LyMa101: Efficacy of Upfront and Maintenance Obinutuzumab in Mantle Cell Lymphoma Treated by DHAP and MRD Driven Maintenance

Sponsor

The Lymphoma Academic Research Organisation (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02896582

Collaborator

(none)

Enrollment

Locations

Arm

101

Anticipated Duration (Months)

2.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Mantle Cell Lymphoma	Drug: Obinutuzumab Drug: Dexamethasone Drug: Aracytine Drug: Cisplatinum Drug: Etoposide Drug: Melphalan Drug: Carmustine	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

86 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 1, 2016

Actual Primary Completion Date :

Mar 1, 2019

Anticipated Study Completion Date :

Mar 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Induction - ASCT - maintenance 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	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+ Other Names: GA GA101 Drug: Dexamethasone 40 mg D1 to D4 in GA-DHAP Drug: Aracytine 2g/m² D1 & D2 in GA-DHAP 400 mg/m² D-6 to -3 in GA-BEAM Other Names: Cytarabine Drug: Cisplatinum 100 mg/m² D1 in GA-DHAP Drug: Etoposide 400 mg/m² D-6 to D-3 in GA-BEAM Drug: Melphalan 140 mg/m² D-2 in GA-BEAM Drug: Carmustine 300 mg/m² D-7 in GA-BEAM Other Names: BiCNU BCNU

Arm

Intervention/Treatment

Experimental: Induction - ASCT - maintenance

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

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+

Other Names:

GA101

Drug: Dexamethasone

40 mg D1 to D4 in GA-DHAP

Drug: Aracytine

2g/m² D1 & D2 in GA-DHAP 400 mg/m² D-6 to -3 in GA-BEAM

Other Names:

Cytarabine

Drug: Cisplatinum

100 mg/m² D1 in GA-DHAP

Drug: Etoposide

400 mg/m² D-6 to D-3 in GA-BEAM

Drug: Melphalan

140 mg/m² D-2 in GA-BEAM

Drug: Carmustine

300 mg/m² D-7 in GA-BEAM

Other Names:

BiCNU

BCNU

Outcome Measures

Primary Outcome Measures

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

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)
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).
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.
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.
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
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.
Treatment duration [9 years]
Average dose [9 years]
Number of premature treatment discontinuation [9 years]
Frequency of premature treatment discontinuation [9 years]
Number of study discontinuation [9 years]
Frequency of study discontinuation [9 years]
Number of adverse events [9 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	CHU d'Amiens	Amiens	France	80480
2	CHU d'Angers	Angers	France	49000
3	CH d'Avignon	Avignon	France	84902
4	CHU de Caen	Caen	France	14033
5	CHU de Clermont Ferrand	Clermont Ferrand	France	63000
6	Hopital Henri Mondor	Créteil	France	94010
7	CHU de Dijon - Hôpital le Bocage	Dijon	France	21034
8	CHU de Grenoble	Grenoble	France	38700
9	CHD Vendée	La Roche sur Yon	France	85925
10	Clinique Victor Hugo	Le Mans	France	72000
11	CHRU Lille - Hôpital Claude Huriez	Lille	France	59037
12	CHU Limoges	Limoges	France	87042
13	CHU Montpellier	Montpellier	France	34295
14	CHU Nantes	Nantes	France	44093
15	Hôpital Saint Louis	Paris	France	75475
16	APHP - Hopital Necker	Paris	France	75743
17	CH Perpignan	Perpignan	France	66046
18	CHU de Haut Leveque	Pessac	France	33604
19	CHU Lyon Sud	Pierre Bénite	France	69130
20	CHU de Poitiers	Poitiers	France	86021
21	Centre Hospitalier Annecy-Genevois	Pringy	France	74374
22	CHU Robert Debré	Reims	France	51092
23	CHU Pontchaillou	Rennes	France	35033
24	Centre Henri Becquerel	Rouen	France	76038
25	Institut de Cancérologie de Loire	Saint priest en Jarez	France	42271
26	CHU de Strasbourg	Strasbourg	France	67091
27	I.U.C.T Oncopole	Toulouse	France	31100
28	CHRU Bretonneau	Tours	France	37044
29	CHU de Brabois	Vandoeuvre les Nancy	France
30	Gustave Roussy Cancer Campus	Villejuif	France	94805