Efficacy of Upfront and Maintenance Obinutuzumab in Mantle Cell Lymphoma Treated by DHAP and MRD Driven Maintenance
- Conditions
- Interventions
- Registration Number
- NCT02896582
- Lead Sponsor
- The Lymphoma Academic Research Organisation
- Brief 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
- Detailed 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-Cytar...
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 86
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Induction - ASCT - maintenance Etoposide Induction : 4 cycles of GA-DHAP every 21 days - Conditioning regimen and ASCT: GA-BEAM + Autologous transplantation - Maintenance : Obinutuzumab every 2 months for 3 years then every month for patients with positive MRD Induction - ASCT - maintenance Obinutuzumab Induction : 4 cycles of GA-DHAP every 21 days - Conditioning regimen and ASCT: GA-BEAM + Autologous transplantation - Maintenance : Obinutuzumab every 2 months for 3 years then every month for patients with positive MRD Induction - ASCT - maintenance Dexamethasone Induction : 4 cycles of GA-DHAP every 21 days - Conditioning regimen and ASCT: GA-BEAM + Autologous transplantation - Maintenance : Obinutuzumab every 2 months for 3 years then every month for patients with positive MRD Induction - ASCT - maintenance Aracytine Induction : 4 cycles of GA-DHAP every 21 days - Conditioning regimen and ASCT: GA-BEAM + Autologous transplantation - Maintenance : Obinutuzumab every 2 months for 3 years then every month for patients with positive MRD Induction - ASCT - maintenance Cisplatinum Induction : 4 cycles of GA-DHAP every 21 days - Conditioning regimen and ASCT: GA-BEAM + Autologous transplantation - Maintenance : Obinutuzumab every 2 months for 3 years then every month for patients with positive MRD Induction - ASCT - maintenance Melphalan Induction : 4 cycles of GA-DHAP every 21 days - Conditioning regimen and ASCT: GA-BEAM + Autologous transplantation - Maintenance : Obinutuzumab every 2 months for 3 years then every month for patients with positive MRD Induction - ASCT - maintenance Carmustine Induction : 4 cycles of GA-DHAP every 21 days - Conditioning regimen and ASCT: GA-BEAM + Autologous transplantation - Maintenance : Obinutuzumab every 2 months for 3 years then every month for patients with positive MRD
- Primary Outcome Measures
Name Time Method Molecular Residual Disease (MRD) in bone marrow after 4 cycles of GA-DHAP 4 cycles (1 cycle is 21 days) 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
- Secondary Outcome Measures
Name Time Method Response according to Cheson 99 5.5 years (2.5 years of treatment and 3 years of maintenance) 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)
Frequency of premature treatment discontinuation 9 years Number of adverse events 9 years Overall response rate (ORR) 5.5 years (2.5 years of treatment and 3 years of maintenance) 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)
Positron Emission Tomography (PET) result 5.5 years (2.5 years of treatment and 3 years of maintenance) 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).
Treatment duration 9 years MRD and after maintenance "on demand" 8.5 years (2.5 years of treatment and 2x3 years of maintenance) 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.
MRD 5.5 years (2.5 years of treatment and 3 years of maintenance) 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.
Progression Free Survival (PFS) 8.5 years (2.5 years of treatment and 2x3 years of maintenance) 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.
Overall survival (OS) 8.5 years (2.5 years of treatment and 2x3 years of maintenance) 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
Number of patients for whom stemm cell collection will fail 3 years Stem cell collection failure will be evaluated after induction treatment
Average dose 9 years Number of premature treatment discontinuation 9 years Number of study discontinuation 9 years Frequency of study discontinuation 9 years Duration of MRD negativity 8.5 years (2.5 years of treatment and 2x3 years of maintenance) 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.
Trial Locations
- Locations (30)
CHU d'Angers
🇫🇷Angers, France
CHU d'Amiens
🇫🇷Amiens, France
CH d'Avignon
🇫🇷Avignon, France
CHU de Dijon - Hôpital le Bocage
🇫🇷Dijon, France
CHU de Caen
🇫🇷Caen, France
CHU de Clermont Ferrand
🇫🇷Clermont Ferrand, France
Clinique Victor Hugo
🇫🇷Le Mans, France
CHU Limoges
🇫🇷Limoges, France
CHU Nantes
🇫🇷Nantes, France
Hôpital Saint Louis
🇫🇷Paris, France
APHP - Hopital Necker
🇫🇷Paris, France
CH Perpignan
🇫🇷Perpignan, France
CHU de Haut Leveque
🇫🇷Pessac, France
CHU Lyon Sud
🇫🇷Pierre Bénite, France
Centre Hospitalier Annecy-Genevois
🇫🇷Pringy, France
CHU de Poitiers
🇫🇷Poitiers, France
CHU Robert Debré
🇫🇷Reims, France
CHU de Strasbourg
🇫🇷Strasbourg, France
Institut de Cancérologie de Loire
🇫🇷Saint priest en Jarez, France
CHU Pontchaillou
🇫🇷Rennes, France
Centre Henri Becquerel
🇫🇷Rouen, France
CHRU Bretonneau
🇫🇷Tours, France
I.U.C.T Oncopole
🇫🇷Toulouse, France
CHD Vendée
🇫🇷La Roche sur Yon, France
CHU de Grenoble
🇫🇷Grenoble, France
Hopital Henri Mondor
🇫🇷Créteil, France
CHRU Lille - Hôpital Claude Huriez
🇫🇷Lille, France
CHU Montpellier
🇫🇷Montpellier, France
CHU de Brabois
🇫🇷Vandoeuvre les Nancy, France
Gustave Roussy Cancer Campus
🇫🇷Villejuif, France