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Inotuzumab Ozogamicin and Blinatumomab in Treating Patients With Newly Diagnosed, Recurrent, or Refractory CD22-Positive B-Lineage Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT03739814
Recruitment Status : Recruiting
First Posted : November 14, 2018
Last Update Posted : April 17, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well inotuzumab ozogamicin and blinatumomab work in treating patients with CD22-positive B-lineage acute lymphoblastic leukemia that is newly diagnosed, has come back, or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as inotuzumab ozogamicin and blinatumomab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Condition or disease Intervention/treatment Phase
B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative CD22 Positive Recurrent B Acute Lymphoblastic Leukemia Refractory B Acute Lymphoblastic Leukemia Biological: Blinatumomab Biological: Inotuzumab Ozogamicin Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Inotuzumab Ozogamicin Followed by Blinatumomab for Ph-Negative CD22-Positive B-Lineage Acute Lymphoblastic Leukemia in Newly Diagnosed Older Adults or Adults With Relapsed or Refractory Disease
Actual Study Start Date : November 16, 2018
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : February 1, 2021


Arm Intervention/treatment
Experimental: Cohort 1 (inotuzumab ozogamicin, blinatumomab)
See Detailed Description
Biological: Blinatumomab
Given IV
Other Names:
  • Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody
  • Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103
  • Blincyto
  • MEDI-538
  • MT-103

Biological: Inotuzumab Ozogamicin
Given IV
Other Names:
  • Besponsa
  • CMC-544
  • Way 207294
  • WAY-207294

Experimental: Cohort 2 (inotuzumab ozogamicin, blinatumomab)
See Detailed Description.
Biological: Blinatumomab
Given IV
Other Names:
  • Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody
  • Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103
  • Blincyto
  • MEDI-538
  • MT-103

Biological: Inotuzumab Ozogamicin
Given IV
Other Names:
  • Besponsa
  • CMC-544
  • Way 207294
  • WAY-207294




Primary Outcome Measures :
  1. Event-free survival [ Time Frame: At 1 year ]
    Will be defined as time from start of treatment to failure to achieve complete response (CR)/complete response with incomplete count recovery (CRi) after completing Course II of blinatumomab, relapse after CR/CRi, progression on study requiring withdrawal from study therapy, or death from any cause


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Time from start of study therapy to death from any cause censored at the last known alive date, assessed up to 10 years ]
    Will be evaluated using the Kaplan-Meier method. A 95% confidence interval for the 1- and 3-year rates will be constructed using a point-wise confidence interval for the survival function based on a log-minus-log transformation. Will also calculate a 95% confidence interval by using a point-wise confidence interval for the survival function based on a log-minus-log transformation.

  2. Relapse-free survival (RFS) [ Time Frame: Time from first CR/CRi to progressive disease (relapse, treatment discontinuation due to health deterioration) or death, assessed up to 10 years ]
    Will be evaluated using the Kaplan-Meier method. A 95% confidence interval for the 1- and 3-year rates will be constructed using a point-wise confidence interval for the survival function based on a log-minus-log transformation. Will also calculate a 95% confidence interval by using a point-wise confidence interval for the survival function based on a log-minus-log transformation.

  3. Event-free survival (EFS) [ Time Frame: Time from start of treatment to failure to achieve CR/CRi after completing Course II of blinatumomab, relapse after CR/CRi, progression on study requiring withdrawal from study therapy, or death from any cause, assessed up to 10 years ]
    Will be evaluated using the Kaplan-Meier method. A 95% confidence interval for the 1- and 3-year rates will be constructed using a point-wise confidence interval for the survival function based on a log-minus-log transformation. Will also calculate a 95% confidence interval by using a point-wise confidence interval for the survival function based on a log-minus-log transformation.

  4. Complete and overall response rate [ Time Frame: Up to 10 years ]
    Point and interval estimates of the rates will be shown using a 95% binomial confidence interval.

  5. Minimal residual disease negativity [ Time Frame: Up to 10 years ]
  6. Allogeneic hematopoietic cell transplantation rate (Cohort 2) [ Time Frame: Up to 10 years ]
    Point and interval estimates of the rate will be shown using a 95% binomial confidence interval.


Other Outcome Measures:
  1. Rate of cytokine release syndrome (Cohort 1) [ Time Frame: Up to 10 years ]
    Point and interval estimates of the rate will be shown using a 95% binomial confidence interval.

  2. Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) of the liver [ Time Frame: Up to 10 years ]
    The rate of, timing of, and risk factors for SOS/VOD of the liver after limited inotuzumab ozogamicin exposure. Point and interval estimates of the rate will be shown using a 95% binomial confidence interval. A summary of the timing and risk factors for SOS/VOD of the liver will be provided.

  3. OS [ Time Frame: Up to 2 years ]
    Will compare between patients achieving CR/CRi and receiving consolidation with allogeneic hematopoietic cell transplantation versus (vs.) patients achieving CR/CRi and receiving consolidation without allogeneic hematopoietic cell transplantation. The median, 1-year, and 2-year OS will be compared between the above two groups. The distribution of OS for each group will be estimated using the Kaplan-Meier method.

  4. RFS [ Time Frame: Up to 2 years ]
    Will compare between patients achieving CR/CRi and receiving consolidation with allogeneic hematopoietic cell transplantation vs. patients achieving CR/CRi and receiving consolidation without allogeneic hematopoietic cell transplantation. The median, 1-year, and 2-year RFS will be compared between the above two groups. The distribution of RFS for each treatment arm will be estimated using the Kaplan-Meier method.

  5. Cumulative incidence of relapse (CIR) [ Time Frame: Up to 2 years ]
    Will compare between patients achieving CR/CRi and receiving consolidation with allogeneic hematopoietic cell transplantation vs. patients achieving CR/CRi and receiving consolidation without allogeneic hematopoietic cell transplantation. Competing risk analysis will be done to compare the relapse rates between the above two groups. In this analysis, death will be considered a competing event. Relapse rates at the 1-year and 2-year time points will be estimated. Other time points of interest may be estimated as well.

  6. Non-relapse mortality [ Time Frame: Up to 2 years ]
    Will compare between patients achieving CR/CRi and receiving consolidation with allogeneic hematopoietic cell transplantation vs. patients achieving CR/CRi and receiving consolidation without allogeneic hematopoietic cell transplantation. Competing risk analysis will be done to compare the mortality rates between the above two groups. In this analysis, relapse will be considered a competing event. Mortality rates at the 1-year and 2-year time points will be estimated. Other time points may be estimated as well.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Pre-registration Eligibility Criteria (Step 0)
  • Submission of bone marrow aspirate and peripheral blood for MRD analysis is mandatory prior to registration; the bone marrow sample should be from the first aspiration (i.e. first pull). Aspirate needle should be redirected if needed to get first pull bone marrow aspirate. It should be initiated as soon as possible after pre-registration. The specimens should be sent to the HEME Biobank.

    • Lumbar Puncture (Spinal Tap) and Intrathecal Methotrexate:

      • Patients may receive the day 1 of course IA dose of intrathecal (IT) methotrexate during the prior-to-registration lumbar puncture (or the venous line placement) to avoid a second lumbar puncture. If the dose is administered prior to registration, then systemic chemotherapy must begin within 7 days of this IT chemotherapy.
  • Registration Eligibility Criteria (Step 1)
  • Morphologic diagnosis of precursor B-cell acute lymphoblastic leukemia (ALL) based on World Health Organization (WHO) criteria. Patients with Burkitt lymphoma/leukemia are not eligible.
  • CD22-positive disease defined as CD22 expression by >= 20% of lymphoblasts by local hematopathology evaluation.
  • Philadelphia chromosome/BCR-ABL1-negative ALL by cytogenetics, fluorescence in situ hybridization (FISH), and/or polymerase chain reaction (PCR). If any test is positive for Philadelphia chromosome/BCR-ABL1, then the patient is ineligible.
  • No active central nervous system (CNS) leukemia (i.e. only CNS-1 disease allowed). Active CNS leukemia is defined as morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed local treatment for active disease within 28 days prior to registration, symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurological dysfunction) within the 28 days prior to registration, and/or known asymptomatic parenchymal CNS mass lesions; see below for additional guidance. Prophylactic intrathecal medication alone is not an exclusion.

    • Categories of CNS Involvement for CNS Evaluation Prior to Registration:

      • CNS 1: CSF has < 5 WBC/uL with cytospin negative for blasts; or >= 10 red blood cell (RBC)/uL with cytospin negative for blasts.
      • CNS 2: CSF has < 5 WBC/uL with cytospin positive for blasts; or >= 10 RBC/uL with cytospin positive for blasts; or >= 10 RBC/uL, WBC/uL >= 5 but less than Steinherz/Bleyer algorithm with cytospin positive for blasts (see below).
      • CNS 3: CSF has >= 5 WBC/uL with cytospin positive for blasts; or >= 10 RBC/uL, >= 5 WBC/uL and positive by Steinherz/Bleyer algorithm (see below); or clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement or hypothalamic syndrome). Steinherz/Bleyer Method of Evaluating Initial Traumatic Lumbar Punctures:

        • If the patient has leukemia cells in the peripheral blood and the lumbar puncture is traumatic and contains >= 5 WBC/uL with blasts, the following algorithm should be used to define CNS disease: CSF WBC/CSF RBC > 2 x (Blood WBC/Blood RBC count)
  • Patients with known or suspected testicular involvement by leukemia are allowed provided that the patient receives concomitant scrotal/testicular radiotherapy.

    • Unilateral or bilateral testicular enlargement should be assessed by ultrasound or other imaging technique. Biopsy is recommended if clinical findings are equivocal or suggestive of hydrocele or a non-leukemic mass, but further assessments are per treating physician discretion.
  • Not pregnant and not nursing.

    • This study involves agents that have known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required.
  • Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
  • No unstable cardiac disease such as myocardial infarction, angina pectoris, uncontrolled heart failure, or uncontrolled cardiac arrhythmia within 6 months of registration.
  • No impaired cardiac function, defined as left ventricular ejection fraction (LVEF) < 45% or New York Heart Association (NYHA) stage III or IV congestive heart failure (CHF).
  • Patients with known human immunodeficiency virus (HIV) infection are eligible if they have been on effective antiretroviral therapy with an undetectable viral load tested within 6 months of registration.
  • Patients with hepatitis B virus (HBV) are eligible only if they meet all the following:

    • On HBV-suppressive therapy.
    • No evidence of active virus.
    • No evidence of HBV-related liver damage.
  • Patients with hepatitis C virus (HCV) are eligible only if they meet all the following:

    • Successfully completed complete-eradication therapy with undetectable viral load.
    • No evidence of HCV-related liver damage.
  • No history of clinically relevant neurologic disorder such as epilepsy, seizure, aphasia, stroke, severe brain injury, structural brain abnormality, benign brain tumor, dementia, Parkinson's disease, movement disorder, cerebellar disease, or other significant CNS abnormalities.
  • No prior additional malignancy (i.e. in addition to ALL) except adequately treated basal- or squamous-cell skin cancer, in situ cervical cancer, stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for >= 2 years.
  • No history of clinically significant ventricular arrhythmia, unexplained non-vasovagal syncope, or chronic bradycardic states such as sinoatrial block or higher degree of atrioventricular block unless a permanent pacemaker has been implanted.
  • No history of chronic liver disease, including cirrhosis.
  • No history of sinusoidal occlusion syndrome/veno-occlusive disease of the liver.
  • No uncontrolled infection or recent history (within 4 months prior to registration) of deep tissue infections such as fasciitis or osteomyelitis.
  • Total bilirubin, serum =< 1.5 x upper limit of normal (ULN)*

    • Except in the event of: 1) Gilbert disease, in which case total bilirubin must be =< 2 x ULN, or 2) elevated bilirubin believed by investigator to be due to leukemic infiltration, in which case total bilirubin must be =< 2 x ULN.
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN
  • Creatinine, serum =< 1.5 ULN OR creatinine clearance >= 40 mL/min
  • QT interval by Fridericia's correction formula (QTcF) =< 470 msec
  • Cohort 1 Patients Only
  • Age >= 60 years.
  • No prior treatment for ALL except a single dose of intrathecal chemotherapy, corticosteroids, hydroxyurea, and/or leukapheresis to reduce peripheral blast count and prevent ALL complications. Allowed therapy may be administered for no more than 14 days and must be completed >= 24 hours prior to the initiation of protocol therapy.
  • No plan for allogeneic or autologous hematopoietic cell transplantation (HCT).
  • Cohort 2 Patients Only:
  • Age >= 18 years.
  • Relapsed or refractory disease in salvage 1 or 2.
  • No isolated extramedullary relapse.
  • Prior allogeneic HCT permitted.
  • Patients with prior allogeneic HCT must have completed transplantation >= 4 months prior to registration.
  • Patients with prior allogeneic HCT must have no evidence of graft-versus-host disease and must have completed immunosuppressive therapy >= 30 days prior to registration.
  • Prior treatment with inotuzumab ozogamicin, blinatumomab, other CD22-directed therapy, or other CD19-directed therapy is not allowed.
  • Prior treatment with rituximab must be completed >= 7 days prior to registration.
  • Prior treatment with other monoclonal antibodies must be completed >= 6 weeks prior to registration.
  • Prior treatment for ALL must be completed >= 14 days prior to registration with the following exceptions: intrathecal chemotherapy, hydroxyurea, corticosteroids, 6-mercaptopurine, methotrexate, vincristine, and/or leukapheresis to reduce circulating absolute lymphoblast count to =< 10,000/uL or prevent complications related to ALL are allowed but must be completed >= 24 hours prior to the initiation of protocol therapy.
  • Patients should have resolution of any acute non-hematologic toxicities of prior therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade =< 1.
  • Peripheral blood absolute lymphoblast count =< 10,000/uL (treatment allowed as above to reduce blast count to =< 10,000/uL)

Information from the National Library of Medicine

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): NCT03739814


Locations
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United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Site Public Contact    858-822-5354    cancercto@ucsd.edu   
Principal Investigator: Matthew J. Wieduwilt         
United States, Delaware
Christiana Care Health System-Christiana Hospital Recruiting
Newark, Delaware, United States, 19718
Contact: Site Public Contact    302-623-4450    KDempsey@christianacare.org   
Principal Investigator: Gregory A. Masters         
United States, Illinois
University of Chicago Comprehensive Cancer Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Site Public Contact    773-702-8222    cancerclinicaltrials@bsd.uchicago.edu   
Principal Investigator: Wendy Stock         
United States, Kansas
University of Kansas Cancer Center Recruiting
Kansas City, Kansas, United States, 66160
Contact: Site Public Contact    913-945-7552    ctnursenav@kumc.edu   
Principal Investigator: Kenneth Byrd         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Site Public Contact    800-600-3606    info@siteman.wustl.edu   
Principal Investigator: Geoffrey L. Uy         
United States, New York
Northwell Health/Center for Advanced Medicine Recruiting
Lake Success, New York, United States, 11042
Contact: Site Public Contact    516-734-8896      
Principal Investigator: Cristina M. Ghiuzeli         
North Shore University Hospital Recruiting
Manhasset, New York, United States, 11030
Contact: Site Public Contact    516-734-8896      
Principal Investigator: Cristina M. Ghiuzeli         
NYP/Weill Cornell Medical Center Recruiting
New York, New York, United States, 10065
Contact: Site Public Contact    212-746-1848      
Principal Investigator: Ellen K. Ritchie         
United States, North Carolina
Wake Forest University Health Sciences Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Site Public Contact    336-713-6771      
Principal Investigator: Bayard L. Powell         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Bhavana Bhatnagar         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Matthew J Wieduwilt Alliance for Clinical Trials in Oncology

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03739814     History of Changes
Other Study ID Numbers: NCI-2018-02484
NCI-2018-02484 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A041703 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A041703 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: November 14, 2018    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Antibodies, Bispecific
Muromonab-CD3
Visilizumab
Antineoplastic Agents, Immunological
Blinatumomab
Inotuzumab Ozogamicin
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Immunosuppressive Agents