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

Sponsor

Fondazione Italiana Linfomi ONLUS (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03159897

Collaborator

(none)

500

Enrollment

Locations

Arms

Anticipated Duration (Months)

10.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Hodgkin Lymphoma	Drug: Doxorubicin Drug: Bleomycin Drug: Vinblastine Drug: Dacarbazine	Phase 3

Detailed Description

The study is devoted to patients affected with advanced stage (IIB-IV) Hodgkin Lymphoma.

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 Design

Study Type:

Interventional

Anticipated Enrollment :

500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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.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.

Masking:

None (Open Label)

Primary Purpose:

Treatment

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).

Actual Study Start Date :

Aug 1, 2017

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Jan 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Comparator arm Patients will receive 2 courses of standard ABVD (ABVD-28, d1, d15, cycles of 28 days) and then proceed to interim PET/CT evaluation. Those with a PET-2-negative scan (score 1-3 on 5PS) will continue with additional 4 ABVD courses while those with a PET-2-positive (score 4-5) scan will be diverted towards an intensification phase with either escalated BEACOPP or HDT plus ASCR, according to the preference of the centre. Upon completion of treatment, patients will be categorized for response (Lugano2014) by comparing actual PET/CT imaging with baseline, whether 6 ABVD cycles or ABVDx2 + intensification phase with BEACOPP or HDT/ASCR. A salvage rescue program will be planned for patients with Stable (<PR) or Progressive Disease. ISRT 30 Gy will be delivered to complete responders (5PS score 1-2-3) on the initial bulky site(s), to focal rests in case of CR scoring 3 on 5PS with a residual size ≥ 2.5 cm and to focal rests uptakes in the event of PR scoring 4 or 5, whichever is the size.	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. Drug: 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. Drug: 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. Drug: 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.
Experimental: Experimental arm Dose-dense and dose-intense ABVD regimen (ABVD DD-DI: intercycle 21 days, d1, d11; doxorubicin 35 mg/m2 DD 1 and 11) is given in cycles 1 to 4 and dose-dense ABVD (ABVD DD: intercycle 21 days, D1 and D11; conventional doxorubicin dose, e.g. 25 mg/m2 DD 1 and 11) is given as cycles 5 and 6). The treatment is not PET-adapted, and only patients with no response or progressive disease at interim FDG-PET as defined by the Lugano Classification (e.g., score 4 or 5 on 5PS with no significant change or with increased uptake matched with baseline and/or new FDG-avid foci consistent with lymphoma) will be diverted to salvage therapy. ISRT 30 Gy will be delivered to responder patients (DS=3), on focal PET-positive rests with a residual size ≥ 2.5 cm and on patients in PR with uptake scoring 4 or 5, whichever is the size.	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. Drug: 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. Drug: 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. Drug: 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.

Arm

Intervention/Treatment

Experimental: Comparator arm

Patients will receive 2 courses of standard ABVD (ABVD-28, d1, d15, cycles of 28 days) and then proceed to interim PET/CT evaluation. Those with a PET-2-negative scan (score 1-3 on 5PS) will continue with additional 4 ABVD courses while those with a PET-2-positive (score 4-5) scan will be diverted towards an intensification phase with either escalated BEACOPP or HDT plus ASCR, according to the preference of the centre. Upon completion of treatment, patients will be categorized for response (Lugano2014) by comparing actual PET/CT imaging with baseline, whether 6 ABVD cycles or ABVDx2 + intensification phase with BEACOPP or HDT/ASCR. A salvage rescue program will be planned for patients with Stable (<PR) or Progressive Disease. ISRT 30 Gy will be delivered to complete responders (5PS score 1-2-3) on the initial bulky site(s), to focal rests in case of CR scoring 3 on 5PS with a residual size ≥ 2.5 cm and to focal rests uptakes in the event of PR scoring 4 or 5, whichever is the size.

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.

Drug: 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.

Drug: 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.

Drug: 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.

Experimental: Experimental arm

Dose-dense and dose-intense ABVD regimen (ABVD DD-DI: intercycle 21 days, d1, d11; doxorubicin 35 mg/m2 DD 1 and 11) is given in cycles 1 to 4 and dose-dense ABVD (ABVD DD: intercycle 21 days, D1 and D11; conventional doxorubicin dose, e.g. 25 mg/m2 DD 1 and 11) is given as cycles 5 and 6). The treatment is not PET-adapted, and only patients with no response or progressive disease at interim FDG-PET as defined by the Lugano Classification (e.g., score 4 or 5 on 5PS with no significant change or with increased uptake matched with baseline and/or new FDG-avid foci consistent with lymphoma) will be diverted to salvage therapy. ISRT 30 Gy will be delivered to responder patients (DS=3), on focal PET-positive rests with a residual size ≥ 2.5 cm and on patients in PR with uptake scoring 4 or 5, whichever is the size.

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.

Drug: Bleomycin

Drug: 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.

Drug: 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.

Outcome Measures

Primary Outcome Measures

Progression Free Survival (PFS) [3 years]
PFS is defined as the interval elapsing from randomization until lymphoma progression or death as a result of any cause.

Secondary Outcome Measures

Complete remission rate (CR rate) [2 months and 6 months]
CR rate is defined as the proportion of patients achieving a CR after 2 months of chemotherapy (interim) and at the end of treatment
PET/CT response rate [after 2 months of chemotherapy]
PET/CT response rate
Event Free Survival (EFS) [3 years]
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)
Disease free survival (DFS) [3 years]
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
Overall survival (OS) [3 years]
OS is defined as the time from entry onto the clinical trial until death as a result of any cause
Toxicity [6 months for acute toxicity and 5 years for late 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).
Quality of life (QoL) [36 months]
QoL will be measured at the baseline, the end of therapy and during follow-up through the EORTC QLQ-C30 questionnaire
Cost-effectiveness analyses [36 months]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	A.O. SS. Antonio e Biagio e Cesare Arrigo - S.C. Ematologia	Alessandria	Italy
2	Università Politecnica delle Marche, Clinica di Ematologia	Ancona	Italy
3	Ospedale C.e G. Mazzoni -U.O.C. di Ematologia	Ascoli Piceno	Italy
4	Azienda Ospedaliera S.Giuseppe Moscati -S.C. Ematologia e Trapianto emopoietico	Avellino	Italy
5	Centro Riferimento Oncologico - S.O.C. Oncologia Medica A	Aviano	Italy
6	AOU Policlinico Consorziale - U.O. Ematologia con Trapianto	Bari	Italy
7	IRCCS Istituto Tumori Giovanni Paolo II	Bari	Italy
8	Ospedale "Monsignor Raffaele Dimiccoli" - Ematologia	Barletta	Italy
9	A.O. Spedali Civili di Brescia - Ematologia	Brescia	Italy
10	Ospedale Antonio Perrino - Ematologia	Brindisi	Italy
11	Fondazione del Piemonte per l'Oncologia - IRCCS - Ematologia	Candiolo	Italy
12	AORN S.Anna e S. Sebastiano - Oncoematologia	Caserta	Italy
13	Ospedale di Castelfranco Veneto - Ematologia	Castelfranco Veneto	Italy
14	ASST Cremona - Ematologia e CRTO	Cremona	Italy
15	Ospedali Riuniti del Canavese	Ivrea	Italy
16	Ospedale Vito Fazzi - Ematologia	Lecce	Italy
17	Ospedale Madonna delle Grazie - Ematologia	Matera	Italy
18	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) - Ematologia	Meldola	Italy
19	Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia	Messina	Italy
20	ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia	Milano	Italy
21	USLL13 - Dipartimento di Scienze Mediche UOC di Oncologia ed Ematologia Oncologica	Mirano	Italy
22	Azienda Ospedaliero-Universitaria Policlinico di Modena - Ematologia	Modena	Italy
23	Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale - Ematologia Oncologica	Napoli	Italy
24	I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1	Padova	Italy	35128
25	Presidio ospedaliero "A. TORTORA"	Pagani	Italy
26	A.O. Ospedali Riuniti Villa Sofia-Cervello - Divisione di Ematologia	Palermo	Italy
27	AOU di Parma - UO Ematologia e CTMO	Parma	Italy
28	IRCCS Policlinico S. Matteo di Pavia - Div. di Ematologia	Pavia	Italy
29	AO di Perugia - Ematologia	Perugia	Italy
30	P.O. Spirito Santo di Pescara - UOS Dipartimentale - Centro di diagnosi e Terapia dei linfomi	Pescara	Italy
31	Ospedale Guglielmo da Saliceto - U.O.Ematologia	Piacenza	Italy
32	A.O.R. "San Carlo" - U.O. Ematologia	Potenza	Italy
33	Ospedale delle Croci - Ematologia	Ravenna	Italy
34	Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS c/o CORE (II piano)	Reggio Emilia	Italy
35	Ospedale degli Infermi di Rimini	Rimini	Italy
36	IRCCS-Centro di riferimento oncologico - UO di ematologia e Trapianto Cellule Staminali	Rionero in Vulture	Italy
37	Policlinico Umberto I - Università "La Sapienza" - Istituto Ematologia -Dipartimento di Biotecnologie Cellulari ed Ematologia	Roma	Italy
38	Policlinico Universitario Campus Bio-Medico - "Area Ematologia Trapianto Cellule Staminali Medicina Trasfusionale e Terapia cellulare"	Roma	Italy
39	Università Cattolica S. Cuore - Ematologia	Roma	Italy
40	Istituto Clinico Humanitas - U.O. Ematologia	Rozzano (MI)	Italy
41	Ematologia e Trapianti A.O. San Giovanni di Dio e Ruggi D'Aragona - U.O. Ematologia	Salerno	Italy
42	Nuovo Ospedale Civile di Sassuolo - Day Hospital Oncologico	Sassuolo	Italy
43	Univ. Perugia Sede Terni - Oncoematologia	Terni	Italy
44	A.O.U. Citta della Salute e della Scienza di Torino - Ematologia Universitaria	Torino	Italy
45	A.O.U. Citta della Salute e della Scienza di Torino - S.C.Ematologia	Torino	Italy
46	A.O. C. Panico - U.O.C Ematologia e Trapianto	Tricase	Italy