Clinical trial NCT03159897: FIL Study on ABVD DD-DI As Upfront Therapy in HL.
Official title: A Randomized, Open-label, Multicenter, Phase III, 2-arm Study Comparing 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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hodgkin Lymphoma
Keywords: advanced stage (IIB-IV)
ABVD DD-DI
PET
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
First posted: 2017-05-19
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 3 years
Secondary outcomes:
measure: Complete remission rate (CR rate)
timeFrame: 2 months and 6 months
measure: PET/CT response rate
timeFrame: after 2 months of chemotherapy
measure: Event Free Survival (EFS)
timeFrame: 3 years
measure: Disease free survival (DFS)
timeFrame: 3 years
measure: Overall survival (OS)
timeFrame: 3 years
measure: Toxicity
timeFrame: 6 months for acute toxicity and 5 years for late toxicity
measure: Quality of life (QoL)
timeFrame: 36 months
measure: Cost-effectiveness analyses
timeFrame: 36 months
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia
city: Ancona
country: Italy
facility: Università Politecnica delle Marche, Clinica di Ematologia
city: Ascoli Piceno
country: Italy
facility: Ospedale C.e G. Mazzoni -U.O.C. di Ematologia
city: Avellino
country: Italy
facility: Azienda Ospedaliera S.Giuseppe Moscati -S.C. Ematologia e Trapianto emopoietico
city: Aviano
country: Italy
facility: Centro Riferimento Oncologico - S.O.C. Oncologia Medica A
city: Bari
country: Italy
facility: AOU Policlinico Consorziale - U.O. Ematologia con Trapianto
city: Bari
country: Italy
facility: IRCCS Istituto Tumori Giovanni Paolo II
city: Barletta
country: Italy
facility: Ospedale "Monsignor Raffaele Dimiccoli" - Ematologia
city: Brescia
country: Italy
facility: A.O. Spedali Civili di Brescia - Ematologia
city: Brindisi
country: Italy
facility: Ospedale Antonio Perrino - Ematologia
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia - IRCCS - Ematologia
city: Caserta
country: Italy
facility: AORN S.Anna e S. Sebastiano - Oncoematologia
city: Castelfranco Veneto
country: Italy
facility: Ospedale di Castelfranco Veneto - Ematologia
city: Cremona
country: Italy
facility: ASST Cremona - Ematologia e CRTO
city: Ivrea
country: Italy
facility: Ospedali Riuniti del Canavese
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi - Ematologia
city: Matera
country: Italy
facility: Ospedale Madonna delle Grazie - Ematologia
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) - Ematologia
city: Messina
country: Italy
facility: Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia
city: Mirano
country: Italy
facility: USLL13 - Dipartimento di Scienze Mediche UOC di Oncologia ed Ematologia Oncologica
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria Policlinico di Modena - Ematologia
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale - Ematologia Oncologica
city: Padova
country: Italy
facility: I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1
city: Pagani
country: Italy
facility: Presidio ospedaliero "A. TORTORA"
city: Palermo
country: Italy
facility: A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia
city: Parma
country: Italy
facility: AOU di Parma - UO Ematologia e CTMO
city: Pavia
country: Italy
facility: IRCCS Policlinico S. Matteo di Pavia - Div. di Ematologia
city: Perugia
country: Italy
facility: AO di Perugia - Ematologia
city: Pescara
country: Italy
facility: P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi
city: Piacenza
country: Italy
facility: Ospedale Guglielmo da Saliceto - U.O.Ematologia
city: Potenza
country: Italy
facility: A.O.R. "San Carlo" - U.O. Ematologia
city: Ravenna
country: Italy
facility: Ospedale delle Croci - Ematologia
city: Reggio Emilia
country: Italy
facility: Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS c/o CORE (II piano)
city: Rimini
country: Italy
facility: Ospedale degli Infermi di Rimini
city: Rionero in Vulture
country: Italy
facility: IRCCS-Centro di riferimento oncologico - UO di ematologia e Trapianto Cellule Staminali
city: Roma
country: Italy
facility: Policlinico Umberto I - Università "La Sapienza" - Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia
city: Roma
country: Italy
facility: Policlinico Universitario Campus Bio-Medico - "Area Ematologia Trapianto Cellule Staminali Medicina Trasfusionale e Terapia cellulare"
city: Roma
country: Italy
facility: Università Cattolica S. Cuore - Ematologia
city: Rozzano (MI)
country: Italy
facility: Istituto Clinico Humanitas - U.O. Ematologia
city: Salerno
country: Italy
facility: Ematologia e Trapianti A.O. San Giovanni di Dio e Ruggi D'Aragona - U.O. Ematologia
city: Sassuolo
country: Italy
facility: Nuovo Ospedale Civile di Sassuolo - Day Hospital Oncologico
city: Terni
country: Italy
facility: Univ. Perugia Sede Terni - Oncoematologia
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza di Torino - Ematologia Universitaria
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza di Torino - S.C.Ematologia
city: Tricase
country: Italy
facility: A.O. C. Panico - U.O.C Ematologia e Trapianto
Study officials:
affiliation: Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale - Napoli
name: Antonio Pinto, MD
role: PRINCIPAL_INVESTIGATOR
References: