G 3139 [GC 3139; Genasense™, BCL2 antisense oligonucleotide, augmerosen] is an antisense oligonucleotide developed by Genta in the USA. It is targeted towards the Bcl-2 protein, which is a potent inhibitor of apoptosis and is overexpressed in many cancers including, follicular lymphomas, breast, colon and prostate cancers, and intermediate/high-grade lymphomas.In August 2000, Genta received Orphan Drug status from the FDA for the use of G 3139 in the treatment of patients with advanced malignant melanoma. G 3139 already has ’fast track’ status with the FDA for this indication in combination with dacarbazine. In September 2001, G 3139 received Orphan Drug status from the FDA for a further three indications: multiple myeloma, acute myelocytic leukaemia, and chronic lymphocytic leukaemia, as well as fast track status for the use of G 3139 in the treatment of multiple myeloma. The company also received approval in Europe for its submitted clinical trial exemption, and the European Medicines Evaluation Agency (EMEA) has accepted Genta's new Orphan Drug Filings. G 3139 now has Orphan Drug status in Europe for the treatment of multiple myeloma and chronic lymphocytic leukaemia.Genta signed a 2-year manufacturing agreement, in December 2000, with Avecia Ltd., to supply it with quantities of G 3139.Clinical studies updateMalignant melanoma:A phase III trial of G 3139 in combination with dacarbazine is underway in patients with malignant melanoma, with the target number for patient enrolment of 270. A phase I/IIa trial of G 3139 and dacarbazine in the treatment of advanced malignant melanoma expressing Bcl-2 is nearing completion at the University of Vienna, Austria.Leukaemia:Genta is planning to pursue additional studies with G 3139 in other indications including chronic lymphocytic leukaemia, acute myelocytic leukaemia. Two trials were initiated in January 2001 in chronic lymphocytic leukaemia (as monotherapy) and acute myeloid leukaemia (in combination with gemtuzumab ozogamicin) at the MD Anderson Cancer Center in the US. Both trials involve patients who have relapsed from front-line therapy. Preclinical studies of G 3139 + gemtuzumab ozogamicin have confirmed the rationale behind this combination therapy. The addition of G 3139 to gemtuzumab ozogamicin greatly increases the number of leukaemia cells undergoing apoptosis compared with gemtuzumab ozogamicin alone. A phase III trial of G 3139vsstandard second-line chemotherapy with fludarabine and cyclophosphamide was initiated in February 2001 in 200 patients with chronic lymphocytic leukaemia. The study will be conducted at 60 centres in the US, Canada and Europe. A phase I study is underway in the US in patients with acute leukaemia who have relapsed or were refractory to standard chemotherapy. The study is being conducted under a NCI Cooperative Research and Development Agreement (CRADA) at Ohio State University. In this study, G 3139 is being used in combination with fludarabine and cytarabine.Multiple myeloma:Genta is conducting a phase III pivotal trial of G 3139 in combination with dexamethasone in the US.Non-Hodgkin's lymphoma:A phase I/II clinical trial (n = 20) has been completed at the Royal Marsden Hospital, London in collaboration with the Institute of Cancer Research, United Kingdom, for the treatment of non-Hodgkin's lymphoma. Genta has initiated a phase II study of the safety and efficacy of G 3139 in combination with conventional chemotherapy drugs at the aforementioned locations in the UK. This trial will enrol patients with non-Hodgkin's lymphoma that were resistant to a standard chemotherapy programme. A phase I/IIa study of G 3139 (administered in combination with cyclophosphamide) in patients with relapsed follicular non-Hodgkin's lymphoma began in 1999.Prostate cancer:Two phase I/IIa clinical trials of G 3139, at Memorial Sloan-Kettering Cancer Center and Sidney Kimmel Cancer Center, USA, are underway for the treatment of prostate cancer. Genta announced the initiation of two additional prostate cancer trials in the US in July 2000. The trials are to be conducted at the Institute for Drug Development, Cancer Therapy Research Center in San Antonio, Texas, and the Memorial Sloan-Kettering Cancer Center in New York. Both will evaluate the use of G 3139 in combination with docetaxel in men with advanced prostate cancer. Two phase I/IIa trials are also in progress at the BC Cancer Agency Vancouver Cancer Centre in Canada, for hormone-resistant metastatic prostate cancer (in combination with mitoxantrone) and relapsed follicular non-Hodgkin's lymphoma (in combination with cyclophosphamide).Other cancers:A phase I/II trial of G 3139, in combination with docetaxel, has been initiated at the Lombardi Cancer Center, Georgetown University Medical Center, Washington DC, USA, for the treatment of breast cancer. A phase I/II study of G 3139 in combination with paclitaxel is also underway at the University of Chicago Medical Center and Ohio State University Hospital, USA, in patients with small cell lung cancer. Genta and the NCI have signed a letter of intent to enter into a Cooperative Research and Development Agreement (CRADA) for the development of G 3139 in cancer. The collaboration will investigate the use of G 3139 in the treatment of colorectal and small cell lung cancers and relapsed or resistant leukaemia. In December 1999, Genta announced that the NCI had begun a phase I/II study of G 3139 in combination with irinotecan in patients with relapsed colorectal cancer. In October 2001, Genta announced that a preclinical trial conducted at the University of Vienna showed enhanced activity of cisplatin, in mice implanted with human stomach cancer, when it was used in combination withG 3139. A 50% increase in survival, and 70% larger antitumour effect was observed in the mice treated with cisplatin in combination with G 3139, compared to those treated with cisplatin only.A patent has been issued providing protection for the composition of G 3139 and its analogues.