Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02390869 |
| Other study ID # |
FIL_RENOIR12 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
May 2014 |
| Est. completion date |
December 2027 |
Study information
| Verified date |
June 2024 |
| Source |
Fondazione Italiana Linfomi - ETS |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
A randomized phase III multicenter trial assessing efficacy and toxicity of a combination of
Rituximab and Lenalidomide (R2) vs Rituximab alone as maintenance after chemoimmunotherapy
with Rituximab-chemotherapy (R-CHT) for relapsed/refractory FL patients not eligible for
autologous transplantation (ASCT)
Description:
Among Non-Hodgkin lymphomas (NHL), Follicular Lymphoma (FL) is the second one in terms of
frequency, accounting for about 25% of all NHL cases in the western hemisphere. A
predominance in females is reported, and the median age at the diagnosis is 60 years.
FL cells originates from normal counterparts germinal B cells. At a molecular level, the
pathology is thought to be dependent on multiple DNA alterations. However, a large amount of
patients (approximately 85%) have t(14;18), with a consequent overexpression of
anti-apoptotic protein BCL-2.
An additional hallmark of pathology is bone marrow involvement (70% of patients), while this
is seldom noticed in other organs. Finally, 20% of patients show high levels of serum lactate
dehydrogenase (LDH) and/or B symptoms.
FL is actually considered an incurable disease. Although FL responds well to initial
chemotherapy, most patients will eventually relapse, requiring multiple subsequent
therapeutic regimens during the course of disease to achieve new period of remission, that
are nevertheless shorter. Relapsed/refractory FL in advanced stage, especially in older
patients, has a relatively poor prognosis, and several patients die for infectious
complications and/or progressive disease. This subset of patients usually do not survive more
than 5 years.
Thus there is a need for new, less toxic and more active treatment in particular for patients
with recurrent disease. The addition of Rituximab to chemotherapy showed a clear benefit in
terms of overall response rate, quality of response, event-free survival and, in most
studies, overall survival; nevertheless, relapses still occur. Moreover Rituximab also proved
highly effective when employed as maintenance treatment either following chemotherapy or
Rituximab-supplemented chemotherapy. The success of Rituximab maintenance led to the
widespread opinion that in the context of indolent lymphomas novel "smart" drugs
characterized by a good safety profile need to be carefully evaluated not only in the
induction but also in the maintenance setting.
Autologous stem cell transplantation and radioimmunotherapy are therapeutic option for
relapsed/refractory FL patients, but can be considered only for younger or fit patients and
can be delivered only in large institutions.
Therefore the search of new, more manageable, therapeutic agents with different mechanisms of
action, especially for elderly or frail patients, is ongoing.
Bendamustine is highly effective in relapsed/refractory indolent non-Hodgkin lymphoma (NHL)
and Mantle Cell Lymphoma (MCL), including patients who are refractory to rituximab and those
previously treated with other alkylating agents. Therefore, bendamustine is now widely used
in this setting and provides another effective treatment option for patients who progress
after CHOP-R. Two phase II studies have combined bendamustine (90 mg/m2 days 2-3 every 28
days) with rituximab (375 mg/m2 day 1) and both reported similar results. The overall
response rate was 90% (60% CR) for the entire patient population, and median Progression-free
survival (PFS) for all patients was 24 months. Based on these encouraging results in the
relapsed/refractory setting, the Study group indolent Lymphomas (StiL) initiated a large,
randomized, phase III trials of bendamustine (90 mg/m2 days 1-2 every 28 days) plus rituximab
(375 mg/m2 day 1). This trial compared B-R with standard CHOP-R (21-day cycles) in previously
untreated patients with indolent NHL and MCL. 549 patients with predominantly stage IV
disease were enrolled, and the treatment groups were well balanced for all baseline
characteristics. Approximately 55% of patients had FL, approximately 20% had MCL, and the
remaining 25% had other indolent lymphomas. Although the overall response rate was similar in
the B-R and CHOP-R arms (93.8% and 93.5%, respectively), the CR rate was significantly higher
in the B-R arm (40.1% compared with 30.8% for CHOP-R; P .03), and the median PFS was
significantly longer in the B-R arm (54.8 months v 34.8 months for CHOP-R; P .0002). No
difference in survival has been observed thus far, further follow-up of this ongoing study
will be required to address whether B-R improves survival compared with CHOP-R. Nevertheless,
bendamustine plus rituximab yielded more durable responses and improved PFS compared with
CHOP-R in previously untreated patients with indolent lymphomas. Moreover, bendamustine plus
rituximab was better tolerated.
Lenalidomide is an immunomodulatory agent with multiple mechanisms of action wich include
antiproliferative activity as well as microenvironmental effects such as inhibition
angiogenesis and stimulation of T-cell mediated response. Lenalidomide given as monotherapy
proved to be active, with an acceptable toxicity profile, in B-cell malignancies such as
multiple myeloma, chronic lymphocytic leukemia, mantle cell lymphoma and diffuse large B-cell
lymphoma.
Recent reports on Lenalidomide in FL, both for untreated and relapsed patients, are
promising.
Forty-three patients with relapsed or refractory indolent non Hodgkin's lymphoma (NHL) were
treated with oral Lenalidomide 25 mg once daily on days 1 to 21 of every 28-day cycle for 52
weeks or until progression. Twenty-two of the 43 patients enrolled had FL In this subgroup
overall response rate was 27%, with a 9% complete remission rate. Most common adverse events
were myelosuppression, fatigue, gastrointestinal events and cutaneous rash, while predominant
grade 3/4 serious adverse events were neutropenia and thrombocytopenia. Despite a median
duration of response longer than 16.5 months, there was a disappointing median
progression-free survival of 4.4 months.
Witzig et al. focused on Lenalidomide 25 mg in monotherapy in relapsed/refractory B-cell
lymphomas. The cohort of patients was 217, 19 of them had a stage III FL. Regarding this
patients subset, ORR was 42%, CR/Cru was 11%, median PFS was 8.9 months, median duration of
response was not reached.
The cytotoxic effect of Rituximab appears to involve CDC, ADCC and induction of apoptosis.
Early studies of Lenalidomide show the potential for high CR rates and long duration of
response in FL and Chronic lymphocytic leukemia (CLL). Recent data suggest that the
modulation of effector cells by Lenalidomide can enhance the antitumor activity of Rituximab
and partially overcome its resistance in cell lines of relapsed/refractory NHL. Lenalidomide
appears in fact to greatly enhance the monocyte and NK-mediated ADCC exerted by Rituximab,
resulting in an increase of cancer cell killing compared to the single drugs. A synergistic
activity between Rituximab and Lenalidomide has been reported in vitro in lymphoma cells and
in animal models. Rituximab-lenalidomide (R2) combination has been consequently tested in
clinical trials, including untreated or relapsed/refractory indolent NHL, with encouraging
results.
The first report about the R2 combination in FL was presented at the 51th ASH meeting by
Dutia M et al. Sixteen patients with relapsed/refractory indolent NHL have been treated with
R2 combination, obtaining a 75% overall response (ORR) rate with an acceptable toxicity;
interestingly, efficacy data seem better in FL patients with a 88% ORR. Moreover, in the
unfavourable subgroups of rituximab refractory and heavily pre-treated patients, ORR rates
were 57% and 70%, respectively. Estimated progression-free survival for all patients is 12
months. The major limitation of the study was the small number of patients, with only 9 FL
patient included in the study.
Twenty-four patients with indolent B-cell lymphoma, previously resistant to Rituximab,
received a Rituximab-Lenalidomide +/- Dexamethasone combination until progression of disease
or unacceptable toxicity; Lenalidomide was administered at the dosage of 10 mg, 28 days per
course. 28 over 45 patients had FL. No further FL group analysis were reported, but the study
allowed to assess that also patients resistant to Rituximab in mono-therapy can benefit from
R2, with or without Dexamethasone, achieving higher ORR (~61%) with relatively durable
responses.
One hundred patients with stage III-IV untreated indolent NHL received the R2 combination in
cycles of 28 days (Lenalidomide 20 mg orally once a day from day 1 to day 21 and Rituximab
375 mg/m2 intravenously on day 1). 49 patients (49%) composed the FL subset.
The outcome of FL patients was extremely positive, considering the ORR (98%) and the CR/CRu
(85%). Moreover, when the R2 treatment was prolonged after 6 courses, a significant
improvement was seen for CR/CRu. Finally, the PFS was 83% for FL patients after 24 months,
and the toxicity profile was acceptable.
In CALGB 50401 randomized study 89 recurrent FL patients were treated with Lenalidomide alone
versus R2 combination. ORR were 49% vs 75% and EFS was 1.2 vs 2.0 with a median follow up of
1.5 years.
Basing on these promising data, other trials proposed the combination of Lenalidomide and
R-CHOP (R2-CHOP), as R-CHOP is the standard treatment for most patients with B-cell
lymphomas. Briefly, both Phase I and Phase I/II trials confirmed the potential of the novel
combination, although a large multi-centre trial is required to confirm the results.
