Clinical and pharmacokinetic phase II study of pegylated liposomal doxorubicin and vinorelbine in heavily pretreated recurrent ovarian carcinoma

D. Katsaros1,*, M. V. Oletti2, I. A. Rigault de la Longrais1, A. Ferrero3, A. Celano2, S. Fracchioli1, M. Donadio4, R. Passera5, L. Cattel5 and C. Bumma2

1 Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, and 5 Department of Science and Drug Technology, University of Turin, Turin; 2 Department of Oncology, San Giovanni Antica Sede Hospital, Turin; 3 Division of Obstetrics and Gynecology, Gynecologic Oncology Unit, Mauriziano Hospital, University of Turin, Turin; 4 Department of Medical Oncology, COES, San Giovanni Battista Hospital, Turin, Italy

* Correspondence to: Dr D. Katsaros, Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, University of Turin, Via Ventimiglia 3, 10126 Turin, Italy. Tel: +39-011-3134459; Fax: +39-011-3134859; Email: dhocc{at}libero.it


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: This multicenter phase II study evaluated feasibility, clinical efficacy, toxicity and pharmacokinetics of the combination of pegylated liposomal doxorubicin (PLD) and vinorelbine (VNR) in patients with platinum–paclitaxel pretreated recurrent ovarian cancer.

Patients and methods: All patients received prior treatment with platinum and paclitaxel. Thirty-two heavily pretreated (median number of chemotherapy regimens two, range one to six) ovarian cancer patients received treatment with PLD 30 mg/m2 and VNR 30 mg/m2 every three weeks for six cycles. Ten patients entered the pharmacokinetic study, five receiving the PLD–VNR and five the VNR–PLD sequence.

Results: In 30 patients evaluated for response and toxicity, the overall response rate was 37% and 10% of patients achieved stable disease. Median time to progression and overall survival were 5.5 months (range 1–10) and 9 months (range 2–16), respectively. Toxicity was generally mild and reversible. VNR AUCtot and plasma levels were considerably higher in the PLD–VNR sequence.

Conclusions: The PLD–VNR regimen exhibits significant activity in heavily pretreated patients, is well tolerated and is associated with encouraging survival. Preliminary pharmacokinetic results suggest the PLD–VNR sequence for further clinical applications. This regimen should be considered as a treatment option in patients with chemotherapy-resistant ovarian cancer.

Key words: ovarian cancer, pegylated liposomal doxorubicin, pharmacokinetics, relapse, survival, vinorelbine


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
For more than 15 years, platinum-based combination chemotherapy has been the gold standard for first-line treatment of advanced epithelial ovarian cancer following cytoreductive surgery [1Go, 2Go]. Despite the high response rate (up to 70%), the majority of patients with advanced ovarian cancer will die of their recurrent disease. Second-line (or further) treatment will thus be administered to a large number of patients. The impact of second-line treatment on survival is generally not very significant, in particular in platinum-resistant or platinum-refractory cases [3Go]. Many different chemotherapeutic agents have been proposed as second-line treatment, but even the most promising of these, such as topotecan, gemcitabine and etoposide, show response rates ranging from 20% to 30%, while time to progression is generally short. New therapeutic agents and combinations are thus still under study, in order to enhance both survival and quality of life in this subset of patients.

Anthracyclines are active against epithelial ovarian cancer, although their role in first-line chemotherapy is still being debated [4Go]. Recently, the AGO-GINECO intergroup demonstrated that the addition of epirubicin to the combination paclitaxel–carboplatin used as first-line treatment of ovarian cancer did not result in a higher overall response rate, progression-free and overall survival, but induced higher toxicity and generated additional costs [5Go].

Liposomal doxorubicin (PLD) is a preparation of doxorubicin hydrocloridic acid that is encapsulated in pegylated liposomes to reduce recognition by the immune system, thus increasing serum half-life and reducing toxicity. Pegylated liposomes have a longer half-life than non-pegylated liposomes because of the coating of methoxipolyethylene glycol polymers, which prevents liposomal detection and destruction by the reticuloendothelial system [6Go]. The release of free drug from the liposomes generally occurs in the range between some days and weeks: the tumor cells are thus exposed to the drug for a much longer period than in the standard 3-week regimen with traditional anthracyclines, the free levels of which drop quickly 24 h after intravenous (i.v.) administration [7Go]. Preclinical studies have reported the superiority of liposomal doxorubicin over free doxorubicin in human ovarian cancer [8Go], and activity against several other tumors [9Go].

Phase II clinical trials in which PLD is used as single agent in the second-line setting have shown response rates (RRs) from 15% to 31% [10Go, 11Go]. The results of a recent phase III trial comparing PLD and topotecan as single agents in recurrent epithelial ovarian carcinoma led to the conclusion that PLD is at least as effective as topotecan in platinum-refractory/resistant ovarian cancer, with a statistically significant survival advantage in platinum-sensitive patients. The toxicity profile of PLD was also significantly better than that of topotecan [12Go, 13Go]. Combinations of PLD with other drugs in the second-line treatment of ovarian cancer are still under study, and as yet no randomized trials with PLD in the second-line setting have been reported. D'Agostino et al. [14Go] recently published promising results of the combination of PLD and gemcitabine, showing an RR of 25% among the platinum-resistant and 45.2% in the platinum-sensitive group. With a similar combination, Goff et al. [15Go] obtained an RR of 24%.

Vinorelbine (VNR) is a vinca alkaloid derivative that shows a better toxicity profile than vincristine and promising activity against advanced epithelial ovarian cancer. Its activity has already been demonstrated by some phase II studies using VNR as single agent in recurrent ovarian cancer [16Go, 17Go].

Many phase I and II studies have been conducted to assess the feasibility and efficacy of combinations of VNR and other cytotoxic agents in recurrent ovarian cancer [18Go, 19Go].

A recent dose-finding study evaluated the combination of PLD and VNR for the treatment of refractory or resistant epithelial ovarian cancer, obtaining an RR of 20.7%, and suggested doses of 30 mg/m2 for PLD on day 1 and of 25 mg/m2 for VNR on days 1 and 8 [20Go].

PLD and VNR have been widely studied to determine their clinical pharmacokinetic (PK) profile in monotherapy, without evaluating any possible interactions [21Go, 22Go]. Both drugs act as P-glycoprotein (P-gp) substrates, being excreted by hepato-biliary pathways. At the same time, PLD liposomal components act as P-gp inhibitors, increasing intracellular PLD accumulation [23Go]; consequently, sequential administration could generate an interaction during the elimination phase. This study investigated the PK interaction between VNR and PLD by administering these drugs in the opposing sequences: PLD–VNR and VNR–PLD.

Based on these very promising data on the efficacy and feasibility of PLD (platinum-sensitive and -resistant patients) alone and in combination with other cytotoxic drugs (VNR, mainly in the platinum-resistant disease), we conducted a clinical and pharmacokinetic phase II multicenter trial of pegylated liposomal doxorubicin (Caelyx®) and VNR (Navelbine®) in heavily pretreated ovarian cancer patients, assessing feasibility, toxicity, efficacy and survival.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
The study was designed as a prospective, multicenter phase II trial. Between February 2001 and October 2003, 32 patients were enrolled in seven Italian centers. Eligibility criteria were: age between 18 and 70 years; platinum- and taxane-pretreated epithelial ovarian cancer; progressive disease with measurable or evaluable disease documented through imaging procedures; life expectancy >3 months; adequate bone marrow, renal and hepatic functions; normal cardiac function evaluated by both ECG and echocardiography (with ejection fraction >52); Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; and written informed consent.

Exclusion criteria were: patients previously treated with anthracyclines (maximum dose 360 mg/m2 for doxorubicin); previous or concurrent neoplasm other than ovarian (with the exception of cutaneous basalioma and cervical intraepithelial neoplasia); and severe cardiac dysfunction or uncontrolled hypertension.

The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines, and was approved by the local ethics committees.

All enrolled patients underwent clinical, serological and imaging evaluation of relapse prior to treatment administration.

Treatment plan
VNR (Navelbine®) was administered at 30 mg/m2 on day 1 every 3 weeks, as an i.v. infusion over 15 min, after dilution in 100 ml normal saline, and PLD (Caelyx®) was administered at 30 mg/m2 on day 1 every 3 weeks, as an i.v. infusion over 30 min, after dilution in 250 ml 5% glucose. Standard antiemetic treatment was given to all patients. Delays or dose modifications were based on toxicity present on each treatment day. Palmar–plantar erythrodysesthesia (PPE) was prevented by oral administration of corticosteroids during the first week after infusion and pyridoxine 100 mg/day during intervals between cycles [12Go]. Treatment was continued for six cycles unless progression, unacceptable toxicity or patient refusal intervened.

Toxicity was evaluated following the National Cancer Institute Common Toxicity Criteria [24Go]. Hematological toxicity was evaluated weekly by complete blood count, while non-hematological toxicity was assessed before each cycle.

PK evaluation
PK were evaluated in 10 patients: the two drugs were administered at standard doses in the opposing sequences (five patients PLD–VNR and five VNR–PLD). Evaluation was carried out during the first cycle of treatment. Only one patient was given both sequences, as an internal control, during the first and second courses of chemotherapy. In the PLD–VNR schedule, i.v. infusion times were 30 min for PLD and 15 min for VNR; blood samples were drawn at 0, 30, 60, 75, 90, 135 and 165 min. In the VNR–PLD sequence, i.v. infusion times were 15 min for VNR and 30 min for PLD; blood samples were drawn at 0, 15, 45, 65, 75 and 105 min. VNR was analyzed through a modified high-performance liquid chromatography procedure [25Go]. To calculate PK parameters, we used a non-compartmental approach with Kinetica 4.1 software (Innaphase Corp., Philadelphia, PA, USA). Statistical analysis was through a non-parametric approach (Mann–Whitney test), using Instat 3.05 software (GraphPad Software, San Diego, CA, USA).

Response assessment
Staging procedures included standard physical examination, ultrasound and computed tomography scan of the abdomen and pelvis, and two-view chest X-ray. Objective responses were evaluated after three cycles and at the end of planned treatment by repeating the staging procedures following the Response Evaluation Criteria for Solid Tumors (RECIST) [26Go]. CA125 levels were evaluated at baseline and after each cycle. Patients who showed disease progression after three cycles were taken off treatment. Response criteria were defined as follows. Complete response: disappearance of all known disease lesions for at least 1 month; partial response: ≥50% decrease of known lesions, without appearance of new ones, for a minimum of 4 weeks; stable disease: >25% decrease or <25% increase of known lesions, without appearance of new ones; progressive disease: >25% increase of any known lesion or appearance of any new one.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients characteristics
Between February 2001 and October 2003, 32 patients entered the study. Patient characteristics are summarized in Table 1. Thirty patients were evaluable for toxicity and response, while two were excluded from the study due to allergic reaction during the first cycle. Median age of patients was 61.5 years (range 42–77; mean 60.34). All patients had advanced disease at the time of first diagnosis (21 stage IIIc, 11 stage IV). Histological types were distributed as follows: 25 serous papillary carcinomas, four undifferentiated tumors, two mucinous and one Mullerian carcinoma. All patients had undergone first-line standard treatment with platinum/taxane regimens. Median progression-free survival was 17.5 months (range 1–43; mean 16.3). Patients enrolled in this study were heavily pretreated, with a median of two previous chemotherapy regimens (range one to six). Site of local or distant relapse included lymph nodes in nine patients, liver in 10, spleen in five, lung in three and skin in one patient, while eight peritoneal carcinomatosis and nine pelvic recurrences were also recorded.


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Table 1. Patient characteristics and response to chemotherapy
(n=32; evaluable patients = 30)

 
Toxicity and compliance with treatment
A total of 148 chemotherapy cycles were administered to the 32 enrolled patients (median four per patient; range one to nine). Overall treatment was well tolerated in this heavily pretreated population. Main toxicities (Table 2) included: alopecia, fatigue, nausea, anemia, leucopenia and PPE. Severe toxicities only occurred in a few patients (one grade 4 and one grade 3 PPE, two cycles with grade 3–4 neutropenia for one patient). There were no treatment-related deaths. Two patients discontinued treatment after one cycle due to allergic reaction, and were excluded from further analyses. Twelve patients discontinued treatment after three cycles owing to evidence of progressive disease.


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Table 2. Toxicity report (number of events)

 
Response
The overall RR was 43.3% after three cycles and 36.7% at the end of treatment (six cycles) (Table 1). Of the 30 evaluable patients, after three cycles of treatment there were nine cases of progressive disease (30%), eight of stable disease (26.7%) and 13 partial responses (43.3%). These data changed at the end of the planned treatment (six cycles) to a total of 16 cases of progressive disease (53.5%), three of stable disease (10%) and 11 (36.7%) responses (10 partial and one complete). The median time to progression for the group as a whole was 5.5 months (range 1–10). During follow-up, we observed 18 disease-related deaths, for a median overall survival of 9 months (range 2–16) as of December 2003, after completion of the planned protocol treatment (see Figure 1).



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Figure 1. Time to progression (TTP) and overall survival (OS) probability for treated patients.

 
Although the trial was not designed to evaluate activity in subsets of patients, it is significant that activity was encouraging in patients with both platinum/paclitaxel-resistant (n=12) and in those with sensitive disease (n=20). We observed same proportion of partial remissions and progressive disease in the resistant group (3/12 and 6/12, respectively) and sensitive group (8/20 and 10/20, respectively). RRs for evaluable patients were also related to various pretreatment characteristics, i.e. performance status (0 versus 1 or 2), number of metastatic sites (one versus more than one), number of previous chemotherapy regimens (two versus more than two) and interval from previous chemotherapy (<6 versus > 6 months). No statistically significant differences were detected.

PK results
On comparing the opposing sequences, some PK parameters of VNR were found to be statistically different (Table 3): in the PLD–VNR sequence, both clearance and elimination rate constant (Kel) were clearly lower. Consequently, a dramatic increase in drug plasma disposition was observed, as is revealed by the total area under the curve (AUCtot) value (P=0.0079). Volumes of distribution were not affected, thus showing that VNR clearance was influenced only by Kel. The maximum plasma concentration (Cmax) was more than double, confirming previous findings [22Go]. To verify that PK differences were actually due to the administration sequence, one patient received the two different sequences, during the first and second courses: PK values were similar to those found in the other patients. In the PLD–VNR sequence, VNR plasma levels were considerably higher than those detected in monotherapy regimens [22Go].


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Table 3. VNR pharmacokinetic results

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study investigated the feasibility and efficacy of combination chemotherapy with PLD and VNR in heavily pretreated advanced ovarian cancer patients. It was based on promising data concerning the activity of these two drugs as single agents in similar patient populations. To our knowledge, this combination had only been tested in ovarian cancer in a dose-finding study [20Go], where it showed encouraging activity justifying a phase II study. We also report for the first time the PK results of the above drug association.

The combination of new drugs with favorable toxicity profiles is the only possible approach to develop polychemotherapy regimens for heavily pretreated ovarian cancer patients: since the goal for these patients is not to achieve a cure, palliation and quality of life remain the most important aims, and excessive toxicity should be avoided. VNR and PLD are very well tolerated when used as single agents. Moreover, their toxicity profiles do not overlap, and their activity against ovarian cancer has been well documented. VNR has shown activity mainly in cisplatin-resistant ovarian cancer, with a favorable toxicity profile [16Go, 17Go].

Anthracyclines are rarely included in first-line treatment regimens for ovarian cancer, so their use in second-line (or further) treatment settings has been considered [27Go, 28Go]. Moreover, the newly available liposomal formulations have increased their possibilities for use, thanks to the reduced cardiac toxicity [29Go]. Several phase II studies have shown these drugs to possess substantial activity in the second-line setting [10Go, 30Go, 31Go]. Clinical studies in lung and breast cancer have shown anthracyclines and VNR to have significant activity [32Go–35Go]. High response rates have been reported with VNR in breast cancer patients pretreated with anthracyclines, suggesting a lack of cross-resistance between the two drugs [36Go, 37Go]. To our knowledge, only one study has evaluated the combination of PLD and VNR in refractory or resistant ovarian cancer [20Go]. The dose escalating study by Tambaro et al. [20Go] demonstrated an RR of 20.7%, and suggested doses of 30 mg/m2 for PLD on day 1 and of 25 mg/m2 for VNR on days 1 and 8.

In our study, we observed an overall response rate of 36.7% after six treatment cycles. In addition, 10% of patients achieved stable disease. Stabilization of disease may translate into survival benefit, especially in the setting of second- and further-line treatments [38Go, 39Go]. These results are very encouraging as the patients enrolled were heavily pretreated and all had received prior paclitaxel. Relapse-free survival, time to progression and overall survival data are consistent with or above those expected for this patient population, with a significantly better toxicity profile [3Go, 15Go, 18Go, 19Go, 40Go, 41Go]. We analyzed the correlation of RR, time to progression and survival with several prognostic factors, namely performance status, number of metastatic sites, number of previous regimens and interval from previous treatment. No significant correlations were found, possibly due to the small patient population. Compared with the results reported by Tambaro et al. [20Go], we found a better RR and a lower toxicity profile. Our population only included patients with measurable disease, different time to progression from first-line treatment (platinum/paclitaxel-sensitive and -resistant disease) and a lower total dose of VNR.

Toxicity was generally mild, with only one grade 4 and one grade 3 PPE, and two cycles with grade 3 neutropenia for one patient. There were no treatment-related deaths. All planned doses of both drugs were administered, with the exception of patients excluded from the study (two patients for allergic reaction and one with grade 3 repeated episodes of mucositis). At the doses employed, PLD induced much lower incidence and toxicity rates of both PPE and mucositis, compared with data reported by Gordon et al. [12Go] in a phase III study with the drug given as a single agent. The incidence of PPE has been found to be both dose- and schedule-dependent [42Go]. Pyridoxine therapy has been utilized to alleviate the onset of PPE during treatment with 5-fluorouracil infusions for metastatic colon cancer [43Go]. This result has been extrapolated for possible treatment for Caelyx-induced PPE, but conclusive studies are lacking [44Go]. Myelotoxicity was mild, reversible and well tolerated. Our data do not enable us to conclude whether there is an additive effect of the two drugs in combination.

PK results are consistent with clinical outcome. Administration of the opposing sequences in two groups of five patients showed that PLD–VNR produced a significantly higher patient exposure to VNR, without increasing hematological toxicity. While fully aware of the limited accrual in our preliminary PK study, we suggest that the PLD–VNR sequence should be tested through further clinical trials. Our current ongoing study will attempt to correlate toxicity, PK parameters and clinical efficacy in a larger subset of patients.

In conclusion, the combination of PLD and VNR in heavily pretreated advanced ovarian cancer patients was found to be a feasible and effective regimen. The low toxicity profile of this combination in both sequences, together with the promising RRs observed in our group of patients, indicate further clinical and PK studies to validate its use in second (or further) line treatment of relapsed ovarian cancer.


    Acknowledgements
 
We thank Drs T. Volpe, S. Lattuada and E. Bertoldo for their contributions of clinical data. D.K., I.A.R. de la L. and S.F. are partially supported by the Italian Association for Cancer Research (AIRC).

Received for publication July 13, 2004. Revision received September 29, 2004. Accepted for publication September 30, 2004.


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 Abstract
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 Patients and methods
 Results
 Discussion
 References
 
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