Fixed Duration Treatment With Combined Pirtobrutinib and Short Course Immuno-chemotherapy in Fit Patients With Previously Untreated Symptomatic Chronic Lymphocytic Leukemia (CLL).

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

Conditions

• CLL (Chronic Lymphocytic Leukemia)

Interventions

DRUG

Pirtobrutinib

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

DRUG

Fludarabine

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

DRUG

Cyclophosphamide

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

DRUG

Obinutuzumab

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 & Collaborators

• French Innovative Leukemia Organisation

  lead OTHER

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-09-01

Primary Completion

2028-09-01

Completion

2033-09-01