Multicentric phase II trial to evaluate the efficacy and safety of Ibrutinib in combination with rituximab in patients with indolent clinical forms of Mantle Cell Lymphoma.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Geltamo

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

13 Jun 2024 → ongoing

Decision date (initial)

2024-06-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-512370-94-00

EudraCT number

2015-004158-17

ClinicalTrials.gov

NCT02682641

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To explore the efficacy of I+R combination as a therapeutic alternative to immuno-chemotherapy (R-CHOP regimen) in indolent forms of MCL by assessing the rate of complete responses achieved at 12 months of treatment.

Secondary objectives 3

1. To evaluate the efficacy of I+R combination along time in terms of secondary endpoints (ORR at 12 months, PFS, response duration, OS, MRD analysis)
2. To determine the safety and tolerability of ibrutinib in combination with rituximab (including evaluation of health-related quality of life (QOL))
3. Biological characterization of indolent forms of MCL and their response to I+R by genomic studies

Conditions and MedDRA coding

Mantle Cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Subjects with confirmed diagnosis of Mantle Cell Lymphoma (World Health Organization Classification, WHO 2008). Classical, small-cell variants and marginal-zone variants can be included.
2. Age 18 years or older.
3. Subjects must not have received any prior therapies (excluding diagnostic splenectomy).
4. Asymptomatic patients.
5. Ann Arbor clinical stages I-IV.
6. Eastern Cooperative Oncology Group (ECOG) performance status <2 (0-1).
7. Subjects with a non-nodal MCL presentation with mainly bone marrow or peripheral blood involvement.
8. Other asymptomatic clinical presentations are acceptable in case of low tumor burden, including nodal MCL with lymph node enlargement ≤ 3 cm in the maximum diameter and with low proliferation index (Ki-67 ≤ 30%).
9. The following laboratory values at screening: ● ● Neutrophil count ≥ 1×10e9/L, Hemoglobin level ≥ 100 g/L or platelet count ≥ 100×10e9/L Transaminases (AST and ALT) ≤ 3 x ULN ●Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin ●Creatinine ≤ 2 x ULN or calculated creatinine clearance ≥ 40 mL/min/1.73m2
10. Stable disease without evidence of clinical progression criteria for at least 3 months. Patients in prolonged therapeutic abstention may be included.
11. Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
12. Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [ß-hCG]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
13. Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

Exclusion criteria 23

1. Aggressive histological variants: blastic and pleomorphic variants (blastoid).
2. Proliferation index measured by Ki-67 > 30%.
3. B-cell monoclonal lymphocytosis with MCL phenotype.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≥2.
5. Presence of B symptoms or any relevant symptoms related to the MCL.
6. Nodal clinical forms with lymph node enlargement > 3 cm (maximum diameter).
7. Cytopenias attributable to MCL: Neutrophil count < 1×10e9/L, Hemoglobin level < 100 g/L or platelet count < 100×10e9/L.
8. Organ dysfunction related to MCL including creatinine level > 2 ULN or altered liver biochemistry (> 3x ULN).
9. Gradual increase in different determinations of serum LDH attributable to MCL that exceeds 20% of the ULN.
10. Known CNS infiltration.
11. Subjects with expected therapy requirement for MCL in a short time (< 3 months).
12. Patients with active hepatitis B or C infection or HIV infection. Positive test results for chronic HBV infection (defined as positive HBsAg serology) or positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing) will be excluded with the following exceptions. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing or antiviral prophylaxis. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
13. Anticoagulation requirement with vitamin K antagonists.
14. Past medical history of stroke or intracranial haemorrhage within 6 months prior to inclusion
15. Required medication with strong CYP3A4/5 inhibitors.
16. Any serious comorbidity that makes the patient unacceptable for receiving the treatment
17. Concomitant or previous malignancies the last 2 years other than basal skin cancer or in situ uterine cervix cancer.
18. Pregnancy or lactation.
19. Major surgery within 4 weeks of inclusion.
20. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
21. Vaccinated with live, attenuated vaccines within 4 weeks of randomization.
22. Uncontrolled systemic infection requiring intravenous (IV) antibiotics.
23. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Rate of complete remission (CR) achieved at 12 months of I+R combination.

Secondary endpoints 5

1. To determine the overall response rate (ORR) at 12 months, Progression free survival (PFS), duration of response (DOR) and overall survival (OS).
2. To determine the rate of negative minimal residual disease (MRD), the time to obtain a molecular response and the median duration of the molecular response in I+R responding patients.
3. Rates of AEs, SAEs, and SUSARs by CTC grade (Version 4.03) during I+R treatment
4. To assess the health-related quality of life (QOL) during treatment.
5. Genomic studies in indolent clinical forms of MCL (IGHV mutational status, DNA copy-number and whole exome sequencing)

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Geltamo

Sponsor organisation

Fundacion Geltamo

Address

Avenida Valdecilla Sn

City

Santander

Postcode

39008

Country

Spain

Scientific contact point

Organisation

Fundacion Geltamo

Contact name

A person designed by the Sponsor

Public contact point

Organisation

Fundacion Geltamo

Contact name

A person designed by the Sponsor

Locations

1 EU/EEA country · 12 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 9 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