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

NCT03677596

Description:

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.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 4

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: B1931030
  • SECONDARY ID: 2018-001557-27
  • NCT ID: NCT03677596

Conditions

  • Leukemia
  • Precursor b-Cell Lymphoblastic Leukemia-Lymphoma
  • ACUTE LYMPHOBLASTIC LEUKEMIA

Interventions

DrugSynonymsArms
inotuzumab ozogamicin-dose level 2BesponsaDose Level 2
Inotuzumab ozogamicin-dose level 1BesponsaDose Level 1

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Dose Level 2ExperimentalInotuzumab 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)
  • inotuzumab ozogamicin-dose level 2
Dose Level 1Active ComparatorInotuzumab 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)
  • Inotuzumab ozogamicin-dose level 1

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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants With Hematologic Remission (Complete Remission [CR]/Complete Remission With Incomplete Hematologic Recovery [CRi])
Time Frame:At the end of treatment (within approximately 6 months from randomization)
Safety Issue:
Description:CR defined the disappearance of leukemia indicated by less than (<) 5 percent (%) marrow blasts & absence of peripheral blood leukemic blasts, with recovery of hematopoiesis defined by absolute neutrophil count (ANC) greater than or equal to (≥)1000 per microliter (/μL) & platelets ≥100,000/μL. C1 extramedullary disease status (i.e. complete disappearance of measurable & non-measurable extramedullary disease with the following exceptions: for participants with at least 1 measurable lesion, all nodal masses greater than (>) 1.5 centimeters (cm) in greatest transverse diameter (GTD) at baseline must have regressed to less than or equal to (≤) 1.5 cm in GTD; all nodal masses ≥1 cm & ≤1.5 cm in GTD at baseline must have regressed to <1 cm GTD or reduced by 75% in sum of products of greatest diameters, no new lesions, spleen & other previously enlarged organs must have regressed in size & must not be palpable) was required. CRi defined as CR except ANC <1000/μL &/or platelets <100,000/μL.

Secondary Outcome Measures

Measure:Frequency of adverse events
Time Frame:At least 9 weeks after last dose
Safety Issue:
Description:Adverse events to be reported during treatment and for at least 9 weeks after last dose. VOD reported for up to 2 years from randomization.
Measure:Minimal residual disease (MRD) negativity
Time Frame:Up to approximately 4 weeks (EoT) from last dose of study drug
Safety Issue:
Description:MRD analysis performed at least once in participants with prior assessment of CR or CRi. Bone marrow aspirates, collected at screening and during the study to be sent to the central laboratory and analyzed using multiparametric flow cytometry. A peripheral blood sample to be provided if a participant had an inadequate bone marrow aspirate at screening. MRD negativity considered to be achieved if the lowest value of MRD from the first date of CR/CRi to EoT was <1 × 10^-4 lasts/nucleated cells.
Measure:Duration of remission (DoR) for Participants Who Achieved CR/CRi
Time Frame:2 years from randomization
Safety Issue:
Description:DoR defined as time from date of first response in responders (CR/CRi) to date of progression or death
Measure:Progression free survival (PFS)
Time Frame:2 years from randomization
Safety Issue:
Description:PFS defined as time from date of randomization to earliest date of the death or progressive disease
Measure:Overall survival (OS)
Time Frame:2 years from randomization
Safety Issue:
Description:OS defined as the time from randomization to date of death due to any cause.
Measure:Rate of hematopoietic stem cell transplantation (HSCT)
Time Frame:2 years from randomization
Safety Issue:
Description:HSCT rate defined as the percentage of participants who underwent HSCT following treatment with inotuzumab ozogamicin
Measure:Post HSCT relapse
Time Frame:2 years from randomization
Safety Issue:
Description:Post HSCT relapse defined as the time from date of HSCT to the date of first relapse post HSCT.
Measure:Post HSCT mortality
Time Frame:2 years from randomization
Safety Issue:
Description:Post HSCT mortality defined as the time from date of HSCT to the date of death due to any cause
Measure:Post HSCT non relapse mortality
Time Frame:2 years from randomization
Safety Issue:
Description:Post HSCT non relapse mortality defined as time from date of HSCT to the date of death due to any cause without prior relapse/progression post HSCT
Measure:Post HSCT relapse related mortality
Time Frame:2 years from randomization
Safety Issue:
Description:Post HSCT relapse related mortality defined as time from date of HSCT to the date of death due to any cause with prior relapse/progression post HSCT.
Measure:Pharmacokinetics, Cmax
Time Frame:Pharmacokinetic sample collections during study drug cycles (each cycle is up to 28 days): Cycle 1 days 1, 4, 8, and 15, Cycle 2 days 1 and 8, Cycle 3 days 1 and 8, and Cycle 4 days 1 and 8.
Safety Issue:
Description:Maximum observed drug concentration (end of the infusion)
Measure:Percentage of patients with positive anti-drug antibody response
Time Frame:Sample collections: prior to first dose of study drug and approximately 4 weeks after the last dose of study drug
Safety Issue:
Description:Testing for anti-drug antibodies, including neutralizing antibodies
Measure:Percentage of patients with laboratory abnormalities (NCI CTCAE grade)
Time Frame:At least 9 weeks after last dose
Safety Issue:
Description:Magnesium, Calcium, Creatinine, Albumin, Alanine aminotransferase, Aspartate aminotransferase, Glucose, Phosphorus, Total Bilirubin, Blood urea nitrogen or urea, Uric acid or urate, Alkaline phosphatase, Lactate dehydrogenase, Gamma glutamyl transpeptidase, Total protein, Amylase and/or Lipase, Platelet Count, White Blood Cell Count (differential), hemoglobin, INR or prothrombin time, Activated partial thromboplastin time.
Measure:Pharmacokinetics, Ctrough
Time Frame:Pharmacokinetic sample collections during study drug cycles (each cycle is up to 28 days): Days 8 and 15 of Cycle 1 and day 8 of cycles 2-4)
Safety Issue:
Description:Drug concentration immediately prior to the next dose administration
Measure:Pharmacokinetics, Clearance
Time Frame:Pharmacokinetic sample collections during study drug cycles (each cycle is up to 28 days): Cycle 1 days 1, 4, 8, and 15, Cycle 2 days 1 and 8, Cycle 3 days 1 and 8, and Cycle 4 days 1 and 8.
Safety Issue:
Description:Volume of plasma cleared of drug per unit of time, calculated using non-linear mixed effects modeling
Measure:Pharmacokinetics, Area under the curve (AUC)
Time Frame:Pharmacokinetic sample collections during study drug cycles (each cycle is up to 28 days): Cycle 1 days 1, 4, 8, and 15, Cycle 2 days 1 and 8, Cycle 3 days 1 and 8, and Cycle 4 days 1 and 8.
Safety Issue:
Description:Calculated using non-linear mixed effects modeling

Details

Phase:Phase 4
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • Leukemia
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • ACUTE LYMPHOBLASTIC leukemia
  • inotuzumab ozogamicin
  • Besponsa
  • transplant

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