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.
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, 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.
NHL Phase II: To assess the efficacy of inotuzumab ozogamicin as measured by DFS at one year
in NHL.
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 each 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 and autologous
transplant
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 autologous transplantation. Patients
must receive their first dose of inotuzumab at or before T+100.
- 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 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 2 Non-Hodgkin's Lymphoma Inclusion Criteria
- 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 autologous transplantation. Patients
must receive their first dose of inotuzumab at or before T+100.
- ECOG Performance status < 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
