Overview
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)
Description
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10-4), orelabrutinib will be withdrawn and participants will turn to follow-up (efficacy assessment and MRD test will be performed according to the follow-up plan); if BM MRD is positive, treatment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.
Eligibility
Inclusion Criteria:
- Age between 18 to 65 years old for both gender.
- Patients have a confirmed diagnosis of CD20-positive chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) and meet criteria to initiate first-line treatment per International Workshop on CLL Working Group (IWCLL) 2018 guidelines
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- At least one measurable disease detected by enhanced computerized tomography (CT) or magnetic resonance imaging (MRI). At least one lymph node with the longest axis >=1.5cm and one measurable vertical dimension.
- With life expectancy > 6 months.
- Patients must meet the following laboratory examination criteria during 14 days before
- entry
Serum bilirubin <1.5 Upper Limit of Normal (ULN), other than gilbert syndrome (defined as
unconjugated bilirubin>80%); Aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) ≤2.5 ULN.
Absolute neutrophil count (ANC)≥0.75×109/L and Platelets≥50×109/L (patients without
exposure to G-CSF or blood transfusion within 7 days and no exposure to )
Exclusion Criteria:
1. Cumulative illness rating scale (CIRS) > 6.
2. Creatinine clearance rate (Ccr) <70 ml/min calculated by Cockcroft-Gault formula or by
24-hour urine analysis.
3. Patients diagnosed as other malignancy except lymphoma, except patients with curative
intent and with no known active disease present for ≥ 5 years before the first dose of
study drug and felt to be at low risk for recurrence by treating physician.
4. Patients with known central nervous system involvement.
5. Patients with progressive multifocal leukoencephalopathy (PML).
6. Patients with history of Richter's Syndrome or suspected Richter's Syndrome.
7. Uncontrolled autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura, e.g.
persistent decreasing hemoglobin or platelet count requiring steroid therapy 4 weeks
before initiation of study.
8. Prior exposure to systemic therapy for CLL/SLL (except for incomplete treatment
regimens fewer than 2 weeks such as antitumor steroid therapy).
9. Prior exposure to live vaccines, immunotherapy or other investigational therapeutic
agent within 4 weeks prior to enrollment.
10. Requiring persistent steroid therapy for other non-antitumor purposes. Systemic
steroid drug use within 7 days of first dose of study drug except regional use of
steroid drug.
11. Uncontrolled or other serious cardiovascular disease, including:
1. New York Heart Association (NYHA) class II or higher congestive heart failure,
unstable angina, myocardial infarction, or clinically significant arrhythmia
requiring medical intervention with a left ventricular ejection fraction (LVEF)
<50% at screening 6 months prior to initial administration of the study drug;
2. Primary cardiomyopathy (such as dilated cardiomyopathy, hypertrophic
cardiomyopathy, rhythmogenesis right ventricular cardiomyopathy, restricted
cardiomyopathy, unshaped cardiomyopathy);
3. Clinically significant prolonged QTc interval, or QTc interval >470 ms in female
and >450 ms in male at screening;
4. Uncontrolled hypertension: on the basis of lifestyle improvement, blood pressure
still fails to reach the standard after application of 2 or more kinds of
reasonable, tolerable and full dose antihypertensive drugs (including diuretics),
or 4 or more kinds of antihypertensive drugs until blood pressure can be
effectively controlled.
12. Active bleeding within 2 months prior to screening, or taking anticoagulant/platelet
drugs, or have a definite bleeding tendency in the investigator's opinion (e.g.,
esophageal varices with bleeding risk, local active ulcer lesions);
13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
14. Clinically significant gastrointestinal abnormalities that may affect drug ingestion,
transport, or absorption (e.g., inability to swallow, chronic diarrhea, intestinal
obstruction, etc.), or total gastrectomy.
15. Major surgery within 4 weeks of first dose of study drug. Diagnostic examination is
not regarded as surgery and insertion of vascular access device excluded from the
criteria.
16. Uncontrolled active systemic fungi, bacteria, virus (e.g. CMV DNA positive by PCR
analysis) or other infections (defined as showing persistent symptoms of infection and
no improvement although appropriate antibiotics or other treatment have been applied),
or requiring intravenous (IV) antibiotics administration.
17. Known human immunodeficiency virus (HIV) infection, or active hepatitis B or C
infection (positive results from PCR analysis).
18. Known hypersensitivity to Orelabrutinib, Fludarabine, Cyclophosphamide or Obinutuzumab
19. Concurrent treatment with strong or moderate cytochrome P450, family 3, subfamily A
(CYP3A) inhibitors or inducers.
20. Any mental or cognitive impairment that may limit their understanding of informed
consent and compliance with the study.
21. Pregnant and lactating women, or women of childbearing age who are unwilling to use
contraception throughout the study period and within 18 months of the last
administration of obinutuzumab or within 180 days of the last administration of any
other study drug (women who were fertile must have a negative serological pregnancy
test within 14 days prior to initiation of study) Male without surgically sterilized
who are unwilling to use contraception throughout the study period and within 180 days
of the last administration of the study drug.
22. Any life-threatening illness, medical condition, or organ system dysfunction that, in
the investigator's opinion, could compromise the subject's safety or put the study
outcomes at undue risk.