Study of Pedi-cRIB: Mini-Hyper-CVD With Condensed Rituximab, Inotuzumab Ozogamicin and Blinatumomab (cRIB) for Relapsed Therapy for Pediatric With B-Cell Lineage Acute Lymphocytic Leukemia

Phase II Study of Pedi-cRIB: Mini-Hyper-CVD With Condensed Rituximab, Inotuzumab Ozogamicin and Blinatumomab (cRIB) for Relapsed Therapy for Pediatric With B-Cell Lineage Acute Lymphocytic Leukemia

To learn if cyclophosphamide, vincristine, and dexamethasone (called mini hyper-CVD) in combination with intrathecal (delivered into the spine) chemotherapy (methotrexate, hydrocortisone, cytarabine) and compressed rituximab, blinatumomab, and inotuzumab ozogamicin (called cRIB) can help to control the disease.

Study Overview

• Status: Recruiting
• Conditions: Leukemia
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Vincristine; Drug: Blinatumomab; Drug: Methotrexate; Drug: Cytarabine; Drug: Mercaptopurine; Drug: Prednisone; Drug: Pegfilgrastim; Drug: Inotuzumab ozogamicin; Drug: Rituximab; Drug: Dexamethasone

Detailed Description

Primary Objective:

--To evaluate the clinical efficacy of the sequential combination of mini-hyper-CVD with inotuzumab ozogamicin and blinatumomab and rituximab in relapsed B-cell acute lymphoblastic leukemia (ALL) patients, based upon the complete response rate (CR).

Secondary Objectives:

• To summarize efficacy per response rate, overall survival (OS), event free survival (EFS), and minimal residual disease (MRD) negativity rate.
• To evaluate the safety of this combination.

Exploratory Objectives:

--To summarize associations between genomic alterations in ALL (current biomarker expression of the disease) with relation to the incidence of transition to HSCT in patients with PR or stable disease (SD) after the induction cycle(s).

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: David McCall, MD; Phone Number: (713) 792-6604; Email: dmccall1@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Contact: David Mc Call, MD; Phone Number: 713-792-6604; Email: dmccall1@mdanderson.org
      • Principal Investigator: David Mc Call, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pediatric, adolescent, or young adult patients with B-ALL as per NCCN v2.2021 and WHO classification in relapse or primary refractory and, either/both of the following: • Unable to receive anthracyclines (see section 3.1.8) or is PEG-asparaginase intolerant.

  • For leukemia: Patients must have ≥ 5% blasts expressing CD19 and CD22 in the bone marrow as assessed by morphology or flow cytometry. However, if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% blasts in the peripheral blood.
  • If patient does not have CD20, they can still be enrolled but will not receive rituximab.
• Performance status: Lansky ≥ 50 for patients who are ≤ 16 years old and Karnofsky ≥ 50% for patients who are > 16 years old.
• Patients with asymptomatic CNS leukemia are eligible (see also Exclusion Criterion 3.2.2.)
• Age > = 1 years of age and less than 25 years of age.

• The following baseline laboratory data:

  • Total serum bilirubin ≤1.5x upper limit of normal (ULN). Patients with known Gilbert's syndrome may have a total bilirubin up to ≤3 x ULN.
  • Adequate renal function per age51 unless related to the disease. Estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 based on local institutional practice for age-appropriate determination (eg, Schwartz formula for pediatric patients or Cockcroft Gault formula for adults).
  • Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤3 x ULN; ≤5 x ULN in case of suspected leukemic liver involvement

• Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-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 30 days after the last treatment and 8 months after the last dose of inotuzumab and 12 months after the last dose of rituximab. 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
  • Abstinence
• Males need to inform the doctor right away if the partner becomes pregnant or suspects pregnancy. While in this study and for 30 days after the last treatment the patient should not donate sperm for the purposes of reproduction. He will need to use a condom while in this study and for 30 days after the last treatment and 5 months after the last dose of inotuzumab.
• Patients with cardiac disease, include but not limited to: (Left ventricular ejection fraction (EF) < 50% (as determined by the Biplane Simpson method) (but not per exclusion criteria 3.2.3.1), or who have received >450mg/m2 of doxorubicin and cannot receive anthracyclines.

Exclusion Criteria:

• Past or current history of a secondary or other primary tumor or a chronic myeloid leukemia (CML) blast crisis with exception of:

  • Curatively treated non-melanomatous skin cancer
  • Other primary solid tumor treated with curative intent and no known active disease present and no treatment administered during the last 2 years
• Presence of clinically significant uncontrolled CNS pathology such as epilepsy, childhood seizure, paresis, aphasia, stroke, severe brain injuries, organic brain syndrome, or psychosis. Presence of the following are allowed: headaches, vomiting, nerve palsy

• Medical history of cardiovascular disease such as:

  ° Clinically significant cardiac disease including congestive heart failure (NYHA class III or IV) or arrhythmia or conduction abnormality requiring medication

• Patients with uncontrolled, active infections (viral, bacterial, or fungal). Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable.
• Known active hepatitis B or C infection or known seropositivity for HIV.
• Patients with liver cirrhosis or other serious active liver disease or with suspected active alcohol abuse.
• Active acute/chronic Graft-versus-Host Disease (GvHD) requiring systemic treatment; or receiving immunosuppression for GvHD prophylaxis within 2 weeks from the start of study therapy.

• If patient has not recovered (as deemed by the investigator) from previous chemotherapy, surgery, radiation before the start of study drugs.

  ° To reduce the circulating blast count or palliation, the following are allowed prior to starting: Single dose intravenous cytarabine, steroids or hydroxyurea. No washout necessary for these agents.

• Females who are pregnant or lactating.
• Male or female subjects of childbearing potential, unwilling to use an approved, effective means of contraception in accordance with institution's standards.
• Other severe, uncontrolled acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated Protocol 2022-0312 V3 Dated 11/9/2023 Property of Leukemia at MD Anderson 17 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 with Trisomy 21, or bone marrow failure syndromes are not eligible.
• Prior history of allergic reaction to any of the agents.
• Patients who are unable or unwilling to comply with all study requirements for clinical visits, examinations, tests, and procedures.
• Patients may be excluded if they are currently enrolled in another ongoing clinical trial with investigational products

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Leukemia CNS1 or 2; Each study block, or cycle, is 28 days. Between every cycle below, Participants will have a 7-day rest period in which no study drug is given.	Drug: Cyclophosphamide; Given by (IV) vein; Other Names: Cytoxan®; Neosar®; Drug: Vincristine; Given by (IV) vein; Drug: Blinatumomab; Given by (IV) vein; Drug: Methotrexate; Given by (IV) vein; Drug: Cytarabine; Given by (IV) vein; Other Names: Ara-C; Cytosine arabinosine hydrochloride; Cytosar®; DepoCyt™; Drug: Mercaptopurine; Given by (IV) vein; Other Names: 6-MP; 6-mercaptopurine; Purinethol®; Drug: Prednisone; Given by PO; Drug: Pegfilgrastim; Given by (IV) vein; Other Names: PEG-G-CSF; NeulastaTM; Drug: Inotuzumab ozogamicin; Given by (IV) vein; Other Names: CMC-544; Drug: Rituximab; Given by (IV) vein; Other Names: Rituxan; Drug: Dexamethasone; Given by (IV) vein; Other Names: Decadron
Experimental: Leukemia CNS 3; Each study block, or cycle, is 28 days. Between every cycle below, Participants will have a 7-day rest period in which no study drug is given.	Drug: Cyclophosphamide; Given by (IV) vein; Other Names: Cytoxan®; Neosar®; Drug: Vincristine; Given by (IV) vein; Drug: Blinatumomab; Given by (IV) vein; Drug: Methotrexate; Given by (IV) vein; Drug: Cytarabine; Given by (IV) vein; Other Names: Ara-C; Cytosine arabinosine hydrochloride; Cytosar®; DepoCyt™; Drug: Mercaptopurine; Given by (IV) vein; Other Names: 6-MP; 6-mercaptopurine; Purinethol®; Drug: Prednisone; Given by PO; Drug: Pegfilgrastim; Given by (IV) vein; Other Names: PEG-G-CSF; NeulastaTM; Drug: Inotuzumab ozogamicin; Given by (IV) vein; Other Names: CMC-544; Drug: Rituximab; Given by (IV) vein; Other Names: Rituxan; Drug: Dexamethasone; Given by (IV) vein; Other Names: Decadron

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0	through study completion; an average of 1 year.

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: David McCall, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2023
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: November 29, 2022
• First Submitted That Met QC Criteria: December 1, 2022
• First Posted (Actual): December 9, 2022

Study Record Updates

• Last Update Posted (Actual): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Dermatologic Agents; Antibiotics, Antineoplastic; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Immunoconjugates; Immunotoxins; Dexamethasone; Cyclophosphamide; Rituximab; Prednisone; Cytarabine; Methotrexate; Vincristine; Mercaptopurine; Blinatumomab; Inotuzumab Ozogamicin
• Other Study ID Numbers: 2022-0312; NCI-2022-10168 (Other Identifier: NCI-CTRP Clinical Trials Registry)

Drug and device information, study documents

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