Ovarian cancer accounts for approximately 3% of all cancers in women and is the fifth leading cause of cancer-related deaths among women with an estimated 22,000 new cases and 14,600 deaths in the U.S. in 2009 [1
]. The standard initial treatment of patients with advanced ovarian cancer, cytoreductive surgery, followed by combination chemotherapy with platinum and paclitaxel, has resulted in response rates of 70% and a median survival of 37 months [2
]. Despite the activity of this combination chemotherapy as first-line treatment, the majority of patients experience recurrence and die of chemotherapy-resistant disease [4
]. One of the challenges confronting oncologists is the management of persistent or recurrent platinum resistant disease.
Platinum refractory or resistant ovarian cancer is defined by the Gynecologic Oncology Group (GOG) as persistent disease or progression within 6 months following platinum-based therapy, and is associated with a low response rate to further treatment, responses of short duration, and a median survival of less than 1 year. The treatment options for platinum resistant patients are limited [5
]. The most widely used approved drugs for this indication are topotecan and pegylated liposomal doxorubicin (PLD). A randomized phase 3 trial comparing these agents showed modest improvement in survival for PLD as compared to topotecan in platinum-sensitive patients [6
]. However, in the platinum resistant population, the objective response rates (ORR) for PLD and topotecan were 12.3% and 6.5%, respectively, which correlated with a median progression-free survival (PFS) of 9.1 weeks and 13.6 weeks and a median survival of 35.6 weeks and 41.3 weeks, respectively [7
]. The frequencies of grade 4 drug related adverse events (AEs) were 71.1% for topotecan and 17.2% for PLD. Combination chemotherapy has not been demonstrated to be better than single-agent therapy in the few small phase 2 studies performed in platinum resistant ovarian cancer. These studies reported increased toxicity without an impact on survival in this population. Platinum resistant ovarian cancer continues to represent a significant unmet medical need requiring the development of new agents and regimens.
Canfosfamide HCl for injection (TELCYTA®
, TLK286), a novel glutathione analog, is currently being developed for the treatment of cancer. Canfosfamide is a conjugate of a glutathione (GSH) analog and an N,N,N',N'-tetrakis(2-chloroethyl) phosphorodiamidate that was designed to be metabolically activated by glutathione-S-transferase P1-1 (GST P1-1), an enzyme that is over-expressed in many human cancers including ovarian cancer. The active cytotoxic phosphorodiamidate is released after cleavage by GST P1-1 [8
]. Canfosfamide treatment, therefore, may result in selective delivery of the cytotoxic moiety to ovarian cancer cells by exploiting the elevated enzymatic activity of GST P1-1 present in these cells.
Preclinical studies showed that canfosfamide inhibited the growth and was cytotoxic to a wide range of established cancer cell lines including those derived from ovarian cancer (OVCAR3, HEY, SK-OV-3) [14
]. Canfosfamide treatment inhibited cancer cell proliferation and induced apoptosis through the activation of the cellular stress response kinase pathway. The molecular events that preceded apoptosis included the activation of stress-activated kinases, including the phosphorylation of the mitogen-activated protein kinase (MAPK) signaling protein, mitogen activated protein kinase kinase 4 (MKK4), in canfosfamide treated cells, as well as the activation of jun-N-terminal kinase (JNK), p38 MAP kinase and caspase 3 [14
The cytotoxic activity of canfosfamide correlated with the expression of GST P1-1. Cancer cells in which GST expression levels were increased by transfection with the GST P1-1 gene, were more sensitive to the cytotoxic effects of canfosfamide than the parental cell lines [16
]. Canfosfamide exhibited increased cytotoxic activity in vitro and in vivo against tumors derived from cancer cells and induced to express elevated levels of GST P1-1, including those with elevated GST P1-1 as a result of acquired resistance to doxorubicin [16
]. Canfosfamide treatment inhibited tumor growth in a range of established human cancer xenografts including those derived from human ovarian cancer.
Canfosfamide was not cross-resistant to carboplatin, cisplatin or paclitaxel in OVCAR3 human ovarian cancer cells [18
]. Canfosfamide treatment synergistically enhanced the cytotoxicity in vitro of a variety of chemotherapeutic agents with different modes of action, including carboplatin, doxorubicin, paclitaxel, and gemcitabine [19
In addition to its favorable preclinical profile, canfosfamide has additional attributes that suggest it would be of interest to evaluate its clinical activity in combination with PLD in platinum resistant ovarian cancer. Canfosfamide has shown single-agent activity in heavily pretreated platinum resistant ovarian cancer patients with an ORR of 15% (95% CI, 5-31) and 19% (95% CI, 7-36) on 2 dose schedules of every 3 weeks and weekly therapy, respectively, by Response Evaluation Criteria In Solid Tumors (RECIST), including a durable complete response (CR) in a platinum refractory patient [20
]. Canfosfamide has been well tolerated in these patients, who often have limited bone marrow reserves or neuropathic residual toxicities. Canfosfamide is generally non-myelosuppressive at the recommended dose and dose schedule and does not have overlapping toxicities with PLD suggesting that canfosfamide should not compromise the dose of PLD. In addition to the preclinical synergy observed with the combination of canfosfamide and doxorubicin in human ovarian cancer cells [19
], doxorubicin has been shown in vitro to increase the expression of GST P1-1 [22
], and consequently, facilitates the activation of canfosfamide. Since canfosfamide has shown activity over a wide range of dose schedules, a clinically-convenient dose schedule of canfosfamide in combination with PLD could be administered every 4 weeks. A phase 1 dose escalation study of canfosfamide at a dose of 500 mg/m2
, 750 mg/m2
, or 960 mg/m2
was administered intravenously (IV) followed by PLD at 40 or 50 mg/m2
IV every four weeks. The primary endpoints of the Phase 1 study were to determine the safety and maximum tolerated dose (MTD) of the combination. There were no dose limiting toxicities (DLTs). The MTD was full doses of both agents. Full doses of canfosfamide in combination with PLD were administered in 88.4% and 87.3% of cycles, respectively. The most common reasons for dose reductions were neutropenia and/or thrombocytopenia as expected with PLD administered at 50 mg/m2
. There were no unexpected or cumulative toxicities [23
Based on the above rationale, this study was conducted to evaluate the safety and efficacy of the combination of canfosfamide with PLD in patients with platinum resistant ovarian cancer.