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

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT02311998

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

83.2

Actual Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Bosutinib Biological: Inotuzumab Ozogamicin Other: Laboratory Biomarker Analysis	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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:

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

1. 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

23 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Apr 16, 2015

Actual Primary Completion Date :

Mar 23, 2022

Actual Study Completion Date :

Mar 23, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (bosutinib, inotuzumab ozogamicin) Patients 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.	Drug: Bosutinib Given PO Other Names: Bosulif SKI 606 SKI-606 Biological: Inotuzumab Ozogamicin Given IV Other Names: Besponsa CMC-544 Way 207294 WAY-207294 Other: Laboratory Biomarker Analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (bosutinib, inotuzumab ozogamicin)

Patients 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.

Drug: Bosutinib

Given PO

Other Names:

Bosulif

SKI 606

SKI-606

Biological: Inotuzumab Ozogamicin

Given IV

Other Names:

Besponsa

CMC-544

Way 207294

WAY-207294

Other: Laboratory Biomarker Analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

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) [At day 28]
Will be observed.
Major hematologic response for relapsed Philadelphia positive acute lymphoblastic leukemia (MaHR) (Phase II) [Up to 16 weeks (cycle 4 of treatment)]
The response will be evaluated along with its 95% confidence interval.
Complete response/complete response with incomplete bone marrow recovery for newly diagnosed Philadelphia positive acute lymphoblastic leukemia or chronic myeloid leukemia or chronic myeloid leukemia- lymphoid blast phase with age >= 60 (Phase II) [Up to 1 year after completion of study treatment]
Will be observed.

Secondary Outcome Measures

Overall major hematologic response (Phase I) [Up to 1 year after completion of study treatment]
Will be observed.
Duration of response (Phase I) [Up to 1 year after completion of study treatment]
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.
Overall survival (OS) (Phase I) [Up to 1 year after completion of study treatment]
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.
Incidence and severity of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase II) [Up to 1 year after completion of study treatment]
Safety data will be summarized by category, severity and frequency.
Duration of response (Phase II) [Up to 1 year after completion of study treatment]
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.
Overall survival (Phase II) [Up to 1 year after completion of study treatment]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)