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Bortezomib-based Regimen for Refractory or Relapsed Acute Lymphoblastic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT06034561
Recruitment Status : Recruiting
First Posted : September 13, 2023
Last Update Posted : April 18, 2024
Sponsor:
Collaborator:
Libbs Farmacêutica LTDA
Information provided by (Responsible Party):
Instituto do Cancer do Estado de São Paulo

Study Description
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Brief Summary:
This is a interventional phase II study aiming to examine the complete response rate of a bortezomib-based salvage regimen in adults with refractory or relapsed acute lymphoblastic leukemia (ALL), seeking to compare outcomes with the available literature and with our historical data on relapsed/refractory ALL.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia, in Relapse Acute Lymphoblastic Leukemia With Failed Remission Drug: Bortezomib Phase 2

Detailed Description:

Acute lymphoblastic leukemia (ALL) is a rare neoplasm in adults, with long-term survival rates approaching 50% with current regimens. Although high rates of complete response are achieved with the first-line therapy, many patients are primary refractory or may further relapse. Arguably, these patients have a more resistant disease with higher risk genetic alterations and a much less likely to be cured, which almost always only can be obtained by a following allogeneic hematopoietic stem-cell transplantation (HSCT). Therefore, strategies to salvage patients with detectable disease after induction blocks or with relapsed disease are crucial to prolong survival and potentially cure those patients, working as a bridge therapy to HSCT. Historically, patients with relapsed/refractory ALL have received multidrug regimens based on high-dose cytarabine, such as fludarabine, cytarabine and idarubicin (FLAG-IDA). Those regimens provide a 30-40% complete response rate with non-negligible toxicity. Recently, new targeted agents such as blinatumomab, inotuzumab, and cellular therapies have arisen for B-lineage disease, even though these agents are not available in the public health setting. Previous studies have tested salvage regimens for ALL encompassing proteasome inhibitors plus highly synergistic drugs (dexamethasone, vincristine, asparaginase, doxorubicin), with exciting outcomes in limited case series. For adults, these regimens are less studied. However, preliminary data suggest that they are less toxic and more potent since patients can receive different drug combinations that they had not been exposed to before. The primary objective of this study is to examine the complete response rate of this regimen in our population, aiming to compare with the available literature and with our historical data on relapsed/refractory ALL. Secondary objectives are:

  1. To determine the safety and feasibility of a bortezomib-based regimen for salvage relapsed/refractory ALL in our setting.
  2. To determine the rate of patients who are able to proceed with HSCT after the treatment.
  3. To calculate event-free survival and overall survival after the salvage regimen for relapsed/refractory ALL.
  4. To calculate the rate of measurable residual disease (MRD) negative status after the treatment.
  5. To examine the rate of febrile neutropenia, liver toxicity, neurotoxicity, and treatment-related mortality after this regimen in relapsed/refractory ALL.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Bortezomib-based Regimen for Refractory or Relapsed Acute Lymphoblastic Leukemia in Adults
Actual Study Start Date : April 1, 2024
Estimated Primary Completion Date : August 2028
Estimated Study Completion Date : August 2029

Resource links provided by the National Library of Medicine

Drug Information available for: Bortezomib

Arms and Interventions
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Arm Intervention/treatment
Experimental: Bortezomib

Patients with refractory or relapsed acute lymphoblastic leukemia will receive one-two courses of salvage regimen composed by:

  • Bortezomib 1.3 mg/m2 I.V. D1,D4,D8,D11;
  • Vincristine 1.5 mg/m2 I.V. (maximum at 2 mg) - D1, D8,D15,D22;
  • Doxorubicin 60 mg/m2 I.V. - D1;
  • Peg-asparaginase 2000 IU/m2 I.V. - D4 and D18;
  • Dexamethasone 20 mg/m2 P.O. or I.V. (divided BID) - D1-D5 and D15-D19
  • Intrathecal chemotherapy: methotrexate 12 mg + dexamethasone 2 mg.
 Drug: Bortezomib
Patients should receive one or two courses of this regimen, aiming to achieve complete remission as a bridge to proceed with allogeneic HSCT.
Other Names:
  • Vincristine
  • Doxorubicin
  • Peg-asparaginase
  • Dexamethasone
  • Methotrexate


Outcome Measures
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Primary Outcome Measures :
  1. Complete response [ Time Frame: 30 days ]
    Disappearance of lymphoid blasts in peripheral blood, with fewer than 5% of lymphoid blasts quantified in the bone marrow aspirate through immunophenotyping.


Secondary Outcome Measures :
  1. Event-free survival [ Time Frame: 1 year ]
    Time interval between study enrollment and the occurrence of an event (non-response, relapse, or death) or last follow-up (censorship).

  2. Overall survival [ Time Frame: 1 year ]
    Time interval between study enrollment and the occurrence of death or last follow-up (censorship).

  3. Rate of MRD-negativity [ Time Frame: 60 days ]
    Absence of pathological lymphoid blasts in a bone marrow sample detected through immunophenotyping with a minimum sensitivity of 10-4.

  4. Rate of allogeneic hematopoietic stem-cell transplantation [ Time Frame: 1 year ]
    Proportion of patients who successfully underwent allogeneic hematopoietic stem-cell transplantation after the study therapy


Eligibility Criteria
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Ages Eligible for Study:   16 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients between 16 and 60 years-old with refractory or relapsed ALL (≥1% of anomalous blasts by flow cytometry in bone marrow or peripheral blood) after one or two lines of therapy, regardless of their phenotype or baseline genetic alteration;
  • Patients are eligible after allogeneic HSCT as long as patients are not actively being treated for graft-versus-host-disease (GvHD).

Exclusion Criteria:

  • Burkitt leukemia;
  • Prior myeloproliferative disease;
  • Drug allergies;
  • Eastern Cooperative Oncology Group (ECOG) scale >2;
  • Total bilirubin>2x upper limit of normal (ULN);
  • Transaminases>5x ULN;
  • Creatinine>2,5 mg/dl;
  • Active uncontrolled infection;
  • History of asparaginase-induced pancreatitis;
  • Prior exposure to bortezomib;
  • Heart failure New York Heart Association (NYHA) Class III or IV;
  • Patients with more than 400mg/m2 lifetime exposure of anthracycline;
  • Severe psychiatric disorder which prevents adequate compliance;
  • Refusal to participate in the study.
Contacts and Locations
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Information from the National Library of Medicine

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): NCT06034561


Contacts
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Contact: Graziela S Silva 551138934677 graziela.sasilva@hc.fm.usp.br
Contact: Bruna Moraes, MSc 551126628112 pesquisa.hematologia@hc.fm.usp.br

Locations
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Brazil
Instituto do Cancer do Estado de Sao Paulo Recruiting
São Paulo, SP, Brazil, 01246000
Contact: Wellington F Silva, MD PhD    551138944677    wellington.fernandes@hc.fm.usp.br   
Sponsors and Collaborators
Instituto do Cancer do Estado de São Paulo
Libbs Farmacêutica LTDA
Investigators
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Principal Investigator: Wellington Silva, MD PhD Instituto do Cancer do Estado de Sao Paulo
More Information
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Responsible Party: Instituto do Cancer do Estado de São Paulo
ClinicalTrials.gov Identifier: NCT06034561    
Other Study ID Numbers: 4009/23
First Posted: September 13, 2023    Key Record Dates
Last Update Posted: April 18, 2024
Last Verified: March 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Instituto do Cancer do Estado de São Paulo:
Acute lymphoblastic leukemia
Bortezomib
Salvage therapy
Bridge therapy
Response rate
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Doxorubicin
Methotrexate
Vincristine
Bortezomib
 Asparaginase
Pegaspargase
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action