Try our beta test site
IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...

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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified May 2017 by Fondazione Italiana Linfomi ONLUS
Sponsor:
Information provided by (Responsible Party):
Fondazione Italiana Linfomi ONLUS
ClinicalTrials.gov Identifier:
NCT03159897
First received: May 15, 2017
Last updated: May 18, 2017
Last verified: May 2017
  Purpose
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 Intervention Phase
Hodgkin Lymphoma
Drug: Doxorubicin
Drug: Bleomycin
Drug: Vinblastine
Drug: Dacarbazine
Phase 3

Study Type: Interventional
Study Design: 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.
Masking: No masking
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).

Resource links provided by NLM:


Further study details as provided by Fondazione Italiana Linfomi ONLUS:

Primary Outcome Measures:
  • Progression Free Survival (PFS) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: after 2 months of chemotherapy ]
    PET/CT response rate

  • Event Free Survival (EFS) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 3 years ]
    OS is defined as the time from entry onto the clinical trial until death as a result of any cause

  • Toxicity [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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


Estimated Enrollment: 500
Anticipated Study Start Date: June 2017
Estimated Study Completion Date: January 2023
Estimated Primary Completion Date: January 2023 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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. 30 Gy Involved Site Radiotherapy (ISRT) will be delivered as consolidation treatment on initial bulky site(s) and 30-36 on focal PET rests scoring ≥ 3 on 5PS.
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. 30-36 Gy ISRT will be delivered as consolidation treatment on focal PET rests scoring ≥3 on 5PS at the end of ABVD DD-DI. No intentional consolidation radiotherapy on the initial bulky area(s) is scheduled.
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.

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 the Comparator arm, consolidation radiotherapy is planned on initial bulky disease sites even if PET negative (DS 1-2) (30 Gy), in patients with PET-negative (DS 3) rests (30 Gy) and in patients with a PET-positive rests (DS 4-5) (36 Gy) even if the residual lesion is not in a bulky lesion. In the Experimental arm, consolidation radiotherapy will be delivered only to rests at treatment completion, without intentional consolidation radiotherapy on the initial bulky, more specifically, in patients with DS3 rests (30 Gy) and in patients with a PET-positive rests (DS 4-5) (36 Gy) even if the residual lesion is not in a bulky lesion.

Blinded independent central reviewing for PET imaging will supervise response categorization at interim and final PET/CT evaluation.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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/1.73 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 2013 European Societies of Hypertension and Cardiology (ESH/ESC) guidelines [71], 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
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03159897

Contacts
Contact: Marina Cesaretti +0039 059 4223165 mcesaretti@filinf.it
Contact: Elena Borgo 00390131206288 eborgo@filinf.it

  Show 60 Study Locations
Sponsors and Collaborators
Fondazione Italiana Linfomi ONLUS
Investigators
Principal Investigator: Antonio Pinto, MD Istituto Nazionale Tumori - IRCCS Fondazione G. Pascale - Napoli
  More Information

Responsible Party: Fondazione Italiana Linfomi ONLUS
ClinicalTrials.gov Identifier: NCT03159897     History of Changes
Other Study ID Numbers: FIL-Rouge
Study First Received: May 15, 2017
Last Updated: May 18, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Fondazione Italiana Linfomi ONLUS:
advanced stage (IIB-IV)
ABVD DD-DI
PET

Additional relevant MeSH terms:
Molecular Mechanisms of Pharmacological Action
Lymphoma
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Doxorubicin
Liposomal doxorubicin
Bleomycin
Vinblastine
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on May 25, 2017