy ii. Patients with
Philadelphia chromosome-positive ALL or CML in lymphoid blast crisis must have exhibited
persistent disease following therapy with a second- or third-generation tyrosine kinase
inhibitor iii. Patients must have ≥5% bone marrow involvement and/or at least one FDG-avid
(PET-avid) measurable extramedullary lesion iv. For patients who have received treatment
for confirmed relapsed or refractory disease otherwise meeting criteria b.i.-b.iii. as
above, within 6 weeks of study enrollment, active disease does not need to be re-confirmed
or present immediately prior to Screening A for the patient to be eligible for
leukapheresis. However, detectable evidence of residual malignancy must be present at
Screening B in order for the patient to be eligible for 131-I apamistamab and CAR T-cell
therapy.
- While prior CD19-targeted therapies, including CAR T-cell therapy, do not exclude
participation, CD19 expression by immunohistochemical staining or flow cytometry must
be confirmed prior to enrollment.
- Age ≥ 18 years of age
- Creatinine clearance ≥50 mL/min as calculated by the Cockroft-Gault formula
- Direct bilirubin ≤2.0 mg/dL, AST and ALT ≤3.0x upper limit of normal (ULN), unless
liver dysfunction is thought to be related to underlying malignancy
- Adequate pulmonary function as assessed by ≥92% oxygen saturation on room air by pulse
oximetry.
- Adequate bone marrow function meeting the following criteria as defined below, without
requiring blood product or granulocyte-colony stimulating factor support in the past 7
days, unless cytopenias are attributed to underlying malignancy in the opinion of the
investigator:
1. Absolute neutrophil count ≥0.5k/µL,
2. Platelets ≥30k/µL,
3. Hemoglobin ≥7g/dL.
- ECOG performance status 0-2.
Participant Exclusion Criteria:
- ECOG performance status ≥3.
- Pregnant or lactating patients. Patients of childbearing age should use effective
contraception while on this study and continue for 1 year after all treatment is
finished.
- Impaired cardiac function (LVEF <40%) as assessed by echocardiogram or MUGA scan
during screening
- Patients with active graft versus host disease following allogeneic hematopoietic cell
transplantation requiring systemic T-cell suppressive therapy are ineligible
- Patients with active autoimmune disease requiring systemic T-cell suppressive therapy
are ineligible
- Patients with following cardiac conditions will be excluded:
1. New York Heart Association (NYHA) stage III or IV congestive heart failure
2. Myocardial infarction ≤6 months prior to enrollment
3. Any history of clinically significant ventricular arrhythmia or unexplained
syncope, not believed to be vasovagal in nature or due to dehydration
4. Any history of severe non-ischemic cardiomyopathy with LVEF ≤20%
- Have current or prior positive test results for human immunodeficiency virus (HIV) or
hepatitis B (HBV) or C (HCV), with the following exceptions:
1. Subjects who have positive HBV test results due to having been previously
vaccinated against hepatitis B, as evidenced by negative hepatitis B surface
antigen (HBsAg), negative anti- hepatitis B core protein (HBc) and positive
antibody to the HBsAg (anti-HBs) are not excluded.
2. Subjects who have antibodies to HCV or who have hepatitis B core antibody, with
undetectable viremia by PCR, and with adequate organ function as defined in the
protocol, are not excluded.
- Patients with uncontrolled systemic fungal, bacterial, viral or other infection are
ineligible.
- Patients with any concurrent active malignancies as defined by malignancies requiring
any therapy other than expectant observation or hormonal therapy, with the exception
of squamous and basal cell carcinoma of skin.
- Patients with history or presence of clinically significant neurological disorders
such as epilepsy, generalized seizure disorder, severe brain injuries are ineligible.
- Any other issue which, in the opinion of the treating physician, would make the
patient ineligible for the study.
- Patients with circulating human anti-mouse antibodies to BC8 noted on initial
screening (see Appendix III)
Subject Inclusion Criteria for 131-I Apamistamab Infusion Patients should meet performance
status and organ function parameters as specified, without known development of an
exclusion criterion, prior to proceeding to 131-I apamistamab infusion. See Section 9.2 re:
screening for treatment.