Ovarian cancer is an important health concern worldwide, it is the fourth leading cause of cancer mortality among women and the majority of patients present with advanced disease.
Since the mid-1990s, maximal surgical debulking in combination with platinum/taxane chemotherapy has been the standard of care in advanced ovarian cancer. But while most women have initial chemosensitivity, more than 70 per cent of patients with advanced disease will experience recurrence within five years.
Immunotherapy
Immunotherapy is a new class of cancer treatment that targets the innate powers of the immune system. Immunotherapies have the potential to be more effective than current treatment by offering longer-term protection against the disease with fewer side effects. However, the use of immunotherapies in ovarian cancer has been hit-and-miss.
Prima BioMed is developing an intradermal cancer vaccine (CVac) that contains dendritic cells primed with a proprietary mannan-MUC1 conjugate, primarily as a maintenance therapy administered after chemotherapy and/or surgery, to delay relapse and control metastases in patients with ovarian cancer. Preliminary data from a phase IIb trial (CAN-003) in patients with epithelial ovarian cancer in first or second remission indicated that vaccine recipients tended to stay in remission longer than those who received standard care. These results lead to the initiation of the registrational phase II/III trial (CANVAS) in patients with advanced ovarian cancer in remission following first-line chemotherapy after optimal debulking surgery (CAN-004). This study is expected to be completed in 2015 and results are eagerly anticipated.
Chemotherapy
There is ample evidence to indicate that angiogenesis is important to the development, progression and poor prognosis of ovarian cancer. Anti-angiogenic agents examined include vascular endothelial growth factor (VEGF) pathway inhibitors (including monoclonal antibodies [mAbs]), tyrosine kinase inhibitors (TKIs), and a soluble receptor decoy, as well as inhibitors of other angiogenic factors and vascular disrupting agents. At present, only one angiogenic inhibitor is approved for the treatment of ovarian cancer. Phase III data of Roche’s VEGF-targeted mAb Avastin (bevacizumab) has demonstrated the efficacy and tolerability of bevacizumab in both the first-line and relapsed settings.
However, no targeted therapies are currently approved in the US for maintenance treatment of ovarian cancer. GlaxoSmithKline’s Votrient (pazopanib) is a multi-kinase angiogenesis inhibitor that not only inhibits the VEGF receptor-2, but also targets platelet-derived growth factor receptor (PDGFR) and c-kit. Initial phase III results of maintenance pazopanib therapy in women with epithelial ovarian, fallopian tube or primary peritoneal cancer are promising, with a significant improvement in progression-free survival (PFS), compared with placebo.
Boehringer Ingelheim’s nintedanib is an orally available, indolinone derivative that suppresses tumour growth by inhibiting three kinases involved in the development of tumour blood vasculature: VEGFR 1, 2 and 3, fibroblast growth factor receptor 1, 2 and 3 (FGFR 1–3) and PDGFR alpha and beta. A phase III multicentre, double-blind, randomised trial investigating the efficacy and safety of nintedanib in combination with carboplatin and paclitaxel, followed by nintedanib maintenance therapy, in patients with advanced ovarian cancer is underway and is expected to be completed in July 2016.
Amgen/Takeda’s trebananib is a recombinant peptide-Fc fusion protein that inhibits the interaction of the endothelial cell-selective Tie2 receptor with its ligands, angiopoietin 1 and 2. Trebananib appears to be closer than nintedanib to approval, given that the primary endpoint (PFS) was achieved in the phase III TRINOVA-1 trial. In this trial, 919 patients with recurrent ovarian, primary peritoneal or fallopian tube cancers were randomised to receive trebananib in combination with paclitaxel, or placebo plus paclitaxel. The key secondary endpoint of overall survival is expected to mature in 2014. Two other phase III studies are ongoing to assess the efficacy of trebananib in combination with paclitaxel and carboplatin as first-line treatment (TRINOVA-3), or that of liposomal doxorubicin ± trebananib in women with recurrent, partially platinum-sensitive or -resistant ovarian cancer (TRINOVA-2).
Monoclonal antibodies
The future of two mAbs with orphan status for ovarian cancer in the EU and US remains uncertain. Menarini Biotech’s abagovomab and Morphotek/ Eisai’s farletuzumab have both had disappointing results in late-stage clinical trials. A large phase II/III trial (MIMOSA) of abagovomab maintenance therapy had been initiated in patients with stage·III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancers after complete response to first-line chemotherapy. Farletuzumab had also entered global phase III trials, in combination with carboplatin and a taxane, in patients with platinum-sensitive ovarian cancer. However, phase III results from both trials failed to achieve their primary endpoints and it appears that the companies are still assessing their options in terms of future development of these mAbs.
Other novel chemotherapeutic agents
Approximately 80–90 per cent of ovarian cancer has been demonstrated to over-express folate receptors. Endocyte’s vintafolide is a folate-targeted conjugate composed of a folate molecule plus a vinca alkaloid, which acts as a microtubule destabilising agent. Vintafolide targets and enters cancer cells via the folate vitamin receptor, which is overexpressed by many types of tumours, while avoiding most normal cells. Once taken up by cancer cells, the microtubule destabilising agent exerts its cytotoxic effects. Phase III studies of vintafolide for the treatment of platinum-resistant ovarian cancer are underway, and Endocyte has filed for EU marketing approval of vintafolide and its companion diagnostic (technetium Tc99m etarfolatide), for use in patients with folate receptor-positive, platinum-resistant ovarian cancer.
A recent entrant into the late-stage ovarian cancer pipeline is Array BioPharma’s MAP kinase inhibitor, ARRY 162. A phase III trial (MILO) is underway to compare ARRY 162 to standard chemotherapy in the treatment of recurrent or persistent low-grade serious ovarian, fallopian tube or peritoneal cancer. US enrolment is underway, with other global sites expected to follow.
BioNumerik Pharmaceuticals’ cositecan is a fourth-generation camptothecin derivative that is a highly lipophilic, DNA topoisomerase I inhibitor. It has been designed to avoid the problems experienced with other camptothecins, such as low oral bioavailability, toxicity, unfavourable metabolism and drug resistance and a global phase III trial in advanced ovarian cancer has been completed. Results of this study have not yet been reported.
Novogen/MEI Pharma’s idronoxil is a isoflavone phenolic hormone analogue derived from genistein. In ovarian cancer, idronoxil selectively inhibits the key pro-survival signalling pathway operating via sphingosine-1-phosphate (S-1-P) and Akt, thereby preventing phosphorylation of key anti-apoptotic proteins such as XIAP (X-linked inhibitor of apoptosis protein). Loss of activity of these proteins restores the ability of chemotherapy-resistant tumour cells to undergo apoptosis in response to chemotherapy. Although a pivotal phase III trial of oral idronoxil in ovarian cancer did not meet the primary or secondary endpoints, MEI Pharma intends to continue development in this indication with the intravenous (IV) formulation of idronoxil.
New formulations of approved treatments
Two formulations of paclitaxel are in phase III development for ovarian cancer. Oasmia Pharmaceutical is developing an encapsulated formulation of paclitaxel for IV administration, based on its micellar platform. Paclitaxel is encapsulated in XR-17 (a compound consisting of two isomeric retinoyl derivatives) and dissolved in Ringer-Acetate solution. As a result of encapsulation, no pre-medication or chemical solvents are needed to administer the drug and the risk of hypersensitivity reactions to paclitaxel is reduced. In addition, XR-17 has detergent-like properties and could affect P-glycoprotein drug binding and reverse the multi-drug resistance mechanism. Initial results of a phase III trial are promising and have been used to support regulatory submission which has been made with the Russian authorities for the treatment of ovarian cancer.
Cell Therapeutics’ paclitaxel poliglumex consists of a biodegradable polyglutamate polymer linked to paclitaxel. By linking paclitaxel to a biodegradable amino acid carrier, the conjugated chemotherapeutic agent is inactive in the bloodstream, sparing normal tissues the toxic side effects of chemotherapy. Blood vessels in tumour tissue are more porous to macromolecules than in normal tissue, thus allowing paclitaxel poliglumex to enter the tumour. Paclitaxel is then activated and released once inside tumour tissue by the action of an enzyme called cathepsin B. A US-based phase III trial evaluating paclitaxel poliglumex as a first-line maintenance therapy for women with ovarian, fallopian tube or peritoneal cavity cancers who have achieved complete remission following standard first-line chemotherapy, is underway and enrolment completion is planned for later in 2013.
Although standard platinum-based chemotherapy results in high response rates, more than 70 per cent of patients with advanced disease will experience recurrence within five years. To address this issue Regulon is developing a liposomal formulation of cisplatin, using its proprietary encapsulation technology. The compound has been shown to preferentially target and fuse with human tumour tissues, thereby delivering its cytotoxic payload more specifically and with less cytotoxicity than naked cisplatin. Phase III clinical trials for ovarian cancer are underway in the US, China and Europe. No results of the phase III trial have been reported yet.
In conclusion, the last couple of years have seen a considerable focus on researching novel treatment strategies to increase survival in ovarian cancer, leading to several promising agents reaching the late-stage of development. In addition, the earlier clinical development landscape is active, with over 50 agents in phase II development. With the majority of these new agents, they will be part of novel treatment strategies that increase primary efficacy, decrease recurrence after primary treatment and improve the response rate for recurrent disease. If a clear clinical advantage can be demonstrated (particularly in the maintenance of remission) with these agents, then their additional costs may be considered worthwhile.