CLINICAL TRIAL / NCT02981628
Inotuzumab Ozogamicin in Treating Younger Patients With B-Lymphoblastic Lymphoma or Relapsed or Refractory CD22 Positive B Acute Lymphoblastic Leukemia
- Interventional
- Recruiting
- NCT02981628
Contact Information
A Phase 2 Study of Inotuzumab Ozogamicin (NSC# 772518) in Children and Young Adults With Relapsed or Refractory CD22+ B-Acute Lymphoblastic Leukemia (B-ALL)
This phase II trial studies how well inotuzumab ozogamicin works in treating younger patients with B-lymphoblastic lymphoma or CD22 positive B acute lymphoblastic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a toxic agent called ozogamicin. Inotuzumab attaches to CD22 positive cancer cells in a targeted way and delivers ozogamicin to kill them.
PRIMARY OBJECTIVE:
I. To determine the morphologic response rate (complete response [CR] + complete response
with incomplete hematologic recovery [CRi]) following one cycle of treatment with inotuzumab
ozogamicin in children with relapsed or refractory CD22+ B acute lymphoblastic leukemia
(B-ALL). (Cohort 1)
SECONDARY OBJECTIVES:
I. To determine the CR/CRi rate following 2 cycles of inotuzumab ozogamicin therapy. (Cohort
1) II. To determine the safety of single agent inotuzumab ozogamicin administered at the
adult recommended phase 2 dose (RP2D) to pediatric patients with relapsed or refractory CD22+
B-ALL. (Cohort 1) III. To determine the level of minimal residual disease (MRD) by flow
cytometry in responding patients. (Cohorts 1 and 2) IV. To determine the incidence, severity,
and outcomes of sinusoidal obstruction syndrome (SOS) of the liver in patients during
inotuzumab ozogamicin therapy and following subsequent treatment, including myeloablative
hematopoietic stem cell transplantation (HSCT). (Cohorts 1 and 2) V. To estimate the 3-year
event-free survival (EFS), 3-year overall survival (OS), and among responders, duration of
CR/CRi for pediatric patients with relapsed or refractory B-ALL treated with inotuzumab
ozogamicin. (Cohort 1) VI. To describe inotuzumab ozogamicin pharmacokinetics and
immunogenicity in pediatric patients in the presence of overt leukemia and in remission.
(Cohort 1) VII. To determine the safe and tolerable dose of inotuzumab ozogamicin in
combination with the augmented modified Berlin-Frankfurt-Munster (mBFM) consolidation
chemotherapy backbone. (Cohort 2)
EXPLORATORY OBJECTIVES:
I. To describe the levels of leukemic blast CD22 surface expression and site density, and to
explore the correlation with cytogenetics and clinical outcomes after treatment with
inotuzumab ozogamicin. (Cohorts 1 and 2) II. To explore potential mechanisms of resistance to
inotuzumab ozogamicin therapy including CD22 splice variants and intracellular signaling
pathways. (Cohorts 1 and 2) III. To explore the impact of inotuzumab ozogamicin on humoral
immune function and peripheral B cell populations. (Cohorts 1 and 2) IV. To describe the
level of MRD by next-generation high-throughput sequencing (HTS) techniques which may detect
low level leukemic blast populations that have altered CD22 expression. (Cohorts 1 and 2) V.
To prospectively explore candidate SOS biomarkers including the endothelial marker of
inflammation Angiopoietin 2 (Ang2) and the hepatic specific complement marker L-ficolin.
(Cohorts 1 and 2) VI. To explore the use of prophylactic ursodeoxycholic acid (UDCA) to
prevent hepatic damage and SOS during inotuzumab ozogamicin therapy and subsequent HSCT.
(Cohorts 1 and 2) VII. To describe the interaction between inotuzumab ozogamicin and chimeric
antigen receptor (CAR) T cell therapy before or after treatment with inotuzumab ozogamicin.
(Cohorts 1 and 2) VIII. To estimate the CR/CRi rate following one cycle of inotuzumab
ozogamicin plus augmented mBFM consolidation chemotherapy (first 42 days) and following 2
cycles within the confines of a pilot study. (Cohort 2)
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT I: Patients receive inotuzumab ozogamicin intravenously (IV) over 60 minutes on days
1, 8, and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence
of disease progression or unacceptable toxicity. (COMPLETE)
COHORT II: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, and 8.
Patients also receive cyclophosphamide IV over 30-60 on day 1; cytarabine IV over 1-30
minutes or subcutaneously (SC) on days 1-4 and 8-11; leucovorin calcium orally (PO) or IV on
days 2, 9, 16, 23 and 37 of cycle 1 and days 9 and 37 of cycle 2; pegaspargase or
calaspargase pegol IV over 1-2 hours or pegaspargase intramuscularly (IM) on day 15; and
vincristine IV on days 15 and 22. Patients receive methotrexate intrathecally (IT) on days 1,
8 and 36 of cycle 1 and day 36 of cycle 2 for CNS 1 patients, days 1, 8, 15, 22 and 36 of
cycle 1, and day 36 of cycle 2 for CNS 2 patients. CNS 3 patients receive methotrexate
intrathecal triple therapy (ITT) IT on days 1, 8, 15, 22 and 36 of cycle 1 and days 8 and 36
of cycle 2. There are 3 dose levels. If excessive toxicity is observed at dose level 1, the
dosing of inotuzumab ozogamicin will be decreased for dose level -1 and 6-mercaptopurine
omitted. If excessive toxicity is observed at this dose, then for dose level -2, the dosing
of inotuzumab ozogamicin and cyclophosphamide will be decreased. Treatment repeats every 42
days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
Patients undergo bone marrow aspiration or biopsy, lumbar puncture, and blood sample
collection throughout the trial. Patients also undergo imaging on screening and on study.
After completion of study treatment, patients are followed up at 30 days, every 3 months for
1 year, and then yearly for 4 years.
Gender
All
Age Group
1 Year to 21 Years
Accepting Healthy Volunteers
No
Inclusion Criteria:
- Patients must be >= 1 year and < 22 years of age at the time of enrollment
- Patients must have B-ALL, or previously diagnosed B lymphoblastic lymphoma (B-LL),
with >= 5% (M2 or M3) bone marrow blasts with or without extramedullary disease
- NOTE: Relapsed patients previously diagnosed with B-lymphoblastic lymphoma (B-LL)
are eligible if they have an M2 or M3 marrow at the time of enrollment on this
study
- Patients with ALL or B-LL who have M2 morphology must have local confirmatory testing
showing >= 5% blasts by flow cytometry, fluorescence in situ hybridization (FISH)
testing or other molecular method
- Leukemic blasts must demonstrate surface expression of CD22 at the time of relapse by
local/institutional flow cytometry of a bone marrow aspirate sample; (assessment of
CD22 using a bright fluorophore such as phycoerythrin [PE] is strongly recommended)
- In the case of an inadequate aspirate sample (dry tap) or if bone marrow aspirate
is unable to be performed due to patient clinical status, flow cytometry of
peripheral blood specimen may be substituted if the patient has at least 1,000/uL
circulating blasts; alternatively, CD22 expression may be documented by
immunohistochemistry of a bone marrow biopsy specimen
- Patients with one of the following:
- Second or greater relapse;
- Primary refractory disease with at least 2 prior induction attempts;
- First relapse refractory to at least one prior re-induction attempt
- Any relapse after HSCT (Cohort 1 ONLY)
Patients with Down syndrome are eligible ONLY for Cohort 1 with:
- Any of above disease status, OR
- First relapse with no prior re-induction attempt NOTE: Patients with Down syndrome or
prior HSCT are NOT eligible for Cohort 2 combination therapy
- Patients with Philadelphia chromosome (Ph)+ ALL must have had two prior therapy
attempts including two different tyrosine kinase inhibitors (TKIs)
- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy, defined as resolution of all such toxicities to =< grade 2
or lower per the inclusion/exclusion criteria prior to entering this study. Apply
to Cohort 2:
- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive. For
agents not listed, the duration of this interval must be discussed with the study
chair and the study-assigned Research Coordinator prior to enrollment.
- A waiting period prior to enrollment is not required for patients receiving
standard cytotoxic maintenance chemotherapy (i.e., corticosteroid, vincristine,
6MP, and/or methotrexate).
- A waiting period is not required for patients receiving a single dose of
intrathecal methotrexate, hydrocortisone, and/or cytarabine within 7 days prior
to enrollment
- >= 14 days must have elapsed after the completion of other cytotoxic therapy,
with the exception of hydroxyurea, for patients not receiving standard
maintenance therapy. For patients who previously received calaspargase pegol, >=
21 days must have elapsed after the last dose. Additionally, patients must have
fully recovered from all acute toxic effects of prior therapy.
- Note: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior
to the start of protocol therapy.
- Anti-cancer agents not known to be myelosuppressive (e.g., not associated with reduced
platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of
agent. For agents not listed, the duration of this interval must be discussed with the
study chair and the study-assigned research coordinator prior to enrollment.
- Anti-cancer agents that are antibodies: >= 21 days must have elapsed from infusion of
last dose of antibody, and toxicity related to prior antibody therapy must be
recovered to grade =< 1. There is an exception for blinatumomab infusions, for which
patients must have been off for at least 3 days and all drug related toxicity must
have resolved to grade 2 or lower as outlined in the inclusion/exclusion criteria.
- Corticosteroids: If used to modify immune adverse events related to prior therapy, >=
14 days must have elapsed since last dose of corticosteroid. A waiting period prior to
enrollment is not required for patients receiving corticosteroid for leukemia
therapy/cytoreduction.
- Radiotherapy: >= 2 weeks must have elapsed since local palliative radiation therapy
(XRT) (small port); >= 3 months must have elapsed if prior cranial or craniospinal XRT
was received, if >= 50% of the pelvis was irradiated, or if total body irradiation
(TBI) was received; >= 6 weeks must have elapsed if other substantial bone marrow
irradiation was given.
- Stem cell transplant or rescue without TBI: For Cohort 1, at least 90 days must have
elapsed since stem cell transplant and at least 30 days from donor lymphocyte
infusion. Patient must have had no more than one previous HSCT and currently have no
evidence of active graft vs. host disease (GVHD). For Cohort 2, no prior HSCT is
allowed.
- Chimeric antigen receptor (CAR) T cell therapy: At least 30 days must have elapsed
from the last CAR-T cell infusion
- Patients must have a performance status corresponding to Eastern Cooperative
Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years
of age and Lansky for patients =< 16 years of age; patients who are unable to
walk because of paralysis, but who are up in a wheelchair, will be considered
ambulatory for the purpose of assessing the performance score
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or
- A serum creatinine based on age/gender as follows:
- 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female)
- 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female)
- 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female)
- 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female)
- 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)
- >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female)
- Direct bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5
x ULN for age; for the purpose of this study, the ULN for ALT will be 45 U/L
Exclusion Criteria:
- Patients with any prior history of SOS irrespective of severity
- Patients with isolated central nervous system (CNS), testicular, or any other
extramedullary site of relapse
- Patients who have been previously treated with inotuzumab ozogamicin
- Patients who have previously received HSCT (Cohort 2 only)
- Patients with Down syndrome (Cohort 2 only)
- History of allergic reaction attributed to compounds of similar or biologic
composition to inotuzumab ozogamicin or other agents in the study
- Note: Patients with history of allergy to pegaspargase/calaspargase pegol are
eligible for enrollment on Cohort 2 if Erwinia formulation of asparaginase can be
obtained
- Patients with active optic nerve and/or retinal involvement are not eligible; patients
who are presenting with visual disturbances should have an ophthalmologic exam and, if
indicated, a magnetic resonance imaging (MRI) to assess optic nerve or retinal
involvement
- Patients who are currently receiving another investigational drug
- Patients who are currently receiving or plan to receive other anti-cancer agents
(except hydroxyurea, which may be continued until 24 hours prior to start of protocol
therapy, and intrathecal chemotherapy)
- Anti-GVHD or agents to prevent organ rejection post-transplant; patients who are
receiving cyclosporine, tacrolimus, or other agents to prevent either
graft-versus-host disease post bone marrow transplant or organ rejection
post-transplant are not eligible for this trial; at least 3 half-lives must have
elapsed after the last dose of GVHD or anti-rejection medications
- Patients who are currently receiving or plan to receive corticosteroids except as
described below
- Systemic corticosteroids may be administered for cytoreduction up to 24 hours
prior to the start of protocol therapy, (Cohort 1 only) for all patients,
corticosteroids may be administered as a premedication for inotuzumab ozogamicin
and as treatment for allergic reactions or for physiologic replacement/stress
dosing of hydrocortisone for documented adrenal insufficiency; corticosteroids
are not allowed for other indications
- Patients with known human immunodeficiency virus (HIV), hepatitis B or C infections;
testing to prove negative status is not required for enrollment unless it is deemed
necessary for usual medical care of the patient
- Patients who have an active uncontrolled infection defined as:
- Positive bacterial blood culture within 48 hours of study enrollment;
- Fever above 38.2 degree Celsius (C) within 48 hours of study enrollment with
clinical signs of infection; fever that is determined to be due to tumor burden
is allowed if patients have documented negative blood cultures for at least 48
hours prior to enrollment and no concurrent signs or symptoms of active infection
or hemodynamic instability
- A positive fungal culture within 30 days of study enrollment or active therapy
for presumed invasive fungal infection
- Patients may be receiving IV or oral antibiotics to complete a course of therapy
for a prior documented infection as long as cultures have been negative for at
least 48 hours and signs or symptoms of active infection have resolved; for
patients with clostridium (C.) difficile diarrhea, at least 72 hours of
antibacterial therapy must have elapsed and stools must have normalized to
baseline
- Active viral or protozoal infection requiring IV treatment
- Patients known to have one of the following concomitant genetic syndromes: Bloom
syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Schwachman
(Schwachman-Diamond-Blackfan) syndrome or any other known bone marrow failure syndrome
- There have been no human studies of inotuzumab ozogamicin in pregnant women and no
reports of exposure in utero; based on nonclinical safety studies, inotuzumab
ozogamicin has the potential to impair human male and female fertility and to
adversely affect human embryo fetal development; women of childbearing potential
should be advised to avoid becoming pregnant while receiving inotuzumab ozogamicin;
there is no information regarding the presence of inotuzumab ozogamicin in human milk,
the effects on the breast-fed infant, or the effects on milk production; because of
the potential for adverse reactions in breast-fed infants, women should not
breast-feed during treatment with inotuzumab ozogamicin and for at least 2 months
after the final dose
- Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained within 7 days prior to enrollment
- Female patients who are sexually active and of reproductive potential are not
eligible unless they agree to use an effective contraceptive method for the
duration of their study participation and for 8 months after the last dose of
inotuzumab ozogamicin
- Men with female partners of childbearing potential should use effective
contraception during treatment with inotuzumab ozogamicin and for at least 5
months after the last dose of inotuzumab ozogamicin
- Lactating females are not eligible unless they agree not to breastfeed their
infants