Clinical trial NCT03161054: Metronomic Chemotherapy in Elderly Non-fit Patients With Aggressive B-Cell Lymphomas
Official title: A Phase II Study of Metronomic Chemotherapy in Elderly Non-fit Patients (>65 Years) With Aggressive B-Cell Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aggressive Non-Hodgkin Lymphoma
Keywords: Metronomic Chemotherapy
Elderly non-fit patients
Aggressive B-Cell lymphomas
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
First posted: 2017-05-19
Enrollment: 21
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: phase II, multicentre, non-randomized study, single arm study
Primary purpose: TREATMENT

Brief summary: This is a phase II study of metronomic chemotherapy in elderly non-fit patients (\>65 years) with aggressive B-Cell lymphomas

Detailed description: Patients eligible for the study will receive 6 courses (q 28 days) of the DEVEC combination, according to the following schedule:

* DE: Prednisone (Deltacortene) 25 mg /day will be orally administered from day 1 to day 28 only in cycle 1 From cycle 2 to 6 it is reduced to three times a week (after breakfast, MON, WED, FRI)
* V: Vinorelbine 30 mg/day will be orally administered three times a week, 3 week on and 1 week off (after breakfast, MON, WED, FRI).
* E: Etoposide 50 mg/day will be orally administered from day 1 to day 14 (before lunch).
* C: Cyclophosphamide 50 mg/day will be orally administered from day 1 to day 21 (after dinner).
* Rituximab: 375 mg/m2 will be administered by IV infusion up to four infusions on days 8, 15, 22, 29, only in patients suitable for infusion treatment and relapsed after \>6 months from last R-chemotherapy. Refractory patients who had received at least 5 doses of Rituximab will not repeat it during the metronomic therapy.

Super-frail patients will not receive etoposide during cycles 1 and 2; etoposide will be included in the treatment schedule starting from cycle 3 at reduced dose (50 mg/day, from day 1 to day 7) only in patients who in cycles 1 and 2 didn't experience hematological toxicity \>G2 and/or non-hematological toxicity \>G1.

In Unfit and Frail patients with hemoglobin level at study entry \<11 gr/dL, will start etoposide will be orally administered at reduced dose (50 mg/day from day 1 to day 7). If hemoglobin will raise to ≥11 gr/dL, at subsequent induction cycles etoposide will be administered at full dose (50 mg/day, from day 1 to day 14), As a preventive measure, to avoid perforation, patients with gastrointestinal visceral involvement will receive a pre-phase therapy with steroids (prednisolone 40mg/m2

) for 6-7 days before starting protocol treatment. Moreover, in these patients the four Rituximab doses will be administered in cycle 2.

Patients in CR, CRu, PR and SD after 2 cycles will continue with additional 4 courses.

At the end of the induction phase patients in CR, CRu and PR (and also in SD at discretion of local investigator) will continue treatment with maintenance therapy including Vinorelbine, Cyclophosphamide, and Prednisone oral combination to be repeated every 28 days for up to 6 cycles, according to the following schedule:

* Cyclophosphamide 50 mg/day will be orally administered from day 1 to day 14 (after dinner).
* Vinorelbine 30 mg/day will be orally administered three times a week, 3 week on and 1 week off (after breakfast, MON, WED, FRI).
* Prednisone 25 mg/day will be orally administered twice a week (after breakfast, MON, FRI).

Patients in CR/CRu at the EOT can continue with a post-maintenance phase at discretion of the local investigator up to 12 months, progression or inacceptable toxicity, according to following schedule:

* Vinorelbine 30 mg/day will be orally administered three times a week, 3 week on and 1 week off (after breakfast, MON, WED, FRI).
* Prednisone 25 mg/day will be orally administered twice a week (after breakfast, MON, FRI).

Patients with evidence of Progressive Disease (PD) at any point will stop treatment.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed diagnosis of aggressive Non-Hodgkin Lymphomas (NHLs) including:

  * LBCL1
  * DLBCL;
  * Grade IIIb follicular lymphoma;
  * BL1;
  * B-Cell unclassifiable lymphomas with features intermediate between DLBCL and BL or between DLBCL and Hodgkin's lymphoma (HL)35;
  * High grade B-cell lymphomas1
* Age \>65 years
* Unfit or frail patients (the latest defined, for the purpose of this study, as those who have a maximum of 1 frail factor) according to the multidimensional geriatric evaluation model of the elderly platform of the FIL, who relapsed/progressed after one or maximum two previous lines of treatment or
* "Super-frail" elderly patients at disease onset: eligible super-frail patients are defined, for the purpose of this study, as those who have a maximum of 2 frail factors, according to the CGA adopted in the elderly platform of the FIL, among those below listed:

  * ADL ≤ 4;
  * IADL ≤ 5;
  * Age ≥ 80 years;
  * 1 CIRS grade 3 or \>8 CIRS grade 2.
* Ann Arbor stage I bulky to IV
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
* Life expectancy \>1-2 months.
* Adequate renal function (creatinine ≤ 2 mg/dl, unless secondary to lymphoma).
* Adequate liver function (bilirubin ≤ 2 mg/dl, unless secondary to lymphoma).
* Absolute neutrophil count (ANC) ≥1500 cells/mmc and platelets ≥ 50,000 cells/mmc, haemoglobin ≥ 9 gr/dl, unless cytopenia is related to bone marrow involvement by lymphoma.
* Availability of adequate care by family members or other caregivers.
* Written informed consent signature.
* Male Subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 3 months following the end or the discontinuation from the study treatment even if he has undergone a successful vasectomy.

Exclusion Criteria:

* Patients who received more than two previous chemotherapy lines.
* Relapsed/refractory patients with fit profile.
* Fit, unfit, and frail patients at disease onset.
* Malabsorption syndrome or other diseases that affect the ability to swallow oral therapy.
* Concomitant malignancy requiring treatment (except non-melanoma skin cancers and in situ carcinoma of the uterine cervix).
* Presence of opportunistic infections in place.
* Seropositive for or active viral infection with hepatitis B virus (HBV):

  1. HBsAg positive;
  2. HBsAg negative, HBcAb positive with detectable viral DNA (Subjects who are HBsAg negative, HBcAb positive, but viral DNA negative are eligible.
* Seropositive and active infection for hepatitis C virus (subjects who are HCV-RNA negative are eligible).
* Known seropositive for or active viral infection with human immunodeficiency virus (HIV).
* Impossibility to give written informed consent.

Primary outcomes:
measure: Complete Remission Rate (CRR)
timeFrame: 30 months
measure: Incidence of adverse events
timeFrame: 30 months
Secondary outcomes:
measure: Overall response rate (ORR)
timeFrame: 30 months
measure: Clinical Benefit
timeFrame: 30 months
measure: Progression Free Survival (PFS)
timeFrame: 36
measure: Event Free Survival (EFS)
timeFrame: 36
measure: Disease Free Survival (DFS)
timeFrame: 36
measure: Overall Survival (OS)
timeFrame: 36
measure: Patient-Reported Outcome (PRO)
timeFrame: 36
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: A.O. Spedali Civili di Brescia - Ematologia
city: Castelfranco Veneto
country: Italy
facility: Ospedale di Castelfranco Veneto - Ematologia
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) - Ematologia
city: Piacenza
country: Italy
facility: Ospedale Guglielmo da Saliceto - 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) - Ematologia
city: Roma
country: Italy
facility: AO Sant'Andrea - Ematologia
city: Sassuolo
country: Italy
facility: Nuovo Ospedale Civile di Sassuolo - Day Hospital Oncologico
city: Siena
country: Italy
facility: AOU Senese - U.O.C. Ematologia
city: Torino
country: Italy
facility: A.O.U. Citta della Salute e della Scienza di Torino - Ematologia Universitaria
Study officials:
affiliation: AUSL - IRCCS Arcispedale Santa Maria Nuova viale Risorgimento 80 42123, Reggio Emilia
name: Francesco Merli, MD
role: PRINCIPAL_INVESTIGATOR
References: