Clinical Trial to Evaluate R-COMP Versus R-CHOP in Newly Diagnosed Patients With Non-localised Diffuse Large B-cell Lymphoma (DLBCL)/Follicular Lymphoma Grade IIIb
Clinical Trial to Evaluate R-COMP Versus R-CHOP in Newly Diagnosed Patients With Non-localised Diffuse Large B-cell Lymphoma (DLBCL)/Follicular Lymphoma Grade IIIb
The Phase II study proposed here assesses the hypothesis that replacing doxorubicin by
 Myocet® in the R-CHOP regimen would yield comparable antitumour efficacy with a lower
 cardiotoxicity for first-line treatment in elderly patients with non-localised
 DLBCL/Follicular lymphoma grade IIIb
Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of
 non-Hodgkin's lymphoma (NHL). This is an aggressive lymphoma, with an incidence in Western
 countries estimated at 5-6 cases/100,000 inhabitants/year that increases with age.

 Treatment for patients with DLBCL is currently based on immunochemotherapy, of which the
 R-CHOP regimen, which includes cyclophosphamide, doxorubicin, vincristine and prednisone
 (CHOP) in combination with the anti-CD20 monoclonal antibody rituximab and is administered
 every 21 days for a total of 6-8 cycles, is the most commonly used.

 Cardiotoxicity is one of the undesirable effects that limit the use of anthracyclines, such
 as doxorubicin, as part of the CHOP regimen, which is caused by the formation of complexes
 between ferric ions and the anthracycline within the myocyte. Because of their oxidative
 properties, these complexes are toxic and produce highly reactive free radicals that damage
 the lipid membrane and lead to the cell death of myocytes. Several studies have linked the
 onset of cardiotoxicity with old age, high cumulative doses of doxorubicin, cardiovascular
 risk factors and previous heart disease, among others. Anthracycline-induced cardiotoxicity
 is cumulative and irreversible. Moreover, left ventricular dysfunction is an important late
 effect in patients with aggressive NHL who survive long term and, according to some studies,
 have received doxorubicin at doses higher than 200 mg/m². Cardiotoxicity may be silent or
 subclinical, which is usually detected as a decrease in left ventricular ejection fraction
 (LVEF), or clinical, with varying degrees of congestive heart failure (CHF). Depending on the
 symptoms, cardiotoxicity also differs between acute, subacute, late or chronic. The first is
 manifested at an early stage, usually as arrhythmia, transient ECG changes or pericarditis,
 among others, is usually reversible, is not detrimental to the continuation of treatment and
 is not associated with subacute and late toxicity.

 Chronic cardiotoxicity could be early or late. Early-onset cardiotoxicity occurs within 1
 year after anthracycline treatment and late-onset cardiotoxicity occurs more than 1 year
 after completion of anthracycline treatment. In the latter two, cardiotoxicity is associated
 with the lesion of cardiomyocytes and is therefore considered irreversible. The incidence of
 cardiotoxicity varies among different studies, depending on patient follow-up or the
 definition of cardiotoxicity used (acute, subacute or late).

 In addition to clinical findings, the determination of LVEF or, more recently, the use of
 biomarkers, are the most commonly used methods to diagnose and assess cardiotoxicity.
 Regarding the identification of biomarkers, troponin I and N-terminal fragment of pro-brain
 natriuretic peptide (NT-proBNP) are the most commonly used and investigated in the context of
 clinical studies. The advantages of using biomarkers include their minimally invasive
 identification, which is less expensive than echocardiography, and, unlike radionuclide
 ventriculography, they avoid irradiation of the patient. Furthermore, the interpretation of
 their results does not depend on the observer's experience, thus avoiding interobserver
 variability. Several studies have shown the role of troponins as indicators of early
 anthracycline-induced cardiotoxicity or other chemotherapeutic agents, which are able to
 predict impaired ventricular function and higher incidence of cardiac events in patients with
 elevated values of this marker compared with patients with normal troponin values. Regarding
 the use of brain natriuretic peptides such as NT-proBNP, several studies have shown a
 correlation between persistently high values of this biomarker and impaired heart function
 parameters, in particular LVEF.

 Myocet® (non-pegylated liposomal doxorubicin) is one of the several strategies developed to
 reduce cardiotoxicity and maintain the therapeutic efficacy of the R-CHOP regimen.
 Non-pegylated liposomal doxorubicin has shown a similar efficacy and less cardiotoxicity than
 conventional doxorubicin in the treatment of women with metastatic breast cancer. In
 addition, several studies in patients with NHL have shown similar response rates with
 regimens containing non-pegylated liposomal doxorubicin to those obtained in historical
 controls with conventional doxorubicin, with a low incidence of clinical and subclinical
 cardiovascular events. The treatment is relatively well tolerated, while myelosuppression is
 its most important toxicity.

 Most of these phase I and II studies (with or without rituximab), which assessed Myocet® in
 combination with cyclophosphamide; vincristine and prednisone, showed that it is an active
 treatment in newly diagnosed patients with aggressive NHL.

 100% of the data registered on CRFs will be source data verified. eCRDs will be used in order
 to register the data. Nine monitoring visits per site will be performed.

 First monitoring vistit will be performed when the first patient is included Second
 monitoring visit willb be performed when the third patient is included Third monitoring visit
 will be perforemd when the fifth patient is included Fourth monitoring visit will be
 performed then the last patient finish study treatment One monitoring visit per year will be
 performed during follow-up phase.

 CRO (Dynamic) Standard Operating Procedures will be used to manage the clinical trial.

 Sample size of the study is based on the hypothesis of a LEVF decrease <55% in the 15% of
 patients assigned to R-CHOP treatment group and 5% of patients assigned to R-COMP treatment
 group.

 Categorical variables were show by absolute and relative frequencies, including the
 confidence interval of 95%.

 For the description of the continuous variables will be use the mean, standard deviation,
 median, mode, minimum and maximum, including the total number of valid values.

 In the case of compare subgroups of patients, will be use for quantitative variables
 parametric tests or nonparametric as characteristics of the variables under study. For
 qualitative variables will be use Chi-square test.

 Statistical analysis was planned with the SAS statistical package version 9.1 or later.

 Two interim analysis will be performed when the last patient peforms the end of treatment
 visit and when the last patient performd the 24 months follow-up visit.

 Final analysis will be performed at the end of the study.
Inclusion Criteria:

 -  ≥60 years of age

 -  Histological confirmed DLBCL/follicular lymphoma grade IIIb by WHO classification,
 with any IPI (International Prognostic Index)

 -  Newly diagnosed, with no previous treatment

 -  Non-localised stage, i.e. lymphoma that does not fit into a single radiotherapy field
 (including clinical stage IA with large tumour mass until stage IV) with at least one
 measurable lesion

 -  ECOG performance status 0 to 2

 -  Present appropriate haematologic, liver (ALT or AST < 2.5 ULN ? upper limit of normal)
 and renal functions (creatinine < 2.5 ULN) , unless changes are secondary to lymphoma

 -  LVEF at rest ? 55%, with no documented history of congestive heart failure (CHF),
 serious arrhythmia or acute myocardial infarction

 Exclusion Criteria:

 -  Clinical stage I without large tumour mass or clinical stage IIA with fewer than three
 affected areas (stage-IIB patients are considered suitable, regardless of the number
 of affected areas)

 -  CNS infiltration

 -  Transformed lymphoma, although with no previous treatment, as well as other
 histological subtypes such as mantle cell lymphoma, peripheral T-cell lymphoma and its
 variants and post-transplant lymphoproliferative syndrome

 -  Clinically significant secondary cardiovascular disease

 -  Signs of any severe, acute or chronic and active infection

 -  Concurrent malignancy or history of other neoplasia except basal cell carcinoma (BCC)
 and cervical or breast carcinoma in situ (CIN)

 -  Patients with positive results in the HBV, HIV or HCV RNA tests

 -  Any previous treatment for DLBCL/follicular lymphoma grade IIIb