Study Evaluating Inotuzumab Ozogamicin (CMC-544) Plus Rituximab In Diffuse Large B-Cell Non-Hodgkin's Lymphoma

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate inotuzumab ozogamicin in combination with rituximab prior to an autologous stem cell transplant (aSCT) in patients with relapsed/refractory diffuse large B-cell Non-Hodgkin's lymphoma.

Official Title
-----------------
An Open-label, Single-arm, Phase 2 Study Of Inotuzumab Ozogamicin Plus Rituximab In Subjects With Relapsed/Refractory Cd22-positive Diffuse Large B-cell Lymphoma, Eligible For Autologous Stem Cell Transplantation

Conditions
-----------------
Lymphoma, B-Cell

Intervention / Treatment
-----------------
* Drug: inotuzumab ozogamicin (CMC-544)
* Drug: rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: CD20/CD22-positive diffuse large B-cell NHL that has relapsed after 1 or 2 prior therapies; one prior therapy must include anthracyclines and one must include rituximab in combination with chemotherapy Relapsed/disease progression within 12 months after start of prior therapy and/or secondary International Prognostic Index (sIPI) score greater than 1 Eligible for autologous stem cell transplant (aSCT) Exclusion Criteria: Prior allogeneic hematopoietic stem cell transplant Within 6 months prior to test article: autologous transplant, treatment with anti-CD22 antibodies, radio-immunotherapy Veno-occlusive disease or sinusoidal obstruction syndrome, chronic liver disease, systemic vasculitides, current or chronic hepatitis B or C infection

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab 375 mg/m^2 + Inotuzumab Ozogamicin 1.8 mg/m^2<br>Inotuzumab ozogamicin, in combination with rituximab, will be administered to patients with relapsed/refractory diffuse large B-cell Non-Hodgkin's lymphoma prior to an autologous stem cell transplant (aSCT). | Drug: inotuzumab ozogamicin (CMC-544)<br>* 1.8 mg/m^2 every 21 days by intravenous infusion, 3 to 6 doses<br>* Other names: cmc-544;Drug: rituximab<br>* 375 mg/m^2 two days before cycle 1 by intravenous infusion; 375 mg/m^2 every 21 days by intravenous infusion, 3 to 6 doses<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) After 3 Cycles of Inotuzumab Ozogamicin Plus Rituximab Therapy | Response criteria based on National Cancer Institute (NCI) International Response Criteria for non-Hodgkin's lymphoma. CR: no detectable clinical & radiographic evidence of disease/disease-related symptoms; lymph nodes/nodal masses regressed to normal size (less than or equal to [≤] 1.5 cm in greatest transverse diameter for nodes greater than [>] 1.5 cm pre-therapy); spleen & other organs (if enlarged pre-therapy) regressed in size & spleen not palpable on physical examination; repeat bone marrow infiltrate clear. PR: > or equal to (≥) 50% decrease in sum of product diameters (SPD) of 6 largest dominant nodes/nodal masses; no increase in size of other nodes, liver, or spleen; splenic & hepatic nodules regressed by ≥ 50% in SPD; involvement of other organs usually assessable & no measurable disease present; no new sites of disease. Participants achieving CR, but with persistent morphologic bone marrow involvement or no bone marrow assessment after treatment were partial responders. | Up to 2 years (9 weeks of 3 21-day cycles and every 3 to 6 months during the long-term follow-up period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Estimate of Progression Free Survival (PFS) 6 Months After Inotuzumab Ozogamicin Plus Rituximab Therapy | PFS; time from date of randomization to earliest date of progression, relapse after CR, death from any cause without progression, start of new treatment for the lymphoma excluding treatments/procedures for consolidation therapy in this protocol, or censored at date of last tumor assessment. Progression: abnormal lymph nodes (long axis > 1.5 cm or long axis 1.1 to 1.5 cm and short axis > 1.0 cm); appearance of any new lesion > 1.5 cm in any axis during or at end of treatment; ≥ 50% increase from nadir in SPD of any previously involved nodes, in a single involved node, or in the size of other lesions; ≥ 50% increase in longest diameter of any single previously identified node > 1.0 cm in short axis. | 6 months after the first dose of inotuzumab ozogamicin | 
| Kaplan-Meier Estimate of PFS 2 Years After Inotuzumab Ozogamicin Plus Rituximab Therapy | PFS; time from date of randomization to earliest date of progression, relapse after CR, death from any cause without progression, start of new treatment for the lymphoma excluding treatments/procedures for consolidation therapy in this protocol, or censored at date of last tumor assessment. Progression: abnormal lymph nodes (long axis > 1.5 cm or long axis 1.1 to 1.5 cm and short axis > 1.0 cm); appearance of any new lesion > 1.5 cm in any axis during or at end of treatment; ≥ 50% increase from nadir in SPD of any previously involved nodes, in a single involved node, or in the size of other lesions; ≥ 50% increase in longest diameter of any single previously identified node > 1.0 cm in short axis. | 2 years after the first dose of inotuzumab ozogamicin | 
| Percentage of Participants With a Response of CR or PR and Who Had Successful Granulocyte Colony Stimulating Factor (G-CSF) Mobilization of Peripheral Blood Stem Cells (PBSCs) Overall and After 3 Cycles of Inotuzumab Ozogamicin Plus Rituximab Therapy | Successful mobilization of PBSC: ≥ 2 x 10^6 cluster of differentiation (CD) 34+ cells per kilogram (cells/kg) after 3 cycles. CR: no detectable clinical & radiographic evidence of disease/disease-related symptoms; lymph nodes/nodal masses regressed to normal size (≤ 1.5 cm in greatest transverse diameter for nodes > 1.5 cm pre-therapy); spleen & other organs (if enlarged pre-therapy) regressed in size & spleen not palpable on physical examination; repeat bone marrow infiltrate clear. PR: ≥ 50% decrease in SPD of 6 largest dominant nodes/nodal masses; no increase in size of other nodes, liver, or spleen; splenic & hepatic nodules regressed by ≥ 50% in SPD; involvement of other organs usually assessable & no measurable disease present; no new sites of disease. Participants achieving CR, but with persistent morphologic bone marrow involvement or no bone marrow assessment post treatment were partial responders. Response includes confirmed CR/PR and unconfirmed CR/PR. | From the first dose to approximately 2 to 3 weeks after 3 cycles of inotuzumab ozogamicin plus rituximab (induction) therapy (up to 12 weeks) and up to approximately 2 to 3 weeks after 6 cycles (up to 21 weeks). | 
| Percentage of Participants With Successful G-CSF Mobilization of PBSC | Successful mobilization of PBSC was defined as ≥ 2 x 10^6 CD34+ cells/kg collected after 3 cycles of inotuzumab ozogamicin plus rituximab therapy. | From the first dose to approximately 2 to 3 weeks after up to 6 cycles of inotuzumab ozogamicin plus rituximab (induction) therapy (up to 21 weeks). | 
| Percentage of Participants Who Underwent Autologous Stem Cell Transplant (aSCT) | Participants underwent high dose chemotherapy and aSCT. In order to proceed to aSCT, participants were required to achieve CR or PR and successful collection of PSBC (≥ 2.0 x 10^6 CD34+ cells/kg collected after 3 cycles). | A minimum of 4 weeks and a maximum of 8 weeks after the last cycle of inotuzumab ozogamicin plus rituximab (induction) therapy (up to 26 weeks). | 
| Event-Free Survival (EFS) After aSCT | EFS was the time (in months) from the date of aSCT to the earliest date of progression, relapse after CR, death from any cause without progression, initiation of a new treatment for the lymphoma or was censored at the date of the last tumor assessment. | From the completion of aSCT through 2 year long-term follow-up period, including but not limited to planned assessments scheduled every 3 to 6 months. | 
| Percentage of Participants With a CR After 3 Cycles of Inotuzumab Ozogamicin Plus Rituximab Therapy | CR: complete disappearance of all detectable clinical & radiographic evidence of disease & disease-related symptoms; lymph nodes & nodal masses regressed to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before therapy); spleen and other organs (if enlarged prior to therapy) regressed in size & spleen not palpable on physical examination; repeat bone marrow infiltrate clear. Response includes confirmed CR and unconfirmed CR. | From the first dose to approximately 2 to 3 weeks after 3 cycles of inotuzumab ozogamicin plus rituximab (induction) therapy (up to 12 weeks). | 
| Overall Survival (OS) | OS was the time (in months) from the date of randomization to the date of death, and censored at the date of last contact if no death occurred. | From randomization until the date of death, or the date of last contact if no death occurred (up to 2 years). | 
| Percentage of Participants With Any Grade 3/4 Laboratory Abnormality During Therapy | The following parameters were analyzed for serum chemistry; blood urea nitrogen (or urea), creatinine, glucose, calcium, sodium, potassium, phosphorus, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, total bilirubin (and direct bilirubin, if total bilirubin was elevated), alkaline phosphatase, uric acid (or urate), albumin and total protein. The following parameters were analyzed for hematology; lymphocytes, basophils, eosinophils, erythrocytes, hematocrit, hemoglobin, leukocytes, monocytes, neutrophils, platelets, prothrombin international normalized ratio, prothrombin time, fibrinogen, and activated partial thromboplastin time. Laboratory test results were graded using the NCI Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE v3.0). | Within 3 days prior each dose of test article, on Day -2, 1, 8, and 15 of Cycles 1 to 3, 2 to 3 weeks after Cycle 3, at the end-of-treatment visit, and every 3 to 6 months during long-term follow-up (up to 2 years). | 
| Percentage of Participants With Treatment-Emergent Adverse Events (AEs) During Inotuzumab Ozogamicin Plus Rituximab Treatment | An AE was any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, or laboratory/physiologic observations occurring in a participant given a test article or in a clinical study; the event may not necessarily have had a causal relationship with the treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; cancer. Treatment-emergent AEs were AEs that emerged after the first dose of the study treatment during the treatment period that were absent pre-treatment, or worsened during the treatment period relative to the pre-treatment state. The severity of all AEs was graded by the investigator using the NCI Common Terminology Criteria for AE Version 3.0 (CTCAE v3.0). | Treatment emergent AEs were collected from time of first dose to end of trial visit (participants not undergoing consolidation treatment) or until consolidation therapy. SAEs were collected from informed consent until end of trial visit (up to 6 months). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diffuse large b-cell lymphoma, inotuzumab ozogamicin, autologous stem cell transplant