Clinical Trials /

Phase I/II Study of Bosutinib in Combination With Inotuzumab Ozogamicin in CD22-positive PC Positive ALL and CML

NCT02311998

Description:

This phase I/II trial studies the side effects and best dose of bosutinib when given together with inotuzumab ozogamicin and to see how well it works in treating patients with acute lymphoblastic leukemia or chronic myeloid leukemia that has come back or does not respond to treatment. Bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotoxins, such as inotuzumab ozogamicin, are antibodies linked to a toxic substance and may help find cancer cells that express CD22 and kill them without harming normal cells. Giving bosutinib together with inotuzumab ozogamicin may be a better treatment for acute lymphoblastic leukemia or chronic myeloid leukemia.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II Study of Bosutinib in Combination With Inotuzumab Ozogamicin in CD22-positive PC Positive ALL and CML
  • Official Title: A Phase I/II Study of Bosutinib in Combination With Inotuzumab Ozogamicin in CD22-Positive Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Lymphoid Blast Phase

Clinical Trial IDs

  • ORG STUDY ID: 2014-0435
  • SECONDARY ID: NCI-2014-02606
  • SECONDARY ID: 2014-0435
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02311998

Conditions

  • B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
  • Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Blasts More Than 5 Percent of Bone Marrow Nucleated Cells
  • CD22 Positive
  • Philadelphia Chromosome Positive, BCR-ABL1 Positive Chronic Myelogenous Leukemia
  • Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Interventions

DrugSynonymsArms
BosutinibBosulif, SKI 606, SKI-606Treatment (bosutinib, inotuzumab ozogamicin)
Inotuzumab OzogamicinBesponsa, CMC-544, Way 207294, WAY-207294Treatment (bosutinib, inotuzumab ozogamicin)

Purpose

This phase I/II trial studies the side effects and best dose of bosutinib when given together with inotuzumab ozogamicin and to see how well it works in treating patients with acute lymphoblastic leukemia or chronic myeloid leukemia that has come back or does not respond to treatment. Bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotoxins, such as inotuzumab ozogamicin, are antibodies linked to a toxic substance and may help find cancer cells that express CD22 and kill them without harming normal cells. Giving bosutinib together with inotuzumab ozogamicin may be a better treatment for acute lymphoblastic leukemia or chronic myeloid leukemia.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and maximum tolerated dose (MTD) of bosutinib in combination with
      inotuzumab ozogamicin in patients with Philadelphia-chromosome positive (Ph+) acute
      lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) in lymphoid blast phase that
      express CD22. (Phase I) II. To determine the efficacy of bosutinib in combination with
      inotuzumab ozogamicin in patients with Ph+ ALL and CML in lymphoid blast phase that express
      CD22. (Phase II)

      SECONDARY OBJECTIVES:

      I. To determine the efficacy of bosutinib in combination with inotuzumab ozogamicin in
      patients with Ph+ ALL and CML in lymphoid blast phase that express CD22. (Phase I) II. To
      determine the duration of response of patients treated with this combination. (Phase I) III.
      To determine the overall survival of patients treated with this combination. (Phase I) IV. To
      determine the effect of the level of pre-treatment expression of CD22 with response to this
      combination. (Phase I) V. To determine the efficacy of this combination according to
      pre-treatment mutation status in the ABL kinase domain. (Phase I) VI. To determine the
      minimal residual disease after treatment with this combination and its impact in long-term
      outcome. (Phase I) VII. To determine the safety bosutinib in combination with inotuzumab
      ozogamicin in patients with Ph+ ALL and CML in lymphoid blast phase that express CD22. (Phase
      II) VIII. To determine the duration of response of patients treated with this combination.
      (Phase II) IX. To determine the overall survival of patients treated with this combination.
      (Phase II) X. To determine the effect of the level of pre-treatment expression of CD22 with
      response to this combination. (Phase II) XI. To determine the efficacy of this combination
      according to pre-treatment mutation status in the abl kinase domain. (Phase II) XII. To
      determine the minimal residual disease after treatment with this combination and its impact
      in long-term outcome. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of bosutinib followed by a phase II study.

      Patients receive bosutinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28
      days in the absence of disease progression or unacceptable toxicity. Patients also receive
      inotuzumab ozogamicin intravenously (IV) over 1 hour on days 1, 8, and 15. Patients with
      confirmed complete response (CR), incomplete blood count recovery (CRi), complete cytogenetic
      response (CCyR) and/or absence of minimal residual disease (MRD) may receive inotuzumab
      ozogamicin IV on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6
      cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 12 weeks for up to 1
      year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (bosutinib, inotuzumab ozogamicin)ExperimentalPatients receive bosutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive inotuzumab ozogamicin IV over 1 hour on days 1, 8, and 15. Patients with confirmed CR, CRi, CCyR and/or absence of MRD may receive inotuzumab ozogamicin IV on day 1 of subsequent cycles. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
  • Bosutinib
  • Inotuzumab Ozogamicin

Eligibility Criteria

        Inclusion Criteria:

          -  Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia
             chromosome must be present at screening (as determined by cytogenetic analysis,
             fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e.,
             BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine
             kinase inhibitors for their CML, and have progressed to lymphoid blast phase are
             eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC)
             Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or
             minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea
             of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week
             duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible;
             patients must have bone marrow blasts > 5% at the time of screening

          -  Expression of CD-22 in >= 20% blasts

          -  Eastern Cooperative Oncology Group (ECOG) performance status score of < or = 2

          -  Serum bilirubin < or = 2.0 mg/dl

          -  Serum creatinine < or = 2.0 mg/dl

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or = 3 x upper
             limit of normal (ULN)

          -  Females of childbearing potential must have a negative serum or urine beta human
             chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the
             first dose of study drugs and must agree to use one of the following effective
             contraception methods during the study and for 30 days following the last dose of
             study drug; effective methods of birth control include: birth control pills, shots,
             implants (placed under the skin by a health care provider) or patches (placed on the
             skin); intrauterine devices (IUDs); condom or occlusive cap (diaphragm or
             cervical/vault caps) used with spermicide; females of non-childbearing potential are
             those who are postmenopausal greater than 1 year or who have had a bilateral tubal
             ligation or hysterectomy

          -  Males who have partners of childbearing potential must agree to use an effective
             contraceptive method during the study and for 30 days following the last dose of study
             drug

          -  Patients or their legally authorized representative must provide written informed
             consent

        Exclusion Criteria:

          -  History of another primary invasive malignancy that has not been definitively treated
             or in remission for at least 2 years; patients with non-melanoma skin cancers or with
             carcinomas in situ are eligible regardless of the time from diagnosis (including
             concomitant diagnoses)

          -  Patients with active unstable angina, concomitant clinically significant active
             arrhythmias, myocardial infarction within 6 months, or congestive heart failure New
             York Heart Association class III-IV; patients with a cardiac ejection fraction (as
             measured by either multi gated acquisition scan [MUGA] or echocardiogram) < 40% are
             excluded

          -  Known evidence of active cerebral/meningeal disease; patients may have history of
             central nervous system (CNS) leukemic involvement if definitively treated with prior
             therapy and no evidence of active disease (defined as >= 2 consecutive spinal fluid
             assessments with no evidence of disease) at that time of registration

          -  Previous treatment with any anti-CD22 directed therapy

          -  Patients with previous allogeneic stem cell transplant (SCT) if they meet either of
             the following criteria:

               -  < 100 days from allogeneic SCT

               -  Active acute or chronic graft-versus-host disease (GvHD), or

               -  Receiving immunosuppressive therapy as treatment for GvHD within the last 7 days

          -  Patients with uncontrolled active infections (viral, bacterial, or fungal) are not
             eligible

          -  Active hepatitis B or C infection, or known seropositivity for human immunodeficiency
             virus (HIV)

          -  Patients with liver cirrhosis or other serious active liver disease or with suspected
             alcohol abuse

          -  History of autoimmune diseases (such as systemic lupus erythematosus [SLE], Wegener's,
             Wegener's granulomatosis, polyarteritis nodosa); Note: Prior autoimmune diseases are
             allowed as long as clinically stable

          -  Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the
             start of study drugs with the following exceptions:

               -  To reduce the circulating lymphoblast count or palliation: steroids, hydroxyurea;
                  no washout necessary for these agents

               -  For ALL maintenance/CML treatment: mercaptopurine, methotrexate, vincristine,
                  single-agent, single-dose of cytarabine and/or tyrosine kinase inhibitors; these
                  agents should be discontinued at least 48 hours prior to start of study drugs;
                  (Note: the interval of time from last dose of any approved tyrosine kinase
                  inhibitor [TKI] to start of protocol treatment is 48 hours regardless of the
                  indication for treatment with the TKI)

          -  Patients who have not recovered from acute non hematologic toxicity (to =< grade 1) of
             all previous therapy prior to enrollment

          -  Females who are pregnant or lactating

          -  Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that in the opinion of the investigator may increase the risk associated
             with study participation or investigational product administration or may interfere
             with the interpretation of study results and/or would make the patient inappropriate
             for enrollment into this study

          -  Patients previously exposed to bosutinib are eligible unless they carry T315I

          -  Patients with T315I mutations will be excluded (this criteria is not applicable for
             the frontline Ph+ ALL or CML-LBC cohort)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of bosutinib defined as the highest dose level in which < 2 patients of 6 develop first course dose limiting toxicity (Phase I)
Time Frame:At day 28
Safety Issue:
Description:Will be observed.

Secondary Outcome Measures

Measure:Overall major hematologic response (Phase I)
Time Frame:Up to 1 year after completion of study treatment
Safety Issue:
Description:Will be observed.
Measure:Duration of response (Phase I)
Time Frame:Up to 1 year after completion of study treatment
Safety Issue:
Description:Estimated using the method of Kaplan-Meier. Cox regression models will be used to determine the relationship with the time-to-events and the potential prognostic factors.
Measure:Overall survival (OS) (Phase I)
Time Frame:Up to 1 year after completion of study treatment
Safety Issue:
Description:Estimated using the method of Kaplan-Meier. Cox regression models will be used to determine the relationship with the time-to-events (e.g., OS) and the potential prognostic factors.
Measure:Incidence and severity of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase II)
Time Frame:Up to 1 year after completion of study treatment
Safety Issue:
Description:Safety data will be summarized by category, severity and frequency.
Measure:Duration of response (Phase II)
Time Frame:Up to 1 year after completion of study treatment
Safety Issue:
Description:Estimated using the method of Kaplan-Meier. Cox regression models will be used to determine the relationship with the time-to-events and the potential prognostic factors.
Measure:Overall survival (Phase II)
Time Frame:Up to 1 year after completion of study treatment
Safety Issue:
Description:Estimated using the method of Kaplan-Meier. Cox regression models will be used to determine the relationship with the time-to-events (e.g., OS) and the potential prognostic factors.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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