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

Hodgkin Lymphoma Clinical Trial

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).

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03159897
• Other study ID #: FIL-Rouge
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: August 1, 2017
• Est. completion date: May 2024

Study information

• Verified date: December 2023
• Source: Fondazione Italiana Linfomi - ETS
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 500
• Est. completion date: May 2024
• Est. primary completion date: November 2, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hodgkin Disease
• Hodgkin Lymphoma
• Lymphoma

Intervention

Drug:
• Doxorubicin
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.
• Bleomycin
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.
• Vinblastine
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.
• Dacarbazine
Dacarbazina Comparator arm: cycle 1-2 (and eventually 3-6): 375 mg/m2 i.v. days 1,15. Experimental arm: cycles 1 to 4: 375 mg/m2 i.v. days 1,11. Cycles 5 and 6: 375 mg/m2 i.v. days 1,11.

Locations

Country	Name	City	State
Italy	A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia	Alessandria
Italy	Università Politecnica delle Marche, Clinica di Ematologia	Ancona
Italy	Ospedale C.e G. Mazzoni -U.O.C. di Ematologia	Ascoli Piceno
Italy	Azienda Ospedaliera S.Giuseppe Moscati -S.C. Ematologia e Trapianto emopoietico	Avellino
Italy	Centro Riferimento Oncologico - S.O.C. Oncologia Medica A	Aviano
Italy	AOU Policlinico Consorziale - U.O. Ematologia con Trapianto	Bari
Italy	IRCCS Istituto Tumori Giovanni Paolo II	Bari
Italy	Ospedale "Monsignor Raffaele Dimiccoli" - Ematologia	Barletta
Italy	A.O. Spedali Civili di Brescia - Ematologia	Brescia
Italy	Ospedale Antonio Perrino - Ematologia	Brindisi
Italy	Fondazione del Piemonte per l'Oncologia - IRCCS - Ematologia	Candiolo
Italy	AORN S.Anna e S. Sebastiano - Oncoematologia	Caserta
Italy	Ospedale di Castelfranco Veneto - Ematologia	Castelfranco Veneto
Italy	ASST Cremona - Ematologia e CRTO	Cremona
Italy	Ospedali Riuniti del Canavese	Ivrea
Italy	Ospedale Vito Fazzi - Ematologia	Lecce
Italy	Ospedale Madonna delle Grazie - Ematologia	Matera
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) - Ematologia	Meldola
Italy	Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia	Messina
Italy	ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia	Milano
Italy	USLL13 - Dipartimento di Scienze Mediche UOC di Oncologia ed Ematologia Oncologica	Mirano
Italy	Azienda Ospedaliero-Universitaria Policlinico di Modena - Ematologia	Modena
Italy	Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale - Ematologia Oncologica	Napoli
Italy	I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1	Padova
Italy	Presidio ospedaliero "A. TORTORA"	Pagani
Italy	A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia	Palermo
Italy	AOU di Parma - UO Ematologia e CTMO	Parma
Italy	IRCCS Policlinico S. Matteo di Pavia - Div. di Ematologia	Pavia
Italy	AO di Perugia - Ematologia	Perugia
Italy	P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi	Pescara
Italy	Ospedale Guglielmo da Saliceto - U.O.Ematologia	Piacenza
Italy	A.O.R. "San Carlo" - U.O. Ematologia	Potenza
Italy	Ospedale delle Croci - Ematologia	Ravenna
Italy	Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS c/o CORE (II piano)	Reggio Emilia
Italy	Ospedale degli Infermi di Rimini	Rimini
Italy	IRCCS-Centro di riferimento oncologico - UO di ematologia e Trapianto Cellule Staminali	Rionero in Vulture
Italy	Policlinico Umberto I - Università "La Sapienza" - Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia	Roma
Italy	Policlinico Universitario Campus Bio-Medico - "Area Ematologia Trapianto Cellule Staminali Medicina Trasfusionale e Terapia cellulare"	Roma
Italy	Università Cattolica S. Cuore - Ematologia	Roma
Italy	Istituto Clinico Humanitas - U.O. Ematologia	Rozzano (MI)
Italy	Ematologia e Trapianti A.O. San Giovanni di Dio e Ruggi D'Aragona - U.O. Ematologia	Salerno
Italy	Nuovo Ospedale Civile di Sassuolo - Day Hospital Oncologico	Sassuolo
Italy	Univ. Perugia Sede Terni - Oncoematologia	Terni
Italy	A.O.U. Citta della Salute e della Scienza di Torino - Ematologia Universitaria	Torino
Italy	A.O.U. Citta della Salute e della Scienza di Torino - S.C.Ematologia	Torino
Italy	A.O. C. Panico - U.O.C Ematologia e Trapianto	Tricase

Sponsors (1)

Lead Sponsor	Collaborator
Fondazione Italiana Linfomi - ETS

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	PFS is defined as the interval elapsing from randomization until lymphoma progression or death as a result of any cause.	3 years
Secondary	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	2 months and 6 months
Secondary	PET/CT response rate	PET/CT response rate	after 2 months of chemotherapy
Secondary	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)	3 years
Secondary	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	3 years
Secondary	Overall survival (OS)	OS is defined as the time from entry onto the clinical trial until death as a result of any cause	3 years
Secondary	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).	6 months for acute toxicity and 5 years for late toxicity
Secondary	Quality of life (QoL)	QoL will be measured at the baseline, the end of therapy and during follow-up through the EORTC QLQ-C30 questionnaire	36 months
Secondary	Cost-effectiveness analyses	Cost-effectiveness analyses. ICER will be calculated by dividing the difference in mean total costs arms by the difference in the mean effects. The ICER will be calculated for the principal clinical effect measures of the trial. (i.e. PFS) and for QALYs. QALYs will be calculated multiplying the amount of time a patient spent in a particular health state by the utilities estimated using the EQ-5D questionnaires	36 months