CLL (Chronic Lymphocytic Leukemia)
Conditions
Brief summary
The evidence base in support of fixed-duration, first-line approaches in medically fit patients with CLL is clearly strengthening, whether through combining targeted agents with immunochemotherapy or through chemotherapy-free combinations. The long-term PB MRD response rates with the investagators fixed-duration (15-month) immunochemotherapy approach remain the best to date, even compared to the new targeted agent combinations of ibrutinib-venetoclax or obinutuzumab-venetoclax. The investigators' phase 2 ICLL07 trial in previously untreated fit CLL patients with a fixed-duration immunochemotherapy approach (with 4 cycles of FC-obinutuzumab and chemosparing strategy) carries a low risk for short and long term toxicities which still exist, including cardiac toxicities probably related to BTK inhibitors, moreover, two patients experienced treatment related myelodysplastic syndrome or acute myeloid leukemia beyond the end of treatment. Follow-up at 5,5 years from treatment start showed a persistent PB MRD benefit beyond end of treatment, high survival rates, and low long term toxicity with no difference in the durability of MRD response between the mutated and unmutated IGHV patients. The investigators aim to explore the safety and efficacy of a fixed duration strategy combining a new BTK inhibitor with a favorable safety profile and a limited number of ICT courses. The main goals and concerns are: i) to ensure deep response and long lasting MRD ii) to reduce the duration of BTKi exposure and the risk of clonal evolution with the appearance of deleterious mutations iii) to limit the risk of hematopoietic secondary cancers (MDS/AML) by excluding patients in whom clonal hematopoiesis of undetermined potential (CHIP) is detected before inclusion and decreasing the number of courses of chemotherapy to 3 cycles. Moreover, patients with TP53 abnormalities will be excluded with a lower cut off (1% versus 10% in the previous studies) iv) to limit the risk of BTKi toxicity by using a non-covalent BTKi
Interventions
DRUGPirtobrutinib
Pirtobrutinib 200 mg QD should be taken at a consistent time on each day for 15 cycles (C1-C15) for oral use. Dosing is intended to be fixed (i.e., not weight-based or BSA-based). Pirtobrutinib may be taken with food or drink but should be taken as consistently as possible. No fasting is required for pirtobrutinib. Refer to Section 10.1.5 for 10.1.5. for prohibited concomitant medication Patients must keep a daily dosing diary to record dosing compliance of oral study treatment by pirtobrutinib. Late doses (i.e., 4 or more hours after scheduled time) should be noted in the dosing diary. Doses late by more than 6 12 hours should not be made up and recorded in the dosing diary as missed. Reasons should be recorded for any missed dose. Vomiting after dosing should be noted in the dosing diary and a vomited dose should not be redosed or replaced. Patients will continue pirtobrutinib dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation
DRUGFludarabine
All patients will receive 3 cycles of FCO administered at 4 weeks intervals (D1 = D29) from cycles 10, 11 and 12. Fludarabine: 40 mg/m² per os, D2 to D4
DRUGCyclophosphamide
All patients will receive 3 cycles of FCO administered at 4 weeks intervals (D1 = D29) from cycles 10, 11 and 12. Cyclophosphamide: 250 mg/m² per os, D2 to D4
DRUGObinutuzumab
All patients will receive 3 cycles of FCO administered at 4 weeks intervals (D1 = D29) from cycles 10, 11 and 12. Obinutuzumab: 1000 mg at D1, D8, D15 Obinutuzumab could be splited for the cycles 1 (100 mg Day 1 + 900 mg Day 2) according to the bulky disease (risk of infusion rate and tumor lysis syndrome). A premedication including an antihistamine (e.g. dexchlorpheniramine; 5 mg IV) and paracetamol (1000 mg, IV) and methylprednisolone 1 mg/kg IV will be administered 30 min prior to the administration of the obinutuzumab infusion
Sponsors
French Innovative Leukemia Organisation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Immunophenotypically confirmed CLL according to IWCLL 2018 guidelines * Binet stage C or Binet stage A and B with active disease could be considered for inclusion according to IWCLL 20108 for initiation of treatment. * Absence of Del(17p) and TP53 mutation in NGS (cut off 1%) * ECOG performance status 0-2 * CIRS (Cumulative Illness Rating Scale) ≤ 6 * Adequate coagulation: defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin (PT) or (international normalized ratio (INR) not greater than 1.5 x ULN * Calculated creatinine clearance ≥ 30 ml/min according to Cockcroft/Gault Formula: (140 - age) × body weight (kg) × 0.85 (if female) serum creatinine (mg/dL) × 72 * Adequate liver function: * Aspartate aminotransferase (AST)/alanine aminotransferase or (ALT) ≤ 3 × the ULN or ≤ 5 × ULN with documented liver involvement, * Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver involvement and/or Gilbert's Disease" * Adequate hematology values: * absolute neutrophil count ≥ 0.75 x 109/L, * platelet count ≥ 50 x 109/L (accordance to the coordinator if linked to the disease), * Hemoglobin ≥ 80g/L Notes: Hgb and platelets: independent of transfusions within 7 days of Screening assessment. ANC: independent of growth factor support within 7 days of Screening assessment. Criteria must be met on C1D1 without transfusion/G-CSF within 7 days of assessment * Prior vaccination to the SARS-Cov-2 virus and SARS-CoV-2 PCR testing (if clinically indicated) and negative result before study treatment administration at each treatment cycle * The patient is able to take oral medications * Signed written informed consent * Willing or able to participate in all required study evaluations and procedures. * Ability to understand the purpose and risks of the study and to provide a signed and dated informed consent form and authorization to use protected health information (in accordance with national and local subject privacy regulations)
Exclusion criteria
1. Presence of Clonal hematopoiesis of indetermined potential or CHIP (To define patients with CHIP: Presence of a myeloid mutation (whatever the mutation) with a VAF \>2% in the granular fraction 2. Binet stage A without active disease according to IWCLL 20108 criteria 3. Life expectancy \< 6 months 4. Current or past history or presence of clinically relevant disorder affecting the central nervous system (CNS) 5. Patient with history of confirmed progressive multifocal leukoencephalopathy (PML) 6. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: \- Uncontrolled and/or active systemic infection (viral, bacterial or fungal): Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with subjects who are ongoing anti-infective treatment and subjects who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment 1. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded. 2. Subjects who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enrollment. Those who are hepatitis C virus PCR positive will be excluded * Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible. * Active and uncontrolled autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA) (isolated positive DAT is not an
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Peripheral blood with undetectable (<10-4) minimal residual disease at month 24 | month 24 |
Secondary
| Measure | Time frame |
|---|---|
| PB MRD at month 9 and 18 and BM MRD at month 24 | month 9, 18 and 24 |
| Progression free survival (PFS), disease-free survival (DFS), event-free survival (EFS), overall survival (OS) and time to next treatment (TTNT) | End of study |
Outcome results
None listed