Inotuzumab Ozogamicin in Treating Younger Patients With B-Lymphoblastic Lymphoma or Relapsed or Refractory CD22 Positive B Acute Lymphoblastic Leukemia
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|ClinicalTrials.gov Identifier: NCT02981628|
Recruitment Status : Recruiting
First Posted : December 5, 2016
Last Update Posted : March 17, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Recurrent B Acute Lymphoblastic Leukemia Recurrent B Lymphoblastic Lymphoma Refractory B Acute Lymphoblastic Leukemia Refractory B Lymphoblastic Lymphoma||Procedure: Biospecimen Collection Procedure: Bone Marrow Aspiration and Biopsy Drug: Calaspargase Pegol Drug: Cyclophosphamide Drug: Cytarabine Procedure: Diagnostic Imaging Biological: Inotuzumab Ozogamicin Drug: Leucovorin Calcium Procedure: Lumbar Puncture Drug: Methotrexate Drug: Pegaspargase Drug: Vincristine||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||80 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|Official Title:||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)|
|Actual Study Start Date :||June 5, 2017|
|Estimated Primary Completion Date :||December 31, 2024|
|Estimated Study Completion Date :||December 31, 2024|
Experimental: Cohort I (inotuzumab ozogamicin)
Patients receive inotuzumab ozogamicin 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)
Biological: Inotuzumab Ozogamicin
Experimental: Cohort II (inotuzumab ozogamicin, mBFM chemotherapy)
See Detailed Description
Procedure: Biospecimen Collection
Undergo blood sample collection
Procedure: Bone Marrow Aspiration and Biopsy
Undergo a bone marrow aspiration and biopsy
Drug: Calaspargase Pegol
Given IV or SC
Procedure: Diagnostic Imaging
Other Name: Medical Imaging
Biological: Inotuzumab Ozogamicin
Drug: Leucovorin Calcium
Given PO or IV
Procedure: Lumbar Puncture
Undergo lumbar puncture
Given IV or IM
- Morphologic response (complete response [CR]+ incomplete hematologic recovery [CRi]) following one cycle of treatment with inotuzumab ozogamicin (Cohort 1) [ Time Frame: Up to 28 days ]The response rate will be estimated using the proportion of eligible/evaluable patients with CR/CRi response. A one-sided lower 95% Agresti-Coull confidence limit will be calculated.
- Morphologic response (CR + CRi) following 2 cycles of inotuzumab ozogamicin therapy (Cohort1) [ Time Frame: Up to 56 days ]The response rate will be estimated using the proportion of eligible/evaluable patients with CR/CRi response.
- Incidence of dose-limiting toxicities at recommended phase II dose (RP2D) (Cohort 1) [ Time Frame: During Cycle 1, up to 28 days ]Evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. For a given reporting period, a patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient.
- Level of minimal residual disease (MRD) assessed in bone marrow by flow cytometry (Cohort 1 and 2) [ Time Frame: Up to 2 cycles ]MRD negativity rates (< 0.01% detectable leukemia cells) will be estimated.
- Incidence of adverse events of sinusoidal obstruction syndrome (SOS) of liver (Cohort 1 and 2) [ Time Frame: Up to 1 year from last dose of Inotuzumab ozogamicin ]Evaluated according to NCI CTCAE version 5.0. The incidence of SOS of the liver in patients during inotuzumab ozogamicin therapy and following subsequent treatment including myeloablative hematopoietic cell transplantation (HSCT) will be described.
- Event free survival (EFS) (Cohort 1) [ Time Frame: From study entry to first event (induction failure, induction death, relapse, second malignancy, remission death), or date of last follow-up for event free subjects, assessed up to 3 years ]The EFS rate will be estimated using Kaplan Meier approach.
- Overall survival (OS) (Cohort 1) [ Time Frame: From the time from study entry to death or date of last follow-up, assessed up to 3 years ]The OS rate will be estimated using Kaplan Meier approach.
- Duration of CR, CRi (Cohort 1) [ Time Frame: Up to 3 years ]Among responding patients, three-year complete continuous response will also be estimated using duration of CR/CRi for the overall responding group and stratified by whether or not the patients proceed to HSCT.
- Pharmacokinetic (PK) parameters, i.e., inotuzumab ozogamicin trough levels (Cohort 1) [ Time Frame: Cycles 1 and 2 (each cycle is 28 days) ]Inotuzumab ozogamicin trough levels (ng/mL) will be determined in serum by validated, high sensitivity liquid chromatography-mass spectrometry (LCMS) assays. Descriptive summary statistics will be provided for the trough levels at scheduled visits for Cycles 1 and 2.
- Immunogenicity (Cohort 1) [ Time Frame: Cycles 1 and 2 ]Enhanced chemiluminescence (ECL) and cell-based assays will be used to detect anti-drug antibodies and neutralizing antibodies to inotuzumab ozogamicin in serum. Inotuzumab ozogamicin trough levels will be compared between patients with and without antibodies.
- Incidence of dose-limiting toxicities at the selected dose level of inotuzumab ozogamicin in combination with the augmented modified Berlin-Frankfurt-Munster (mBFM) consolidation chemotherapy (Cohort 2) [ Time Frame: Up to cycle 1 (each cycle is 42 days) ]Evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. For a given reporting period, a patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient.
- Changes in CD22 surface expression (Cohorts 1 and 2) [ Time Frame: Baseline, post Cycle 1, and at time of relapse ]Exploratory analysis of CD22 will focus primarily on the comparison of paired pre-treatment and post-treatment samples at the following times, 1) End of cycle 1 and 2) at relapse to evaluate for changes in CD22 expression pre and post-inotuzumab ozogamicin. Specifically, samples will be evaluated for change in CD22 expression that occurs over time to study the role of CD22 expression as it relates to resistance to therapy or mechanism for relapse. Correlation between changes in CD22 expression and patient's clinical response to inotuzumab ozogamicin as well as cytogenetic/molecular features will be described, in particular to explore the association of CD22-negative subpopulations in patients with KMT2A-rearranged acute lymphoblastic leukemia (ALL).
- Change in CD22 site density (Cohorts 1 and 2) [ Time Frame: Baseline, post Cycle 1, and at time of relapse ]Exploratory analysis of CD22 will focus primarily on the comparison of paired pre-treatment and post-treatment samples at the following times, 1) End of cycle 1 and 2) at relapse to evaluate for changes in CD22 site density pre and post-inotuzumab ozogamicin. Samples will be evaluated for any change in CD22 site density that occurs over time and to evaluate for the emergence of a CD22 "dim" or "negative" population to study the role of CD22 site density as it relates to resistance to therapy or mechanism for relapse. Correlation between changes in CD22 site density and patient's clinical response to inotuzumab ozogamicin as well as cytogenetic/molecular features will be described, in particular to explore the association of CD22-negative subpopulations in patients with KMT2A-rearranged acute lymphoblastic leukemia (ALL).
- Leukemic blast CD22 splice variants (Cohorts 1 and 2) [ Time Frame: Baseline, post-Cycle 1, and at time of relapse ]Will be analyzed by ribonucleic acid-sequencing (RNA-Seq). The MAJIQ and VOILA software will be used to identify splicing variations in CD22 from RNA Seq and to quantitate the percent spliced in (PSI) of the alternative exons. CD22 protein levels will be determined by immunoblotting of whole cell protein lysates using several anti-CD22 antibodies recognizing either extracellular or intracellular domains. Both protein sizes and preservation of individual epitopes will be assessed and correlated with alterations in exon inclusion.
- Intracellular signaling pathways in leukemic blasts treated with inotuzumab ozogamicin (Cohorts 1 and 2) [ Time Frame: Baseline up to 5 years ]Peripheral blood samples will be evaluated by comprehensive protein profiling using CyTOF panels for the two major areas of analyses, surface immunophenotyping to assess the developmental stage of both normal and abnormal B cells and measure their responses to inotuzumab ozogamicin , as well as intracellular epitopes to assess the cellular consequences of treatment with inotuzumab ozogamicin. Exploratory analysis will be performed using Cytobank software tools (viSNE, SPADE and CITRUS) for subpopulations clustering, dimensionality reduction and hierarchical organization.
- Changes in peripheral blood absolute B cell numbers and maturation of developing B cell populations with inotuzumab ozogamicin therapy (Cohorts 1 and 2) [ Time Frame: Baseline up to 5 years ]Descriptive statistics will be used to characterize patterns of B-cell development including selective loss of subsets. Changes in B cell number and subsets will be described, and exploratory analysis will be conducted to assess their correlation with clinical features including immunoglobulin levels, occurrence of infections, and need for intravenous immunoglobulin (IVIG) replacement during inotuzumab ozogamicin therapy.
- Level of MRD by next-generation high-throughput sequencing (HTS) techniques (Cohorts 1 and 2) [ Time Frame: Up to 2 cycles ]Compared to MRD measured by flow cytometry. MRD levels at each bone marrow evaluation time point will be measured by standard flow cytometry (MRD-negative defined as < 0.01% or 1 leukemic cell in 10-4 nucleated cells). At the end of cycles 1 and 2, MRD will also be assessed by HTS. The correlation between the measurements with each technique will be described and the sensitivity of flow-based MRD methodology in the setting of CD22-targeted therapy will be explored.
- Serum levels of candidate SOS biomarkers Ang2 and L ficolin (Cohorts 1 and 2) [ Time Frame: Up to 12 months from last dose of inotuzumab ozogamicin ]Correlated with clinical development of SOS. Descriptive statistics will be used to characterize clinical features of patients experiencing SOS. L-ficolin and Ang2 absolute levels and change in level over time with inotuzumab ozogamicin exposure will be evaluated and correlated with development of SOS. Biomarker levels will be compared using simple comparative statistics between subgroups.
- Incidence of SOS in patients who receive prophylaxis with ursodeoxycholic acid (UDCA) during inotuzumab ozogamicin therapy (Cohorts 1 and 2) [ Time Frame: Up to 12 months from last dose of inotuzumab ozogamicin ]Descriptive statistics will be used to characterize clinical features of patients experiencing SOS, potential clinical risk factors, and the impact of ursodeoxycholic acid prophylaxis.
- Interaction between CAR- T therapy and inotuzumab ozogamicin (Cohorts 1 and 2) [ Time Frame: Up to 5 years ]Will be evaluated by incidence of hematologic DLT in patients with CAR-T therapy prior to inotuzumab ozogamicin, incidence of post-inotuzumab ozogamicin CAR-T therapy, time to CAR-T therapy after inotuzumab ozogamicin, and B-cell recovery prior to CAR-T therapy after inotuzumab ozogamicin. Will be summarized using descriptive statistics.
- Morphologic response (CR/CRi) (Cohort 2) [ Time Frame: Up to 2 cycles (each cycle is 42 days) ]Will be estimated using the proportion of eligible/evaluable patients with CR/CRi response. Analysis will be mostly descriptive.
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|Ages Eligible for Study:||1 Year to 21 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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 (dose levels 1 and -1) if Erwinia formulation of asparaginase can be obtained
- If Cohort 2 is enrolling at dose level -2, then patients who cannot receive asparaginase due to prior allergy, toxicity, or lack of access may enroll
- NOTE: patients on AALL1621 are not eligible to co-enroll on AALL1931
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02981628
|Principal Investigator:||Maureen M O'Brien||Children's Oncology Group|
|Responsible Party:||Children's Oncology Group|
|Other Study ID Numbers:||
NCI-2016-01494 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AALL1621 ( Other Identifier: Children's Oncology Group )
AALL1621 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
|First Posted:||December 5, 2016 Key Record Dates|
|Last Update Posted:||March 17, 2023|
|Last Verified:||March 2023|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Immune System Diseases
Physiological Effects of Drugs