Inotuzumab Ozogamicin Post-Transplant For Acute Lymphocytic Leukemia and Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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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) and Non-Hodgkin's Lymphoma (NHL). Inotuzumab ozogamicin is considered experimental in this study.

Detailed Description
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Study Design This is a Phase I/II study of inotuzumab ozogamicin for the treatment of patients who underwent allogeneic transplantation for ALL or who underwent autologous transplant for NHL and have a high risk of relapse. For ALL and NHL, respectively, the Phase I portion of this study will be a 3+3 dose escalation trial. For ALL patients, this is followed by a phase 2 cohort at the recommended Phase 2 dose (RP2D). Participants will receive study treatment up to 12 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 ALL Phase I: To define a post hematopoietic stem cell transplantation maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of inotuzumab ozogamicin in ALL. NHL Phase I: To define a post hematopoietic stem cell transplantation MTD and RP2D of inotuzumab ozogamicin in NHL. ALL Phase II: To assess the efficacy of inotuzumab ozogamicin as measured by diseasefree survival (DFS) at one year in ALL. Secondary Objective(s) Phase 1 (for each cohort): 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 (ALL participants). To evaluate the pharmacokinetics of inotuzumab ozogamicin post autologous transplant (NHL participants). Phase 2 (for all cohort): 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 in this cohort of participants (ALL participants). 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

Official Title
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Inotuzumab Ozogamicin Post-Transplant For Acute Lymphocytic Leukemia and Non-Hodgkin's Lymphoma

Conditions
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Acute Lymphocytic Leukemia, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Inotuzumab Ozogamicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1 Acute Lymphoblastic Leukemia Inclusion Criteria Diagnosis of CD22-positive Acute Lymphoblastic Leukemia Patients who underwent an allogeneic hematopoietic stem cell transplantation from any donor source for acute lymphocytic leukemia Patients who are between T+40 and T+100 after allogeneic transplantation. Patients must receive their first dose of inotuzumab at or before T+100. Patients who have/are either: Transplanted in hematologic first complete remission with evidence of minimal residual disease within 45 days of allogeneic transplantation ---Pre- or Post-Transplant Minimal Residual Disease defined by: ----Any detectable ALL (by flow cytometry, cytogenetics, or PCR techniques) as per clinical indication. In second or third complete remission at the time of allogeneic transplantation Treated with reduced intensity regimens or non-myeloablative conditioning regimens Lymphoid blast crisis of CML Are relapsed or refractory to at least 1 line of chemotherapy Philadelphia-like ALL Patients who have evidence of donor chimerism after allogeneic transplantation. ECOG Performance status < 2 Participants must have ANC > 1,000/µL for 3 days and platelet transfusion independence as defined as a platelet count > 50,000/µL for 7 days. Able to adhere to the study visit schedule and other protocol requirements. Participants must have the ability to understand and the willingness to sign a written informed consent document. Phase 1 Non-Hodgkin's Lymphoma Inclusion Criteria Diagnosis of CD22-positive B-cell Non-Hodgkin's Lymphoma -- Patients with 1) Diffuse large B cell lymphoma; 2) Transformed indolent lymphoma; 3) CLL/SLL with Richter's transformation and 4) High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements. Patients must have received an autologous hematopoietic stem cell transplant under one of the following conditions: Achieved partial remission (defined as Deauville 4 on PET/CT) after treatment with platinum - containing salvage regimen; Failed first platinum - containing salvage regimen and achieved complete or partial remission after two separate lines of platinum - containing regimen; Had a second autologous hematopoietic stem cell transplant after achieving complete or partial remission with the first autologous transplant; or Had relapsed or refractory disease involving the bone marrow prior to receiving salvage therapy; The patient's lymphoma must be CD22 positive either by immunohistochemistry or flow cytometry analysis. Patients who are between T+40 and T+100 after cell therapy. Patients who received myeloablative conditioning must start between T+70 and T+100. Patients must receive their first dose of inotuzumab at or before T+100. ECOG Performance status ≤ 2 Age ≥ 16 years, ≤ 75 years Participants must have ANC > 1,000/µL for 3 days and platelet transfusion independence as defined as a platelet count > 50,000/µL for 7 days. Able to adhere to the study visit schedule and other protocol requirements. Participants must have the ability to understand and the willingness to sign a written informed consent document. Phase 2 Acute Lymphoblastic Leukemia Inclusion Criteria Diagnosis of CD22-positive Acute Lymphoblastic Leukemia Patients who underwent an allogeneic hematopoietic stem cell transplantation from any donor source for acute lymphocytic leukemia Patients who are between T+40 and T+100 after allogeneic transplantation Patients who have/are either: Transplanted in hematologic first complete remission with evidence of minimal residual disease within 45 days of allogeneic transplantation ---Post-Transplant Minimal Residual Disease defined by: ----Any detectable ALL (by flow cytometry, cytogenetics, or PCR techniques) as per clinical indication. In second or third complete remission at the time of allogeneic transplantation Treated with reduced intensity regimens as defined per institutional standard of practice Lymphoid blast crisis of CML Are relapsed or refractory to at least 1 line of chemotherapy Philadelphia-like ALL Patients who have > 80% donor chimerism after allogeneic transplantation. Philadelphia chromosome positive ALL must have failed at least 1 TKI ECOG Performance status < 1 pre-transplant evaluation, see 10.1.1 Participants must have ANC > 1,000/µL for 3 days and platelet transfusion independence as defined as a platelet count > 50,000/µL for 7 days. Able to adhere to the study visit schedule and other protocol requirements. Participants must have the ability to understand and the willingness to sign a written informed consent document. Phase 1 and 2 Exclusion Criteria: Patients with clinical evidence of disease progression prior to enrollment 4.5.2 Persistent prior treatment toxicities Grade 2 and above according to NCI CTCAE Version 4.03 (with the exception for alopecia, neuropathy, etc.) For patients with NHL: Active central nervous system or meningeal involvement by lymphoma. Patients with a history of CNS or meningeal involvement must be in a documented remission. For patients with ALL: active central nervous system involvement with ALL. Patients with inadequate organ function as defined by: Creatinine clearance < 30ml/min Bilirubin > 2X institutional upper limit of normal AST (SGOT) > 2X institutional upper limit of normal ALT (SGPT) > 2X institutional upper limit of normal GVHD grade III or IV (for patients with a prior allogeneic transplant). Active acute or chronic GVHD of the liver (for patients with a prior allogeneic transplant) History of VOD Active malignancy Patients with uncontrolled inter-current illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situationsthat would limit compliance with study requirements. Pregnant or breastfeeding women are excluded from this study because inotuzumab ozogamicin may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with inotuzumab ozogamicin, breastfeeding should be discontinued if the mother is treated with inotuzumab ozogamicin. These potential risks may also apply to other agents used in this study. Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy Serologic statusreflecting active hepatitis B or C infection. Patientsthat are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.) Participation in any other investigational drug study or had exposure to any other investigational agent, device, or procedure, within 21 days (or 5 half-lives, whichever is greater) Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data. Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inotuzumab Ozogamicin<br>Phase I: A maximum of 12 cycles will be allowed and doses will be adjusted in 0.1mg/m2 increments using a dose escalation scale depending on tolerability. Total range of dose levels for ALL participants is 0.1-0.6mg/m^2 and for NHL participants 0.2-0.8mg/m^2 Dosing in the NHL cohort will start at Dose Level 0 (0.3mg/m^2) or one dose level below the ALL cohort maximum tolerated dose (MTD), whichever is higher. Phase II: ALL participants: Will be enrolled until all Phase I ALL participants have been followed and assessed for toxicity for at least 4 weeks after the fourth treatment dose of inotuzumab ozogamicin or 4 weeks after the participant goes off treatment, whichever comes first. Doses to be administered will be determined in the phase I portion of the study. The ALL cohort recommended phase 2 dose has been determined to be 0.6mg/m2. Repeat cycles every 28 days for up to 12 cycles | Drug: Inotuzumab Ozogamicin<br>* Inotuzumab ozogamicin, IV, 28 day cycles ALL 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) NHL Phase 1 dosages: 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) Dose Level 4 (0.7 mg/m^2) Dose Level 5 (0.8 mg/m^2)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I MTD | Defined post hematopoietic stem cell transplantation MTD | Up to 112 days (16 weeks) | 
| Phase I DLTs | Frequency of DLTs during the first two cycles in ALL-participants and NHL-participants, reported separately | Up to 112 days (16 weeks) | 
| Phase II Median DFS | Efficacy as measured by phase II DFS at one year in ALL cohort, 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 ALL Phase II cohort, 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 | At 3 months after initial treatment | 
| Phase II Median DFS | Efficacy as measured by phase II DFS at one year in ALL cohort, 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 ALL Phase II cohort, 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 | At 6 months after initial treatment | 
| Phase II Median DFS | Efficacy as measured by phase II DFS at one year in ALL cohort, 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 ALL Phase II cohort, 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 | At 9 months after initial treatment | 
| Phase II Median DFS | Efficacy as measured by phase II DFS at one year in ALL cohort, 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 ALL Phase II cohort, 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 | At 1 year after initial treatment | 
| Phase II Median DFS | Efficacy as measured by phase II DFS at one year in ALL cohort, 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 ALL Phase II cohort, 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 | Post first dose of inotuzumab ozogamicin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I Median DFS | Efficacy as measured by phase I DFS at one year in each cohort. 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 | At 3 months after initial treatment | 
| Phase I Median DFS | Efficacy as measured by phase I DFS at one year in each cohort. 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 | At 6 months after initial treatment | 
| Phase I Median DFS | Efficacy as measured by phase I DFS at one year in each cohort. 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 | At 9 months after initial treatment | 
| Phase I Median DFS | Efficacy as measured by phase I DFS at one year in each cohort. 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 | At 1 year after initial treatment | 
| Phase I Median DFS | Efficacy as measured by phase I DFS at one year in each cohort. 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 | Post first dose of inotuzumab ozogamicin | 
| Phase I NRM | Phase I NRM in each cohort, defined as time from date of first dose to death due to any cause without prior relapse. Criteria used: For ALL, evidence of disease in the blood or bone marrow (flow cytometry or PCR); for lymphoma typically physical exam findings or CT scans Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 3 months after initial treatment | 
| Phase I NRM | Phase I NRM in each cohort, defined as time from date of first dose to death due to any cause without prior relapse. Criteria used: For ALL, evidence of disease in the blood or bone marrow (flow cytometry or PCR); for lymphoma typically physical exam findings or CT scans Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 6 months after initial treatment | 
| Phase I NRM | Phase I NRM in each cohort, defined as time from date of first dose to death due to any cause without prior relapse. Criteria used: For ALL, evidence of disease in the blood or bone marrow (flow cytometry or PCR); for lymphoma typically physical exam findings or CT scans Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 9 months after initial treatment | 
| Phase I NRM | Phase I NRM in each cohort, defined as time from date of first dose to death due to any cause without prior relapse. Criteria used: For ALL, evidence of disease in the blood or bone marrow (flow cytometry or PCR); for lymphoma typically physical exam findings or CT scans Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 1 year after initial treatment | 
| Phase I NRM | Phase I NRM in each cohort, defined as time from date of first dose to death due to any cause without prior relapse. Criteria used: For ALL, evidence of disease in the blood or bone marrow (flow cytometry or PCR); for lymphoma typically physical exam findings or CT scans Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | Post first dose of inotuzumab ozogamicin on day 1 cycle 1 | 
| Phase I Relapse | Phase I relapse rate, defined as in each cohort, defined as time from date of first dose to the date of first relapse. Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 3 months after initial treatment | 
| Phase I Relapse | Phase I relapse rate, defined as in each cohort, defined as time from date of first dose to the date of first relapse. Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 6 months after initial treatment | 
| Phase I Relapse | Phase I relapse rate, defined as in each cohort, defined as time from date of first dose to the date of first relapse. Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 9 months after initial treatment | 
| Phase I Relapse | Phase I relapse rate, defined as in each cohort, defined as time from date of first dose to the date of first relapse. Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 1 year after initial treatment | 
| Phase I Relapse | Phase I relapse rate, defined as in each cohort, defined as time from date of first dose to the date of first relapse. Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | Post first dose of inotuzumab ozogamicin on day 1 cycle 1 | 
| Phase I Relapse-related mortality | Phase I Relapse-related mortality in each cohort, defined time from date of first dose to death due to any cause with prior relapse Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 3 months after initial treatment | 
| Phase I Relapse-related mortality | Phase I Relapse-related mortality in each cohort, defined time from date of first dose to death due to any cause with prior relapse Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 6 months after initial treatment | 
| Phase I Relapse-related mortality | Phase I Relapse-related mortality in each cohort, defined time from date of first dose to death due to any cause with prior relapse Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 9 months after initial treatment | 
| Phase I Relapse-related mortality | Phase I Relapse-related mortality in each cohort, defined time from date of first dose to death due to any cause with prior relapse Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 1 year after initial treatment | 
| Phase I Relapse-related mortality | Phase I Relapse-related mortality in each cohort, defined time from date of first dose to death due to any cause with prior relapse Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | Post first dose of inotuzumab ozogamicin on day 1 cycle 1 | 
| Phase I Median OS | Phase I OS, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | At 3 months after initial treatment | 
| Phase I Median OS | Phase I OS, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | At 6 months after initial treatment | 
| Phase I Median OS | Phase I OS, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | At 9 months after initial treatment | 
| Phase I Median OS | Phase I OS, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | At 1 year after initial treatment | 
| Phase I Median OS | Phase I OS, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | Post first dose of inotuzumab ozogamicin on day 1 cycle 1 | 
| Phase I pharmacokinetic (PK) parameters - Cmax (NHL cohort only) | Phase I PK parameters (NHL cohort only) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 1 Day 1 (C1D1) after 0 hours (each cycle is 28 days) | 
| Phase I pharmacokinetic (PK) parameters - Cmax (NHL cohort only) | Phase I PK parameters (NHL cohort only) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 1 Day 1 (C1D1) after 1 hour (each cycle is 28 days) | 
| Phase I pharmacokinetic (PK) parameters - Ctrough (NHL cohort only) | Phase I PK parameters (NHL cohort only) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 1 Day 1 (C1D1) after 4 hours (each cycle is 28 days) | 
| Phase I pharmacokinetic (PK) parameters - Ctrough (NHL cohort only) | Phase I PK parameters (NHL cohort only) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | at Cycle 1 Day 7 (C1D7) (each cycle is 28 days) | 
| Phase I pharmacokinetic (PK) parameters - Ctrough (NHL cohort only) | Phase I PK parameters (NHL cohort only) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | at Cycle 2 Day 1 (C2D1) after 0 hours (each cycle is 28 days) | 
| Phase I pharmacokinetic (PK) parameters - Ctrough (NHL cohort only) | Phase I PK parameters (NHL cohort only) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | at Cycle 2 Day 1 (C2D1) after 1 hour (each cycle is 28 days) | 
| Phase I pharmacokinetic (PK) parameters - Ctrough (NHL cohort only) | Phase I PK parameters (NHL cohort only) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | at Cycle 4 Day 1 (C4D1) after 0 hours (each cycle is 28 days) | 
| Phase I pharmacokinetic (PK) parameters - Ctrough (NHL cohort only) | Phase I PK parameters (NHL cohort only) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | at Cycle 4 Day 1 (C4D1) after 1 hour (each cycle is 28 days) | 
| Phase I Incidence of myeloid toxicity | Number of patients who develop myeloid toxicity while on study, defined as grade of anemia, neutropenia and thrombocytopenia CTCAE 4 | At 1 year | 
| Phase I Incidence of secondary graft failure | Number of patients who develop secondary graft failure while on study, defined as: Either cytopenias after initial engraftment (ANC <500/µL), with (a) donor chimerism of less than 5% or (b) falling donor chimerism with intervention such as second transplant or donor lymphocyte infusion (DLI) or (c) patient death due to cytopenias, and fall in donor chimerism, even if chimerism was >5%. Exclusion criteria for diagnosis of GF were (a) disease relapse (b) graft versus host disease or (c) other causes of cytopenias such as, viral infections, or drug induced | At 1 year | 
| Phase I incidence of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) | Safety profile of intervention as measured by incidence of VOD/SOS disease in the phase I portion of the study, defined as the occurrence of 2 of the following 3 clinical criteria: Total serum bilirubin level >34 μmol/L (>2.0 mg/dL). An increase in liver size from baseline or development of right upper quadrant pain of liver origin. Sudden weight gain >2.5% during any 72-hour period after infusion of investigational product because of fluid accumulation or development of ascites. | At 1 year | 
| Phase I rate of VOD/SOS - number of participants affected | Safety profile of intervention as measured by number of participants affected by VOD/SOS disease in the phase I portion of the study, defined as the occurrence of 2 of the following 3 clinical criteria: Total serum bilirubin level >34 μmol/L (>2.0 mg/dL). An increase in liver size from baseline or development of right upper quadrant pain of liver origin. Sudden weight gain >2.5% during any 72-hour period after infusion of investigational product because of fluid accumulation or development of ascites. | At 1 year | 
| Phase I - Percent of participants with grade 3 + AE/SAEs | Phase I safety profile of intervention as measured by percent of participants with grade 3 + AE/SAEs | At 1 year | 
| Phase II Non-relapse mortality (NRM) | Phase II Non-relapse mortality (NRM) in ALL cohort, defined as time from date of first dose to death due to any cause without prior relapse. Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 3 months after initial treatment | 
| Phase II Relapse | Phase II relapse rate, defined as in ALL cohort, defined as time from date of first dose to the date of first relapse. Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 6 months after initial treatment | 
| Phase II Relapse | Phase II relapse rate, defined as in ALL cohort, defined as time from date of first dose to the date of first relapse. Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 9 months after initial treatment | 
| Phase II Relapse-related mortality | Phase II Relapse-related mortality in ALL cohort, defined time from date of first dose to death due to any cause with prior relapse Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | At 1 year after initial treatment | 
| Phase II Relapse-related mortality | Phase II Relapse-related mortality in ALL cohort, defined time from date of first dose to death due to any cause with prior relapse Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI | Post first dose of inotuzumab ozogamicin on day 1 cycle 1 | 
| Phase II Median OS | Phase II OS in ALL cohort, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | At 3 months after initial treatment | 
| Phase II Median OS | Phase II OS in ALL cohort, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | At 6 months after initial treatment | 
| Phase II Median OS | Phase II OS in ALL cohort, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | At 9 months after initial treatment | 
| Phase II Median OS | Phase II OS in ALL cohort, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | At 1 year after initial treatment | 
| Phase II Median OS | Phase II OS in ALL cohort, defined from time from date of first dose to death due to any cause, estimated using Kaplan-Meier, reported as median and 95% CI Difference in time-to-event endpoints will be tested using a 1-sided log-rank test at a significance level of 0.10 | Post first dose of inotuzumab ozogamicin on day 1 cycle 1 | 
| Phase II Response Rate | Defined as the proportion of patients with a best overall response of eradicating MRD in this cohort of patients at the time each patient discontinues treatment with Inotuzumab Ozogamicin | At 3 months after initial treatment | 
| Phase II Response Rate | Defined as the proportion of patients with a best overall response of eradicating MRD in this cohort of patients at the time each patient discontinues treatment with Inotuzumab Ozogamicin | At 6 months after initial treatment | 
| Phase II Response Rate | Defined as the proportion of patients with a best overall response of eradicating MRD in this cohort of patients at the time each patient discontinues treatment with Inotuzumab Ozogamicin | At 9 months after initial treatment | 
| Phase II Response Rate | Defined as the proportion of patients with a best overall response of eradicating MRD in this cohort of patients at the time each patient discontinues treatment with Inotuzumab Ozogamicin | At 1 year after initial treatment | 
| Phase II Response Rate | Defined as the proportion of patients with a best overall response of eradicating MRD in this cohort of patients at the time each patient discontinues treatment with Inotuzumab Ozogamicin | Post first dose of inotuzumab ozogamicin on day 1 cycle 1 | 
| Phase II Incidence of myeloid toxicity | Number of patients who develop myeloid toxicity while on study, defined as grade of anemia, neutropenia and thrombocytopenia CTCAE 4 | At 1 year | 
| Phase II Incidence of secondary graft failure | Number of patients who develop secondary graft failure while on study, defined as: Either cytopenias after initial engraftment (ANC <500/µL), with (a) donor chimerism of less than 5% or (b) falling donor chimerism with intervention such as second transplant or donor lymphocyte infusion (DLI) or (c) patient death due to cytopenias, and fall in donor chimerism, even if chimerism was >5%. Exclusion criteria for diagnosis of GF were (a) disease relapse (b) graft versus host disease or (c) other causes of cytopenias such as, viral infections, or drug induced | At 1 year after initial treatment | 
| Phase I incidence of VOD/SOS | Safety profile of intervention as measured by incidence of VOD/SOS disease in the phase I portion of the study, defined as the occurrence of 2 of the following 3 clinical criteria: Total serum bilirubin level >34 μmol/L (>2.0 mg/dL). An increase in liver size from baseline or development of right upper quadrant pain of liver origin. Sudden weight gain >2.5% during any 72-hour period after infusion of investigational product because of fluid accumulation or development of ascites. | At 1 year | 
| Phase II rate of VOD/SOS - number of participants affected | Safety profile of intervention as measured by number of participants affected by VOD/SOS disease in the phase I portion of the study, defined as the occurrence of 2 of the following 3 clinical criteria: Total serum bilirubin level >34 μmol/L (>2.0 mg/dL). An increase in liver size from baseline or development of right upper quadrant pain of liver origin. Sudden weight gain >2.5% during any 72-hour period after infusion of investigational product because of fluid accumulation or development of ascites. | At 1 year | 
| Phase II pharmacokinetic (PK) parameters - Cmax (ALL cohort) | Phase II PK parameter (ALL cohort) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 1 Day 1 (C1D1) after 0 hours (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Cmax (ALL cohort) | Phase II PK parameter (ALL cohort) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 1 Day 1 (C1D1) after 1 hour (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Cmax (ALL cohort) | Phase II PK parameter (ALL cohort) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 1 Day 1 (C1D1) after 4 hours (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Cmax (ALL cohort) | Phase II PK parameter (ALL cohort) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 1 Day 7 (C1D7) (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Cmax (ALL cohort) | Phase II PK parameter (ALL cohort) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 2 Day 1 (C2D1) after 0 hours (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Cmax (ALL cohort) | Phase II PK parameter (ALL cohort) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 2 Day 1 (C2D1) after 1 hour (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Cmax (ALL cohort) | Phase II PK parameter (ALL cohort) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 4 Day 1 (C4D1) after 0 hours (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Cmax ( ALL cohort) | Phase II PK parameter (ALL cohort) Cmax is maximum concentration. Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 4 Day 1 (C4D1) after 1 hour (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Ctrough (ALL cohort) | Phase II PK parameter (ALL cohort) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 1 Day 1 (C1D1) after 0 hours (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Ctrough ( ALL cohort) | Phase II PK parameter (ALL cohort) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle1 Day 1 (C1D1) after 1 hour (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Ctrough (ALL cohort) | Phase II PK parameter (ALL cohort) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle1 Day 1 (C1D1) after 4 hours (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Ctrough (ALL cohort) | Phase II PK parameter (ALL cohort) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 1 Day 7 (C1D7) (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Ctrough (ALL cohort) | Phase II PK parameter (ALL cohort) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 2 Day 1 (C2D1) after 0 hours (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Ctrough (ALL cohort) | Phase II PK parameter (ALL cohort) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 2 Day 1 (C2D1) after 1 hour (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Ctrough (ALL cohort) | Phase II PK parameter (ALL cohort) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 4 Day 1 (C4D1) after 0 hours (each cycle is 28 days) | 
| Phase II pharmacokinetic (PK) parameters - Ctrough (ALL cohort) | Phase II PK parameter (ALL cohort) Ctrough is lowest concertration of Inotuzumab in the blood.Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean, its associated geometric %CV) of inotuzumab ozogamicin serum concentrations will be presented in tabular form by cycle, day, nominal time and cohort for the PK concentration analysis population. | At Cycle 4 Day 1 (C4D1) after 1 hour (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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allogeneic hematopoietic stem cell transplantation, donor chimerism