Phase I Study of Inotuzumab With Augmented BFM Re-Induction for Patients With Relapsed/Refractory B-cell ALL
Phase 1
Active, not recruiting
- Conditions
- B-cell Acute Lymphoblastic Leukemia
- Interventions
- Registration Number
- NCT03962465
- Lead Sponsor
- University of Virginia
- Brief Summary
In the proposed study, escalating doses of inotuzumab ozogamicin will be added to a standard pediatric inspired re-induction regimen and administered to patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Two re-induction regimens will be tested (one without pegaspargase and one including pegaspargase) and participants will be followed for disease status, allogeneic hematopoietic cell transplant (allo HCT), veno-occlusive disease following allo HCT, and overall survival.
- Detailed Description
Inotuzumab ozogamicin has been studied as a single agent in refractory and relapsed ALL. In the relapsed setting, inotuzumab ozogamicin has been shown to achieve complete remission (CR) in 81% of patients and minimal residual disease (MRD) negativity in 78% of patients who achieve CR. In the proposed study, escalating doses of inotuzumab ozogamicin will be added to a standard pediatric inspired re-induction regimen and administered to patients with relapsed or refractory B-cell ALL. Two re-induction regimens will be tested. The first regimen is a 3-drug regimen comprised of prednisone, vincristine, and daunorubicin. The second is a 4-drug regimen comprised of prednisone, vincristine, daunorubicin, and pegaspargase. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-ARA-C) will be included for central nervous system (CNS) prophylaxis with both the 3-drug and 4-drug regimens. We hypothesize that combining inotuzumab ozogamicin with these regimens is safe and will improve CR rates, successful transition to allo HCT, and overall survival in patients with relapsed or refractory B-ALL.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 36
Inclusion Criteria
- Provision of signed and dated informed consent form
- Stated willingness to comply with all study procedures and availability for the duration of the study
- Diagnosed with CD-22 positive* B-cell Acute Lymphoblastic Leukemia or B-cell Lymphoblastic Lymphoma (Philadelphia chromosome negative) * For the purposes of this study, CD-22 positive will be defined based on the analysis completed for diagnostic purposes.
- Male or female, aged 16-60 years
- ECOG performance status of 0-2
- Left ventricular ejection fraction ≥ 50% measured by echocardiogram or MUGA
- Either relapsed following remission after initial induction therapy or refractory to induction therapy
- Adequate organ function, including serum creatinine ≤ 1.6 mg/dL OR creatinine clearance >50 ml/min by Cockgroft-Gault formula, bilirubin ≤ 1.5 mg/dL (except in patients with Gilbert's disease), AST, ALT and alkaline phosphatase ≤ 3 x upper limit of normal (elevation exceeding this threshold of either AST OR ALT would not meet eligibility)
- For females of reproductive potential: negative pregnancy test
- For females and males of reproductive potential: agreement to use adequate contraception during study participation and for an additional 1 year after the end of study treatment
- Agreement to adhere to Lifestyle Considerations throughout study duration and for 1 year following last study treatment.
Exclusion Criteria
- Past receipt of a total of ≥ 300 mg/m^2 doxorubicin equivalents (600 mg/m^2 daunorubicin, 60 mg/m^2 idarubicin, 75 mg/m^2 mitoxantrone)
- Current or past history of pancreatitis
- QT interval on electrocardiogram (ECG) > 0.45 by Framingham formula
- Known congestive heart failure
- Known allergy to asparaginase (only an exclusion criteria for participants enrolling in part 2)
- Presence of central nervous system (CNS) disease
- Pregnancy or lactation
- Chronic liver disease including chronic active hepatitis and/or cirrhosis
- Active Hepatitis B virus (HBV) by core antibody, surface antigen (HBsAg) or viral load
- Active Hepatitis C virus (HCV) (positive antibody test confirmed by viral load if antibody test is positive)
- Known history of infection with Human Immunodeficiency Virus (HIV)
- Active or uncontrolled infections
- Abnormal baseline hepatic ultrasound (including Dopplers)
- Prior allogeneic stem cell transplant
- Prior use of inotuzumab ozogamicin
- Known diagnosis of hemochromatosis with iron overload
- Treatment with steroids or hydroxyurea for more than 7 days with each within the 2 weeks prior to registration -that is, each is allowed for up to 7 days
- Gastrointestinal tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease, or inability to swallow medications.
- Philadelphia chromosome positive B-cell ALL
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 3-drug re-induction regimen with inotuzumab Daunorubicin One cycle of a 3-drug regimen comprised of standard doses of prednisone, vincristine, and daunorubicin with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 3-drug re-induction regimen with inotuzumab Vincristine One cycle of a 3-drug regimen comprised of standard doses of prednisone, vincristine, and daunorubicin with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 3-drug re-induction regimen with inotuzumab Cytarabine One cycle of a 3-drug regimen comprised of standard doses of prednisone, vincristine, and daunorubicin with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 3-drug re-induction regimen with inotuzumab Methotrexate One cycle of a 3-drug regimen comprised of standard doses of prednisone, vincristine, and daunorubicin with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 3-drug re-induction regimen with inotuzumab Inotuzumab ozogamicin One cycle of a 3-drug regimen comprised of standard doses of prednisone, vincristine, and daunorubicin with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 3-drug re-induction regimen with inotuzumab Prednisone Pill One cycle of a 3-drug regimen comprised of standard doses of prednisone, vincristine, and daunorubicin with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 4-drug re-induction regimen with inotuzumab Prednisone Pill One cycle of a 4-drug regimen comprised of standard doses of prednisone, vincristine, daunorubicin, and pegaspargase with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 4-drug re-induction regimen with inotuzumab Vincristine One cycle of a 4-drug regimen comprised of standard doses of prednisone, vincristine, daunorubicin, and pegaspargase with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 4-drug re-induction regimen with inotuzumab Cytarabine One cycle of a 4-drug regimen comprised of standard doses of prednisone, vincristine, daunorubicin, and pegaspargase with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 4-drug re-induction regimen with inotuzumab Methotrexate One cycle of a 4-drug regimen comprised of standard doses of prednisone, vincristine, daunorubicin, and pegaspargase with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 4-drug re-induction regimen with inotuzumab Inotuzumab ozogamicin One cycle of a 4-drug regimen comprised of standard doses of prednisone, vincristine, daunorubicin, and pegaspargase with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 4-drug re-induction regimen with inotuzumab Daunorubicin One cycle of a 4-drug regimen comprised of standard doses of prednisone, vincristine, daunorubicin, and pegaspargase with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2) 4-drug re-induction regimen with inotuzumab Pegaspargase One cycle of a 4-drug regimen comprised of standard doses of prednisone, vincristine, daunorubicin, and pegaspargase with inotuzumab ozogamicin at a reduced dose. Intrathecal methotrexate (IT-methotrexate) and intrathecal cytarabine (IT-Ara-C) will be included for CNS prophylaxis. IV inotuzumab ozogamicin will be given at a reduced dose (may vary from a total cycle dose of 0.4 mg/m\^2 to 0.9 mg/m\^2)
- Primary Outcome Measures
Name Time Method Characterization of Adverse Events (CTCAE version 5) All adverse events occurring through 30 days following last dose of inotuzumab ozogamicin. A characterization of all adverse events experienced by patients receiving these drug combinations. Also, any SAEs deemed related to study treatment, including veno-occlusive disease, will be captured at any time while the participant is on-study.
Dose-limiting toxicities From initiation of inotuzumab ozogamicin through 30 days following the last dose of inotuzumab ozogamicin The number of dose-limiting toxicities will be used to determine the maximum tolerated dose combination for these combinations of drugs
Informative course of treatment For each participant, up to the 29 days of study treatment Percent of patients that receive enough treatment to be informative to the study
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (4)
University of Wisconsin
🇺🇸Madison, Wisconsin, United States
University of Virginia
🇺🇸Charlottesville, Virginia, United States
Vanderbilt-Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
VCU Massey Cancer Center
🇺🇸Richmond, Virginia, United States