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Adjustment of Chemotherapy Duration in Follicular Lymphoma According to Minimal Residual Disease Status (FLMRD)

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ClinicalTrials.gov Identifier: NCT04934930
Recruitment Status : Recruiting
First Posted : June 22, 2021
Last Update Posted : June 22, 2021
Sponsor:
Collaborators:
Rabin Medical Center
Tel-Aviv Sourasky Medical Center
Assuta Ashdod Hospital
Ziv Medical Center
Information provided by (Responsible Party):
Meir Medical Center

Brief Summary:

Follicular lymphoma (FL) is a chronic indolent malignancy, where treatment with 6 cycles of bendamustine obinutuzumab (BO) is highly effective but at a cost of increased adverse events.

Tumor specific DNA can be traced in blood and bone marrow of follicular lymphoma patients even after therapy, and when detected after lymphoma treatment it is referred to as minimal residual disease (MRD).

MRD elimination after effective lymphoma treatment is a marker for deep response and correlates with prolonged remission.

In this study we aim to omit chemotherapy after 4 cycles of treatment in patients achieving MRD elimination after 3 months of therapy, as well as complete metabolic response on positron emission computed tomography (PET-CT), hoping to preserve treatment effectiveness while reducing adverse events.


Condition or disease Intervention/treatment Phase
Follicular Lymphoma Drug: Bendamustin Drug: Obinutuzumab Phase 2

Detailed Description:

Follicular lymphoma (FL) is the second most common type of non-Hodgkin's lymphoma, with an estimated incidence of 3.18 cases per 100000 people a year in the United States The disease is characterized by an indolent behavior, where often treatment is unnecessary at diagnosis, and a "watch & wait" approach is the standard of care for asymptomatic patients. FL is also a highly responsive disease for immuno-chemotherapeutic combinations, although most patients will eventually relapse. Since the disease is incurable & indolent in nature, the therapeutic strategy should aim for disease control, while using treatments with high safety profile in order to minimize the chance for life threatening adverse events.

Therapy with rituximab cyclophosphamide, doxorubicin, vincristine & prednisone (R-CHOP) combination & subsequent rituximab maintenance therapy for 24 months shows excellent results with a median progression free survival (PFS) of above a decade.

The more recent GALLIUM trial has shown that combining the monoclonal antibody obinutuzumab with chemotherapy is even more efficacious compared to rituximab combinations. When different combinations were examined in this trial the best results were achieved with the bendamustine-obinutuzumab (BO) combination with 3 year PFS of 84%. Unfortunately the trial also revealed a downside for this effective combination with higher rate of fatal adverse events among patients receiving 6 cycles of bendamustine combinations.

In patients with acute leukemia evaluation for minimal residual disease (MRD) is a routine procedure, and the nature & length of treatment are guided by MRD status at different time points during therapy.

Among FL patients treated with obinutuzumab-chemotherapy combinations, it has been shown that after 3 cycles of treatment about 90% of patients were MRD negative. In addition MRD negativity at the end of induction in either peripheral blood or bone marrow was found to be associated with improved outcomes in patients with 1st line treatment for FL as well as in the relapsed setting.

These findings raise the possibility for an MRD based treatment approach, where the duration of chemotherapy could be guided by MRD status at mid-induction. Eliminating chemotherapy while continuing immunotherapy after achievement of MRD negativity & complete metabolic remission on PET-CT at mid-induction could reduce treatment toxicity, while potentially preserving efficacy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Prospective multicenter, single arm, phase II study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Adjustment of Chemotherapy Duration in Follicular Lymphoma Patients According to Peripheral Blood or Bone Marrow Minimal Residual Disease Status
Actual Study Start Date : January 29, 2020
Estimated Primary Completion Date : August 1, 2025
Estimated Study Completion Date : August 1, 2025


Arm Intervention/treatment
Experimental: Reduced number of bendamustine cycles in patients with mid-induction MRD negativity
Patients with follicular lymphoma treated with obinutuzumab bendamustine & achieving MRD negativity as well as complete metabolic response on PET-CT at mid-induction would continue obinutuzumab treatment while omitting bendamustin after 4 cycles.
Drug: Bendamustin
Chemotherapy
Other Name: Ribomustin

Drug: Obinutuzumab
Immunotherapy
Other Name: Gazyva




Primary Outcome Measures :
  1. Progression free survival among patients treated with 4 cycles of BO & 2 additional cycles of obinutuzumab. [ Time Frame: Progression free survival will be assessed 24 months after the end of induction. ]
    Progression-free survival is defined as the time from randomization to the earliest event of progression, relapse, or death from any cause. progression-free survival, is assessed by the investigator.


Secondary Outcome Measures :
  1. Progression of disease within 24 months (POD24) [ Time Frame: POD24 will be assessed at 24 months after treatment initiation ]
    POD24 is defined as disease progression or death due to disease progression occurring within 24 months after treatment initiation, as assessed by the investigator.

  2. Overall survival among patients treated with 4 cycles of BO & 2 additional cycles of obinutuzumab. [ Time Frame: Overall survival will be assessed 24 months after the end of induction. ]
    Overall survival is defined as the time from study initiation to death from any cause.

  3. The rate of MRD negativity persistence at 12 months among patients treated with 4 cycles of BO & 2 additional cycles of obinutuzumab. [ Time Frame: Persistence of MRD negativity will be assessed 12 months after study initiation. ]
    MRD will be assessed at mid-induction, end of induction and subsequently every 6 months.

  4. The proportion of adverse events among patients treated with 4 cycles of BO & 2 additional cycles of obinutuzumab. [ Time Frame: The proportion of various adverse events will be assessed until 24 months from the end of induction. ]
    The proportion of various adverse events will be assessed as documented by the investigator.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 and above.
  2. FL grade I-IIIa, according to world health organization (WHO) classification, in patients who were not previously treated with chemotherapy, have a high tumor bulk & an indication for treatment, as defined by the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria.
  3. Eastern Cooperative Oncology Group (ECOG) performance status grade 0-2.
  4. The presence of a molecular marker in bone marrow or peripheral blood for MRD assessment.

Exclusion Criteria:

  1. FL grade IIIb.
  2. HIV infection.
  3. HBsAg positivity.
  4. Active malignancy other than FL
  5. Pregnancy or lactation.

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): NCT04934930


Contacts
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Contact: Uri Abadi, MD 972-9-7472786 uri.abadi@clalit.org.il

Locations
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Israel
Meir medical center Recruiting
Kfar Saba, Israel
Contact: Uri Abadi, MD    972-9-7472786    uri.abadi@clalit.org.il   
Sponsors and Collaborators
Meir Medical Center
Rabin Medical Center
Tel-Aviv Sourasky Medical Center
Assuta Ashdod Hospital
Ziv Medical Center
Investigators
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Principal Investigator: Uri Abadi, MD Meir Medical Center
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Responsible Party: Meir Medical Center
ClinicalTrials.gov Identifier: NCT04934930    
Other Study ID Numbers: MMC-19-0209
First Posted: June 22, 2021    Key Record Dates
Last Update Posted: June 22, 2021
Last Verified: June 2021
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
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Follicular
Neoplasm, Residual
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Neoplastic Processes
Pathologic Processes
Bendamustine Hydrochloride
Obinutuzumab
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological