Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial

Maria Teresa Solomn 4 Julio Csar Selva 2 Javier Figueredo 1 Jos Vaquer 8 Carolina Toledo 7 Nelson Quintanal 6 Silvia Salva 5 Rafael Domngez 10 Jos Alert 9 Jorge Juan Marinello 9 Mauricio Catal 1 Martha Gonzlez Griego 3 Juan Antonio Martell 3 Patricia Lorenzo Luaces 0 Javier Ballesteros 13 Niurys de-Castro 11 Ferdinand Bach 12 Tania Crombet 0 0 Center of Molecular Immunology , PO BOX 16040, Havana 11600 , Cuba 1 Center for Medical and Surgical Research , Havana , Cuba 2 Lucia Iniguez Hospital , Holguin , Cuba 3 National Center for Clinical Trials , Havana , Cuba 4 Calixto Garcia Hospital , Havana , Cuba 5 Hermanos Ameijeiras Hospital , Havana , Cuba 6 Luis Diaz Soto Hospital , Havana , Cuba 7 Maria Curie Hospital , Havana , Cuba 8 Arnaldo Milian Hospital , Santa Clara , Cuba 9 National Institute of Oncology and Radiobiology , Havana , Cuba 10 Saturnino Lora Hospital , Santiago de Cuba , Cuba 11 Institute of Pharmacy and Food , Havana , Cuba 12 Oncoscience AG , Wedel , Germany 13 University of the Basque Country , Havana , Spain Background: The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. Methods: A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. Results: The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. Conclusions: In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation. Trial registration: Cuban National Register for clinical trials (No. 1745) (http://registroclinico.sld.cu/ensayos). - Background High-grade gliomas (HGG) are the most common primary tumors in the central nervous system (CNS) in adults [1]. Despite remarkable advances in cancer research and in neurosurgery, radiotherapy and chemotherapy, these patients still face a poor prognosis, pointing towards an urgent need for new therapeutic approaches [2]. Standard treatment for HGG usually entails surgery followed by radiotherapy plus chemotherapy. Temozolomide is the drug of choice since 2005 for glioblastoma multiforme (GBM) patients [3], but unfortunately, it is not available in Cuba, due to the commercial restrictions imposed by the US embargo. However, since the survival benefit of radio-chemotherapy is so limited [4], patients with brain tumors are considered candidates for clinical trials that evaluate new drugs, radiosensitizers or new accelerated/hyperfractionated radiation schemes. Therefore, we decided to evaluate the efficacy of radiation plus an anti-EGFR antibody vs. radiation plus placebo in a controlled double blind trial, in newly diagnosed patients with grade III/IV astrocytomas. The Epidermal Growth Factor Receptor (EGFR) is a membrane-bound receptor that has been shown to have a major role in the pathogenesis and progression of different cancers [5]. EGFR is greatly expressed in HGG patients and gene amplification represents one of the most frequent alterations in this tumor type [6]. Moreover, EGFR plays a fundamental role in gliomagenesis. According Mazzoleni and co-workers, cancer stem cells (CSC) isolated from glioma patients, need to express EGFR to promote experimental tumorigenesis and EGFR-expressing initiating cells display the most malignant phenotype [7]. In summary, EGFR is well validated as a primary contributor of HGG initiation and progression [8]. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain. The antibody was obtained by humanization of the murine antibody ior egf/r3 [9]. Because nimotuzumab has a 10 fold lower affinity to the EGFR, as compared to cetuximab, its capacity to bind EGFR is heavily dictated by cell receptor density [10]. Nimotuzumab preclinical and clinical characterizations have been summarized before [11-13]. A distinguishing feature of nimotuzumab compared to other mAbs of the EGFR class, is the lack of severe skin toxicity as well as severe hypomagnesemia [14]. Two hypotheses have been posed to explain this lack of skin toxicity of nimotuzumab: according Garrido [10], nimotuzumab requires bivalent binding for stable attachment to the cellular surface, leading to selectively binding to cells that express moderate to high EGFR levels. Accordingly, nimotuzumab will selectively target tumors, and not normal tissues. Instead, Talavera built a computer model of the nimotuzumab-EGFR complex [15], where nimotuzumab blocks ligand binding, but allows the receptor to adopt its active conformation, warranting the basal level of signaling needed for the survival of non-tumor cells [15]. This type of binding is analogous to the binding of trastuzumab to the HER-2 receptor [16]. Nimotuzumab safety profile permits up to 800 mg doses in adults [17] or 150250 mg/m2 in children, without safety concerns [13]. In the nonclinical setting, nimotuzumab has been evaluated in the glioma cell line U87MG. Co-administration of the antibody with radiation increased the radiosensitivity, resulting in a delay of tumor growth. The antibody reduced angiogenesis and the total number of radioresistant cancer stem cells [18]. In a separate study, nude mice that had an intra-cerebral implant of the U87MG cell line were treated with nimotuzumab labelled with 111Indium. Radioactivity was measured after organ explantation. Results showed a clear time-dependant increase in 111indium nimotuzumab uptake in the tumour in contrast to all other organs [19]. The capacity of the antibody of crossing the bloodbrain barrier (BBB) was studied also by radioimmunscitigraphy using nimotuzumab labelled wi (...truncated)