This study is a multi-center, open-label, single-arm, non-randomized phase II clinical study in order to evaluate the safety and efficacy of Orelabrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA-101) (oFCG) in the Treatment of Newly Diagnosed Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL)
Patients eligible for enrollment will receive 7-day lead-in therapy of orelabrutinib 150 mg once daily, followed by 3 cycles of orelabrutinib, fludarabine, cyclophosphamide, and obinutuzumab (oFCG) at 28-day intervals. After 3 cycles, bone marrow (BM) minimal residual disease (MRD) detection and efficacy evaluation (iwCLL2018 guidelines) are conducted. If BM MRD is negative (\<10-4), patients will receive be treated with orelabrutinib plus obinutuzumab in 4-6 cycles; If BM MRD is positive (≥10-4), patients will receive the same regimen in 4-6 cycles as in previous 3 cycles. After 6 cycles of treatment, BM MRD detection and efficacy assessment will be conducted again. If BM MRD is negative (\<10-4), orelabrutinib monotherapy will be administered in 7-12 cycles; If BM MRD is positive (≥10-4), treatment with orelabrutinib plus obinutuzumab will be administered in 7-12 cycles. After 12 cycles of treatment, BM MRD detection and efficacy evaluation will be performed. If BM MRD is negative (\<10-4), orelabrutinib will be withdrawn and participants will turn to follow-up (efficacy assessment and MRD test will be performed according to the follow-up plan); if BM MRD is positive, treatment with orelabrutinib monotherapy will be administered in 13-24 cycles (continued even if BM MRD test was negative). After 24 cycles, if BM MRD is negative, the drug can be stopped and participants turn to follow-up. If BM MRD is positive, treatment can be continued until disease progression or be ceased by investigator due to no benefit from continued treatment, and BM MRD can be tested as planned. The trial is expected to end 36 months after enrollment of the last patient. If the subjects continue to require subsequent treatment with orelabrutinib, the sponsor will coordinate with the manufacturer and continue to provide the monotherapy treatment.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
25
150 mg capsules administered orally once daily (28-day cycles). Until 12 or 24 cycles and following BM undetectable MRD, or disease progression, or intolerant toxicity.
1000 mg administered intravenously once on Day 1, 8, 15 of first cycle and on Day 1 of following cycles for maximal 12 cycles (28-day cycles).
25mg/m2/day administered intravenously on Day 1-3 for every cycle (at most 6 cycles, 28-day cycles).
Department of Haematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital
Nanjin, Jiangsu, China
RECRUITINGBM undetectable MRD rate after 6 cycles
Participants who achieve bone marrow (BM) undetectable Minimal Residue Disease (uMRD) after 6 cycles detecting by four-color flow cytometry with a detection level of 10-4.
Time frame: at the end of 6 cycles(each cycle is 28 days)
BM and PB undetectable MRD ratev after 3, 12, 24 cycles.
participants who achieve BM uMRD (\<10-4) on other important evaluation time-point (e.g. after 3, 12 and 24 cycles) except after 6 cycles. participants who achieve peripheral blood (PB) uMRD (\<10-4) on important evaluation time-point.
Time frame: at the end of 3, 12, 24 cycles(each cycle is 28 days)
Objective Response Rate (ORR)
Response assessed after 3 and 6 cycles and up to approximately 3 years.
Time frame: at the end of 3, 6 cycles and up to approximately 3 years.(each cycle is 28 days)
Complete Remission Rate (CRR)
Response assessed after 3 and 6 cycles and up to approximately 3 years.
Time frame: at the end of 3, 6 cycles and up to approximately 3 years.(each cycle is 28 days)
Duration of Response (DOR)
DOR is defined as duration in days from the data of initial documentation of objective response to the date of first documented evidence of progressive disease (PD) or death from any cause. Response and PD are defined according to iwCLL 2018 guidelines.
Time frame: up to approximately 2, 3 years
Progression Free Survival (PFS)
PFS is defined as duration from the date of enrollment to date of progressive disease, replase, or death from any cause, whichever occurs first. PD are defined according to iwCLL 2018 guidelines.
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250mg/m2/day administered intravenously on Day 1-3 for every cycle (at most 6 cycles, 28-day cycles).
Time frame: up to 3 years
Overall Survival (OS)
OS is defined as the time from the date of enrollment to the date of the participant's death from any cause.
Time frame: up to 3 years
Incidence of adverse events (AEs)
Treatment emergent adverse events (TEAE), severe adverse events (SAEs), adverse events of special interest (AESIs) and therapy-related AEs will be recorded and graded will be summarized by grade according to CTCAE (version 5.0).
Time frame: through study completion, an average of 4 year"