Informations générales (source: ClinicalTrials.gov)
A Phase II, Multicenter, Open-label Study Evaluating Glofitamab in Combination With Venetoclax Plus Zanubrutinib or Venetoclax Alone in Subjects With Untreated or Relapsed/Refractory High-risk Mantle-cell Lymphoma (GLOASIS)
Interventional
Phase 2
The Lymphoma Academic Research Organisation (Voir sur ClinicalTrials)
février 2025
mars 2032
05 avril 2025
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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC RENE HUGUENIN INSTITUT CURIE | 10/04/2025 13:11:53 | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Aphp - Hopital Henri Mondor - Créteil - France | Louise ROULIN, MD | Contact (sur clinicalTrials) | |||
| Centre Henri Becquerel - Rouen - France | Fabrice JARDIN, MD | Contact (sur clinicalTrials) | |||
| Chu de Lille - Hopital Claude Huriez - Lille - France | Franck MORSCHHAUSER, Pr | Contact (sur clinicalTrials) | |||
| Chu de Montpellier - Montpellier - France | Charles HERBEAUX, MD | Contact (sur clinicalTrials) | |||
| Chu de Nantes - Nantes - France | Benoit TESSOULIN, MD | Contact (sur clinicalTrials) | |||
| Chu de Reims - Hopital Robert Debre - Reims - France | Eric DUROT, MD | Contact (sur clinicalTrials) | |||
| Chu Dijon Bourgogne - Dijon - France | Steeve CHEVREUX, MD | Contact (sur clinicalTrials) | |||
| Chu Lyon-Sud - Pierre-Bénite - France | Violaine SAFAR, MD | Contact (sur clinicalTrials) | |||
| Chu Pontchaillou - Rennes - France | Roch HUOT, Pr | Contact (sur clinicalTrials) | |||
| Institut Curie - Saint-Cloud - France | Clémentine SARKOZY, MD | Contact (sur clinicalTrials) | |||
| Institut Curie - Site Saint-Cloud - Saint-Cloud - France | Clémentine SARKOZY, MD | Contact (sur clinicalTrials) | |||
| Institut de Cancerologie Strasbourg Europe - Strasbourg - France | Luc-Matthieu FORNECKER, MD | Contact (sur clinicalTrials) | |||
| Institut Paoli Calmettes - Marseille - France | Noël ROBIN, MD | Contact (sur clinicalTrials) | |||
Critères
Tous
Inclusion Criteria:
In cohort A, subject must meet the following inclusion criteria:
1. 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.
2. Primary refractory subjects (ie with a progressive disease) to the BTKi and
Venetoclax combination will not be eligible.
In cohort B, subject must meet the following inclusion criterion:
3. Subject must be R/R MCL and refractory or progressive to a BTK inhibitor given in a
previous line of treatment (the number of treatment lines is not limited). If first
progression, time from diagnosis (defined as D1C1 of the first treatment line) to
inclusion (defined as the date of ICF signature) must be superior to 24 months.
4. 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.
In cohort C, subject must meet the following inclusion criteria:
5. Subject not previously treated for mantle cell lymphoma.
6. Subject at high risk of relapse presenting at least two of the following risk
factors:
1. TP53 mutation, del17p, or p53 expression (IHC) > 50%,
2. blastoïd variant,
3. complex karyotype,
4. c-myc rearrangement (FISH),
5. Ki67≥30%,
6. high MIPI score, (or MIPI simplified)
7. 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:
7. Subject is ≥ 18 years and < 80 years of age at the time of signing the informed
consent form (ICF).
8. Subject understood and voluntarily signed and dated an informed consent prior to any
study-specific assessments/procedures being conducted.
9. Subject with histologically proven mantle cell lymphoma (latest WHO classification).
The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cyclin
D1 or the t(11;14) translocation. Diagnostic tissue should be available for central
pathology review and ancillary molecular studies.
10. Bi-dimensionally measurable disease defined by at least one single node or tumor
lesion ≥ 1.5 cm assessed by CT scan, or one bi-dimensionally measurable (≥1 cm)
extranodal lesion, as measured on CT scan, and/or clinical examination.
11. Stage II-IV disease,
12. ECOG performance status of 0, 1, 2.
13. Life expectancy of more than 3 months.
14. Adequate renal function as demonstrated by a creatinine clearance > 30 mL/min;
calculated by the Cockcroft Gault formula or MDRD formula.
15. Adequate hepatic function per local laboratory reference range as follow (unless if
due to lymphoma involvement):
1. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5x upper limit
of normal (ULN)
2. Bilirubin < 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
non-hepatic origin. in which case total bilirubin should be < 3 x ULN).
16. Women of childbearing potential (WOCBP) (refer to section 14.7 for more details)
must have negative results for highly effective urine/serum pregnancy test 10-14
days prior to Day 1 of Cycle 1 and within 24 hours prior to day 1 Cycle 1 prior to
initiating study treatment and agree to abstain from becoming pregnant or
breastfeeding during study participation and until at least 18 months after C1 with
Obinutuzumab, or 3 months after the final dose of tocilizumab (if applicable), or 2
months after the final dose of Glofitamab, or or 1 month after the final dose of
Zanubrutinib (if applicable), or 30 days after the final dose of Venetoclax,
whichever is longer. WOCBP agree to remain abstinent (from heterosexual intercourse)
or use two methods of contraception, and to refrain from donating eggs, during the
treatment period and for at least 18 months after the final dose of Obinutuzumab, 3
months after the final dose of tocilizumab (if applicable), 2 months after the final
dose of Glofitamab, 1 month after the final dose of Zanubrutinib (if applicable),
and 30 days after the final dose of Venetoclax (refer to section 14.6).
17. Men of reproductive potential (refer to section 14.6 for more details) agree to
remain abstinent (from heterosexual intercourse) or use effective methods of birth
control with a non-pregnant female partner of childbearing potential or a pregnant
female partner and to refrain from donating sperm, during the treatment period and
for at least 3 months after the final dose of Obinutuzumab, 2 months after the final
dose of Glofitamab, 2 months after the final dose tocilizumab (if applicable), 30
days after the final dose of Venetoclax, 1 week after the final dose of Zanubrutinib
(if applicable).
18. Adequate bone marrow function as defined by:
1. Absolute neutrophil count (ANC) ≥ 1000/mm3, except for subjects with bone
marrow involvement in which ANC must be ≥ 500/mm3.
2. Platelet ≥ 75,000/mm3, except for subjects with bone marrow involvement in
which the platelet count must be ≥ 50,000/mm3 .
19. Subject covered by any social security system (France).
20. Subject who understands and speaks one of the country official languages unless
local regulation authorizes independent translators.
21. Subject with a SARS-COV2 vaccination status in line with local National
guidelines/recommendations (COSV, ANRS MIE).
22. Subject must be willing and able to comply with protocol-mandated hospitalization
upon administration of the first two doses of Glofitamab. Subject must also be
willing to comply with all study-related procedures.
23. Adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1
(hematological toxicities excepted)
-
In cohort A, subject must meet the following inclusion criteria:
1. 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.
2. Primary refractory subjects (ie with a progressive disease) to the BTKi and
Venetoclax combination will not be eligible.
In cohort B, subject must meet the following inclusion criterion:
3. Subject must be R/R MCL and refractory or progressive to a BTK inhibitor given in a
previous line of treatment (the number of treatment lines is not limited). If first
progression, time from diagnosis (defined as D1C1 of the first treatment line) to
inclusion (defined as the date of ICF signature) must be superior to 24 months.
4. 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.
In cohort C, subject must meet the following inclusion criteria:
5. Subject not previously treated for mantle cell lymphoma.
6. Subject at high risk of relapse presenting at least two of the following risk
factors:
1. TP53 mutation, del17p, or p53 expression (IHC) > 50%,
2. blastoïd variant,
3. complex karyotype,
4. c-myc rearrangement (FISH),
5. Ki67≥30%,
6. high MIPI score, (or MIPI simplified)
7. 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:
7. Subject is ≥ 18 years and < 80 years of age at the time of signing the informed
consent form (ICF).
8. Subject understood and voluntarily signed and dated an informed consent prior to any
study-specific assessments/procedures being conducted.
9. Subject with histologically proven mantle cell lymphoma (latest WHO classification).
The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cyclin
D1 or the t(11;14) translocation. Diagnostic tissue should be available for central
pathology review and ancillary molecular studies.
10. Bi-dimensionally measurable disease defined by at least one single node or tumor
lesion ≥ 1.5 cm assessed by CT scan, or one bi-dimensionally measurable (≥1 cm)
extranodal lesion, as measured on CT scan, and/or clinical examination.
11. Stage II-IV disease,
12. ECOG performance status of 0, 1, 2.
13. Life expectancy of more than 3 months.
14. Adequate renal function as demonstrated by a creatinine clearance > 30 mL/min;
calculated by the Cockcroft Gault formula or MDRD formula.
15. Adequate hepatic function per local laboratory reference range as follow (unless if
due to lymphoma involvement):
1. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5x upper limit
of normal (ULN)
2. Bilirubin < 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of
non-hepatic origin. in which case total bilirubin should be < 3 x ULN).
16. Women of childbearing potential (WOCBP) (refer to section 14.7 for more details)
must have negative results for highly effective urine/serum pregnancy test 10-14
days prior to Day 1 of Cycle 1 and within 24 hours prior to day 1 Cycle 1 prior to
initiating study treatment and agree to abstain from becoming pregnant or
breastfeeding during study participation and until at least 18 months after C1 with
Obinutuzumab, or 3 months after the final dose of tocilizumab (if applicable), or 2
months after the final dose of Glofitamab, or or 1 month after the final dose of
Zanubrutinib (if applicable), or 30 days after the final dose of Venetoclax,
whichever is longer. WOCBP agree to remain abstinent (from heterosexual intercourse)
or use two methods of contraception, and to refrain from donating eggs, during the
treatment period and for at least 18 months after the final dose of Obinutuzumab, 3
months after the final dose of tocilizumab (if applicable), 2 months after the final
dose of Glofitamab, 1 month after the final dose of Zanubrutinib (if applicable),
and 30 days after the final dose of Venetoclax (refer to section 14.6).
17. Men of reproductive potential (refer to section 14.6 for more details) agree to
remain abstinent (from heterosexual intercourse) or use effective methods of birth
control with a non-pregnant female partner of childbearing potential or a pregnant
female partner and to refrain from donating sperm, during the treatment period and
for at least 3 months after the final dose of Obinutuzumab, 2 months after the final
dose of Glofitamab, 2 months after the final dose tocilizumab (if applicable), 30
days after the final dose of Venetoclax, 1 week after the final dose of Zanubrutinib
(if applicable).
18. Adequate bone marrow function as defined by:
1. Absolute neutrophil count (ANC) ≥ 1000/mm3, except for subjects with bone
marrow involvement in which ANC must be ≥ 500/mm3.
2. Platelet ≥ 75,000/mm3, except for subjects with bone marrow involvement in
which the platelet count must be ≥ 50,000/mm3 .
19. Subject covered by any social security system (France).
20. Subject who understands and speaks one of the country official languages unless
local regulation authorizes independent translators.
21. Subject with a SARS-COV2 vaccination status in line with local National
guidelines/recommendations (COSV, ANRS MIE).
22. Subject must be willing and able to comply with protocol-mandated hospitalization
upon administration of the first two doses of Glofitamab. Subject must also be
willing to comply with all study-related procedures.
23. Adverse events from prior anti-cancer therapy must have resolved to Grade ≤ 1
(hematological toxicities excepted)
-
Subject who meets any of the following criteria will be excluded from enrollment in the
study study for cohort A, B and C:
1. Proven or previously known CD20 negative status on FFPE IHC at time of MCL relapse
or diagnosis.
2. For subjects in Cohort A and B: previously refractory to treatment by BTK inhibitor
and Bcl-2 therapy combination.
3. Any prior therapy with a bispecific antibody targeting CD3 and CD20.
4. Current or past history of central nervous system or meningeal involvement by
lymphoma.
5. 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 <25 mg/day prednisone or equivalent is allowed
within 2 weeks prior to Obinutuzumab infusion.
6. LVEF < 50% as determined by echocardiography or isotopic method.
7. 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
8. 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),
9. Major surgery within 28 days before screening.
10. Require the use of anticoagulation by warfarin or equivalent vitamin K antagonists
(e.g., phenprocoumone)
11. Requires treatment with a moderate or a strong CYP3A inhibitor or inducer..
12. 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.
13. Known hypersensitivity to active substances or to any of the excipients. Or
Contraindication to any study treatments.
14. Known allergy to all xanthine oxidase inhibitors or rasburicase.
15. Previously documented G6DP deficiency.
16. Severe prior reactions to anti CD20 monoclonal antibodies or prior significant
toxicity (other than thrombocytopenia) with Bcl-2 inhibitor.
17. Prior treatment with systemic immunosuppressive medications (including, but not
limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-tumor necrosis factor agents), within 2 weeks or five half-lives (whichever is
shorter) prior to first dose of study treatment.
18. Unable to swallow capsules or disease significantly affecting gastrointestinal
function such as malabsorption syndrome, resection of the stomach or small bowel,
bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or
complete bowel obstruction.
19. History of severe bleeding disorder such as hemophilia A, hemophilia B, von
Willebrand disease, or history of spontaneous bleeding requiring blood transfusion
or other medical intervention.
20. Current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis,
neurodegenerative disease: or intracranial hemorrhage: Subjects with a history of
stroke or intracranial hemorrhage who have not experienced a stroke or transient
ischemic attack or intracranial hemorrhage within the past 2 years and have no
residual neurologic deficits, as judged by the investigator, are allowed.
21. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) at study enrollment or any major episode
of infection (as evaluated by the investigator) within 4 weeks prior to the first
study treatment.
22. Known Human Immunodeficiency Virus (HIV), for subjects with unknown HIV status, HIV
testing will be performed at screening if required by local regulations.
23. Positive test results for hepatitis C virus (HCV) antibody: Subjects who are
positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
24. Positive test results for hepatitis B virus (HBV) infection (defined as positive
HbsAg serology) Subjects with occult or prior HBV infection (defined as negative
HbsAg and positive HbcAb) may be included if HBV DNA is undetectable, provided that
they are willing to undergo DNA testing on Day 1 of every cycle and every three
months for at least 12 months after the last cycle of study treatment and
appropriate antiviral therapy.
25. Positive SARS-CoV-2 test within 7 days prior to enrollment. Rapid antigen test
result is also acceptable.
26. Documented SARS-CoV-2 infection within 6 months of first study treatment (Cycle 1
Day 1): Subjects may be eligible if they have no persistent respiratory symptoms, no
evidence of lung infiltrates on chest CT, and have a negative PCR during the first
30 days prior to first study treatment (Cycle 1 Day 1)
27. Suspected or latent tuberculosis (confirmed by positive interferon-γ release assay)
28. Known or suspected chronic active Epstein-Barr viral infection or evidence of
positive HTLV1 serology.
29. Any life-threatening illness, medical condition, or organ system dysfunction which,
in the investigator opinion, could compromise the subject's safety, interfere with
the absorption or metabolism of study treatments, or put the study outcomes at undue
risk.
30. Prior allogenic SCT is allowed if no active GVHD and no active immune-suppressive
treatment (to be discussed with the medical monitor).
31. Active autoimmune disease requiring treatment:
1. Subjects with a history of autoimmune-related hypothyroidism on a stable dose
of thyroid-replacement hormone may be eligible.
2. Subjects with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
3. Subjects with a history of autoimmune hepatitis, systemic lupus erythematosus,
inflammatory bowel disease, vascular thrombosis associated with
antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, multiple
sclerosis, or glomerulonephritis will be excluded.
4. Subjects with a history of immune thrombocytopenic purpura, autoimmune
hemolytic anaemia, Guillain-Barré syndrome, myasthenia gravis, myositis
rheumatoid arthritis, vasculitis, or other autoimmune diseases will be excluded
unless they have not required systemic therapy in the last 12 months.
32. Subject with history of confirmed progressive multifocal leukoencephalopathy (PML)
33. Active malignancy other than the one treated in this research. Prior history of
malignancies unless the subject has been free of the disease for ≥ 2 years. However,
subjects with the following history/concurrent conditions are allowed:
1. Basal or squamous cell carcinoma of the skin
2. Carcinoma in situ of the cervix
3. Carcinoma in situ of the breast
4. Incidental histologic finding of prostate cancer (T1a or T1b) using the tumor,
nodes, metastasis [TNM] clinical staging system.
34. Pregnant, planning to become pregnant or lactating WOCBP.
35. Any significant medical conditions, laboratory abnormality or psychiatric illness
likely to interfere with participation or understanding of study requirements
(according to the investigator's decision).
36. Severe or debilitating pulmonary disease, history of interstitial lung disease,
noninfectious pneumonitis, or uncontrolled lung diseases, including but not limited
to pulmonary fibrosis and acute lung diseases.
37. Known or suspected history of HLH unless related to lymphoma.
38. Clinically significant history of cirrhotic liver disease, ongoing, drug-induced
liver injury, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary
cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of
the liver, or portal hypertension.
39. INR or PT > 1.5 x ULN, or Quick percentage < 70% (if Quick percentage used in lieu
of time-based units for reporting PT), in the absence of therapeutic
anticoagulation.
40. aPTT >1.5 x ULN in the absence of therapeutic anticoagulation or a lupus
anticoagulant.
41. Prior solid organ transplantation.
42. Person deprived of his/her liberty by a judicial or administrative decision.
43. Person hospitalized without consent.
44. Adult person under legal protection.
NB: for 42, 43, 44 if there is an individual benefit for such subjects, an Ethics
Committee will have to be informed case by case.
-