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

Study Overview
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Brief Summary
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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
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If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study and whether or not you have received earlier treatment for leukemia. Up to 36 participants will be enrolled in Part 1 of the study, and up to 44 participants will be enrolled in Part 2. If you are enrolled in Part 2, you will receive bosutinib at the highest dose that was tolerated in Part 1. All participants in Parts 1 and 2 will receive the same dose of inotuzumab ozogamicin. Study Drug Administration. You will take bosutinib tablets by mouth 1 time each day with food. If you miss or vomit a dose of bosutinib, do not take make up the dose. Wait and take your next dose as scheduled the next day. You will also receive inotuzumab ozogamicin by vein over about 1 hour on Days 1, 8, and 15 of each 28-day cycle. If the doctor thinks it is needed, you may switch to a different dosing schedule and receive inotuzumab ozogamicin 1 time every 4 weeks. You will be given standard drugs (such as acetaminophen/paracetamol, antihistamines, and/or steroids) to help decrease the risk of side effects. If your doctor thinks it is needed, you may also receive hydroxyurea to control your white blood cell count while you are on study. You may ask the study staff for information about how these drugs are given and their risks. Follow-Up After your end-of-treatment visit or call, you will be called 1 time about every 12 weeks (for up to 1 year) and asked about any anti-cancer therapy you may have started. This call will last about 5 minutes. After completion of study treatment, patients are followed up every 12 weeks for up to 1 year.

Official Title
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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

Conditions
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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, B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1

Intervention / Treatment
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* Drug: Bosutinib
* Biological: Inotuzumab Ozogamicin


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bosutinib, inotuzumab ozogamicin) Phase I Dose 1<br>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<br>* Given PO<br>* Other names: SKI-606;Biological: Inotuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-207294;|
| Experimental: Treatment (bosutinib, inotuzumab ozogamicin) Phase II<br>Patients receive bosutinib at the Maximum Tolerated Dose from the Phase I dose part, 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<br>* Given PO<br>* Other names: SKI-606;Biological: Inotuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-207294;|
| Experimental: Treatment (bosutinib, inotuzumab ozogamicin) Phase I Dose 2<br>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<br>* Given PO<br>* Other names: SKI-606;Biological: Inotuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-207294;|
| Experimental: Treatment (bosutinib, inotuzumab ozogamicin) Phase I Dose 3<br>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<br>* Given PO<br>* Other names: SKI-606;Biological: Inotuzumab Ozogamicin<br>* Given IV<br>* Other names: WAY-207294;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Bosutinib All Phase I Participants | 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). Dose levels assessed were dose 1 = 300 mg, dose 2 = 400 mg, and dose 3 = 500 mg. | At day 28 | 
| Number of Participants With a Major Hematologic Response | Major Hematologic Response i(MaHR) is defined as Complete Response (CR) + Complete Remission without Incomplete Blood Count Recovery (CRi). CR was defined as absence of circulating blasts with bone marrow blasts <5% and recovery of neutrophil count to ≥1.0 x 10^9/L and platelet count to ≥100 x10^9/L. The CRi was defined as meeting criteria for CR except for neutrophil and/or platelet recovery. Response was assessed by bone marrow analysis after each cycle of therapy until attainment of CR/CRi. | Up to 6 years, 11 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Estimated using the method of Kaplan-Meier. Response date to loss of response or last follow up. | Up to 6 years, 11 months | 
| Overall Survival (OS) | Estimated using the method of Kaplan-Meier. Time from date of treatment start until date of death due to any cause or last Follow-up. | Up to 6 years, 11 months |