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

• ClinicalTrials.gov Identifier: NCT02896582
• Recruitment Status: Active, not recruiting
• First Posted: September 12, 2016
• Last Update Posted: March 15, 2024
• Sponsor: The Lymphoma Academic Research Organisation
• Information provided by (Responsible Party): The Lymphoma Academic Research Organisation

Tracking Information

• First Submitted Date: September 6, 2016
• First Posted Date: September 12, 2016
• Last Update Posted Date: March 15, 2024
• Actual Study Start Date: October 2016
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 12, 2016)

Molecular Residual Disease (MRD) in bone marrow after 4 cycles of GA-DHAP [ Time Frame: 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

Original Primary Outcome Measures (submitted: September 6, 2016)

MRD in bone marrow after 4 cycles of GA-DHAP [ Time Frame: 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

Current Secondary Outcome Measures (submitted: September 12, 2016)

• Response according to Cheson 99 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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" [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 3 years ]
  Stem cell collection failure will be evaluated after induction treatment
• Duration of MRD negativity [ Time Frame: 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 [ Time Frame: 9 years ]
• Average dose [ Time Frame: 9 years ]
• Number of premature treatment discontinuation [ Time Frame: 9 years ]
• Frequency of premature treatment discontinuation [ Time Frame: 9 years ]
• Number of study discontinuation [ Time Frame: 9 years ]
• Frequency of study discontinuation [ Time Frame: 9 years ]
• Number of adverse events [ Time Frame: 9 years ]

Original Secondary Outcome Measures (submitted: September 6, 2016)

• Response according to Cheson 99 after 3 years of maintenance [ Time Frame: 5.5 years ]
  Response after 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) after 3 years of maintenance [ Time Frame: 5.5 years ]
  Response after 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 after 3 years of maintenance [ Time Frame: 5.5 years ]
  PET result after 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 after 3 years of maintenance [ Time Frame: 5.5 years ]
  Molecular residual disease (MRD) after 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" [ Time Frame: 8.5 years ]
  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) [ Time Frame: 8.5 years ]
  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) [ Time Frame: 8.5 years ]
  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
• Stem cell collection failure [ Time Frame: 3 years ]
  Stem cell collection failure will be evaluated after induction
• Duration of MRD negativity [ Time Frame: 8.5 years ]
  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 [ Time Frame: 9 years ]
• Average dose [ Time Frame: 9 years ]
• Number of premature treatment discontinuation [ Time Frame: 9 years ]
• Frequency of premature treatment discontinuation [ Time Frame: 9 years ]
• Number of study discontinuation [ Time Frame: 9 years ]
• Frequency of study discontinuation [ Time Frame: 9 years ]
• Number of adverse events [ Time Frame: 9 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: 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+
  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 Name: 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

Study Arms

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

Interventions:

• Drug: Obinutuzumab
• Drug: Dexamethasone
• Drug: Aracytine
• Drug: Cisplatinum
• Drug: Etoposide
• Drug: Melphalan
• Drug: Carmustine

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 12, 2019): 86
• Original Estimated Enrollment (submitted: September 6, 2016): 83
• Estimated Study Completion Date: March 2025
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT02896582
• Other Study ID Numbers: LyMa101
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: The Lymphoma Academic Research Organisation
• Original Responsible Party: Same as current
• Current Study Sponsor: The Lymphoma Academic Research Organisation
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Steven Le Gouill, Pr; Nantes University Hospital
• Principal Investigator: Olivier Hermine, Pr; Hopital Necker - Paris

• PRS Account: The Lymphoma Academic Research Organisation
• Verification Date: March 2024