First line treatment with VeNEtoclaX and ibruTinib induction followed by obinutuzumab intenSificaTion Exclusively in CLL/SLL Patients not in complete remission and/or with detectable bone marrow minimal residual disease (NEXT STEP trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

11 Sep 2024 → ongoing

Decision date (initial)

2024-09-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Janssen-Cilag · AbbVie B.V.

External identifiers

EU CT number

2022-502808-72-00

EudraCT number

2019-002528-34

ClinicalTrials.gov

NCT04639362

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To evaluate the efficacy of 6 cycles ibrutinib/obinutuzumab in converting patients who are not in CR or who have detectable MRD on combination ibrutinib and venetoclax in uMRD (BM) CR

Secondary objectives 7

1. To explore the kinetics of CLL clearance on protocol and in follow up within the different compartments (PB, BM, LN) by regular test methods (MRD, PET -CT and BM)
2. To measure the conventional response and outcomes of the combination ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
3. To evaluate prognostic parameters for response on ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
4. To evaluate safety of ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
5. Exploratory: To explore kinetics of CLL clearance on protocol and in follow up within different compartments (PB, BM, LN) by novel test methods (MRD, PET - CT, fine needle aspiration (FNA) of LN)
6. Exploratory: To evaluate the impact on immunity (e.g. expression of CD20 and CXCR4/CD5) of ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
7. Exploratory: To evaluate quality of life (QoL) during and after ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Documented CLL or SLL requiring treatment according to IWCLL criteria, including minimal required markers (CD5/CD19/CD23 triple positive with light chain restriction)
2. WHO performance status 0-3 stage 3 only if attributable to CLL/SLL
3. No prior treatment for CLL/SLL
4. Age at least 18 years
5. Adequate BM function defined as: - Hb > 5 mmol/l or Hb > 8 g/dL. - Absolute neutrophil count (ANC) ≥ 0.75 x 109/L or 750/μL. - Platelet count ≥ 50 x 109/L or 50,000 /μL; Unless directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy.
6. Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 30 l/min (Cockcroft-Gault); Please note: in case eGFR or CrCl is <50ml/min the patient needs to be considered high risk for TLS
7. Adequate liver function as indicated: - Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 x ULN. - Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of nonhepatic origin)
8. Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and activated partial thromboplastin time (aPTT) <1.5 x ULN
9. Negative serological testing for hepatitis B virus (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis C virus (hepatitis C antibody). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative PCR result before enrollment. Those who are PCR positive will be excluded.
10. Ability and willingness to adhere to the study visit schedule and other protocol requirements.
11. Patient is capable of giving informed consent.
12. Written informed consent.

Exclusion criteria 23

1. Transformation of CLL (Richter's transformation)
2. Malignancies other than CLL/SLL currently requiring systemic therapy or not being treated incurative intention before or showing signs of progression after curative treatment
3. Patient with CNS involvement
4. Known allergy to xanthine oxidase inhibitors and/or rasburicase
5. Intolerance of exogenous protein administration
6. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products
7. Active fungal, bacterial, and/or viral infection that requires systemic therapy
8. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.)
9. Patient known to be HIV-positive
10. Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists
11. History of stroke or intracranial hemorrhage within 6 months prior to registration
12. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease) (CTCAE grade IIIIV);
13. Severe pulmonary dysfunction (CTCAE grade III-IV)
14. Patient with Child Pugh C
15. Severe neurological or psychiatric disease (CTCAE grade III-IV);
16. Vaccination with live vaccines within 28 days prior to registration
17. Use of any other experimental drug or therapy within 28 days prior to registration
18. Major surgery within 28 days prior to registration
19. Steroid therapy within 10 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 20 mg of dose equivalents of prednisolone daily to control autoimmune phenomenon's, or replacement/stress corticosteroids
20. Pregnant women and nursing mothers
21. Fertile men or women of childbearing potential unless: (1) surgically sterile or ≥ 2 years after the onset of menopause, and/or (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device, sexual abstinence or barrier method of contraception in conjunction with spermicidal jelly during study treatment and in female patients for 3 months after end of induction treatment and 18 months after end of treatment with obinutuzumab and male patients for 6 months after end of treatment
22. Current participation in other clinical trial;
23. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. BM uMRD CR 3 months after end of intensification with ibrutinib/obinutuzumab in patients who were not in CR or who had detectable MRD on combination ibrutinib and venetoclax.

Secondary endpoints 18

1. BM uMRD CR 9 months after registration 2 in all subjects
2. Best BM MRD level during on protocol
3. MRD level in BM and PB at different time points on protocol and in follow up
4. Best response by IWCLL on protocol
5. Response by IWCLL at different time points
6. Response by Deauville criteria on PET scan at different time points
7. Progression free survival (PFS), defined as time from registration 1 and from registration 2 to progression or death from any cause, whichever comes first
8. Event free survival (EFS), defined as time from registration 1 and from registration 2 to start new CLL treatment, progression or death, whichever comes first
9. Overall survival (OS), defined as time from registration 1 and from registration 2 to death from any cause
10. Treatment free interval (TFI), defined as date of last protocol treatment to start date of first CLL treatment off protocol, or death from any cause whichever comes first
11. Predictive value of prognostic markers at diagnosis on uMRD and ORR by IWCLL and Deauville criteria at end of ibrutinib/venetoclax and ibrutinib/obinutuzumab;
12. CTCAE grade ≥2 toxicities
13. IWCLL hematological grade ≥ 2 toxicities
14. Exploratory: MRD level in BM and PB at different time points on protocol and in follow up by novel techniques
15. Exploratory: Quantification of lesions on 18F-FDG PET-CT at different time points
16. Exploratory: Amount of CLL cells in LN biopsy and FNA
17. Exploratory: Immune cell subsets and function at different time points
18. Exploratory: QoL at different time points on protocol and in follow up

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Sponsor organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015GD

Country

Netherlands

Scientific contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

Dhr. A.P Kater

Public contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

HOVON

Third parties 4

Locations

2 EU/EEA countries · 18 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 17 files

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

Application history

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