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

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ClinicalTrials.gov Identifier: NCT02896582
Recruitment Status : Active, not recruiting
First Posted : September 12, 2016
Last Update Posted : May 6, 2019
Sponsor:
Information provided by (Responsible Party):
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

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 86 participants
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 : October 2016
Actual Primary Completion Date : March 2019
Estimated Study Completion Date : March 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

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 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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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)

  2. 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)

  3. 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).

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. Number of patients for whom stemm cell collection will fail [ Time Frame: 3 years ]
    Stem cell collection failure will be evaluated after induction treatment

  9. 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.

  10. Treatment duration [ Time Frame: 9 years ]
  11. Average dose [ Time Frame: 9 years ]
  12. Number of premature treatment discontinuation [ Time Frame: 9 years ]
  13. Frequency of premature treatment discontinuation [ Time Frame: 9 years ]
  14. Number of study discontinuation [ Time Frame: 9 years ]
  15. Frequency of study discontinuation [ Time Frame: 9 years ]
  16. Number of adverse events [ Time Frame: 9 years ]


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02896582


Locations
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France
CHU d'Amiens
Amiens, France, 80480
CHU d'Angers
Angers, France, 49000
CH d'Avignon
Avignon, France, 84902
CHU de Caen
Caen, France, 14033
CHU de Clermont Ferrand
Clermont Ferrand, France, 63000
Hopital Henri Mondor
Créteil, France, 94010
CHU de Dijon - Hôpital le Bocage
Dijon, France, 21034
CHU de Grenoble
Grenoble, France, 38700
CHD Vendée
La Roche sur Yon, France, 85925
Clinique Victor Hugo
Le Mans, France, 72000
CHRU Lille - Hôpital Claude Huriez
Lille, France, 59037
CHU Limoges
Limoges, France, 87042
CHU Montpellier
Montpellier, France, 34295
CHU Nantes
Nantes, France, 44093
Hôpital Saint Louis
Paris, France, 75475
APHP - Hopital Necker
Paris, France, 75743
CH Perpignan
Perpignan, France, 66046
CHU de Haut Leveque
Pessac, France, 33604
CHU Lyon Sud
Pierre Bénite, France, 69130
CHU de Poitiers
Poitiers, France, 86021
Centre Hospitalier Annecy-Genevois
Pringy, France, 74374
CHU Robert Debré
Reims, France, 51092
CHU Pontchaillou
Rennes, France, 35033
Centre Henri Becquerel
Rouen, France, 76038
Institut de Cancérologie de Loire
Saint priest en Jarez, France, 42271
CHU de Strasbourg
Strasbourg, France, 67091
I.U.C.T Oncopole
Toulouse, France, 31100
CHRU Bretonneau
Tours, France, 37044
CHU de Brabois
Vandoeuvre les Nancy, France
Gustave Roussy Cancer Campus
Villejuif, France, 94805
Sponsors and Collaborators
The Lymphoma Academic Research Organisation
Investigators
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Principal Investigator: Steven Le Gouill, Pr CHU Nantes
Principal Investigator: Olivier Hermine, Pr Hopital Necker - Paris

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Responsible Party: The Lymphoma Academic Research Organisation
ClinicalTrials.gov Identifier: NCT02896582     History of Changes
Other Study ID Numbers: LyMa101
First Posted: September 12, 2016    Key Record Dates
Last Update Posted: May 6, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Dexamethasone
Etoposide
Melphalan
Obinutuzumab
Carmustine
Cisplatin
Cytarabine
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors