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

Phase I/II Study of the Combination of Inotuzumab Ozogamycin (CMC-544) With Low-Intensity Chemotherapy in Patients With Acute Lymphoblastic Leukemia (ALL)

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.

Study Overview

• Status: Recruiting
• Conditions: Recurrent B Acute Lymphoblastic Leukemia; Refractory B Acute Lymphoblastic Leukemia; B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative; B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Recurrent Burkitt Lymphoma; Refractory Burkitt Lymphoma; High Grade B-Cell Lymphoma, Not Otherwise Specified; High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements; Burkitt-Like Lymphoma With 11q Aberration
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Cyclophosphamide; Drug: Mercaptopurine; Drug: Prednisone; Drug: Methotrexate; Drug: Vincristine; Biological: Rituximab; Biological: Inotuzumab Ozogamicin; Drug: Cytarabine; Drug: Dexamethasone; Biological: Blinatumomab

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.

• Study Type: Interventional
• Enrollment (Estimated): 276
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Elias Jabbour, MD; Phone Number: 713-792-7026; Email: ejabbour@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Contact: Elias Jabbour; Phone Number: 713-792-7026; Email: ejabbour@mdanderson.org
      • Principal Investigator: Elias Jabbour

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.

2. 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:

   1. ECOG performance status ≥ 2
   2. Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina)
   3. Severe pulmonary disorder (e.g., DLCO ≤ 65% or FEV1 ≤ 65%)
   4. Creatinine clearance < 45 mL/min, and
   5. Hepatic disorder with total bilirubin > 1.5 x upper limit of normal
   1. If they achieved CR, they are assessable only for event-free and overall survival, or
   2. If they failed to achieve CR, they are assessable for CR, event-free, and overall survival
3. 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.
4. Zubrod performance status 0-3.
5. 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.
6. Provision of written informed consent.
7. Patients in first remission are eligible.
8. 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:

1. Newly diagnosed Burkitt's Leukemia or Lymphoma, T-cell ALL or lymphoblastic lymphoma.
2. Patient with active heart disease (NYHA class > 3 as assessed by history and physical examination).
3. Patients with a cardiac ejection fraction (as measured by either MUGA or echocardiogram) < 40% are excluded.
4. Patients with active hepatitis are excluded.
5. Pregnant or breast-feeding women are excluded.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (inotuzumab ozogamicin, combination chemotherapy); See Detailed Description Arm I	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Drug: Mercaptopurine; Given PO; Drug: Prednisone; Given PO; Drug: Methotrexate; Given IT, IV, and PO; Drug: Vincristine; Given IV; Biological: Rituximab; Given IV; Biological: Inotuzumab Ozogamicin; Given IV; Drug: Cytarabine; Given IT and IV; Drug: Dexamethasone; Given IV or PO; Biological: Blinatumomab; Given CIVI
Experimental: Arm II (inotuzumab ozogamicin, combination chemotherapy); See Detailed Description Arm II	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Drug: Mercaptopurine; Given PO; Drug: Prednisone; Given PO; Drug: Methotrexate; Given IT, IV, and PO; Drug: Vincristine; Given IV; Biological: Rituximab; Given IV; Biological: Inotuzumab Ozogamicin; Given IV; Drug: Cytarabine; Given IT and IV; Drug: Dexamethasone; Given IV or PO; Biological: Blinatumomab; Given CIVI
Experimental: Arm III (inotuzumab ozogamicin, combination chemotherapy); See Detailed Description Arm III	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Methotrexate; Given IT, IV, and PO; Drug: Vincristine; Given IV; Biological: Rituximab; Given IV; Biological: Inotuzumab Ozogamicin; Given IV; Drug: Cytarabine; Given IT and IV; Drug: Dexamethasone; Given IV or PO; Biological: Blinatumomab; Given CIVI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	28 days
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.	2 years
Response rate in refractory-relapsed acute lymphoblastic leukemia (ALL) (Phase II)	The precise complete remission (CR) and marrow CR rate will be defined.	Up to 5 years
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.	Up to 1 year

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Elias Jabbour, MD, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• Zhao Y, Short NJ, Kantarjian HM, Chang TC, Ghate PS, Qu C, Macaron W, Jain N, Thakral B, Phillips AH, Khoury J, Garcia-Manero G, Zhang W, Fan Y, Yang H, Garris RS, Nasr LF, Kriwacki RW, Roberts KG, Konopleva M, Jabbour EJ, Mullighan CG. Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL. Blood. 2024 Jul 4;144(1):61-73. doi: 10.1182/blood.2024023930.
• Jabbour E, Short NJ, Senapati J, Jain N, Huang X, Daver N, DiNardo CD, Pemmaraju N, Wierda W, Garcia-Manero G, Montalban Bravo G, Sasaki K, Kadia TM, Khoury J, Wang SA, Haddad FG, Jacob J, Garris R, Ravandi F, Kantarjian HM. Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial. Lancet Haematol. 2023 Jun;10(6):e433-e444. doi: 10.1016/S2352-3026(23)00073-X. Epub 2023 May 12.
• Kantarjian H, Haddad FG, Jain N, Sasaki K, Short NJ, Loghavi S, Kanagal-Shamanna R, Jorgensen J, Khouri I, Kebriaei P, Alvarado Y, Kadia T, Paul S, Garcia-Manero G, Dabaja B, Yilmaz M, Jacob J, Garris R, O'Brien S, Ravandi F, Jabbour E. Results of salvage therapy with mini-hyper-CVD and inotuzumab ozogamicin with or without blinatumomab in pre-B acute lymphoblastic leukemia. J Hematol Oncol. 2023 May 2;16(1):44. doi: 10.1186/s13045-023-01444-2.

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2011
• Primary Completion (Estimated): December 25, 2027
• Study Completion (Estimated): December 25, 2027

Study Registration Dates

• First Submitted: June 9, 2011
• First Submitted That Met QC Criteria: June 10, 2011
• First Posted (Estimated): June 13, 2011

Study Record Updates

• Last Update Posted (Estimated): December 18, 2025
• Last Update Submitted That Met QC Criteria: December 16, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Infections; Virus Diseases; Neoplasms by Histologic Type; DNA Virus Infections; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Epstein-Barr Virus Infections; Herpesviridae Infections; Tumor Virus Infections; Hemic and Lymphatic Diseases; Burkitt Lymphoma; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Carbohydrates; Alkaloids; Polycyclic Compounds; Glycosides; Indoles; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Purines; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Nucleosides; Pterins; Pteridines; Pregnadienetriols; Pregnadienediols; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Arabinonucleosides; Aminopterin; Aminoglycosides; Antibodies, Monoclonal, Murine-Derived; Sulfhydryl Compounds; Calicheamicins; Rituximab; Inotuzumab Ozogamicin; Dexamethasone; Methotrexate; Prednisone; Cyclophosphamide; Cytarabine; Vincristine; Mercaptopurine; blinatumomab
• Other Study ID Numbers: 2010-0991 (Other Identifier: M D Anderson Cancer Center); NCI-2011-01123 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No