VeRitAs: Activity and Safety of Front-line Venetoclax and Rituximab in Young and Fit Patients With Chronic Lymphocytic Leukemia

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03455517

Collaborator

(none)

Enrollment

Locations

Arm

Anticipated Duration (Months)

2.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Fludarabine, cyclophosphamide, and rituximab (FCR) is the gold treatment for fit and young patients with Chronic Lymphoid Leukemia (CLL). However, patients with a mutation known as IGVH unmutated and patients with a particular characteristic known as 'disrupted TP53' show an inferior outcome after FCR in terms of survival. Venetoclax as a single agent or combined with rituximab is an effective treatment for relapsed/refractory patients with IGVH unmutated CLL and/or del(17p) and is associated with a high rate of clinical responses.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloid Leukemia	Drug: Venetoclax Drug: Rituximab	Phase 2

Detailed Description

Fludarabine, cyclophosphamide, and rituximab (FCR) is the gold treatment for fit and young (age ≤65 years) patients with CLL. However, IGVH unmutated patients and patients with disrupted TP53 show an inferior outcome after FCR in terms of PFS and OS. Venetoclax as a single agent or combined with rituximab is an effective treatment for relapsed/refractory patients with IGVH unmutated CLL and/or del(17p) and is associated with a high rate of clinical responses and MRD-negative responses. The achievement of a MRD negative response in CLL is the best treatment endpoint since it is associated with an improved PFS.

In treatment-naive patients with unmutated IGVH and/or disrupted TP53 the venetoclax and rituximab combination could be a more effective regimen than FCR with a 15% increase in the CR rate.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

77 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Multicenter, prospective, interventional, single arm studyMulticenter, prospective, interventional, single arm study

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Activity and Safety of Front-linevenetoclax and Rituximab Association (VeRiTAs) in Young and Fit Patients With Chronic Lymphocytic Leukemia (CLL) and Umutated IGVH and/or Disrupted TP53. A Phase 2 Multicenter Study

Actual Study Start Date :

Oct 31, 2018

Actual Primary Completion Date :

Sep 5, 2021

Anticipated Study Completion Date :

Aug 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Veritas Step 1. All patients: venetoclax 5-weeks dose-titration phase with weekly increases in the dose of venetoclax. Step 2. All patients will receive 6 courses of the VR combination. Step 3. After 6 courses of VR combination: 3a. Patients with no response will be off treatment; 3b. Patients with clinical response (CR or PR) after 6 courses of VR combination will receive venetoclax as a single agent for 6 months. Then, patients will be observed clinically until disease progression or until month 36.	Drug: Venetoclax Venetoclax and rituximab association Drug: Rituximab Venetoclax and rituximab association

Arm

Intervention/Treatment

Experimental: Veritas

Step 1. All patients: venetoclax 5-weeks dose-titration phase with weekly increases in the dose of venetoclax. Step 2. All patients will receive 6 courses of the VR combination. Step 3. After 6 courses of VR combination: 3a. Patients with no response will be off treatment; 3b. Patients with clinical response (CR or PR) after 6 courses of VR combination will receive venetoclax as a single agent for 6 months. Then, patients will be observed clinically until disease progression or until month 36.

Drug: Venetoclax

Venetoclax and rituximab association

Drug: Rituximab

Venetoclax and rituximab association

Outcome Measures

Primary Outcome Measures

Number of patients achieving complete response (CR) [At 15 months from treatment start, which is the end of treatment]

Secondary Outcome Measures

Number of patients achieving response [At 15 months from treatment start, which is the end of treatment]
Overall response rate (ORR)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients older than18 years and 65 years or less.
Diagnosis of CLL meeting the IWCLL 2008 criteria.
Total CIRS <6, creatinine clearance >30 ml/min [Cockcroft-Gault]) and ECOG performance status of 0-1.
No prior treatment.
Umutated IGVH and/or disrupted TP53.
Active disease meeting at least 1 of the following the IWCLL 2008 criteria for treatment requirement.
Adequate bone marrow function without transfusion <2 weeks of screening as follows: absolute neutrophil count (ANC) ≥1.0 x 109/L (growth factors administration is allowed); platelets ≥30 x 109/L. If thrombocytopenia due to BM involvement, platelets should be ≥ 30 x 109/L; hemoglobin value ≥8.0 g/dl.
Adequate renal and hepatic function per local reference laboratory reference ranges
Female patients of childbearing potential and non-sterile male patients must practice at least one of method of birth control with partner(s) beginning with initial treatment administration and continuing to 12 months after the last dose of Rituximab.
Male patients must agree to refrain from sperm donation, from initial treatment administration until 12 months after the last dose of Rituximab.
A signed informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

Exclusion Criteria:

Any significant concurrent, uncontrolled medical condition or organ system dysfunction and/or laboratory abnormality or psychiatric disease, which, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk or prevent the subject from signing the informed consent form.
Transformation of CLL to aggressive NHL (Richter's transformation or pro-lymphocytic leukemia).
History of other malignancies Pregnant or lactating females.
Inadequate renal function: CrCl <30 mL/min.
Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
Subject is known to be positive for HIV.
Evidence of other clinically significant uncontrolled condition(s)
Prior or concomitant fruits and/or specific drugs.

Contacts and Locations

Locations

	Site	City	Country
1	Aon Ss. Antonio E Biagio E C. Arrigo - Alessandria - Soc Ematologia	Alessandria	Italy
2	Area Vasta N. 5 Ascoli Piceno - S. Benedetto Del Tronto, Presidio Ospedaliero Av5 Osp. Gen. Prov.Le "C.G.Mazzoni" - Uoc Ematologia	Ascoli Piceno	Italy
3	Asl Di Asti, Ospedali Riuniti - Presidio Ospedaliero Cardinal G. Massaia - Sc Oncologia	Asti	Italy
4	Aou Consorziale Policlinico - Bari - Uo Ematologia Con Trapianto	Bari	Italy
5	Aou Di Bologna - Policlinico S. Orsola-Malpighi - Uoc Ematologia	Bologna	Italy
6	Ao Brotzu, Presidio Ospedaliero A. Businco - Cagliari - Sc Ematologia E Ctmo	Cagliari	Italy
7	Ao Di Catanzaro "Pugliese-Ciaccio", Presidio Ospedaliero "Ciaccio - de Lellis" - Ematologia	Catanzaro	Italy
8	Aou Arcispedale Sant'Anna - Cona (Fe) - Uoc Ematologia E Fisiopatologia Della Coagulazione	Cona	Italy
9	Aso S. Croce E Carle - Cuneo - Sc Ematologia	Cuneo	Italy
10	Asl Lecce, Ospedale 'V. Fazzi' - Uo Ematologia	Lecce	Italy
11	I.R.S.T. Srl Irccs - Meldola - Sc Oncologia Medica	Meldola	Italy
12	Ao Ospedali Riuniti "Papardo Piemonte" - Po Papardo - Messina - Sc Ematologia	Messina	Italy
13	Asst Grande Ospedale Metropolitano Niguarda - Milano - Sc Ematologia	Milano	Italy
14	Fondazione Irccs Ca' Granda, Ospedale Maggiore Policlinico - Milano - Ematologia - Padiglione Marcora	Milano	Italy
15	Irccs Ospedale S. Raffaele - Milano - Unità Neoplasie Linfocitarie B	Milano	Italy
16	Aou Di Modena - Sc Ematologia	Modena	Italy
17	Aou Maggiore Della Carita' Di Novara - Scdu Ematologia	Novara	Italy
18	Aou Di Padova - Uo Ematologia	Padova	Italy
19	Asl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia	Pagàni	Italy
20	Ao Di Perugia, Ospedale S. Maria Della Misericordia - Ematologia E Trapianto Midollo Osseo	Perugia	Italy
21	Asl Di Piacenza, Ospedale "Guglielmo Da Saliceto" - Ematologia E Centro Trapianti	Piacenza	Italy
22	Ausl Della Romagna, Ospedale "Santa Maria Delle Croci" - Ravenna - Ematologia	Ravenna	Italy
23	Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli" Po E. Morelli - Reggio Calabria - Uoc Ematologia	Reggio Calabria	Italy
24	Ausl Di Reggio Emilia - Arcispedale Santa Maria Nuova, Irccs - Sc Ematologia	Reggio Emilia	Italy
25	Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia	Rimini	Italy
26	Fondazione Policlinico Universitario Agostino Gemelli Irccs - Roma - Area Ematologica	Roma	Italy
27	Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia	Roma	Italy
28	Ao S. Maria - Terni - Sc Onco Ematologia	Terni	Italy
29	Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia - Università Degli Studi Di Torino	Torino	Italy
30	Aou Città Della Salute E Della Scienza, Ospedale S. Giovanni Battista Molinette - Torino - Sc Ematologia 2	Torino	Italy
31	Ospedale Mauriziano Umberto I - Torino - Scdu Ematologia	Torino	Italy