Inotuzumab Ozogamicin Post-Transplant For Acute Lymphocytic Leukemia
Summary
This study has two phases, Phase I and Phase II. The main goal of the Phase I portion of this research study is to see what doses post-transplant inotuzumab ozogamicin can safely be given to subjects without having too many side effects. The Phase II portion of this study is to see what side effects are seen with medication after transplant. Inotuzumab ozogamicin is a combination of an antibody and chemotherapy which has been shown to have significant activity against relapsed/refractory acute lymphocytic leukemia (ALL). Inotuzumab ozogamicin is considered experimental in this study.
Detailed description
Study Design This is a Phase I/II study of inotuzumab ozogamicin for the treatment of patients who underwent allogeneic transplantation for ALL and have a high risk of relapse. The Phase I portion of this study will be a 3+3 dose escalation trial. This is followed by a phase 2 cohort at the recommended Phase 2 dose (RP2D). Participants will receive study treatment up to 4 cycles until relapse of disease, unacceptable toxicity, or death, whichever occurs first Phase I: Inotuzumab Ozogamicin Dosing Escalation Subjects will be assessed for safety and tolerability (including adverse events, serious adverse events, and clinical/laboratory assessments) using a continuous monitoring approach. Phase II: Inotuzumab Ozogamicin Subjects will be assessed for safety and tolerability (including adverse events, serious adverse events, and clinical/laboratory assessments) using a continuous monitoring approach. In order to be included in the safety profile endpoint review, subjects must have received at least of 1 cycle of treatment. Primary Objective Phase I: To define a post hematopoietic stem cell transplantation maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of inotuzumab ozogamicin. Phase II: To assess the efficacy of inotuzumab ozogamicin as measured by diseasefree survival (DFS) at one year. Secondary Objective(s) Phase I: * To evaluate disease-free survival (DFS), nonrelapse mortality (NRM), relapse, relapse-related mortality and overall survival (OS) at 1 year. * To determine safety profile of inotuzumab ozogamicin after transplant including the incidence of myeloid toxicity and secondary graft failure and the rate of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS). * To determine if inotuzumab ozogamicin at these doses is effective at eradicating minimal residual disease in this cohort of participants Phase II: * To assess additional evidence of efficacy and safety as measured by non-relapse mortality (NRM), relapse, relapse-related mortality and overall survival (OS) at 1 year. * To determine if inotuzumab ozogamicin at these doses is effective at eradicating MRD. * To confirm the safety profile of inotuzumab ozogamicin therapy after transplant including myeloid toxicity, secondary graft failure, and the rate of VOD/SOS. * To evaluate the pharmacokinetics of inotuzumab ozogamicin post allogeneic transplant
Arms & interventions
- DrugInotuzumab Ozogamicin
Inotuzumab ozogamicin, IV, 28 day cycles Phase 1 dosages: Dose Level -2 (0.1 mg/m\^2) Dose Level -1 (0.2 mg/m\^2) Dose Level 0 (0.3 mg/m\^2) Dose Level 1 (0.4 mg/m\^2) Dose Level 2 (0.5 mg/m\^2) Dose Level 3 (0.6 mg/m\^2)
Outcome measures
Primary
Phase I MTD
Defined post hematopoietic stem cell transplantation MTD
Time frame: Up to 112 days (16 weeks)
Phase I DLTs
Frequency of DLTs during the first two cycles in ALL-participants
Time frame: Up to 112 days (16 weeks)
Phase II Median DFS
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
Time frame: At 3 months after initial treatment
Phase II Median DFS
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
Time frame: At 6 months after initial treatment
Phase II Median DFS
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
Time frame: At 9 months after initial treatment
Phase II Median DFS
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
Time frame: At 1 year after initial treatment
Phase II Median DFS
Efficacy as measured by phase II DFS at one year, estimated using Kaplan-Meier, reported as median and 2-sided 80% and 95% Confidence Interval (CI) DFS is defined as "Time from date of first dose to the date of disease progression (ie,objective progression, relapse from CR/CRi), or death due to any cause, whichever occurs first (including post-study treatment follow-up disease assessments)". Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 In Phase II, the null hypothesis of H0: DFS at 1-year ≤ 55% versus the alternative hypothesis of Ha: DFS at 1-year ≥ 75% using 1-sided alpha of 10% will be tested
Time frame: Post first dose of inotuzumab ozogamicin
Secondary
Phase I Median DFS
Time frame: At 3 months after initial treatment
Phase I Median DFS
Time frame: At 6 months after initial treatment
Phase I Median DFS
Time frame: At 9 months after initial treatment
Phase I Median DFS
Time frame: At 1 year after initial treatment
Phase I Median DFS
Time frame: Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days
Phase I NRM
Time frame: At 3 months after initial treatment
Phase I NRM
Time frame: At 6 months after initial treatment
Phase I NRM
Time frame: At 9 months after initial treatment
Phase I NRM
Time frame: At 1 year after initial treatment
Phase I NRM
Time frame: Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days
Phase I Relapse
Time frame: At 3 months after initial treatment
Phase I Relapse
Time frame: At 6 months after initial treatment
Phase I Relapse
Time frame: At 9 months after initial treatment
Phase I Relapse
Time frame: At 1 year after initial treatment
Phase I Relapse
Time frame: Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days
Phase I Relapse-related mortality
Time frame: At 3 months after initial treatment
Phase I Relapse-related mortality
Time frame: At 6 months after initial treatment
Phase I Relapse-related mortality
Time frame: At 9 months after initial treatment
Phase I Relapse-related mortality
Time frame: At 1 year after initial treatment
Phase I Relapse-related mortality
Time frame: Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days
Phase I Median OS
Time frame: At 3 months after initial treatment
Phase I Median OS
Time frame: At 6 months after initial treatment
Phase I Median OS
Time frame: At 9 months after initial treatment
Phase I Median OS
Time frame: At 1 year after initial treatment
Phase I Median OS
Time frame: Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days
Phase I Incidence of myeloid toxicity
Time frame: At 1 year
Phase I Incidence of secondary graft failure
Time frame: At 1 year
Phase I incidence of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)
Time frame: At 1 year
Phase I rate of VOD/SOS - number of participants affected
Time frame: At 1 year
Phase I - Percent of participants with grade 3 + AE/SAEs
Time frame: At 1 year
Phase II Non-relapse mortality (NRM)
Time frame: At 3 months after initial treatment
Phase II Relapse
Time frame: At 6 months after initial treatment
Phase II Relapse
Time frame: At 9 months after initial treatment
Phase II Relapse-related mortality
Time frame: At 1 year after initial treatment
Phase II Relapse-related mortality
Time frame: Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days
Phase II Median OS
Time frame: At 3 months after initial treatment
Phase II Median OS
Time frame: At 6 months after initial treatment
Phase II Median OS
Time frame: At 9 months after initial treatment
Phase II Median OS
Time frame: At 1 year after initial treatment
Phase II Median OS
Time frame: Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days
Phase II Response Rate
Time frame: At 3 months after initial treatment
Phase II Response Rate
Time frame: At 6 months after initial treatment
Phase II Response Rate
Time frame: At 9 months after initial treatment
Phase II Response Rate
Time frame: At 1 year after initial treatment
Phase II Response Rate
Time frame: Post first dose of inotuzumab ozogamicin on Day 1, Cycle 1, where cycle length is 28 days
Phase II Incidence of myeloid toxicity
Time frame: At 1 year
Phase II Incidence of secondary graft failure
Time frame: At 1 year after initial treatment
Phase I incidence of VOD/SOS
Time frame: At 1 year
Phase II rate of VOD/SOS - number of participants affected
Time frame: At 1 year
Phase II pharmacokinetic (PK) parameters - Cmax
Time frame: At Cycle 1 Day 1 (C1D1) after 0 hours (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Cmax
Time frame: At Cycle 1 Day 1 (C1D1) after 1 hour (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Cmax
Time frame: At Cycle 1 Day 1 (C1D1) after 4 hours (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Cmax
Time frame: At Cycle 1 Day 7 (C1D7) (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Cmax
Time frame: At Cycle 2 Day 1 (C2D1) after 0 hours (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Cmax
Time frame: At Cycle 2 Day 1 (C2D1) after 1 hour (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Cmax
Time frame: At Cycle 4 Day 1 (C4D1) after 0 hours (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Cmax
Time frame: At Cycle 4 Day 1 (C4D1) after 1 hour (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Ctrough
Time frame: At Cycle 1 Day 1 (C1D1) after 0 hours (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Ctrough
Time frame: At Cycle1 Day 1 (C1D1) after 1 hour (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Ctrough
Time frame: At Cycle1 Day 1 (C1D1) after 4 hours (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Ctrough
Time frame: At Cycle 1 Day 7 (C1D7) (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Ctrough
Time frame: At Cycle 2 Day 1 (C2D1) after 0 hours (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Ctrough
Time frame: At Cycle 2 Day 1 (C2D1) after 1 hour (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Ctrough
Time frame: At Cycle 4 Day 1 (C4D1) after 0 hours (each cycle is 28 days)
Phase II pharmacokinetic (PK) parameters - Ctrough
Time frame: At Cycle 4 Day 1 (C4D1) after 1 hour (each cycle is 28 days)
Eligibility criteria
Study locations (7)
The University of Kansas Cancer Center
Westwood, Kansas, 66205
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
University of Nebraska Medical Center
Omaha, Nebraska, 68106
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
Cleveland, Ohio, 44106-5065
Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
Cleveland, Ohio, 44195
The James Cancer Hospital and Solove Research Institute
Columbus, Ohio, 43210
References
- Davis KL, Yao CC, Zimmerman JAO, Rau RE. Immunotherapy in B-Cell Acute Lymphoblastic Leukemia. J Natl Compr Canc Netw. 2025 Dec;23(12):e257067. doi: 10.6004/jnccn.2025.7067.(PubMed)
- Metheny LL, Sobecks R, Cho C, Fu P, Margevicius S, Wang J, Ciarrone L, Kopp S, Convents RD, Majhail N, Caimi PF, Otegbeye F, Cooper BW, Gallogly M, Malek E, Tomlinson B, Gerds AT, Hamilton B, Giralt S, Perales MA, de Lima M. A multicenter study of posttransplantation low-dose inotuzumab ozogamicin to prevent relapse of acute lymphoblastic leukemia. Blood Adv. 2024 Mar 26;8(6):1384-1391. doi: 10.1182/bloodadvances.2023011514.(PubMed)