A Study Of Two Inotuzumab Ozogamicin Doses in Relapsed/ Refractory Acute Lymphoblastic Leukemia Transplant Eligible Patients

Study Overview
=================
Brief Summary
-----------------
This study will explore 2 different doses of inotuzumab ozogamicin including the dose that is approved and a lower dose. The main purpose of this study is to evaluate whether a dose of inotuzumab ozogamicin, lower than the approved dose, could be recommended for adult patient with relapsed or refractory ALL who may be at higher risk for severe liver problems after inotuzumab ozogamicin treatment and stem cell transplant (a potentially curative therapy that can replace cancer cells with healthy cells). Efficacy and safety of the 2 doses will be evaluated.

Official Title
-----------------
A PHASE 4, OPEN-LABEL, RANDOMIZED STUDY OF TWO INOTUZUMAB OZOGAMICIN DOSE LEVELS IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA ELIGIBLE FOR HEMATOPOIETIC STEM CELL TRANSPLANTATION AND WHO HAVE RISK FACTOR(S) FOR VENO-OCCLUSIVE DISEASE

Conditions
-----------------
Leukemia, Precursor b-Cell Lymphoblastic Leukemia-Lymphoma, ACUTE LYMPHOBLASTIC LEUKEMIA

Intervention / Treatment
-----------------
* Drug: inotuzumab ozogamicin-dose level 2
* Drug: Inotuzumab ozogamicin-dose level 1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Relapsed or refractory precursor CD22 positive B cell ALL with M2 or M3 marrow (≥5% blasts) and who are eligible for HSCT; Have 1 or more of the following risk factors for developing VOD: Due to receive Salvage 2 or greater; Prior HSCT; Age ≥55 years. Ongoing or prior hepatic disease which may include a prior history of hepatitis or drug induced liver injury, as well as hepatic steatosis, nonalcoholic steatohepatitis, baseline elevations of bilirubin > upper limit of normal (ULN) and ≤1.5 x ULN. Ph+ ALL patients must have failed treatment with at least 1 second or third generation tyrosine kinase inhibitor and standard multi agent induction chemotherapy; Patients in Salvage 1 with late relapse should be deemed poor candidates for reinduction with initial therapy; Patients with lymphoblastic lymphoma and bone marrow involvement 5% lymphoblasts by morphologic assessment; Age 18 years to 75 years; Eastern Cooperative Oncology Group (ECOG) performance status 0 2; Adequate liver function, including total serum bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome, and aspartate and alanine aminotransferase (AST and ALT) ≤2.5 x ULN; Serum creatinine ≤1.5 x ULN or any serum creatinine level associated with a measured or calculated creatinine clearance of >=40 mL/min; Male and female patients of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for a minimum of 8 months (females) and 5 months (males) after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active. Female subjects of nonchildbearing potential must meet at least 1 of the following criteria: Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state; Have undergone a documented hysterectomy and/or bilateral oophorectomy; Have medically confirmed ovarian failure. All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study; patients with mental capacity which requires the presence of a legally authorized representative will be excluded from the study; Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Exclusion Criteria: Isolated extramedullary relapse (ie, testicular or central nervous system); Burkitt's or mixed phenotype acute leukemia based on the WHO 2008 criteria; Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS directed local treatment for active disease within the prior 28 days, symptomatic CNS leukemia (ie, cranial nerve palsies or other significant neurologic dysfunction) within 28 days. Prophylactic intrathecal medication is not a reason for exclusion; Prior chemotherapy within 2 weeks before randomization with the following exceptions: To reduce the circulating lymphoblast count or palliation: ie, steroids, hydroxyurea or vincristine; For ALL maintenance: mercaptopurine, methotrexate, vincristine, thioguanine, and/or tyrosine kinase inhibitors. Patients must have recovered from acute non hematologic toxicity (to Grade 1 or less) of all previous therapy prior to enrollment. Prior monoclonal antibodies within 6 weeks of randomization, with the exception of rituximab which must be discontinued at least 2 weeks prior to randomization; Prior inotuzumab ozogamicin treatment or other anti CD22 immunotherapy within 6 months before randomization; Prior allogeneic hematopoietic stem cell transplant (HSCT) within 90 days before randomization. Patients must have completed immunosuppression therapy for treatment of graft versus host disease (GvHD) prior to enrollment. At randomization, patients must not have Grade 2 or higher acute GvHD, or extensive chronic GvHD; Peripheral absolute lymphoblast count >=10,000 /L (treatment with hydroxyurea and/or steroids/vincristine is permitted within 2 weeks of randomization to reduce the white blood cell [WBC] count); Known systemic vasculitides (eg, Wegener's granulomatosis, polyarteritis nodosa, systemic lupus erythematosus), primary or secondary immunodeficiency (such as human immunodeficiency virus [HIV] infection or severe inflammatory disease); Active hepatitis B infection as evidenced by hepatitis B surface antigen, active hepatitis C infection (must be anti-hepatitis C antibody negative or hepatitis C ribonucleic acid negative), or known seropositivity for HIV. HIV testing may need to be performed in accordance with local regulations or local practice; Major surgery within 4 weeks before randomization; Unstable or severe uncontrolled medical condition (eg, unstable cardiac function or unstable pulmonary condition); Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been definitely treated with radiation or surgery. Patients with previous malignancies are eligible provided that they have been disease free for >=2 years; Patients with active heart disease or the presence of New York Heart Association (NYHA) stage III or IV congestive heart failure; QTcF >470 msec (based on the average of 3 consecutive electrocardiogram [ECGs]); Myocardial infarction within 6 months before randomization; History of clinically significant ventricular arrhythmia, or unexplained syncope not believed to be vasovagal in nature, or chronic bradycardic states such as sinoatrial block or higher degrees of atrioventricular (AV) block unless a permanent pacemaker has been implanted; Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (eg, hypokalemia, hypocalcemia, hypomagnesemia); Prior confirmed or ongoing hepatic veno occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS), or other serious or current ongoing liver disease such as cirrhosis or nodular regenerative hyperplasia; Administration of live vaccine within 6 weeks before randomization; Evidence of uncontrolled current serious active infection (including sepsis, bacteremia, fungemia) or patients with a recent history (within 4 months) of deep tissue infections such as fascitis or osteomyelitis; Patients who have had a severe allergic reaction or anaphylactic reaction to any humanized monoclonal antibodies; Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female subjects of childbearing potential who are unwilling or unable to use highly effective contraception as outlined in this protocol for the duration of the study and for a minimum of 8 months (females) and 5 months (males) after the last dose of investigational product; Investigative site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study; Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation (up through the end of treatment visit); Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study will be conducted in 2 phases: a run in phase and a randomized phase. Run in phase: a total of up to 22 patients will be enrolled to receive the starting dose of 1.2 mg/m2/cycle (dose level 2). A Simon Two Stage optimal design will be used. If acceptable efficacy (CR/CRi and MRD negativity) is observed in the run in phase, the study will enter the randomized phase. Randomized phase: if acceptable efficacy is observed in the run in phase, the study will enter the randomized phase. A total of approximately 80 patients will be randomized (1:1) to 1 of 2 dose levels of inotuzumab ozogamicin (40 patients per dose level).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 2<br>Inotuzumab ozogamicin at starting dose 1.2 mg/m2/cycle (administered in 3 divided doses). Most patients expected to receive 2 or 3 cycles (cycle length 21 to 28 days) | Drug: inotuzumab ozogamicin-dose level 2<br>* Inotuzumab ozogamicin (BESPONSA™) is a CD22 targeted antibody drug conjugate (ADC) approved by US FDA for treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL). The approved starting dose is 1.8mg/m2/cycle. This treatment arm evaluates a lower starting dose of 1.2mg/m2/cycle.<br>* Other names: Besponsa;|
| Active Comparator: Dose Level 1<br>Inotuzumab ozogamicin at starting dose 1.8 mg/m2/cycle (administered in 3 divided doses). Most patients expected to receive 2 or 3 cycles (cycle length 21 to 28 days) | Drug: Inotuzumab ozogamicin-dose level 1<br>* Inotuzumab ozogamicin (BESPONSA™) is a CD22 targeted antibody drug conjugate (ADC) approved by US FDA for treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL). The approved starting dose of 1.8mg/m2/cycle is administered in this treatment arm.<br>* Other names: Besponsa;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Veno-occlusive Disease (VOD) | VOD happened when the small blood vessels that lead into the liver and were inside the liver become blocked. VOD is defined as: a. Classical VOD (first 21 days after HSCT): Bilirubin>=2 mg/dL and 2 (or more) of the following criteria must also be present: 1. Painful hepatomegaly; 2. Weight gain >5%; 3. Ascites. b. Late onset VOD (>21 days after HSCT): Classical VOD beyond Day 21; or Histologically proven VOD; or Two or more of the following criteria must be present: 1. Bilirubin >2 mg/dL; 2. Painful hepatomegaly; 3. Weight gain >5%; 4. Ascites. and hemodynamical and/or ultrasound evidence of VOD. | 2 years from randomization | 
| Rate of Hematologic Remission (Complete Response [CR] / Complete Response With Incomplete Hematologic Recovery[CRi]) | CR is defined as a disappearance of leukemia as indicated by<5% marrow blasts and the absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by absolute neutrophil count (ANC)>=1000/µL and platelets>=100000/µL. C1 extramedullary disease status is required. CRi is defined as CR except with ANC <1000/µL and/or platelets <100000/µL. C1 defined as complete disappearance of all measurable and non-measurable extramedullary disease with the exception of lesions with following must be true: For participants with>= 1 measurable lesion, all nodal masses>1.5cm in greatest transverse diameter (GTD) at baseline (last assessment before 1st dose of study treatment) must must have regressed to>=1.5cm in GTD and all nodal masses>=1cm & <=1.5cm in GTD at baseline have regressed to <1cm GTD or must have reduced by 75% in sum of products of greatest diameters. No new lesions. Spleen and other previously enlarged organs must have regressed in size and must not be palpable. | From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (All Causalities) | Adverse event (AE) = any untoward medical occurrence in participant who received study treatment without regard to possibility of causal relationship. On-treatment period was defined as the period starting with the 1st dose of study treatment through 63 days after last dose or 1 day before start day of new anticancer therapy, whichever occurred first. 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 inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All VOD cases were reported as SAE. Grades of severity were defined by Common terminology criteria for adverse events (CTCAE) v3.0. Grade 3=severe adverse event; Grade 4=life-threatening consequences; urgent intervention indicated. Grade 5=death related to AE. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks) | 
| Number of Participants With Treatment-Emergent Adverse Events (Treatment-related) | Adverse event (AE) = any untoward medical occurrence in participant who received study treatment without regard to possibility of causal relationship. Treatment emergent AEs (TEAEs) were defined as AEs that reported the period starting with the first dose of study treatment drug through 63 days after last dose or 1 day before start day of new anticancer therapy, whichever occurred first. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Grades of severity were defined by CTCAE v3.0. Grade 3 = severe adverse event; Grade 4 = life-threatening consequences; urgent intervention indicated. Grade 5 = death related to AE. Causality of TEAEs were assessed by the Investigator. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks) | 
| Number of Participants With Treatment-Emergent Serious Adverse Events (Post-HSCT) | 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 inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. All SAEs occurred after HSCT were reported in this OM. Results were reported as of the data cutoff date on 21 Sep 2022. | Starting from the first transplant after inotuzumab ozogamicin treatment and including the entire duration of subsequent follow up (approximately 52 weeks)) | 
| Shift Summary of Hematology Laboratory Test Results From Grade <=2 at Baseline to Grade 3 or 4 Post-Baseline | Baseline assessment was defined as the last assessment performed on or prior to the date of the first dose of study treatment. Following Parameters were analyzed for laboratory assessment: Hematology (Activated partial thromboplastin time prolonged, Anemia, Hemoglobin increased, International normalization rate (INR) increased, Leukocytosis, Lymphocyte count decreased, Lymphocyte count increased, Neutrophil count decreased, Platelet count decreased, White blood cell decreased). Grades of severity were defined by CTCAE v3.0. Grade 2 = moderate adverse event; Grade 3= severe adverse event; Grade 4 = life-threatening consequences; urgent intervention indicated. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks) | 
| Shift Summary of Chemistry Laboratory Test Results From Grade <=2 at Baseline to Grade 3 or 4 Post-Baseline | Baseline assessment was defined as the last assessment performed on or prior to the date of the first dose of study treatment. Following Parameters were analyzed for laboratory assessment: Chemistry (Alanine aminotransferase increased, Alkaline phosphatase increased, Aspartate aminotransferase increased, Blood bilirubin increased, Chronic kidney disease, Creatinine increased, Gamma glutamyl transpeptidase (GGT) increased, Hypercalcemia, Hyperglycemia, Hyperkalemia, Hypermagnesemia, Hypernatremia, Hypoalbuminemia, Hypocalcemia, Hypoglycemia, Hypokalemia, Hypomagnesemia, Hyponatremia, Hypophosphatemia, Lipase increased and Serum amylase increased). Grades of severity were defined by CTCAE v3.0. Grade 2 = moderate adverse event; Grade 3= severe adverse event; Grade 4 = life-threatening consequences; urgent intervention indicated. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment drug through 63 days after last dose (approximately 52 weeks) | 
| Number of Participants Achieving a CR/CRi With Minimal Residual Disease (MRD) Negativity | MRD was assessed by flow cytometry for CD22 and other cell surface markers associated with B-cell ALL. In participants who achieved CR/CRi, MRD negativity was defined as defined as <1 abnormal cell/10^4 nucleated cells by flow cytometry per central laboratory analysis. | At screening, once at Day 16-28 of Cycles 1 and 2, or until CR/CRi and MRD negativity were achieved, then after every 1-2 cycles as clinically indicated, and at EOT visit (maximum of 2.5 years) | 
| Duration of Remission (DoR) in Participants Achieving CR/CRi | DoR was defined as time from date of first response in responders (CR/CRi) to the date of disease progression (i.e., objective progression, relapse from CR/CRi, including post-study treatment follow-up disease assessments) or death due to any cause, whichever occurs first. DoR was estimated using Kaplan-Meier methods. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years | 
| Progression-Free Survival | PFS was defined as time from date of randomization to the date of disease progression (i.e., objective progression, relapse from CR/CRi, including post-study treatment follow-up disease assessments), death due to any cause, or starting new induction therapy/post-therapy HSCT without achieving CR/CRi, whichever occured first. PFS was estimated using Kaplan-Meier methods. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years | 
| Overall Survival | Overall survival was defined as the time from date of first dose of study treatment to death due to any cause. Participants without confirmation of death were censored at the date that the participant was last known to be alive. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years | 
| Number of Participant Received HSCT Post Inotuzumab Ozogamicin Treatment | Participants who underwent HSCT after inotuzumab ozogamicin treatment. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years | 
| The Cumulative Incidence Rate of Post-HSCT Relapse at Month 12 | Post-HSCT relapse is defined as the time from date of first HSCT after inotuzumab ozogamicin treatment to the date of first relapse post-HSCT. Cumulative incidence rates of an event at a particular timepoint were estimated with the CI calculated based on the cumulative incidence function using the method described by Kalbfleisch RL and Prentice JD. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment to Month 12 | 
| Number of Participants With Post-HSCT Mortality | Post-HSCT Mortality was defined as the time from date of first HSCT after inotuzumab ozogamicin treatment to death due to any cause. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years | 
| Number of Participants With Post HSCT Non-Relapse Mortality | Post HSCT non-relapse mortality was defined as time from date of first HSCT after inotuzumab ozogamicin treatment to death due to any cause without prior relapse. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years | 
| Number of Participants With Post HSCT Relapse-Related Mortality | Post HSCT Relapse-Related Mortality was defined as time from date of first HSCT after inotuzumab ozogamicin treatment to death due to any cause with prior relapse. Results were reported as of the data cutoff date on 21 Sep 2022. | From first dose of study treatment of 6 cycles till follow-up up to 2 years, in total approximately 2.5 years | 
| Mean Predose Concentrations (Ctrough) of Inotuzumab Ozogamicin | Ctrough was defined as the mean Predose concentration of study treatment. | Pre-dose on Cycle 1 Day 1, 8 and 15, and on Day1 and 8 of Cycle 2, 3 and 4. | 
| Number of Participants With Positive Anti-Drug Antibody (ADA) | ADA incidence is defined as combined results of treatment-boosted and treatment-induced ADA-positive participants. The immunogenicity of inotuzumab ozogamicin was evaluated using a validated electrochemiluminescence (ECL)-based immunoassay. | At Day 1 of every cycle prior to the beginning of inotuzumab ozogamicin infusion and at the EOT visit, up to approximately 52 weeks. | 
| Number of Participants With Positive Neutralizing Antibody (NAb) | NAb incidence is defined as combined results of treatment-boosted and treatment-induced NAb-positive participants. The immunogenicity of inotuzumab ozogamicin was evaluated using a validated electrochemiluminescence (ECL)-based immunoassay. | At Day 1 of every cycle prior to the beginning of inotuzumab ozogamicin infusion and at the EOT visit, up to approximately 52 weeks. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, ACUTE LYMPHOBLASTIC leukemia, inotuzumab ozogamicin, Besponsa, transplant