Clinical trial NCT02896582: Efficacy of Upfront and Maintenance Obinutuzumab in Mantle Cell Lymphoma Treated by DHAP and MRD Driven Maintenance
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Mantle Cell Lymphoma
Lead sponsor: The Lymphoma Academic Research Organisation
Sponsor class: OTHER
First posted: 2016-09-12
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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-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.

Eligibility criteria: 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

Primary outcomes:
measure: Molecular Residual Disease (MRD) in bone marrow after 4 cycles of GA-DHAP
timeFrame: 4 cycles (1 cycle is 21 days)
Secondary outcomes:
measure: Response according to Cheson 99
timeFrame: 5.5 years (2.5 years of treatment and 3 years of maintenance)
measure: Overall response rate (ORR)
timeFrame: 5.5 years (2.5 years of treatment and 3 years of maintenance)
measure: Positron Emission Tomography (PET) result
timeFrame: 5.5 years (2.5 years of treatment and 3 years of maintenance)
measure: MRD
timeFrame: 5.5 years (2.5 years of treatment and 3 years of maintenance)
measure: MRD and after maintenance "on demand"
timeFrame: 8.5 years (2.5 years of treatment and 2x3 years of maintenance)
measure: Progression Free Survival (PFS)
timeFrame: 8.5 years (2.5 years of treatment and 2x3 years of maintenance)
measure: Overall survival (OS)
timeFrame: 8.5 years (2.5 years of treatment and 2x3 years of maintenance)
measure: Number of patients for whom stemm cell collection will fail
timeFrame: 3 years
measure: Duration of MRD negativity
timeFrame: 8.5 years (2.5 years of treatment and 2x3 years of maintenance)
measure: Treatment duration
timeFrame: 9 years
measure: Average dose
timeFrame: 9 years
measure: Number of premature treatment discontinuation
timeFrame: 9 years
measure: Frequency of premature treatment discontinuation
timeFrame: 9 years
measure: Number of study discontinuation
timeFrame: 9 years
measure: Frequency of study discontinuation
timeFrame: 9 years
measure: Number of adverse events
timeFrame: 9 years
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU d'Amiens
city: Angers
country: France
facility: CHU d'Angers
city: Avignon
country: France
facility: CH d'Avignon
city: Caen
country: France
facility: CHU de Caen
city: Clermont Ferrand
country: France
facility: CHU de Clermont Ferrand
city: Créteil
country: France
facility: Hopital Henri Mondor
city: Dijon
country: France
facility: CHU de Dijon - Hôpital le Bocage
city: Grenoble
country: France
facility: CHU de Grenoble
city: La Roche sur Yon
country: France
facility: CHD Vendée
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Lille
country: France
facility: CHRU Lille - Hôpital Claude Huriez
city: Limoges
country: France
facility: CHU Limoges
city: Montpellier
country: France
facility: CHU Montpellier
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: APHP - Hopital Necker
city: Perpignan
country: France
facility: CH Perpignan
city: Pessac
country: France
facility: CHU de Haut Leveque
city: Pierre Bénite
country: France
facility: CHU Lyon Sud
city: Poitiers
country: France
facility: CHU de Poitiers
city: Pringy
country: France
facility: Centre Hospitalier Annecy-Genevois
city: Reims
country: France
facility: CHU Robert Debré
city: Rennes
country: France
facility: CHU Pontchaillou
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint priest en Jarez
country: France
facility: Institut de Cancérologie de Loire
city: Strasbourg
country: France
facility: CHU de Strasbourg
city: Toulouse
country: France
facility: I.U.C.T Oncopole
city: Tours
country: France
facility: CHRU Bretonneau
city: Vandoeuvre les Nancy
country: France
facility: CHU de Brabois
city: Villejuif
country: France
facility: Gustave Roussy Cancer Campus
Study officials:
affiliation: Nantes University Hospital
name: Steven Le Gouill, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hopital Necker - Paris
name: Olivier Hermine, Pr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Le Gouill S, Beldi-Ferchiou A, Alcantara M, Cacheux V, Safar V, Burroni B, Guidez S, Gastinne T, Canioni D, Thieblemont C, Maisonneuve H, Bodet-Milin C, Houot R, Oberic L, Bouabdallah K, Bescond C, Damaj G, Jaccard A, Daguindau N, Moreau A, Tilly H, Ribrag V, Delfau-Larue MH, Hermine O, Macintyre E. Molecular response after obinutuzumab plus high-dose cytarabine induction for transplant-eligible patients with untreated mantle cell lymphoma (LyMa-101): a phase 2 trial of the LYSA group. Lancet Haematol. 2020 Nov;7(11):e798-e807. doi: 10.1016/S2352-3026(20)30291-X. Epub 2020 Sep 21.
citation: Bailly C, Carlier T, Berriolo-Riedinger A, Casasnovas O, Gyan E, Meignan M, Moreau A, Burroni B, Djaileb L, Gressin R, Devillers A, Lamy T, Thieblemont C, Hermine O, Kraeber-Bodere F, Le Gouill S, Bodet-Milin C. Prognostic value of FDG-PET in patients with mantle cell lymphoma: results from the LyMa-PET Project. Haematologica. 2020 Jan;105(1):e33-e36. doi: 10.3324/haematol.2019.223016. Epub 2019 Aug 1. No abstract available.