Clinical trial to evaluate combination
regimen of recombinant human interleukin-7to treat metastatic
breast cancer
26 May 2011
Cytheris SA, a clinical stage biopharmaceutical company
focused on research and development of new therapies for immune
modulation, the Centre Léon Bérard (Lyon), the major cancer research and
treatment center for the Rhône-Alpes region of France, and ImmunID
Technologies SAS (Grenoble), a diagnostic company specialized in
innovative immunomonitoring tests and services, have announced
initiation of a Phase IIa clinical trial that will evaluate multiple
combinations of recombinant human interleukin-7 (CYT107), the
investigational multifunctional cytokine under development by Cytheris,
and a chemotherapeutic agent, XELODA (R) (capecitabine,
Roche/Genentech), in the treatment of metastatic breast cancer.
The trial is designed to explore the optimal schedule for delivery of
CYT107 during standard capecitabine chemotherapy, with the aim of immune
reconstitution and collection of preliminary data on the impact of
CYT107 on severe hematological toxicity and tumor progression in second
line metastatic breast cancer patients. The immunorestorative properties
of IL‑7, which include its ability to provide T cells to attack any
residual disease, are expected to have a significant impact on survival
in this patient population, where a low CD4 T cell count associated with
poor receptor diversity detected before initiation of chemotherapy is a
known predictive factor indicating overall survival of less than six
months compared to almost two years for non-lymphopenic patients.
Conducted as a collaborative effort of the Centre Léon Bérard (the study
sponsor), ImmunID Technologies, and Cytheris, the study, known as
ELYPSE-7, is designed to evaluate whether CYT107 treatment is able to
correct lymphopenia post-chemotherapy in advanced cancer patients and
whether the correction of this lymphopenia by restoration of the immune
system will result in a broadening of the repertoire of T cells and a
reduction in the risk of severe haematological toxicity, tumor
progression and early death.
The study is based on many years
of research conducted by the team of Jean-Yves Blay, MD, PhD, professor
of medicine at the Université Claude Bernard, Lyon, and the current
president of the European Organization for Research and Treatment of
Cancer (EORTC).
Lymphopenia (<1000 Lymphocytes/microliters) or
CD4+ T cell lymphopenia (<450/microliters) detected prior to initiation
of chemotherapy as well as Divpenia (R) (low diversity of the T cell
repertoire) are known to be predictive factors for toxicity and death in
patients with metastatic solid tumors. Correction of this condition
through an immunotherapeutic approach would therefore represent a
potential paradigm shift in the treatment of patients with various types
of cancer,” commented Dr. Blay. “In the SEMTOF trial, which included a
total of 70 metastatic breast cancer patients in first line treatment, a
low T cell receptor (TCR) repertoire diversity (Divpenia (R), as defined
and measured by ImmunID Technologies) was associated with a short
overall survival of up to six months. Median survival of severely
divpenic patients was less than six months, compared to more than 22
months for the remaining patients who were not in this severely
lymphopenic state. The outcome of the ELYPSE-7 study is thus expected to
have significant implications for overall survival and tumor progression
in patients with advanced cancers, including ovarian cancer, metastatic
breast cancer, non-Hodgkin lymphoma, and sarcoma.”
Qualitative
and quantitative alterations of local and circulating immune cells have
been identified as playing an important role in breast cancer
progression. In a series of studies including more than 3000 patients,
Dr. Blay’s team has shown that lymphopenia is found in 20-25 per cent of
patients with advanced cancers, including 20 per cent of untreated
patients with metastatic breast cancer. In a large series of patients it
was observed that lymphopenia is associated with a 20 per cent and 50
per cent risk of early death at one and three months and that T cell CD4
lymphopenia is also an independent risk factor for early death and
toxicity in these patients.
“In a recent review article
(Mackall C et al. Nat Rev Immunol. 2011 May; 11(5):330-42) entitled
“Harnessing the Biology of IL-7 for Therapeutic Application”, the
authors conclude that despite the impressive biological effects of IL-7
on T cell populations, the essential issue regarding clinical
development of this cytokine is the need to show that the biological
effects of IL‑7 translate to improved clinical outcomes such as
prolonged survival or cure,” said Michel Morre, DVM, president and CEO
of Cytheris. “Such proof of concept can only be obtained by carrying out
careful clinical trials in targeted populations who are at greatest risk
owing to T cell immunodeficiency, precisely the goal of the ELYPSE-7
study.”
About the Study
ELYPSE-7 is a randomised, monocentric,
double-blind Phase IIa study evaluating the impact of IL-7 immunotherapy
on CD4 lymphopenia and TCR repertoire diversity, risks of severe
haematological toxicity and tumor progression in metastatic breast
cancer patients. Twenty-four patients will be enrolled at a single
center (Centre Léon Bérard, Lyon, France) where the study is under the
direction of Isabelle Ray-Coquard, MD, PhD, principal investigator.
The duration of the investigation for each patient will include a
study drug treatment period of at least 12 weeks (including three x
three-week cycles of chemotherapy) and a follow-up period for a
maximum of one year (or until disease progression). Chemotherapy
will be extended until disease progression, unacceptable toxicity,
or willingness to stop. The inclusion period is expected to be six
months with the treatment period and follow-up lasting up to one
year.
All patients will receive standard anti-cancer therapy prescribed
for second line metastatic breast cancer patients: XELODA (R)
(capecitabine) at an oral dose of 2500mg/day for 14 days over a
21-day cycle period. In addition, all patients will be randomly
allocated in a factorial design to one of the following four study
arms:
- Arm one: (Placebo Group) Patients will receive Placebo
before the start of chemotherapy (at D0, D7 and D14) and during
the third cycle of chemotherapy (D63, D70 and D77).
- Arm two: (Pre-IL-7 Treatment Group) Patients will receive
CYT107 (one subcutaneous injection at ten micrograms/kg/week for
three weeks) before the first cycle of chemotherapy (at D0, D7
and D14) and will receive the placebo during the third cycle of
chemotherapy (D63, D70 and D77).
- Arm three: (Concomitant IL-7 Treatment Group) Patients will
receive Placebo before the first cycle of chemotherapy (D0, D7
and D14) and will receive CYT107 (one subcutaneous injection at
ten micrograms/kg/week for three weeks) during the third cycle
of chemotherapy (at D63, D70 and D77).
- Arm four: (Pre- and Concomitant IL-7 Treatment) Patients
will receive CYT107 (one subcutaneous injection at ten
micrograms/kg/week for three weeks) before the first cycle of
chemotherapy (D0, D7 and D14) and again (one subcutaneous
injection at ten micrograms/kg/week for three weeks) during the
third cycle of chemotherapy (D63, D70 and D77).
The primary endpoint of the study is the evolution of patient CD4
counts from D0 to W12 with repeated measures at D0, W3, W9, and W12.
This will help in defining the optimal schedule of CYT107
administration during chemotherapy, based on the restoration of
patient CD4 counts.
Secondary endpoints include the impact of CYT107 treatment on the
incidence of severe hematological toxicity as indicated by the
number of patients experiencing any type of hematological Adverse
Event (including anemia, thrombopenia, lymphopenia, or neutropenia)
of Grade ≥ three from D0 to W12. At this stage, the quality of T
cell repertoire diversity reconstitution will also be assessed.
About Recombinant Human
Interleukin-7 (CYT107)
Recombinant human interleukin-7
(CYT107) is a critical immune-modulator for immune T-cell recovery
and enhancement. As a growth factor and cytokine physiologically
produced by marrow or thymic stromal cells and other epithelia, IL-7
has a critical and, at some steps, a non-redundant stimulating
effect on T lymphocyte development, notably on thymopoiesis and,
downstream from the thymus, on homeostatic expansion of peripheral
T-cells.
Clinical trials including more than
180 patients in Europe, North America, South Africa and Taiwan have
demonstrated the potential of IL-7 to expand and protect CD4 and CD8
T-cells. Currently, Cytheris is conducting multiple international
investigations of IL-7 in HIV, HCV, HBV, post-BMT and cancer.
Additional studies include a NIAID/NIH-sponsored trial (ICICLE) in
idiopathic CD4 lymphocytopenia (ICL); a cancer vaccine study in
children with Ewing's sarcoma family of tumors or similar genetic
tumors sponsored by US National Cancer Institute; and, a
multi-company/institutional study (EraMune 01) sponsored by ORVACS
(the international HIV organization funded by the French Bettencourt
Schueller Foundation) aimed at attacking the HIV viral reservoir.
Source: Cytheris