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

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ClinicalTrials.gov Identifier: NCT03677596
Recruitment Status : Recruiting
First Posted : September 19, 2018
Last Update Posted : September 27, 2019
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE July 27, 2018
First Posted Date  ICMJE September 19, 2018
Last Update Posted Date September 27, 2019
Actual Study Start Date  ICMJE July 1, 2019
Estimated Primary Completion Date August 19, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 17, 2018)
  • 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) ]
    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.
  • Rate of veno-occlusive disease (VOD) [ Time Frame: 2 years from randomization ]
    Defined as the percentage of participants with VOD. VOD was defined as one of the following (a) the occurrence of bilirubin >=2mg/dL with 2 or more of the following: painful hepatomegaly, weight gain >5%, or ascites, or (b) histologically proven VOD, or (c) 2 or more of the following with hemodynamic and /or ultrasound evidence of VOD: bilirubin >=2mg/dL, painful hepatomegaly, weight gain >5%, or ascites.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03677596 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 17, 2018)
  • Frequency of adverse events [ Time Frame: At least 9 weeks after last dose ]
    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.
  • Minimal residual disease (MRD) negativity [ Time Frame: Up to approximately 4 weeks (EoT) from last dose of study drug ]
    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.
  • Duration of remission (DoR) for Participants Who Achieved CR/CRi [ Time Frame: 2 years from randomization ]
    DoR defined as time from date of first response in responders (CR/CRi) to date of progression or death
  • Progression free survival (PFS) [ Time Frame: 2 years from randomization ]
    PFS defined as time from date of randomization to earliest date of the death or progressive disease
  • Overall survival (OS) [ Time Frame: 2 years from randomization ]
    OS defined as the time from randomization to date of death due to any cause.
  • Rate of hematopoietic stem cell transplantation (HSCT) [ Time Frame: 2 years from randomization ]
    HSCT rate defined as the percentage of participants who underwent HSCT following treatment with inotuzumab ozogamicin
  • Post HSCT relapse [ Time Frame: 2 years from randomization ]
    Post HSCT relapse defined as the time from date of HSCT to the date of first relapse post HSCT.
  • Post HSCT mortality [ Time Frame: 2 years from randomization ]
    Post HSCT mortality defined as the time from date of HSCT to the date of death due to any cause
  • Post HSCT non relapse mortality [ Time Frame: 2 years from randomization ]
    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
  • Post HSCT relapse related mortality [ Time Frame: 2 years from randomization ]
    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.
  • 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. ]
    Maximum observed drug concentration (end of the infusion)
  • 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 ]
    Testing for anti-drug antibodies, including neutralizing antibodies
  • Percentage of patients with laboratory abnormalities (NCI CTCAE grade) [ Time Frame: At least 9 weeks after last dose ]
    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.
  • 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) ]
    Drug concentration immediately prior to the next dose administration
  • 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. ]
    Volume of plasma cleared of drug per unit of time, calculated using non-linear mixed effects modeling
  • 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. ]
    Calculated using non-linear mixed effects modeling
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study Of Two Inotuzumab Ozogamicin Doses in Relapsed/ Refractory Acute Lymphoblastic Leukemia Transplant Eligible Patients
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE 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)
Primary Purpose: Treatment
Condition  ICMJE
  • Leukemia
  • Precursor b-Cell Lymphoblastic Leukemia-Lymphoma
  • ACUTE LYMPHOBLASTIC LEUKEMIA
Intervention  ICMJE
  • Drug: inotuzumab ozogamicin-dose level 2
    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.
    Other Name: Besponsa
  • Drug: Inotuzumab ozogamicin-dose level 1
    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.
    Other Name: Besponsa
Study Arms  ICMJE
  • Experimental: Dose Level 2
    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)
    Intervention: Drug: inotuzumab ozogamicin-dose level 2
  • Active Comparator: Dose Level 1
    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)
    Intervention: Drug: Inotuzumab ozogamicin-dose level 1
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 17, 2018)
102
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 18, 2025
Estimated Primary Completion Date August 19, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com
Listed Location Countries  ICMJE Australia,   Poland,   Singapore,   Taiwan,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03677596
Other Study ID Numbers  ICMJE B1931030
2018-001557-27 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP