Phase I/II Study of Bosutinib in Combination With Inotuzumab Ozogamicin in CD22-positive PC Positive ALL and CML
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| ClinicalTrials.gov Identifier: NCT02311998 |
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Recruitment Status :
Completed
First Posted : December 9, 2014
Last Update Posted : April 5, 2022
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| 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 |
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.
| Study Type : | Interventional (Clinical Trial) |
| 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 : | April 16, 2015 |
| Actual Primary Completion Date : | March 23, 2022 |
| Actual Study Completion Date : | March 23, 2022 |
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: Bosutinib
Given PO
Other Names:
Biological: Inotuzumab Ozogamicin Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies |
- 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 ]Will be observed.
- Major hematologic response for relapsed Philadelphia positive acute lymphoblastic leukemia (MaHR) (Phase II) [ Time Frame: 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) [ Time Frame: Up to 1 year after completion of study treatment ]Will be observed.
- Overall major hematologic response (Phase I) [ Time Frame: Up to 1 year after completion of study treatment ]Will be observed.
- Duration of response (Phase I) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Up to 1 year after completion of study treatment ]Safety data will be summarized by category, severity and frequency.
- Duration of response (Phase II) [ Time Frame: 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) [ Time Frame: 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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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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
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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)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02311998
| United States, Texas | |
| M D Anderson Cancer Center | |
| Houston, Texas, United States, 77030 | |
| Principal Investigator: | Nitin Jain | M.D. Anderson Cancer Center |
| Responsible Party: | M.D. Anderson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT02311998 |
| Other Study ID Numbers: |
2014-0435 NCI-2014-02606 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 2014-0435 ( Other Identifier: M D Anderson Cancer Center ) |
| First Posted: | December 9, 2014 Key Record Dates |
| Last Update Posted: | April 5, 2022 |
| Last Verified: | March 2022 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Blast Crisis Philadelphia Chromosome Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases |
Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases Translocation, Genetic Chromosome Aberrations Pathologic Processes Cell Transformation, Neoplastic Carcinogenesis Neoplastic Processes Inotuzumab Ozogamicin Antineoplastic Agents, Immunological Antineoplastic Agents Antibiotics, Antineoplastic |