Efficacy of Upfront and Maintenance Obinutuzumab in Mantle Cell Lymphoma Treated by DHAP and MRD Driven Maintenance

Mantle Cell Lymphoma Clinical Trial

— LyMa101  

Official title:

Phase II Study to Evaluate the Efficacy of Upfront Obinutuzumab in Mantle Cell Lymphoma Patients Treated by DHAP Followed by Autologous Transplantation Plus Obinutuzumab Maintenance Then MRD Driven Maintenance

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02896582
• Other study ID #: LyMa101
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 2016
• Est. completion date: March 2025

Study information

• Verified date: March 2024
• Source: The Lymphoma Academic Research Organisation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a multicentric, single arm phase II trial to evaluate the efficacy of upfront obinutuzumab in mantle cell lymphoma patients treated by Cisplatinum-Cytarabine-Dexamethasone (DHAP) followed by autologous transplantation plus obinutuzumab maintenance then Molecular Residual Disease (MRD) driven maintenance

Description:

Patients will be recruited over 2 years. They must have a histologically proven diagnosis of mantle cell lymphoma, be aged from 18 to 65 years at the time of registration. Patients must be eligible for autologous transplant and not previously treated for their lymphoma at inclusion. Patients will receive 4 cycles of Obinutuzumab (GA101) and Cisplatinum-Cytarabine-Dexamethasone (GA-DHAP) every 21 days followed by Autologous Stem Cell Transplant (ASCT) using a GA101-Carmustine- Etoposide- Cytarabine- Melphalan (GA-BEAM) conditioning regimen plus a Obinutuzumab maintenance for 3 years then a Obinutuzumab maintenance on demand according to MRD status. Stem cells will be collected after cycle 3 and/or 4 of GA-DHAP.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 86
• Est. completion date: March 2025
• Est. primary completion date: March 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age = 18 and age = 65

• Histologically confirmed (according to the World Health Organization (WHO) classification) mantle cell lymphoma. The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cyclin D1 or the t(11;14) translocation.

• Bone marrow aspiration performed at inclusion for MRD analyses

• Eligible for autologous stem cell transplant

• Previously untreated MCL

• Stage Ann Arbor II-IV in need of treatment

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2

• Life expectancy of more than 3 months

• Written informed consent

• Patient affiliated by any social security system

Exclusion Criteria:

• Severe cardiac disease: York Heart Association (NYHA) grade 3-4

• Impaired liver (ALanine Amino Transferase (ALAT)/ASparagin Amino Transferase (ASAT) = 2.5 Upper Limit of Normal (ULN), bilirubin = 1.5 ULN), renal (calculated creatinine clearance < 50 ml/min) or other organ function which will interfere with the treatment, if not related to lymphoma.

• History of chronic liver disease

• Hepatic veno-occlusive disease or sinusoidal obstruction syndrome

• Any of the following laboratory abnormalities, if not result of a BM infiltration:

• Absolute Neutrophils Count (ANC) <1,500 /mm3 (1.5 x 109/L)

• Platelet counts < 75,000/mm3 (75 x 109/L)

• Pregnancy/Nursing mothers

• Fertile men or women of childbearing potential unless:

• surgically sterile or = 2 years after the onset of menopause

• willing to use a highly effective contraceptive method

• Patients with a malignancy that has been treated but not with curative intent, unless the malignancy has been in remission without treatment for = 5 years prior to enrollment. Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix are eligible.

• Known seropositivity for Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) or other active infection uncontrolled by treatment.

• Viral infection with hepatitis B virus (HBV) defined as hepatitis B surface antigen (HBsAg) positive and/or Hepatitis B core antibody (anti-HBc) positive Note: Patients who are immune due to hepatitis B vaccination or natural infection (HBs Ag and anti-HBc negative, anti-HBs positive) are eligible. But the patients who are immune due to hepatitis B natural infection should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis reactivation

• Prior history of Progressive Multifocal Leukoencephalopathy (PML)

• Vaccination with a live vaccine a minimum of 28 days prior to inclusion (Prolonged B cell depletion)

• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products

• Psychiatric illness or condition which could interfere with their ability to understand the requirements of the study.

• Person deprived of his/her liberty by a judicial or administrative decision

• Person hospitalized without consent

• Adult person under legal protection

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma

Intervention

Drug:
• Obinutuzumab
1000 mg D1, D8, D15 in GA-DHAP 1000 mg D-8 in GA-BEAM 1000 mg every 2 months for 3 years then every month if MRD+
• Dexamethasone
40 mg D1 to D4 in GA-DHAP
• Aracytine
2g/m² D1 & D2 in GA-DHAP 400 mg/m² D-6 to -3 in GA-BEAM
• Cisplatinum
100 mg/m² D1 in GA-DHAP
• Etoposide
400 mg/m² D-6 to D-3 in GA-BEAM
• Melphalan
140 mg/m² D-2 in GA-BEAM
• Carmustine
300 mg/m² D-7 in GA-BEAM

Locations

Country	Name	City	State
France	CHU d'Amiens	Amiens
France	CHU d'Angers	Angers
France	CH d'Avignon	Avignon
France	CHU de Caen	Caen
France	CHU de Clermont Ferrand	Clermont Ferrand
France	Hopital Henri Mondor	Créteil
France	CHU de Dijon - Hôpital le Bocage	Dijon
France	CHU de Grenoble	Grenoble
France	CHD Vendée	La Roche sur Yon
France	Clinique Victor Hugo	Le Mans
France	CHRU Lille - Hôpital Claude Huriez	Lille
France	CHU Limoges	Limoges
France	CHU Montpellier	Montpellier
France	CHU Nantes	Nantes
France	APHP - Hopital Necker	Paris
France	Hôpital Saint Louis	Paris
France	CH Perpignan	Perpignan
France	CHU de Haut Leveque	Pessac
France	CHU Lyon Sud	Pierre Bénite
France	CHU de Poitiers	Poitiers
France	Centre Hospitalier Annecy-Genevois	Pringy
France	CHU Robert Debré	Reims
France	CHU Pontchaillou	Rennes
France	Centre Henri Becquerel	Rouen
France	Institut de Cancérologie de Loire	Saint priest en Jarez
France	CHU de Strasbourg	Strasbourg
France	I.U.C.T Oncopole	Toulouse
France	CHRU Bretonneau	Tours
France	CHU de Brabois	Vandoeuvre les Nancy
France	Gustave Roussy Cancer Campus	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
The Lymphoma Academic Research Organisation

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Molecular Residual Disease (MRD) in bone marrow after 4 cycles of GA-DHAP	to evaluate the efficacy of upfront Obinutuzumab (GA101) at the molecular level (MRD) in bone marrow after induction in patients with previously untreated Mantle Cell Lymphoma (MCL) treated by DHAP	4 cycles (1 cycle is 21 days)
Secondary	Response according to Cheson 99	Response after 2.5 years of treatment and 3 years of maintenance will be evaluated. Assessment of response will be based on the International Workshop to Standardize Response criteria for Non Hodgkin Lymphoma (NHL) (Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 1999)	5.5 years (2.5 years of treatment and 3 years of maintenance)
Secondary	Overall response rate (ORR)	Response after 2.5 years of treatment and 3 years of maintenance will be evaluated. Assessment of response will be based on the International Workshop to Standardize Response criteria for NHL (Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 1999)	5.5 years (2.5 years of treatment and 3 years of maintenance)
Secondary	Positron Emission Tomography (PET) result	PET result after 2.5 years of treatment and 3 years of maintenance will be evaluated. Assessment of PET will be based on Lugano 2014 criteria (according to Cheson & al. Journal of Clinical Oncology 2015).	5.5 years (2.5 years of treatment and 3 years of maintenance)
Secondary	MRD	Molecular residual disease (MRD) after 2.5 years of treatment and 3 years of maintenance will be evaluated. Assessment of MRD will be based on molecular level in bone marrow (BM) according to the European Mantle Cell Lymphoma network (EU-MCL) guidelines.	5.5 years (2.5 years of treatment and 3 years of maintenance)
Secondary	MRD and after maintenance "on demand"	Molecular residual disease (MRD) after maintenance "on demand" will be evaluated. Assessment of MRD will be based on molecular level in BM according to EU MCL network guidelines.	8.5 years (2.5 years of treatment and 2x3 years of maintenance)
Secondary	Progression Free Survival (PFS)	PFS is defined as the time from inclusion into the study to the first observation of documented disease progression or death due to any cause. If a subject has not progressed or died, PFS will be censored at the time of last visit with adequate assessment.	8.5 years (2.5 years of treatment and 2x3 years of maintenance)
Secondary	Overall survival (OS)	OS will be measured from the date of inclusion to the date of death from any cause. Alive patients will be censored at their last contact date	8.5 years (2.5 years of treatment and 2x3 years of maintenance)
Secondary	Number of patients for whom stemm cell collection will fail	Stem cell collection failure will be evaluated after induction treatment	3 years
Secondary	Duration of MRD negativity	Duration of MRD negativity is defined as the time from the date of attainment the first negative MRD to the date of positive MRD. Duration or MRD negativity would be assessed for patients with at least one MRD negativity and as survival endpoint.	8.5 years (2.5 years of treatment and 2x3 years of maintenance)
Secondary	Treatment duration		9 years
Secondary	Average dose		9 years
Secondary	Number of premature treatment discontinuation		9 years
Secondary	Frequency of premature treatment discontinuation		9 years
Secondary	Number of study discontinuation		9 years
Secondary	Frequency of study discontinuation		9 years
Secondary	Number of adverse events		9 years