A Study Of Two Inotuzumab Ozogamicin Doses in Relapsed/ Refractory Acute Lymphoblastic Leukemia Transplant Eligible Patients
Condition: Leukemia; Precursor b-Cell Lymphoblastic Leukemia-Lymphoma; ACUTE LYMPHOBLASTIC LEUKEMIA
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Intervention: inotuzumab ozogamicin-dose level 2; Inotuzumab ozogamicin-dose level 1
Intervention description: 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.; 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.
Intervention MeSH terms: Inotuzumab Ozogamicin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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)
Enrollment: 102.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; ACUTE LYMPHOBLASTIC leukemia; inotuzumab ozogamicin; Besponsa; transplant

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Relapsed or refractory precursor CD22 positive B cell ALL with M2 or M3 marrow (≥5%
             blasts) and who are eligible for HSCT;

          2. Have 1 or more of the following risk factors for developing VOD:

               1. Due to receive Salvage 2 or greater;

               2. Prior HSCT;

               3. Age ≥55 years.

               4. 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.

          3. Ph+ ALL patients must have failed treatment with at least 1 second or third generation
             tyrosine kinase inhibitor and standard multi agent induction chemotherapy;

          4. Patients in Salvage 1 with late relapse should be deemed poor candidates for
             reinduction with initial therapy;

          5. Patients with lymphoblastic lymphoma and bone marrow involvement 5% lymphoblasts by
             morphologic assessment;

          6. Age 18 years to 75 years;

          7. Eastern Cooperative Oncology Group (ECOG) performance status 0 2;

          8. 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;

          9. Serum creatinine ≤1.5 x ULN or any serum creatinine level associated with a measured
             or calculated creatinine clearance of >=40 mL/min;

         10. 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:

               1. 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;

               2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;

               3. Have medically confirmed ovarian failure. All other female subjects (including
                  female subjects with tubal ligations) are considered to be of childbearing
                  potential.

         11. 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;

         12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
             and other study procedures.

        Exclusion Criteria:

          1. Isolated extramedullary relapse (ie, testicular or central nervous system);

          2. Burkitt's or mixed phenotype acute leukemia based on the WHO 2008 criteria;

          3. 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;

          4. Prior chemotherapy within 2 weeks before randomization with the following exceptions:

               1. To reduce the circulating lymphoblast count or palliation: ie, steroids,
                  hydroxyurea or vincristine;

               2. 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.

          5. Prior monoclonal antibodies within 6 weeks of randomization, with the exception of
             rituximab which must be discontinued at least 2 weeks prior to randomization;

          6. Prior inotuzumab ozogamicin treatment or other anti CD22 immunotherapy within 6 months
             before randomization;

          7. 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;

          8. 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);

          9. 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);

         10. 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;

         11. Major surgery within 4 weeks before randomization;

         12. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function or
             unstable pulmonary condition);

         13. 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;

         14. Patients with active heart disease or the presence of New York Heart Association
             (NYHA) stage III or IV congestive heart failure;

         15. QTcF >470 msec (based on the average of 3 consecutive electrocardiogram [ECGs]);

         16. Myocardial infarction within 6 months before randomization;

         17. 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;

         18. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging
             drug (eg, hypokalemia, hypocalcemia, hypomagnesemia);

         19. 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;

         20. Administration of live vaccine within 6 weeks before randomization;

         21. 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;

         22. Patients who have had a severe allergic reaction or anaphylactic reaction to any
             humanized monoclonal antibodies;

         23. 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;

         24. 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;

         25. 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);

         26. 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.