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Inotuzumab Ozogamicin

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Phase I:

A maximum of 4 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 participants is 0.1-0.6mg/m\^2.

Phase II:

Participants will be enrolled until all Phase I 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 recommended phase 2 dose is 0.3mg/m2. Repeat cycles every 28 days for up to 4 cycles

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)

Leland Metheny, MD

Ron Sobecks, MD

Nausheen Ahmed, MD

Roman Shapiro, MD

Vijaya Bhatt, MD

Christina Cho, MD

Leland Metheny

Sumithira Vasu, MBBS

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.

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

Inotuzumab Ozogamicin Post-Transplant For Acute Lymphocytic Leukemia

Defined post hematopoietic stem cell transplantation MTD

Frequency of DLTs during the first two cycles in ALL-participants

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

Efficacy as measured by phase I 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

Phase I NRM, 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).

Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI

Phase I NRM , 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).

Reported as Cumulative Incidence and 2-sided 80% CI and 2-sided 95% CI

Phase I relapse rate, 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

Phase I Relapse-related mortality, 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

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

Number of patients who develop myeloid toxicity while on study, defined as grade of anemia, neutropenia and thrombocytopenia CTCAE 4

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

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.

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.

Phase I safety profile of intervention as measured by percent of participants with grade 3 + AE/SAEs

Phase II Non-relapse mortality (NRM), 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

Phase II relapse rate, 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

Phase II Relapse-related mortality, 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

Phase II 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

Defined as the proportion of patients with a best overall response of eradicating MRD at the time each patient discontinues treatment with Inotuzumab Ozogamicin

Phase II PK parameter

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, and nominal time for the PK concentration analysis population.

Phase II PK parameter

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, and nominal time for the PK concentration analysis population.

Spots Global Cancer Trial Database for donor chimerism