A phase II clinical trial of pegylated liposomal doxorubicin and carboplatin plus bevacizumab in patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer

Abstract

Objective

To assess the safety and efficacy of pegylated liposomal doxorubicin (PLD), carboplatin, plus bevacizumab in patients with ovarian, fallopian tube, or primary peritoneal cancer.

Methods

Patients with platinum-sensitive, recurrent disease received PLD 30 mg/m² and carboplatin area under the curve (AUC) 5 on Day 1 plus bevacizumab 10 mg/kg on Days 1 and 15 of every 28-day cycle, for a maximum of 10 cycles. The primary endpoint was objective response rate (ORR) [complete + partial response]; additional endpoints were safety, duration of response, progression-free survival (PFS), and time to progression (TTP).

Results

Of the 54 patients enrolled, 15 (27.8%) completed the study treatment as planned. Intent-to-treat (all enrolled patients) ORR was 72.2% (95% CI: 58.4, 83.5). Median duration of response was 11.9 months (95% CI: 9.3, not estimable) and median TTP was 13.9 months (95% CI: 11.4, 16.0). PFS was virtually the same as TTP. Three (5.6%) patients discontinued therapy due to disease progression, and another 3 (5.6 %) patients discontinued therapy due to serious adverse events (Grade 4 thrombocytopenia, Grade 3 small/large intestinal obstruction/small intestinal perforation, and Grade 3 abdominal abscess). Fifty (92.6%) patients had ≥ 1 adverse event of interest, most commonly neutropenia (42.6%), hypertension (37.0%), stomatitis (37.0%), proteinuria (37.0%), and palmar–plantar erythrodysesthesia (27.8%). No appreciable decreases in left-ventricular ejection fraction were observed.

Conclusion

Most patients responded to PLD, carboplatin, and bevacizumab combination therapy. The safety profile was consistent with the known toxicities of these agents. These findings present a potential treatment option for women with ovarian, fallopian tube, or primary peritoneal cancer.

Introduction

After cancer of the uterine corpus, ovarian cancer ranks second among gynecologic malignancies and accounts for approximately 3% of all cancers among women [1]. A majority of women with ovarian carcinoma are diagnosed with advanced-stage disease since early-stage disease is generally asymptomatic. Although most patients initially respond positively to surgery and first-line chemotherapy consisting of platinum- and taxane-based therapy, a majority of patients will eventually relapse with poor long-term survival [2], [3], [4], [5]. If relapse of advanced ovarian cancer occurs, the focus usually shifts to trying to extend life, control symptoms, and maintain quality of life. Prognosis for patients with this disease can often be determined from the length of time between the last dose of initial chemotherapy and recurrence of the disease. Patients who experience a relapse-free interval greater than 6 months from the initial platinum/taxane therapy are classified as having “platinum-sensitive” disease and will most likely respond positively to second-line chemotherapy treatment. Conversely, patients who relapse prior to 6 months from the last dose of initial therapy typically experience a worse prognosis and are considered to have “platinum-resistant” disease [6].

In patients with platinum-sensitive recurrent ovarian cancer (ROC), platinum-based combination therapy has become the standard. Several randomized trials have compared single-agent platinum therapy with platinum-based combinations [7], [8]. In parallel studies, the investigators from the International Collaborative Ovarian Neoplasm 4 (ICON4) and Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) 2.2 trials compared platinum plus with paclitaxel combination therapy with conventional platinum-based chemotherapy. When both trials were combined, paclitaxel and platinum treatment yielded superior improvements in median progression-free survival (PFS) (12 vs 9 months) and median survival (29 vs 24 months) when compared with conventional platinum-based therapy [8]. In the ICON4 trial, however, the study results have been challenged, given that the majority of patients had not received a taxane as part of their first-line therapy. A second study, AGO-OVAR 2.5, randomized patients with platinum-sensitive disease to carboplatin in combination with gemcitabine or to carboplatin alone. The combination arm was associated with an improved response rate (47.2% vs 30.9%) and PFS (8.6 vs 5.8 months) without a difference in overall survival (18.0 vs 17.3 months). In this study, the majority (70.8%) of patients were previously treated with a platinum–taxane regimen [9].

As all of these combination trials have had some limiting toxicities, such as peripheral neuropathy, myelosuppression, and mucositis, there was a need to explore other combinations with carboplatin. In addition, there has been a growing interest to study the effects of adding targeted therapies with differing mechanisms of action to enhance the activity of current cytotoxic regimens used in ovarian cancer to potentially further improve patient outcomes [10].

In patients with platinum-sensitive ROC, pegylated liposomal doxorubicin (PLD) as compared with topotecan was associated with significantly longer median PFS (28.9 vs 23.3 weeks, p = 0.037) and median overall survival (108 vs 71.1 weeks, p = 0.008) [11]. Moreover, studies have demonstrated favorable response and survival rates when PLD is combined with carboplatin for the treatment of recurrent, platinum-sensitive disease [12], [13], [14], [15].

Bevacizumab is a recombinant humanized immunoglobulin G1 monoclonal antibody that binds to and inhibits the activity of vascular endothelial growth factor (VEGF) [16]. The effects of bevacizumab for the treatment of ROC have been explored in several phase II clinical trials as a single agent [10], [17] and in combination therapy [18], [19]; however, no data currently exist to evaluate the efficacy and safety of bevacizumab in combination with carboplatin and PLD for the treatment of ovarian cancer. The need for a treatment combination with carboplatin that may be more effective and with fewer toxicities than previously studied regimens led to the development of this phase II, single-arm study in patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer.