Study of Pixantrone in CD20+ Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the efficacy of Pixantrone with rituximab, ifosfamide and etoposide as measured by the overall metabolic response rate after 2 cycles of treatment or at permanent treatment discontinuation.

Official Title
-----------------
A Multicentre, Phase II, Open Label, Single Arm Study of Pixantrone in Patients With CD20-positive Relapsed or Refractory Aggressive Non-Hodgkin Lymphoma Treated With Rituximab, Ifosfamide and Etoposide.

Conditions
-----------------
Aggressive Non-Hodgkin Lymphoma

Intervention / Treatment
-----------------
* Drug: Pixantrone
* Other: Ifosfamide
* Other: Etoposide
* Other: Rituximab
* Procedure: Transplant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven CD20+ aggressive non-Hodgkin lymphoma (diffuse large B-cell lymphoma (DLBCL), de novo or transformed DLBCL from previously untreated low grade non-Hodgkin lymphoma or grade 3b follicular lymphoma) as per the World Health Organization (WHO) 2016 criteria Relapsed or refractory disease, defined as follows: Patients eligible for ASCT who failed to achieve a Complete Response (CR) after at least one salvage therapy (eg, Rituximab-Etoposide- Methylprednisolone - Cytarabine - Cisplatin (R-ESHAP) or Rituximab- Dexamethasone- High-dose Cytarabine - Cisplatin (R-DHAP), patients who were previously refractory to Rituximab-Ifosfamide-Cytarabine-Etoposide (R-ICE) (stable disease or progressive disease) are not eligible to the study) Or patients in first relapse after Autologous Stem Cell Transplant (ASCT) Or patients not eligible for ASCT who failed to achieve a CR after at least one prior treatment (and no more than 4 previous lines) or in relapse after at least one prior treatment (and no more than 4 previous lines). Age > or =18 years Eastern Cooperative Oncology Group (ECOG) performance status < or = 2 Subjects must have evaluable disease based on positron emission tomography (PET-CT) scan Minimum life expectancy of 6 months Signed written informed consent Patient covered by any social security system Men must agree to use a barrier method of contraception during the treatment period and until 6 months after the last dose of chemotherapy Women of childbearing potential must agree to use an adequate method of contraception, such as oral contraceptives, intrauterine device, or barrier method of contraception during the treatment period and until 12 months after the last dose of chemotherapy Exclusion Criteria: Any other histological type of lymphoma (Burkitt lymphoma, mantle-cell lymphoma…) Any history of previously treated indolent non-Hodgkin lymphoma Symptomatic central nervous system or meningeal involvement by the lymphoma Contraindication to any drug contained in the Pixantrone with rituximab, ifosfamide and etoposide regimen Treatment with any investigational drug within 28 days before the first study drug administration Any of the following lab abnormalities unless related to the lymphoma or bone marrow infiltration: Absolute neutrophil count (ANC) < 1.0 G/L Platelet count < 100 G/L Creatinine clearance < 40 mL/min for patients < 70 y, or creatinine clearance < 60 mL/min for patients > or = 70 y, by Modification of Diet in Renal Disease (MDRD) method. Total bilirubin level > 1,5 x Upper Limit of Normal (ULN) Serum ASpartate Transaminase (AST) or ALanine Transaminase (ALT)> 2,5x ULN Known Human Immunodeficiency Virus (HIV) positive Active hepatitis C virus (HCV) (Positive HCV serology with positive Polymerase Chain Reaction (PCR) for HCV RNA) Active hepatitis B (HB) : HBsAg positive HBsAg negative, Ac anti-HBs positive and/or Ac anti-HB core (HBc) positive (Patients who are seropositive due to a history of hepatitis B vaccine are eligible. Patients with Ac anti-HBs positive and/or Ac anti-HBc positive and no history of hepatitis B vaccine are eligible only if PCR for HB virus DNA is negative) Cumulative dose of doxorubicine or equivalent > 450mg/m2 Left ventricular ejection fraction (LVEF) < 50% measured by echocardiography or isotopic method Congestive heart failure (any stage from New York Heart Association (NYHA) classification) Uncontrolled arterial hypertension Severe rhythmic heart disease Uncontrolled ischemic heart disease, including patients with stable angina Significant valvular heart disease History of a myocardial infarction within 6 months prior to enrolment Pregnant or lactating females Prior history of malignancies with the exception of non-melanoma skin tumors (basal cell or squamous cell carcinoma) or in situ cervical carcinoma Any serious active disease or co-morbid medical condition according to the investigator's decision Adult person unable to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness Use of any standard or experimental anti-cancer drug therapy within 28 days before the first study drug administration Use of corticosteroids prior to baseline PET-CT 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Pixantrone plus rituximab, ifosfamide and etoposide. | Drug: Pixantrone<br>* 6 cycles - dose = 80mg/m²<br>* Other names: Pixuvri;Other: Ifosfamide<br>* 6 cycles - 1500 mg/m2<br>* Other names: Holoxan;Other: Etoposide<br>* 6 cycles - 150 mg/m2<br>* Other names: Vepeside;Other: Rituximab<br>* 6 cycles - 375 mg/m2<br>* Other names: Mabthera;Procedure: Transplant<br>* after 2 or 6 cycles<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Metabolic Response rate (OMR) according to local investigator | by local investigator according to Lugano classification 2014 | After 42 days of treatment (2 cycles) or at permanent treatment discontinuation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Metabolic Response rate (CMR) according to local investigator | according to local investigator | After 42 days of treatment (2 cycles of 21 days) or at permanent treatment discontinuation. | 
| Overall Metabolic Response rate (OMR) according to central review | according to local investigator | After 42 days of treatment (2 cycles of 21 days) or at permanent treatment discontinuation. | 
| Complete Metabolic Response rate (CMR) according to central review | according to local investigator | After 42 days of treatment (2 cycles of 21 days) or at permanent treatment discontinuation. | 
| Number of Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | After 42 or 126 days of treatment (2 or 6 cycles of 21 days) or at permanent treatment discontinuation. | 
| Number of patients for whom Partial Metabolic Response (PMR) is transformed into CMR |  | After 42 days of treatment (2 cycles of 21 days) or at permanent treatment discontinuation. | 
| Rate of ASCT | Number of patients who perform an ASCT out of total number of patients | After 42 days of treatment (2 cycles of 21 days) or at permanent treatment discontinuation. | 
| Success of stem cell collection after treatment | Rate of successful stem cell collection | After 42 days of treatment (2 cycles of 21 days) or at permanent treatment discontinuation. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diffuse Large B-Cell Lymphoma (DLBCL), relapsed or refractory