search
Back to results

Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia

Primary Purpose

B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative, Burkitt-Like Lymphoma With 11q Aberration

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Blinatumomab
Cyclophosphamide
Cytarabine
Dexamethasone
Inotuzumab Ozogamicin
Laboratory Biomarker Analysis
Mercaptopurine
Methotrexate
Prednisone
Rituximab
Vincristine
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients aged 60 years or older with previously untreated ALL pre-B, Philadelphia chromosome (Ph-) negative or (Ph+) positive ALL; minimal prior therapy (less than 1 week of steroids, vincristine, and/or 1 dose of anthracycline or alkylating agents) are allowed
  • Patients unfit >= 18 - < 60 years of age with previously untreated ALL pre- B, Philadelphia chromosome (Ph-) negative or (Ph+) positive ALL (includes patients initiated on first cycle of hyper-CVAD before cytogenetics known; these patients could have received one or two cycles of chemotherapy with or without other tyrosine kinase inhibitors (TKIs) and still eligible; these patients are defined as having at least one of the below comorbidities:

    • Eastern Cooperative Oncology Group (ECOG) performance status >= 2
    • Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina)
    • Severe pulmonary disorder (e.g., carbon monoxide diffusing capability test [DLCO] =< 65% or forced expiratory volume in 1 second [FEV1] =< 65%)
    • Creatinine clearance < 45 mL/min, and
    • Hepatic disorder with total bilirubin > 1.5 x upper limit of normal

      • If they achieved complete remission (CR), they are assessable only for event-free and overall survival, or
      • If they failed to achieve CR, they are assessable for CR, event-free, and overall survival
  • Zubrod performance status 0-3
  • Bilirubin =< 1.95 mg/dL
  • Serum glutamate pyruvate transaminase (SGPT) or serum glutamic oxaloacetic transaminase (SGOT) =< 3 x upper limit of normal (ULN) unless considered due to tumor
  • Estimated creatinine clearance >= 50 mL/min/1.73 m^2
  • Even if organ function abnormalities are considered due to tumor, the upper limit for bilirubin is =< 2.6 mg/dL and creatinine =< 3 mg/dL
  • Provision of written informed consent
  • Patients in first remission are eligible
  • Patients with refractory-relapsed ALL, Burkitt lymphoma, Burkitt-like lymphoma with 11q aberration, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphoma not otherwise specified with marrow involvement of any age are eligible

Exclusion Criteria:

  • Newly diagnosed Burkitt's leukemia or lymphoma, T-cell ALL or lymphoblastic lymphoma
  • Patient with active heart disease (New York Heart Association [NYHA] class >= 3 as assessed by history and physical examination)
  • Patients with a cardiac ejection fraction (as measured by either multigated acquisition scan [MUGA] or echocardiogram) < 40% are excluded
  • Patients with active hepatitis are excluded
  • Pregnant or breast-feeding women are excluded

Sites / Locations

  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Arm I (inotuzumab ozogamicin, combination chemotherapy)

Arm II (inotuzumab ozogamicin, combination chemotherapy)

Arm III (inotuzumab ozogamicin, combination chemotherapy)

Arm Description

See Detailed Description Arm I

See Detailed Description Arm II

See Detailed Description Arm III

Outcomes

Primary Outcome Measures

Maximum tolerated dose of inotuzumab ozogamicin based on incidence of dose limiting toxicities (Phase I)
Defined as non-hematologic grade 3 or 4 toxicities during the first course. Toxicities will be monitored using the method of Thall, Simon, and Estey. Adverse events will be summarized and toxicity rate will be estimated with a 90% credible interval.
Progression free survival (PFS) in frontline elderly acute lymphoblastic leukemia (ALL) (Phase II)
Bayesian time-to-event model will be used. Kaplan and Meier product limit method will be used to estimate the PFS along with the 95% confidence intervals for the median PFS. Univariate and multivariate Cox proportional hazards regression models will be used to identify prognostic factors.
Response rate in refractory-relapsed acute lymphoblastic leukemia (ALL) (Phase II)
The precise complete remission (CR) and marrow CR rate will be defined.
Survival in refractory-relapsed acute lymphoblastic leukemia (ALL) (Phase II)
The median and 1-year survival rate will be defined. Kaplan and Meier product limit method will be used to estimate the overall survival (OS) along with the 95% confidence intervals for the median OS. Univariate and multivariate Cox proportional hazards regression models will be used to identify prognostic factors.

Secondary Outcome Measures

Full Information

First Posted
June 9, 2011
Last Updated
October 3, 2023
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)
search

1. Study Identification

Unique Protocol Identification Number
NCT01371630
Brief Title
Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia
Official Title
Phase I/II Study of the Combination of Inotuzumab Ozogamycin (CMC-544) With Low-Intensity Chemotherapy in Patients With Acute Lymphoblastic Leukemia (ALL)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 26, 2011 (Actual)
Primary Completion Date
December 25, 2025 (Anticipated)
Study Completion Date
December 25, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase I/II trial studies the side effects and best dose of inotuzumab ozogamicin and to see how well it works when given together with combination chemotherapy in treating patients with acute lymphoblastic leukemia. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a toxic agent called N-acetyl-gamma-calicheamicin dimethyl hydrazide (CalichDMH). Inotuzumab attaches to CD22 positive cancer cells in a targeted way and delivers CalichDMH to kill them. Immunotherapy with monoclonal antibodies, such as blinatumomab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving inotuzumab ozogamicin together with combination chemotherapy may be a better treatment for acute lymphoblastic leukemia.
Detailed Description
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of inotuzumab ozogamicin (inotuzumab ozogamycin) in combination with low-intensity chemotherapy in elderly patients (age 60 or older) with acute lymphoblastic leukemia (ALL). (Phase I) II. Evaluate the efficacy of inotuzumab ozogamycin in combination with low-intensity chemotherapy in elderly and unfit to receive intensive therapy patients with ALL. (Phase II) III. To evaluate the side effects of the treatment. (Phase II) IV. Evaluate the regimen efficacy in refractory-relapsed ALL. (Phase II) EXPLORATORY OBJECTIVES: I. To identify genomic alterations in adult ALL predictive for response and long-term outcomes with the combination of hyper-CVD (cyclophosphamide, dexamethasone, methotrexate, and cytarabine) + inotuzumab + blinatumomab. II. To evaluate the impact of next generation sequencing (NGS)-based minimal residual disease (MRD) assay on outcomes and to compare with standard flow cytometry MRD assays. OUTLINE: This is a phase I, dose-escalation study of inotuzumab ozogamicin followed by a phase II study. Patients are assigned to 1 of 3 arms. ARM I (UNTREATED): CYCLES 1, 3, 7, AND 9: Patients receive cyclophosphamide intravenously (IV) over approximately 3 hours twice daily (BID) on days 1-3; vincristine IV over 30 minutes on days 1 and 8; dexamethasone IV or orally (PO) on days 1-4 and 11-14; inotuzumab ozogamicin IV over approximately 1 hour on day 3 of cycle 1 and day 2 or 3 of cycle 3; methotrexate intrathecally (IT) on day 2 of cycles 1 and 3; and cytarabine IT on day 8 of cycles 1 and 3. Patients may also receive rituximab IV on days 1 and 8 of cycles 1 and 3. Cycles alternate every 3-4 weeks in the absence of disease progression or unacceptable toxicity. CYCLES 2, 4, 8, AND 10: Patients receive methotrexate IV over approximately 2 hours and then continuously over approximately 22 hours on day 1; cytarabine IV over approximately 3 hours BID on days 2-3; inotuzumab ozogamicin IV over approximately 1 hour on day 2 or 3 of cycles 2 and 4; cytarabine IT on day 5 of cycles 2 and 4; and methotrexate IT on day 8 of cycles 2 and 4. Patients may also receive rituximab IV on days 1 and 8 of cycles 2 and 4. Cycles alternate every 3-4 weeks in the absence of disease progression or unacceptable toxicity. CYCLES 5-8: Patients receive blinatumomab as a continuous intravenous infusion (CIVI) on days 1-29. Patients also receive dexamethasone IV over 15-30 minutes on day 1 and 3 of cycle 5 and then day 1 of cycles 6-8. Treatment repeats every 42 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive mercaptopurine PO BID and methotrexate PO once weekly for 3 years. Patients also receive vincristine IV over 30 minutes once monthly and prednisone PO daily five times a month for 1 year. Patients receive blinatumomab CIVI on days 1-28 of cycles 4, 8, 12, and 16. Cycles repeat every 42 days for 3 years in the absence of disease progression or unacceptable toxicity. ARM II (RELAPSED/REFRACTORY): CYCLES 1, 3, AND 5: Patients receive cyclophosphamide IV over approximately 3 hours BID on days 1-3; vincristine IV over 30 minutes on day 1; rituximab IV over 2-6 hours on days 1 and 8 of cycles 1 and 3; dexamethasone IV or PO on days 1-4; inotuzumab ozogamicin IV over 1 hour on days 2 and 8; methotrexate IT on day 2 of cycles 1 and 3; cytarabine IT on day 8 of cycles 1 and 3; and blinatumomab CIVI on days 4-21. Cycles alternate every 4 weeks in the absence of disease progression or unacceptable toxicity. CYCLES 2, 4, AND 6: Patients receive methotrexate IV over 24 hours on day 1; cytarabine IV over approximately 3 hours BID on days 2-3; rituximab IV over 2-6 hours on days 1 and 8 of cycles 2 and 4; inotuzumab ozogamicin IV over 1 hour on days 2 and 8 of cycles 2 and 4; cytarabine IT on day 2 of cycles 2 and 4, methotrexate IT on day 8 of cycles 2 and 4; and blinatumomab CIVI on days 4-21. Cycles alternate every 4 weeks in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive mercaptopurine PO BID and methotrexate PO once weekly for 3 years. Patients also receive vincristine IV over 30 minutes once monthly and prednisone PO daily five times a month for 1 year. Patients receive blinatumomab CIVI on days 1-28 of cycles 4, 8, 12, and 16. Cycles repeat every 42 days for 3 years in the absence of disease progression or unacceptable toxicity. ARM III (70 YEARS AND OLDER): INDUCTION CYCLE (CYCLE 1): Patients receive dexamethasone IV or PO on days 1-4; vincristine IV over 30 minutes on day 1; inotuzumab ozogamicin IV over 1 hour on days 1 and 8 of cycle 1; blinatumomab CIVI on days 15-28. Patients may also receive rituximab IV on days 2 and 9. INTRATHECAL PROPHYLAXIS: Patients receive methotrexate IT alternating with cytarabine IT on days 2 and 8 of cycles 1 and 3, and cytarabine IT alternating with methotrexate IT on days 2 and 8 of cycles 2 and 4. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-5): Patients receive blinatumomab CIVI on days 1-28; inotuzumab ozogamicin IV over 1 hour on days 1 and 8 of cycles 2-4. Patients may also receive rituximab IV on days 2 and 9 of cycles 2-4. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and every 4 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative, Burkitt-Like Lymphoma With 11q Aberration, High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements, High Grade B-Cell Lymphoma, Not Otherwise Specified, Recurrent B Acute Lymphoblastic Leukemia, Recurrent Burkitt Lymphoma, Refractory B Acute Lymphoblastic Leukemia, Refractory Burkitt Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
276 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm I (inotuzumab ozogamicin, combination chemotherapy)
Arm Type
Experimental
Arm Description
See Detailed Description Arm I
Arm Title
Arm II (inotuzumab ozogamicin, combination chemotherapy)
Arm Type
Experimental
Arm Description
See Detailed Description Arm II
Arm Title
Arm III (inotuzumab ozogamicin, combination chemotherapy)
Arm Type
Experimental
Arm Description
See Detailed Description Arm III
Intervention Type
Biological
Intervention Name(s)
Blinatumomab
Intervention Description
Given CIVI
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Intervention Description
Given IT and IV
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
Given IV or PO
Intervention Type
Biological
Intervention Name(s)
Inotuzumab Ozogamicin
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Mercaptopurine
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Intervention Description
Given IT, IV, and PO
Intervention Type
Drug
Intervention Name(s)
Prednisone
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
Rituximab
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Vincristine
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Maximum tolerated dose of inotuzumab ozogamicin based on incidence of dose limiting toxicities (Phase I)
Description
Defined as non-hematologic grade 3 or 4 toxicities during the first course. Toxicities will be monitored using the method of Thall, Simon, and Estey. Adverse events will be summarized and toxicity rate will be estimated with a 90% credible interval.
Time Frame
28 days
Title
Progression free survival (PFS) in frontline elderly acute lymphoblastic leukemia (ALL) (Phase II)
Description
Bayesian time-to-event model will be used. Kaplan and Meier product limit method will be used to estimate the PFS along with the 95% confidence intervals for the median PFS. Univariate and multivariate Cox proportional hazards regression models will be used to identify prognostic factors.
Time Frame
2 years
Title
Response rate in refractory-relapsed acute lymphoblastic leukemia (ALL) (Phase II)
Description
The precise complete remission (CR) and marrow CR rate will be defined.
Time Frame
Up to 5 years
Title
Survival in refractory-relapsed acute lymphoblastic leukemia (ALL) (Phase II)
Description
The median and 1-year survival rate will be defined. Kaplan and Meier product limit method will be used to estimate the overall survival (OS) along with the 95% confidence intervals for the median OS. Univariate and multivariate Cox proportional hazards regression models will be used to identify prognostic factors.
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients age 60 years or older with previously untreated ALL pre-B, Philadelphia chromosome (Ph-) negative or (Ph+) positive ALL Minimal prior therapy (less than 1 week of steroids, vincristine, and/or 1 dose of anthracycline or alkylating agents) are allowed. Patients unfit ≥ 18 - < 60 years of age with previously untreated ALL pre- B, Philadelphia chromosome (Ph-) negative or (Ph+) positive ALL (includes patients initiated on first cycle of hyper-CVAD before cytogenetics known. These patients could have received one or two cycles of chemotherapy with or without other TKIs and still eligible. These patients are defined as having at least one of the below comorbidities: ECOG performance status ≥ 2 Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina) Severe pulmonary disorder (e.g., DLCO ≤ 65% or FEV1 ≤ 65%) Creatinine clearance < 45 mL/min, and Hepatic disorder with total bilirubin > 1.5 x upper limit of normal If they achieved CR, they are assessable only for event-free and overall survival, or If they failed to achieve CR, they are assessable for CR, event-free, and overall survival Patients age 60 years and older unfit for intensive chemotherapy with one or more comorbidities (e.g., renal insufficiency, heart disease, cardio-vascular disease, uncontrolled hypertension, diabetes, respiratory problems, among others) and a PS of ≥ 1. All ages of Jehovah's witness are eligible. Zubrod performance status 0-3. Adequate liver function (bilirubin < 1.95 mg/dL and SGPT or SGOT < 3 x upper limit of normal [ULN], unless considered due to tumor), and renal function (estimated creatinine clearance ≥50 mL/min/1.73 m2). Even if organ function abnormalities are considered due to tumor, the upper limit for bilirubin is < 2.6 mg/dL and creatinine < 3 mg/dL. Provision of written informed consent. Patients in first remission are eligible. Patients with refractory-relapsed ALL, Burkitt lymphoma, Burkitt-like lymphoma with 11q aberration, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphoma not otherwise specified with marrow involvementBof any age are eligible. Exclusion Criteria: Newly diagnosed Burkitt's Leukemia or Lymphoma, T-cell ALL or lymphoblastic lymphoma. Patient with active heart disease (NYHA class > 3 as assessed by history and physical examination). Patients with a cardiac ejection fraction (as measured by either MUGA or echocardiogram) < 40% are excluded. Patients with active hepatitis are excluded. Pregnant or breast-feeding women are excluded.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Elias Jabbour, MD
Phone
713-792-7026
Email
ejabbour@mdanderson.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elias Jabbour, MD
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Elias Jabbour
Phone
713-792-7026
Email
ejabbour@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Elias Jabbour

12. IPD Sharing Statement

Citations:
PubMed Identifier
35622074
Citation
Shi Z, Zhu Y, Zhang J, Chen B. Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia. Hematology. 2022 Dec;27(1):642-652. doi: 10.1080/16078454.2022.2074704.
Results Reference
derived
PubMed Identifier
29352703
Citation
Kantarjian H, Ravandi F, Short NJ, Huang X, Jain N, Sasaki K, Daver N, Pemmaraju N, Khoury JD, Jorgensen J, Alvarado Y, Konopleva M, Garcia-Manero G, Kadia T, Yilmaz M, Bortakhur G, Burger J, Kornblau S, Wierda W, DiNardo C, Ferrajoli A, Jacob J, Garris R, O'Brien S, Jabbour E. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018 Feb;19(2):240-248. doi: 10.1016/S1470-2045(18)30011-1. Epub 2018 Jan 16.
Results Reference
derived
PubMed Identifier
28859185
Citation
Jabbour E, Ravandi F, Kebriaei P, Huang X, Short NJ, Thomas D, Sasaki K, Rytting M, Jain N, Konopleva M, Garcia-Manero G, Champlin R, Marin D, Kadia T, Cortes J, Estrov Z, Takahashi K, Patel Y, Khouri MR, Jacob J, Garris R, O'Brien S, Kantarjian H. Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial. JAMA Oncol. 2018 Feb 1;4(2):230-234. doi: 10.1001/jamaoncol.2017.2380.
Results Reference
derived
Links:
URL
http://www.mdanderson.org
Description
MD Anderson Cancer Center

Learn more about this trial

Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia

We'll reach out to this number within 24 hrs