EORTC Launches a Platform for pan-European Trials in Rare Tumors

Cutaneous T-cell lymphoma (CTCL) is a rare disease with an incidence on the order of one to two persons in 100 000. Consequently, trials designed to study CTCL have been small and sporadic; there is an umet need with respect to treatment for this disease. For some patients, CTCL is low level and life long, and the standard of care for early stage disease is skin-directed. However, there are no defined standards of care for advanced stages of the disease. There is a need for a large coordinated clinical research trial for CTCL, especially for recurrent patients and patients in the intermediate to advanced stages of the disease.

Due to the low incidence of CTCL, any study of this disease would need to establish broad international cooperation. Likewise, being able to organize an inclusive network of experts, one that has complementary areas of expertise, i.e., including dermatologists, pathologists, and lymphoma specialists, would be an advantage.

The Setting: A Rare Tumor and an Unmet Need

CTCL is a unique setting in which to address a rare tumor with a multidisciplinary treatment approach, clearly a setting targeted by EORTC scientific strategy. Therefore, the EORTC Headquarters Early Project Optimization Department (EPOD) coordinated efforts to support the Cutaneous Lymphoma Task Force in developing and implementing a scientific strategy that would result in clinical trials with strong translational research components and lead to improved standards of care for CTCL.

The EORTC CTCL European Platform is the result of this effort. It consists of three studies: one geared towards patients, such as newly diagnosed patients, who have not previously been treated for the disease, a second study designed to investigate whether a rational combination of treatment agents could overcome resistance or increase efficacy over monotherapies, and a third study for advanced stage patients who have progressed on prior systemic chemotherapy.

The Process: Developing the EORTC CTCL European Platform

EPOD orchestrated the development of this CTCL European platform in concert with Dr. Sean Whittaker, past Chair, Dr. Robert Knobler, former Chair, and Dr. Martine Bagot, Chair of the EORTC Cutaneous Lymphoma Task Force. The EORTC Cutaneous Lymphoma Task Force is the predominant European network for CTCL. It has set guideline standards for CTCL, has published key papers on treatment strategies for CTCL, and is seen as providing worldwide leadership in the field of primary Cutaneous Lymphomas. In terms of conducting clinical trials, the Cutaneous Lymphoma Task Force is in a unique position to federate European efforts to recruit patients and can rely on the expertise of the EORTC Headquarters in clinical trial operations and methodology.

The EORTC Cutaneous Lymphoma Task Force worked closely with EPOD at all stages of project development since September 2007. A strategy meeting was organized in January 2008 to gather experts in CTCL, from both the EORTC and internationally, in order to reach consensus on a master plan. A protocol development group was immediately formed, and outlines were developed.

Through EPOD’s efforts, pharmaceutical industry partnerships followed. Partnerships were formed with Celgene for the study geared towards patients who had not previously been treated for the disease, Merck and Johnson & Johnson for the study investigating whether a rational combination of treatment agents could overcome resistance or increase efficacy over monotherapies, and the European Group for Bone Marrow Transplantation (EBMT) for the study for advanced stage patients who had progressed on prior systemic chemotherapy. EPOD also facilitated contacts and discussions with international cooperative groups such as the National Cancer Institute of the US.

In September 2008 the EORTC CTCL European Platform was received enthusiastically and garnered overwhelming support from many institutions.

The Outcome

Within the EORTC CTCL European Platform, the phase III EORTC 21081 trial will focus on chemonaive patients with advanced disease. This trial will also include patients who have progressed from early stage disease or even patients who have been treated for early stage disease with treatments other than intravenous chemotherapy. The idea is to include patients likely to respond to debulking treatment (with either gemcitabine or liposomal doxorubicin chemotherapy, and optionally, local radiation therapy, if needed) and answer the question of whether it is possible to provide maintenance therapy that will slow down or halt disease progression. Following completion of the debulking therapy, patients are given lenalidomide (Revlimid™) as maintenance therapy for up to a year. Lenalidomide is now used clinically for the treatment of some kinds of myelodysplastic syndrome and multiple myeloma and has been used experimentally in other lymphomas with promising results.

In patients with mycosis fungoides or Sézary Syndrome for whom first line chemotherapy has failed, the phase III EORTC 21082 trial will compare progression free survival in patients receiving suberoylanilide hydroxamic acid (SAHA, Vorinostat™) in combination with bortezomib (Velcade™) to those receiving only SAHA. We know that essentially all patients with advanced stage CTCL will continue to progress on treatment, so this trial is designed to see if a rational combination of treatment agents can overcome resistance or increase efficacy over monotherapies. Here, the chosen combination of agents is SAHA with bortezomib. SAHA, which is approved by the FDA for the skin manifestations of CTCL, is a potent inhibitor of histone deacetylase, and addition or removal of histone acetyl groups influences whether specific genes are turned on or off. Bortezomib, meanwhile, inhibits the 26S proteosome, a mechanism by which proteins are degraded. Individually, SAHA and Bortezomib have been shown to be active against CTCL. Using SAHA and Bortezomib in combination has shown promise in both multiple myeloma and mantle cell lymphoma, and some smaller studies suggest that this synergistic approach might be effective for CTCL.

Finally, there are also plans in development with the EBMT to conduct a trial for patients with advanced CTCL who have progressed on prior systemic chemotherapy. Patients in this trial will receive a reduced intensity conditioning protocol followed by allogeneic stem cell transplant. An embedded study of photophoresis as a post-transplant maintenance treatment is also planned for this trial.

Coordinated strategic project development

The recipe for success in developing the EORTC CTCL European Platform was an EPOD coordinated strategic project development, the commitment of dedicated members of the Cutaneous Lymphoma Task Force, and the availability of a sound proposal that helped generate the interest of industrial partners.

John Bean, John Welch, Lucile Serfass, Sean Whittaker and Denis Lacombe on behalf of EORTC Headquarters and the Cutaneous Lymphoma Task Force