Clinical trial NCT04934930: Adjustment of Chemotherapy Duration in Follicular Lymphoma According to Minimal Residual Disease Status
Official title: Adjustment of Chemotherapy Duration in Follicular Lymphoma Patients According to Peripheral Blood or Bone Marrow Minimal Residual Disease Status
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Follicular Lymphoma
Lead sponsor: Meir Medical Center
Sponsor class: OTHER
Collaborators: name: Rabin Medical Center
name: Tel-Aviv Sourasky Medical Center
name: Assuta Ashdod Hospital
name: Ziv Medical Center
First posted: 2021-06-22
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective multicenter, single arm, phase II study
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Progression free survival among patients treated with 4 cycles of BO & 2 additional cycles of obinutuzumab.
timeFrame: Progression free survival will be assessed 24 months after the end of induction.
Secondary outcomes:
measure: Progression of disease within 24 months (POD24)
timeFrame: POD24 will be assessed at 24 months after treatment initiation
measure: Overall survival among patients treated with 4 cycles of BO & 2 additional cycles of obinutuzumab.
timeFrame: Overall survival will be assessed 24 months after the end of induction.
measure: The rate of MRD negativity persistence at 12 months among patients treated with 4 cycles of BO & 2 additional cycles of obinutuzumab.
timeFrame: Persistence of MRD negativity will be assessed 12 months after study initiation.
measure: The proportion of adverse events among patients treated with 4 cycles of BO & 2 additional cycles of obinutuzumab.
timeFrame: The proportion of various adverse events will be assessed until 24 months from the end of induction.
Other outcomes:
Locations:
city: Kfar Saba
country: Israel
facility: Meir medical center
Study officials:
affiliation: Meir Medical Center
name: Uri Abadi, MD
role: PRINCIPAL_INVESTIGATOR
References: