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

Primary Purpose

Mantle Cell Lymphoma

Status
Active
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Obinutuzumab
Dexamethasone
Aracytine
Cisplatinum
Etoposide
Melphalan
Carmustine
Sponsored by
The Lymphoma Academic Research Organisation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mantle Cell Lymphoma

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • CHU d'Amiens
  • CHU d'Angers
  • CH d'Avignon
  • CHU de Caen
  • CHU de Clermont Ferrand
  • Hopital Henri Mondor
  • CHU de Dijon - Hôpital le Bocage
  • CHU de Grenoble
  • CHD Vendée
  • Clinique Victor Hugo
  • CHRU Lille - Hôpital Claude Huriez
  • CHU Limoges
  • CHU Montpellier
  • CHU Nantes
  • Hôpital Saint Louis
  • APHP - Hopital Necker
  • CH Perpignan
  • CHU de Haut Leveque
  • CHU Lyon Sud
  • CHU de Poitiers
  • Centre Hospitalier Annecy-Genevois
  • CHU Robert Debré
  • CHU Pontchaillou
  • Centre Henri Becquerel
  • Institut de Cancérologie de Loire
  • CHU de Strasbourg
  • I.U.C.T Oncopole
  • CHRU Bretonneau
  • CHU de Brabois
  • Gustave Roussy Cancer Campus

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Induction - ASCT - maintenance

Arm Description

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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)
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)
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).
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.
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.
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.
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
Number of patients for whom stemm cell collection will fail
Stem cell collection failure will be evaluated after induction treatment
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.
Treatment duration
Average dose
Number of premature treatment discontinuation
Frequency of premature treatment discontinuation
Number of study discontinuation
Frequency of study discontinuation
Number of adverse events

Full Information

First Posted
September 6, 2016
Last Updated
January 9, 2023
Sponsor
The Lymphoma Academic Research Organisation
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1. Study Identification

Unique Protocol Identification Number
NCT02896582
Brief Title
Efficacy of Upfront and Maintenance Obinutuzumab in Mantle Cell Lymphoma Treated by DHAP and MRD Driven Maintenance
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 2016 (Actual)
Primary Completion Date
March 2019 (Actual)
Study Completion Date
March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The Lymphoma Academic Research Organisation

4. Oversight

Data Monitoring Committee
No

5. 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mantle Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
86 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Induction - ASCT - maintenance
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Obinutuzumab
Other Intervention Name(s)
GA, GA101
Intervention Description
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+
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Intervention Description
40 mg D1 to D4 in GA-DHAP
Intervention Type
Drug
Intervention Name(s)
Aracytine
Other Intervention Name(s)
Cytarabine
Intervention Description
2g/m² D1 & D2 in GA-DHAP 400 mg/m² D-6 to -3 in GA-BEAM
Intervention Type
Drug
Intervention Name(s)
Cisplatinum
Intervention Description
100 mg/m² D1 in GA-DHAP
Intervention Type
Drug
Intervention Name(s)
Etoposide
Intervention Description
400 mg/m² D-6 to D-3 in GA-BEAM
Intervention Type
Drug
Intervention Name(s)
Melphalan
Intervention Description
140 mg/m² D-2 in GA-BEAM
Intervention Type
Drug
Intervention Name(s)
Carmustine
Other Intervention Name(s)
BiCNU, BCNU
Intervention Description
300 mg/m² D-7 in GA-BEAM
Primary Outcome Measure Information:
Title
Molecular Residual Disease (MRD) in bone marrow after 4 cycles of GA-DHAP
Description
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
Time Frame
4 cycles (1 cycle is 21 days)
Secondary Outcome Measure Information:
Title
Response according to Cheson 99
Description
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)
Time Frame
5.5 years (2.5 years of treatment and 3 years of maintenance)
Title
Overall response rate (ORR)
Description
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)
Time Frame
5.5 years (2.5 years of treatment and 3 years of maintenance)
Title
Positron Emission Tomography (PET) result
Description
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).
Time Frame
5.5 years (2.5 years of treatment and 3 years of maintenance)
Title
MRD
Description
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.
Time Frame
5.5 years (2.5 years of treatment and 3 years of maintenance)
Title
MRD and after maintenance "on demand"
Description
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.
Time Frame
8.5 years (2.5 years of treatment and 2x3 years of maintenance)
Title
Progression Free Survival (PFS)
Description
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.
Time Frame
8.5 years (2.5 years of treatment and 2x3 years of maintenance)
Title
Overall survival (OS)
Description
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
Time Frame
8.5 years (2.5 years of treatment and 2x3 years of maintenance)
Title
Number of patients for whom stemm cell collection will fail
Description
Stem cell collection failure will be evaluated after induction treatment
Time Frame
3 years
Title
Duration of MRD negativity
Description
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.
Time Frame
8.5 years (2.5 years of treatment and 2x3 years of maintenance)
Title
Treatment duration
Time Frame
9 years
Title
Average dose
Time Frame
9 years
Title
Number of premature treatment discontinuation
Time Frame
9 years
Title
Frequency of premature treatment discontinuation
Time Frame
9 years
Title
Number of study discontinuation
Time Frame
9 years
Title
Frequency of study discontinuation
Time Frame
9 years
Title
Number of adverse events
Time Frame
9 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Steven Le Gouill, Pr
Organizational Affiliation
Nantes University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Olivier Hermine, Pr
Organizational Affiliation
Hopital Necker - Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU d'Amiens
City
Amiens
ZIP/Postal Code
80480
Country
France
Facility Name
CHU d'Angers
City
Angers
ZIP/Postal Code
49000
Country
France
Facility Name
CH d'Avignon
City
Avignon
ZIP/Postal Code
84902
Country
France
Facility Name
CHU de Caen
City
Caen
ZIP/Postal Code
14033
Country
France
Facility Name
CHU de Clermont Ferrand
City
Clermont Ferrand
ZIP/Postal Code
63000
Country
France
Facility Name
Hopital Henri Mondor
City
Créteil
ZIP/Postal Code
94010
Country
France
Facility Name
CHU de Dijon - Hôpital le Bocage
City
Dijon
ZIP/Postal Code
21034
Country
France
Facility Name
CHU de Grenoble
City
Grenoble
ZIP/Postal Code
38700
Country
France
Facility Name
CHD Vendée
City
La Roche sur Yon
ZIP/Postal Code
85925
Country
France
Facility Name
Clinique Victor Hugo
City
Le Mans
ZIP/Postal Code
72000
Country
France
Facility Name
CHRU Lille - Hôpital Claude Huriez
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
CHU Limoges
City
Limoges
ZIP/Postal Code
87042
Country
France
Facility Name
CHU Montpellier
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
CHU Nantes
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
Hôpital Saint Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Facility Name
APHP - Hopital Necker
City
Paris
ZIP/Postal Code
75743
Country
France
Facility Name
CH Perpignan
City
Perpignan
ZIP/Postal Code
66046
Country
France
Facility Name
CHU de Haut Leveque
City
Pessac
ZIP/Postal Code
33604
Country
France
Facility Name
CHU Lyon Sud
City
Pierre Bénite
ZIP/Postal Code
69130
Country
France
Facility Name
CHU de Poitiers
City
Poitiers
ZIP/Postal Code
86021
Country
France
Facility Name
Centre Hospitalier Annecy-Genevois
City
Pringy
ZIP/Postal Code
74374
Country
France
Facility Name
CHU Robert Debré
City
Reims
ZIP/Postal Code
51092
Country
France
Facility Name
CHU Pontchaillou
City
Rennes
ZIP/Postal Code
35033
Country
France
Facility Name
Centre Henri Becquerel
City
Rouen
ZIP/Postal Code
76038
Country
France
Facility Name
Institut de Cancérologie de Loire
City
Saint priest en Jarez
ZIP/Postal Code
42271
Country
France
Facility Name
CHU de Strasbourg
City
Strasbourg
ZIP/Postal Code
67091
Country
France
Facility Name
I.U.C.T Oncopole
City
Toulouse
ZIP/Postal Code
31100
Country
France
Facility Name
CHRU Bretonneau
City
Tours
ZIP/Postal Code
37044
Country
France
Facility Name
CHU de Brabois
City
Vandoeuvre les Nancy
Country
France
Facility Name
Gustave Roussy Cancer Campus
City
Villejuif
ZIP/Postal Code
94805
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32971036
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.
Results Reference
derived
PubMed Identifier
31371411
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.
Results Reference
derived

Learn more about this trial

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

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