A phase II trial of belimumab in combination with rituximab/venetoclax in patients with refractory or relapsed chronic lymphocytic leukemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Tuebingen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

19 Jan 2022 → 12 Nov 2025

Decision date (initial)

2024-07-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

GlaxoSmithKline

External identifiers

EU CT number

2024-511474-68-00

EudraCT number

2020-002622-87

ClinicalTrials.gov

NCT05069051

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To assess efficacy (MRD response) of belimumab in combination with rituximab/venetoclax in CLL compared to treatment with rituximab/venetoclax alone.

Secondary objectives 7

1. To assess safety of belimumab and rituximab/venetoclax in patients with relapsed or refractory CLL
2. To evaluate overall response rate (ORR)
3. To evaluate progression free survival (PFS)
4. To evaluate overall survival (OS)
5. To assess further efficacy markers of belimumab in combination with rituximab/venetoclax in CLL compared to control
6. To evaluate duration of response (DOR)
7. Pharmacokinetics of belimumab in CLL patients

Conditions and MedDRA coding

refractory or relapsed chronic lymphocytic leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Male or female ≥18 years of age.
2. Diagnosis of CLL/SLL established according to iwCLL criteria
3. Refractory or relapsed CLL that warrants treatment (according to modified criteria for initiation of therapy (Hallek et al., 2018))
4. CLL relapsing after any line of treatment that included radiotherapy, chemotherapy, immunotherapy, or small molecules. Patients who relapse after a previous therapy with venetoclax can be included in the study in case of a late relapse (i.e. >18 months after venetoclax was discontinued.
5. Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, or small molecules) for the treatment of CLL ≥2 weeks before study treatment excluding systemic corticosteroids for symptomatic control.
6. All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before treatment (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity [Grade 1 or 2 permitted], or bone marrow parameters [any of Grade 1, 2, 3, or 4 permitted]).
7. Required baseline laboratory data (within 4 weeks prior to treatment)
8. Negative serological Hepatitis B and C test or negative PCR in case of positive serological test without evidence of an active infection, negative HIV test within 6 weeks prior to treatment.
9. Written informed consent of the subject
10. Eastern Cooperative Oncology Group [ECOG] < 3.

Exclusion criteria 22

1. (Suspicion of) transformation of CLL (i.e. Richter’s transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
2. Early relapse (i.e <18 months) after any line of treatment that included venetoclax.
3. IgG < 4 g/L under substitution of immunoglobulins
4. Malignancies other than CLL currently requiring systemic therapies
5. Evidence of active systemic bacterial (e.g. tuberculosis), fungal, or viral infection (e.g., CMV) at the time of initiation of therapy.
6. Confirmed progressive multifocal leukencephalopathy (PML)
7. Known history of drug-induced liver injury (DILI), chronic/active hepatitis C (HCV), chronic/active hepatitis B (HBV).
8. Requirement of therapy with strong CYP3A4 inhibitors/ inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin Kantagonists
9. Active inflammatory bowel disease.
10. History of prior allogeneic bone marrow or organ transplantation.
11. Ongoing immunosuppressive therapy. Subjects may use topical, enteric, or inhaled corticosteroids as therapy for comorbidities and systemic steroids for autoimmune anemia and/or thrombocytopenia. Ongoing use of low-dose systemic corticosteroids (≤5 mg/day of methylprednisolone or equivalent) for rheumatologic conditions is permitted.
12. History of primary immunodeficiency
13. Concurrent participation in another therapeutic clinical trial.
14. History of serious suicide risk including any suicidal behaviour in the last 6 months
15. Live vaccination 30 days prior to treatment.
16. Hypersensitivity known from medical history to one of the drugs used or their ingredients or to drugs with a similar chemical structure
17. Simultaneous participation in another interventional clinical trial (including within the last 4 weeks before inclusion)
18. Addictions or other illnesses that do not allow the person concerned to assess the nature and extent of the clinical trial and its possible consequences
19. Pregnant or breastfeeding women
20. Women of childbearing potential, except women who meet the following criteria: A.) post-menopausal (12 months natural amenorrhoea or 6 months amenorrhoea with serum FSH > 40 U/ml) B.) postoperative (6 weeks after bilateral ovarectomy with or without hysterectomy) C.) regular and correct use of a contraceptive method with a Pearl Index < 1% per year, which will have to be continued for up to four months after the discontinuation of the study drug D.) sexual abstinence E.) Vasectomy of the partner
21. Male subjects who are able to father a child, except men who meet the following criteria: a. willingness to abstain from heterosexual intercourse or use a protocol-recommended method contraception from the screening visit throughout the study treatment period and for four months following the last dose of study drug b. refrain from sperm donation from screening visit throughout the study treatment period and for 90 days following the last dose of study drug.
22. Indications that the subject is unlikely to adhere to the protocol (e.g., lack of compliance)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by flow cytometry at EOI

Secondary endpoints 12

1. Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) through EOT
2. Frequency and severity of adverse events (AEs) and serious adverse events (SAEs) through EOS
3. Incidence of suicidal behavior, as determined by Columbia-Suicide Severity Rating Scale (CSSRS)
4. Number and percentage of overall response rate (ORR) according to iwCLL criteria: PR, CR, and CRi at EOT, as assessed by the investigator at EOI and EOT
5. DOR status as time from best ORR of CR, CRi, or PR until progression
6. Negativity rate of MRD in PB and BM measured by flow cytometry at EOI, every 3 months during maintenance therapy and at EOS
7. TTNT as time from d1 to next other CLL treatment
8. Overall and progression free survival
9. Overall and progression free survival of patients with 17p deletion
10. Absolute changes in number and percentage of subjects in lymphocyte subset counts (B, T, NK cells) on day28, d1 of each cycle, EOI and thereafter every 4 weeks until EOT from baseline.
11. Pharmacokinetics of belimumab as assessed as follows: o Observed belimumab concentration at c1d1, EOI and EOT
12. Overall quality of life scores (EORTC QLQ C-30) until EOS

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Tuebingen AöR

Sponsor organisation

Universitaetsklinikum Tuebingen AöR

Address

Otfried-Mueller-Strasse 10, Nordstadt Nordstadt

City

Tuebingen

Postcode

72076

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

KKE Translationale Immunologie, Universitaetsklinikum Tuebingen

Public contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

KKE Translationale Immunologie, Universitaetsklinikum Tuebingen

Locations

1 EU/EEA country · 2 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 5 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