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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Dexamethasone
* Drug: Aracytine
* Drug: Cisplatinum
* Drug: Etoposide
* Drug: Melphalan
* Drug: Carmustine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 4 cycles (1 cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 5.5 years (2.5 years of treatment and 3 years of maintenance) | 
| 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) | 5.5 years (2.5 years of treatment and 3 years of maintenance) | 
| 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). | 5.5 years (2.5 years of treatment and 3 years of maintenance) | 
| 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. | 5.5 years (2.5 years of treatment and 3 years of maintenance) | 
| 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. | 8.5 years (2.5 years of treatment and 2x3 years of maintenance) | 
| 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. | 8.5 years (2.5 years of treatment and 2x3 years of maintenance) | 
| 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 | 8.5 years (2.5 years of treatment and 2x3 years of maintenance) | 
| Number of patients for whom stemm cell collection will fail | Stem cell collection failure will be evaluated after induction treatment | 3 years | 
| 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. | 8.5 years (2.5 years of treatment and 2x3 years of maintenance) | 
| 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 |