A phase 3 multicenter, randomised, prospective, open-label trial of fixed-duration (12 cycles) venetoclax/ obinutuzumab vs. fixed-duration (15 cycles) venetoclax/ pirtobrutinib vs. MRD-guided venetoclax/ pirtobrutinib in patients with previously untreated chronic lymphocytic leukaemia (CLL)/ small lymphocytic lymphoma (SLL) aiming to establish measurement of individual residual disease for adjustment of treatment duration to improve outcomes (CLL18/ MOIRAI)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Of Cologne

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Jun 2025 → ongoing

Decision date (initial)

2025-04-06

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

AbbVie Inc. · F. Hoffmann-La Roche Ltd. · Eli Lilly & Co.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

The primary objective of the study is to compare the efficacy of MRD-guided Venetoclax/Pirtobrutinib vs fixed-duration (15 cycles) Venetoclax/Pirtobrutinib and MRD-guided Venetoclax/Pirtobrutinib vs. fixed-duration (12 cycles) Venetoclax/Obinutuzumab by measuring progression-free survival (PFS) in patients with previously untreated chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL).

Secondary objectives 9

1. To evaluate MRD levels by different types of measurement from different materials at the final restaging (three months after end of treatment) and at selected other time points
2. Overall response rate (ORR) as assessed by iwCLL guidelines at the final restaging (three months after end of treatment) and at selected other time points
3. Complete response (CR) rate as assessed by iwCLL guidelines at the final restaging (three months after end of treatment) and at selected other time points
4. Duration of response (DOR) as assessed by iwCLL guidelines
5. Time to next treatment (TTNT)
6. Treatment-free survival (TFS)
7. Overall survival (OS)
8. Safety and tolerability of MRD-guided Ven-Pirto, fixed-duration Ven-Pirto, and fixed-duration Ven-Obi
9. Best response as assessed by iwCLL guidelines until one year after end of treatment

Conditions and MedDRA coding

small lymphocytic lymphoma (SLL)

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Documented CLL/SLL requiring treatment according to iwCLL criteria with a CLL phenotype cell count >10-2 tracked by flow cytometry at screening.
2. Adequate bone marrow function as indicated by: - an absolute neutrophil count ≥ 1 x 10⁹/l - a hemoglobin value ≥8.0 g/dL without transfusions during the last 7 days unless directly attributable to CLL/SLL (e.g. bone marrow infiltration) and - a platelet count ≥ 25 x 10⁹/l unless due to the CLL/SLL, in this case, platelet count should be ≥ 10.000/µl without transfusion during the last 7 days.
3. Adequate renal function, as indicated by a creatinine clearance ≥30ml/min calculated according to the MDRD-formula or an equally accurate method (e.g. 24 hr. urine collection)
4. Adequate liver function as indicated by: - a total bilirubin≤ 2 x the institutional upper limit of normal (ULN) value, and - AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL/SLL or to Gilbert’s Syndrome.
5. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last dosage of obinutuzumab), negative testing for hepatitis-C (HCV-RNA PCR) and negative HIV test within 6 weeks prior to registration
6. Age ≥ 18 years
7. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status
8. Life expectancy ≥ 6 months
9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.

Exclusion criteria 15

1. Any prior CLL- or SLL-specific therapies, except for corticosteroid treatment administered due to necessary immediate intervention (within the last 10 days before start of study treatment only dose equivalents up to 20 mg prednisolone per day are permitted).
2. Decompensated auto-immune cytopenia (defined as ongoing drop in hemoglobin (AIHA) or in platelets (ITP) in spite of prednisolone and/or intravenous immunoglobulins treatment).
3. (Suspicion of) transformation of CLL/SLL (i.e. Richter`s transformation) or central nervous system (CNS) involvement.
4. (Suspicion of) progressive multifocal leukoencephalopathy (PML).
5. Malignant neoplasm other than CLL/SLL unless in remission and unlikely to adversely impact on patient´s life expectancy, defined as curatively treated non-melanoma skin cancer or other neoplasias treated curatively ≥1 year ago, without signs of progression and not currently requiring systemic therapies (with the exception of ongoing anti-hormonal therapy).
6. Active infection requiring systemic treatment, including HIV, HBV and HCV
7. Increased risk of bleeding, e.g. due to: - known bleeding disorder - anticoagulant therapy with phenprocoumon or other vitamin K antagonists (anticoagulation with a direct oral Xa or thrombin inhibitor (DOAC) or heparin) is permitted) - major surgery ≤4 weeks prior to randomization - stroke or intracranial hemorrhage ≤ 6 months of randomization
8. Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4 or any other life-threatening illness, medical condition or organ system dysfunction that – in the investigator´s opinion - could compromise the patient`s safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tab-lets or impaired resorption in the gastrointestinal tract)
9. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
10. Fertile men or women of childbearing potential unless: - surgically sterile or ≥ 2 years after the onset of menopause, or - willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for the required time period thereafter (at least one and up to 18 months after end of study treatment depending of study drug(s) used, see chapter 2.2.2.1 Known risks relevant with all study drugs).
11. Vaccination with a live vaccine ≤ 28 days prior to registration
12. Use of investigational agents which might interfere with the study drug within 28 days prior to registration
13. Legal incapacity
14. Prisoners or subjects who are institutionalized by regulatory or court order
15. Persons who are in dependence to the sponsor or an investigator

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS)

Secondary endpoints 8

1. Measurable residual disease (MRD) levels by different types of measurement from different materials at final restaging (performed 3 months after end of treatment in all patients - except for patients that show progression of CLL disease or Richter transformation before this point of time - which differs depending on the duration of treatment) and selected other time points during and after treatment
2. Overall response rate (ORR) and complete response (CR) rate at the final restaging and selected other time points
3. Duration of response (DOR)
4. Time to next treatment (TTNT)
5. Treatment-free survival (TFS)
6. Overall survival (OS)
7. Safety parameters: Type, frequency and severity of - adverse events (AEs) - adverse events of particular interest (AEPI)
8. Best response assessed until 1 year after end of treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Of Cologne

Sponsor organisation

University Of Cologne

Address

Albertus-Magnus-Platz 1

City

Cologne

Postcode

50923

Country

Germany

Scientific contact point

Organisation

University Of Cologne

Contact name

Paula Cramer

Public contact point

Organisation

University Of Cologne

Contact name

Paula Cramer

Third parties 25

Locations

14 EU/EEA countries · 158 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 143 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications