Phase II Study of Glofitamab With Venetoclax +/- Zanubrutinib in High-risk Mantle-cell Lymphoma

NCT06558604 | Recruiting Phase 2 DMC

• 1 other identifier: GLOASIS
• Study Type: interventional
• Target: 100
• Locations: 2 countries
• Sites: 16

Brief Summary

This open-label, multicenter, three cohorts, phase II study is designed to assess a combination of Zanubrutinib/Venetoclax/Glofitamab or Venetoclax/Glofitamab in high-risk subjects with either first line or R/R Mantle Cell Lymphoma (MCL). Three independent cohorts will be run:

• Cohort A will include subjects with a primary refractory or progressive disease within 24 months from initiation of first line treatment (POD 24).
• Cohort B will be open for subjects with R/R MCL and refractory or progressive to a BTK inhibitor given previously (\>24 months if first line).
• Cohort C will only enrol newly diagnosed and untreated MCL subjects with very high-risk features.

Conditions

Lymphoma, Mantle-Cell

Keywords

POD24; BTKI failure; High risk; 18 to 79 years

Outcome Measures

Primary Outcomes (1)

• PFS at the end of C17 (each cycle is 21 days)

  The primary efficacy endpoint is the PFS at 12 months (end of C17) from first dose of study treatment, in each cohort: Zanubrutinib/Venetoclax/Glofitamab for cohorts A and C, Venetoclax/Glofitamab for cohort B, as determined by imaging central review (Lugano 2014 criteria),

  end of cycle 17 (each cycle is 21 days)

Secondary Outcomes (9)

• Overall Response Rate (ORR) and Complete Response Rate (CRR)

  End of C3 (each cycle is 21 days), end of C6 (each cycle is 21 days), end of C12 (each cycle is 21 days), end of C17 (each cycle is 21 days), end of C26 (each cycle is 21 days))

• PFS at the end of C17 as determined by investigator

  end of cycle 17 (each cycle is 21 days)

• Duration of response (DOR)

  72 months

• Event-free survival (EFS)

  74 months

• Disease Free Survival (DFS)

  74 months

Study Arms (3)

Cohort A - POD24

EXPERIMENTAL

* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Zanubrutinib PO 320 mg total daily dose (QD) From C1D2 continuously until end C35 * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35

Drug: Obinutuzumab; Drug: Glofitamab; Drug: Venetoclax Oral Product

Cohort B - BTKI failure

EXPERIMENTAL

* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35

Drug: Obinutuzumab; Drug: Glofitamab; Drug: Venetoclax Oral Product

Cohort C - first Line

EXPERIMENTAL

* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Zanubrutinib PO 320 mg total daily dose (QD) From C1D2 continuously until end C35 * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35

Drug: Obinutuzumab; Drug: Glofitamab; Drug: Venetoclax Oral Product; Drug: Zanubrutinib Oral Capsule

Interventions

Obinutuzumab DRUG

1000 mg/40mL

Also known as: Gazyvaro

Cohort A - POD24; Cohort B - BTKI failure; Cohort C - first Line

Glofitamab DRUG

10mg/mL

Also known as: Columvi 10 mg

Cohort A - POD24; Cohort B - BTKI failure; Cohort C - first Line

Venetoclax Oral Product DRUG

10mg, 50mg and 100mg tablets

Also known as: Venclyxto

Cohort A - POD24; Cohort B - BTKI failure; Cohort C - first Line

Zanubrutinib Oral Capsule DRUG

80mg capsules

Also known as: Zanubrutinib (BGB-3111)

Cohort C - first Line

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be primary refractory or in progression within 24 months from initiation of first line treatment (POD24 defined as time between D1C1 of the first treatment line and ICF signature)) (including an anti-CD20 combined with chemotherapy). Subject previously exposed to BTK inhibitor at first line is eligible. Subject in failure of CAR-T cell first line is eligible.
• Primary refractory subjects (ie with a progressive disease) to the BTKi and Venetoclax combination will not be eligible.
• Subject previously exposed to Bcl-2 therapy and/or relapsing post CAR-T cell therapy is eligible, except if they presented a progressive disease under BTKi and Venetoclax combination.
• Subject not previously treated for mantle cell lymphoma.
• Subject at high risk of relapse presenting at least two of the following risk factors:
• TP53 mutation, del17p, or p53 expression (IHC) \> 50%,
• blastoïd variant,
• complex karyotype,
• c-myc rearrangement (FISH),
• Ki67≥30%,
• high MIPI score, (or MIPI simplified)
• high MIPI-combined score ((ie high MIPI score + Ki67≥30%): this criterion alone is sufficient.
• Subject must meet all of the following additional criteria to be enrolled in the study for cohort A, B and C:
• Subject is ≥ 18 years and \< 80 years of age at the time of signing the informed consent form (ICF).
• Subject understood and voluntarily signed and dated an informed consent prior to any study-specific assessments/procedures being conducted.

You may not qualify if:

• Subject who meets any of the following criteria will be excluded from enrollment in the study study for cohort A, B and C:
• Proven or previously known CD20 negative status on FFPE IHC at time of MCL relapse or diagnosis.
• For subjects in Cohort A and B: previously refractory to treatment by BTK inhibitor and Bcl-2 therapy combination.
• Any prior therapy with a bispecific antibody targeting CD3 and CD20.
• Current or past history of central nervous system or meningeal involvement by lymphoma.
• Use of any standard or experimental anti-cancer drug therapy including biological agents (e.g. monoclonal antibodies) within 30 days of the start (Day 1) of study treatment, except for BTKi for subjects included in cohort B, that can be pursued until C1D1. and except for topical treatment or hormone treatment if criterion 33 is respected. Corticosteroid treatment ≤ 1 mg/kg/day prednisone or equivalent is allowed within 2 weeks prior to Obinutuzumab infusion.
• LVEF \< 50% as determined by echocardiography or isotopic method.
• Clinically significant cardiovascular disease such as uncontrolled, unstable or symptomatic arrhythmias, unstable angina, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class III (moderate) or Class IV(severe) cardiac disease as defined by the New York Heart Association Functional Classification or Objective Assessment Class C or D cardiac disease. Heart rate-corrected QT interval \> 480 milliseconds based on Fridericia's formula.; History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place; Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements, at screening, showing systolic blood pressure \> 170 mmHg and diastolic blood pressure \> 105 mmHg and/or uncontrolled hypertension with systolic blood pressure\>140mmHg despite a well conduct hypertensive treatment for at least 6 months
• Hemoglobin level \< 8g/dL; Absolute Neutrophil count \<1 G/L (\<0,5G/L if related to lymphoma); Platelets \< 75 G/L (\< 50 G/L if related to lymphoma),
• Major surgery within 28 days before screening.
• Require the use of anticoagulation by warfarin or equivalent vitamin K antagonists (e.g., phenprocoumone)
• Requires treatment with a moderate or a strong CYP3A inhibitor or inducer..
• Vaccinated with live, attenuated vaccines within 4 weeks of enrollment (except COVID vaccine) or anticipation that such a live attenuated vaccine will be required during the study.
• Known hypersensitivity to active substances or to any of the excipients. Or Contraindication to any study treatments.
• Known allergy to all xanthine oxidase inhibitors or rasburicase.

Sponsors & Collaborators

• BeiGene: collaborator
• Hoffmann-La Roche: collaborator
• The Lymphoma Academic Research Organisation: lead

Study Sites (16)

Az Sint-Jan Brugge - Oostende Av

Bruges, Belgium

RECRUITING

Institut Jules Bordet

Brussels, Belgium

RECRUITING

Chu de Liege

Liège, Belgium

RECRUITING

Chu Ucl Namur - Site Godinne

Yvoir, Belgium

RECRUITING

Aphp - Hopital Henri Mondor

Créteil, France

RECRUITING

Chu Dijon Bourgogne

Dijon, France

RECRUITING

Chu de Lille - Hopital Claude Huriez

Lille, France

RECRUITING

Institut Paoli Calmettes

Marseille, France

RECRUITING

Chu de Montpellier

Montpellier, France

RECRUITING

Chu de Nantes

Nantes, France

RECRUITING

Chu Lyon-Sud

Pierre-Bénite, France

RECRUITING

Chu de Reims - Hopital Robert Debre

Reims, France

RECRUITING

Chu Pontchaillou

Rennes, France

RECRUITING

Centre Henri Becquerel

Rouen, France

RECRUITING

Institut Curie

Saint-Cloud, France

RECRUITING

Institut de Cancerologie Strasbourg Europe

Strasbourg, France

RECRUITING

MeSH Terms

Conditions

Lymphoma, Mantle-Cell

Interventions

obinutuzumab; glofitamab; zanubrutinib

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Steven LE GOUILL, Pr

  Institut Curie

  STUDY CHAIR

• Clementine SARKOZY, MD

  Institut Curie

  STUDY CHAIR

• Louise ROULIN, MD

  Hôpital Henri-Mondor - AP-HP

  STUDY CHAIR

• Gilles CROCHET, MD

  CHU Dinant Godinne UCL Namur - YVOIR

  STUDY CHAIR

Central Study Contacts

Julie JULIE ASSEMAT

CONTACT

+33 (4) 27 01 27 51; julie.assemat@lysarc.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 3 cohorts

Study Record Dates

• First Submitted: July 24, 2024
• First Posted: August 16, 2024
• Study Start: February 21, 2025
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): March 1, 2032
• Last Updated: February 11, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

BE (4); FR (12)