FIL Study on ABVD DD-DI as Upfront Therapy in HL.

Fondazione Italiana Linfomi - ETS500 enrolled

Overview

The FIL-Rouge is a randomized, open-label, multicenter, phase III, 2-arm study. The primary objective is to compare efficacy and tolerability of the intensified variant 'dose-dense/dose-intense ABVD' (ABVD DD-DI) with an interim PET response-adapted ABVD program as upfront therapy in advanced-stage classical Hodgkin Lymphoma (HL).

The study is devoted to patients affected with advanced stage (IIB-IV) Hodgkin Lymphoma. The study aims to compare the efficacy of two alternative ABVD-based strategies, the first one (Comparator arm) based on a PET-2-adaptation, the second (Experimental arm) relying on a straight dose- and time-intensified schedule, devoid of any PET-adaptation. In the Comparator arm, the patients will receive two courses of standard ABVD (ABVD-28). Those with a PET-2 negative scan (Deauville Score 1-3) will proceed with additional 4 ABVD courses while those with a PET-2-positive scan (Deauville score 4-5) will be diverted towards a deferred intensification with either escalated BEACOPP or HDT plus ASCR , according to the preference of the Center. In the Experimental arm, patients are treated with three cycles of a dose-dense/dose-intense ABVD (ABVD DD-DI) \[e.g. a modified ABVD including the single escalation of doxorubicin to 35 mg/m2 (70 mg/m2 per cycle) and a three-weekly recycle time for all drugs (e.g. administration of all 4 drugs at days 1 and 11 of each cycle)\]. Those with a progressive disease or non-responder patients according to PET/CT imaging at interim evaluation (after cycle 3) as categorized with Lugano 2014 Classification will be diverted to salvage strategies. The other patients will receive one additional course of ABVD DD-DI followed by two courses of dose-dense three-weekly ABVD (ABVD DD) (e.g. administration of all four drugs at days 1 and 11 of each cycle at the conventional doses, including doxorubicin at 25 mg/m2). In both treatment arms 30 Gy Involved Site Radiotherapy (ISRT) is scheduled for those patients PET-negative (DS=3) with residual tumor rests ≥ 2.5 cm and for PET-positive patients in PR (DS= 4 or 5) regardless of the size of the rests. The single reference dose is 2.0 Gy daily and fractionation is five times per week. Only in the Comparator arm the patients in CR (final score 1-3 according to 5PS by central review panel decision) will receive adjuvant ISRT at the initial bulky site(s) for a total reference dose of 30 Gy in single daily fractions of 2.0 Gy, five times weekly. Blinded independent central reviewing for PET imaging will supervise response categorization at interim and final PET/CT evaluation.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

500

Conditions

Hodgkin Lymphoma

Interventions

DoxorubicinDRUG

Comparator arm: cycle 1-2 (and eventually 3-6): 25 mg/m2 i.v. days 1,15. Experimental arm: Cycles 1 to 4: 35 mg/m2 i.v. days 1,11. Cycles 5 and 6: 25 mg/m2 i.v. days 1,11.

BleomycinDRUG

Bleomicina Comparator arm: cycle 1-2 (and eventually 3-6): 10,000 units/m2 i.v. days 1,15. Experimental arm: cycles 1 to 4: 10,000 units/m2 i.v. days 1,11. Cycles 5 and 6: 10,000 units/m2 i.v. days 1,11.

VinblastineDRUG

Vinblastina Comparator arm: cycle 1-2 (and eventually 3-6): 6 mg/m2 i.v. days 1,15. Experimental arm: cycles 1 to 4: 6 mg/m2 i.v. days 1,11. Cycles 5 and 6: 6 mg/m2 i.v. days 1,11.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histologically confirmed classical HL * Previously untreated disease * Age 18-60 years * Ann Arbor stage IIB with extranodal involvement and/or mediastinal bulk, III and IV (Appendix A) * At least one target PET-avid bidimensionally assessable lesion * Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 (Appendix B) * Adequate organ and marrow function as defined below: absolute neutrophil count \>1,0 x109/L, platelets \>75 x109/L * Total bilirubin \<2 mg/dl without a pattern consistent with Gilbert's syndrome * Aspartate Transaminase and Alanine Transaminase (AST/ALT) \<3 X institutional Upper Limits of Normality (ULN) * Creatinine within normal institutional limits or creatinine clearance \>50 mL/min/1.72 m2 (Appendix C) * Females of childbearing must have a negative pregnancy test at medical supervision even if had been using effective contraception * Life expectancy \> 6 months * Able to adhere to the study visit schedule and other protocol requirements * Sign (or their legally acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. * Access to PET-CT scans facilities qualified by FIL Exclusion Criteria: * Nodular Lymphocyte Predominant HL * Ann Arbor stage IIB without extranodal involvement and/or mediastinal bulky * Prior chemotherapy or radiation therapy * Pregnant or lactating females * Known hypertension (as defined by the updated Guidelines \[76\]), cardiac arrhythmia, conduction abnormalities, ischemic cardiopathy, left ventricular hypertrophy or left ventricular ejection fraction (LVEF) ≤50% at echocardiography. * Abnormal QTc interval prolonged (\>450 msec in males; \>470 msec in women) * Diffusion lung capacity for CO (DLCO) and/or forced expiratory volume in the 1st second (FEV1) tests \<50% of predicted not related to impaired respiratory capacity due to airway compression by mediastinal masses or parenchymal lymphoma * Known cerebral or meningeal disease (HL or any other etiology) * Prior history of malignancies unless the patient has been free of the disease for five years. Exceptions include the following: basal cells carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast and prostate cancer with TNM stage of T1a or T1b * Uncontrolled infectious disease * Human immunodeficiency virus (HIV) positivity or active infectious A, B or C hepatitis. HBsAg-negative patients with anti-HBc antibody and can be enrolled provided that Hepatitis B Virus (HBV)-DNA are negative and that antiviral treatment with nucleos(t)ide analogs is provided * Uncompensated diabetes * Refusal of adequate contraception * Any medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment.

Locations (46)

Outcomes

Primary Outcomes

Progression Free Survival (PFS)

PFS is defined as the interval elapsing from randomization until lymphoma progression or death as a result of any cause.

Time frame: 3 years

Secondary Outcomes

Complete remission rate (CR rate)

CR rate is defined as the proportion of patients achieving a CR after 2 months of chemotherapy (interim) and at the end of treatment

Time frame: 2 months and 6 months

PET/CT response rate

Time frame: after 2 months of chemotherapy

Event Free Survival (EFS)

EFS will be measured from the time from entry onto a study to any treatment failure including disease progression, or discontinuation of treatment for any reason (e.g., disease progression, toxicity, patient preference, initiation of new treatment lacking documented progression, or death)

Time frame: 3 years

Disease free survival (DFS)

DFS will be measured from the time of occurrence of disease-free state or attainment of a CR to disease recurrence or death as a result of lymphoma or acute toxicity of treatment

Time frame: 3 years

Overall survival (OS)

OS is defined as the time from entry onto the clinical trial until death as a result of any cause

Time frame: 3 years

Toxicity

Acute severe toxicity, acute and delayed pulmonary toxicity, acute and delayed cardiac toxicity. Late toxicity and second malignancies. The severity of the toxicities will be classified according to definitions of Common Terminology Criteria for Adverse Event (CTCAE) version 4.3. It will be determined by the incidence of severe, life- threatening (CTCAE grade 3, 4 and 5) and/or serious adverse events (Infusion-related reactions).

Data from ClinicalTrials.gov

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