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Annals of Oncology Advance Access originally published online on November 9, 2005
Annals of Oncology 2006 17(1):93-96; doi:10.1093/annonc/mdj032
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© 2005 European Society for Medical Oncology

Pegylated liposomal doxorubicin and carboplatin in advanced gynecologic tumors: a prospective phase I/II study of the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR)

A. du Bois1,*, A. Burges2, W. Meier3, J. Pfisterer4, B. Schmalfeldt5, B. Richter6, C. Jackisch7, A. Staehle8, R. Kimmig9, G. Elser10 On behalf of AGO-OVAR Germany

1 HSK, Dr Horst Schmidt Klinik, Department of Gynecology & Gynecologic Oncology, Wiesbaden; 2 University of Muenchen-Grosshadern, Department of Gynecology & Obstetrics, Muenchen; 3 Evangelisches Krankenhaus Duesseldorf, Department of Gynecology & Obstetrics, Duesseldorf; 4 University of Schleswig-Holstein, Campus Kiel, Department of Gynecology & Obstetrics, Kiel; 5 Technical University Muenchen, Department of Gynecologiy & Obstetrics, Muenchen; 6 University of Dresden, Department of Gynecology & Obstetrics, Dresden; 7 University of Muenster, Department of Gynecology & Obstetrics, Muenster; 8 St-Vincentius-Hospital, Department of Gynecology & Obstetrics, Karlsruhe; 9 University of Essen, Department of Gynecologic & Obstetrics, Essen; 10 AGO-OVAR, Central Study Office, Wiesbaden, Germany

* Correspondence to: Professor Dr A. du Bois, HSK, Dr Horst Schmidt Klinik, Department of Gynecology & Gynecologic Oncology, Ludwig-Erhard-Str. 100, D-65199 Wiesbaden, Germany. Tel: +49-611-433203; Fax: +49-611-433205; E-mail: dubois.hsk-wiesbaden{at}uumail.de


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 References
 
Background: Single-agent platinum and single-agent pegylated liposomal doxorubicin (PLD) are both effective in the treatment of gynecologic malignancies. Based on evidence that combination platinum-containing regimens offer superior efficacy versus single-agent regimens, we conducted this study to determine the maximum tolerated dose (MTD) of PLD in combination with carboplatin.

Patients and methods: In this phase I/II dose-finding study, six courses of PLD (20, 30, 40 or 50 mg/m2) and carboplatin (AUC 6) were administered every 28 days to women with advanced gynecologic malignancies. Three to six patients were treated at each dose level; an additional 12 patients were treated at the MTD.

Results: PLD 40 mg/m2 was identified as the MTD when administered with carboplatin. Five of 18 patients experienced a dose-limiting toxicity at the MTD; two patients had grade 3/4 neutropenia, and one each had grade 3 emesis and grade 3 thrombocytopenia and thrombosis. No patient developed cardiotoxicity. In 11 patients evaluable for response, there were two complete responses, two partial responses and four patients with stable disease.

Conclusions: The MTD for PLD when administered in combination with carboplatin is 40 mg/m2. This regimen is well tolerated and offers promising activity in women with advanced gynecologic malignancies.

Key words: carboplatin, gynecologic neoplasm, pegylated liposomal doxorubicin


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 References
 
A progression-free or overall survival advantage in women with relapsed advanced ovarian cancer is generally associated with the use of platinum-based doublets [1Go, 2Go]. However, these regimens may have toxicities that limit their use in some women. For example, platinum–taxane combinations are associated with alopecia and neurotoxicity [1Go, 3Go] and platinum–gemcitabine combinations with hematological toxicity [2Go]. Thus, efforts are underway to identify equally efficacious but less toxic platinum doublets.

The efficacy of pegylated liposomal doxorubicin (PLD) (Caelyx®; Schering-Plough International, Kenilworth, NJ, USA) in women with relapsed ovarian cancer was demonstrated in studies comparing single-agent PLD with paclitaxel [4Go] or topotecan [5Go, 6Go]. PLD was associated with a lower risk of musculoskeletal disorders and alopecia versus paclitaxel [4Go] and fewer grade 3/4 toxicities versus topotecan [5Go, 6Go]. Unlike experience with conventional doxorubicin, patients treated with PLD report hand–foot syndrome (HFS) and stomatitis [4Go, 5Go]. However, the efficacy and tolerability profile of single-agent PLD in advanced ovarian cancer support evaluation of a PLD–carboplatin doublet in this setting.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 References
 
This prospective, open-label, multicenter phase I/II dose-finding study was conducted to determine the maximum tolerable dose (MTD) and dose-limiting toxicities (DLT) associated with the combination of PLD and carboplatin in women with advanced gynecologic malignancies. All patients provided signed informed consent. The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and according to Good Clinical Practice guidelines. The protocol was reviewed and accepted by local ethics committees and performed according to German laws.

eligibility criteria
Women enrolled in the study had a histological diagnosis of malignancy originating from the ovaries, the Fallopian tube or the uterus. Patients with epithelial ovarian cancer must have completed a platinum-containing chemotherapy regimen for first-line treatment at least 6 months prior to study entry. Women with other malignancies could be either chemotherapy-naïve or suffering from relapsed disease after receiving at most one prior treatment. Prior radiation therapy to ≤25% of the hematopoietic system was permitted, but must have been completed at least 6 weeks before study entry. Hormonal therapy must have been stopped within 10 days of study entry and immunotherapy at least 4 weeks prior to study entry. Enrollment required an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 or Karnofsky score >60, age ≥18 years, estimated life expectancy >12 weeks, and normal hematologic, renal and hepatic function. Pre-existing National Cancer Institute (NCI) grade 2 motor or sensory neurotoxicity, active infection or other serious medical infection, history of heart disease, or pregnancy were cause for exclusion.

treatment schedule
Three to six patients received one of four different dose levels of PLD plus carboplatin. Treatment was repeated every 28 days for six courses. PLD was administered as a 30-min intravenous infusion at doses of 20, 30, 40 or 50 mg/m2. Dose escalation in individual patients was not allowed. Carboplatin at a dose of AUC 6 using the Calvert's formula [7Go] was administered as a 30-min intravenous infusion. The maximum absolute carboplatin dose per cycle was limited to 800 mg. Further therapy beyond six courses could be given at the investigator's discretion. However, these additional courses were not evaluated for DLT or considered for the definition of MTD.

Treatment was delayed in patients experiencing serious hematological and/or non-hematological toxicity. If the toxicity did not improve adequately to allow continuation of treatment by day 35, the patient was removed from the study. If a DLT (Table 1) occurred in 0 of 3 patients at one dose level during the first three chemotherapy courses, the next three patients were enrolled at the next highest PLD dose level. If one patient experienced a DLT at one dose level, the next three patients were enrolled at the same dose for a total of six patients treated at that dose level. The dose of PLD was escalated to the next dose level only if no further DLT occurred in the second set of three patients. If a DLT occurred in two or more patients treated at the same dose level, the previous dose was defined as the MTD and dose escalation was stopped. An additional 12 patients were treated at the MTD, for a total of 15–18 patients treated at the MTD. If no more than three of 15 or four of 18 patients experienced a DLT during the first three cycles of treatment at the MTD, this dose would be the recommended dose for further studies.


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  		Table 1. Definition of DLTs

 
Antiemetics were administered prophylactically. Recommended treatment was with dexamethasone 20 mg and a single dose of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist. Granulocyte colony-stimulating factor was not administered prophylactically, but was permitted at the discretion of the physician in the event of persistent myelosuppression.

assessments
The MTD and the dose at which DLT occurred were the primary study end points and were identified as described above. A history was taken and physical and laboratory examinations performed prior to study entry. The physical examination included neurological examination, electrocardiogram, echocardiogram [to determine left ventricular ejection fraction (LVEF)], imaging procedures (for staging of disease) and assessment of general condition (via ECOG performance status [2Go]). The laboratory examination included blood count, blood chemistry, and pregnancy testing if indicated. A weekly blood count with differential was performed to assess hematological recovery. In patients not meeting the hematological thresholds for administration of the next dose (see Table 1), the frequency of complete blood count with differential was increased to twice weekly until the threshold was met. Baseline assessments were repeated 4–6 weeks after receipt of the last study medication. Three months after completion of all therapy, toxicity assessment and physical examination were repeated, with the exception of electrocardiogram and echocardiogram, which were performed only in patients who experienced noteworthy cardiac events during chemotherapy or an absolute decline in LVEF of ≥10 percentage points from baseline to previous assessment. Tumor response was assessed every third cycle using standard WHO criteria [3Go]. All patients with progressive disease or receiving at least three courses of study medication were evaluable for tumor response.

Adverse events were recorded prior to each cycle of treatment and rated according to the NCI common toxicity criteria (version 2.0), except for palmar–plantar erythrodysesthesia (PPE) or HFS, which were classified according to WHO criteria. All patients receiving at least one cycle of study medication were evaluable for toxicity.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 References
 
From January 2001 to July 2003, nine participating centers screened 45 patients. Nine patients failed eligibility criteria for the following reasons: glomerular filtration rate <60 ml/min (three), inadequate primary treatment for ovarian cancer (one), cardiac failure (two), more than one prior therapy (one) and for technical reasons (one). Thirty-six patients were enrolled in the study. Median age was 58.5 years (range 31–78). Most had a diagnosis of ovarian cancer (42%) and most had received one line of chemotherapy (53%) prior to study entry (Table 2).


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  		Table 2. Baseline characteristics

 
During the MTD identification phase, six patients received treatment at a PLD dose of 20 mg/m2, six at 30 mg/m2 and six at 40 mg/m2. One patient experienced a DLT at each of these dose levels during the first three cycles, with grade 3 emesis being the DLT in two patients. Four of six patients treated with PLD 50 mg/m2 experienced a DLT during the first three cycles and one additional patient experienced a DLT during cycle 5. At this dose, DLTs were primarily hematological; one patient experienced both dose-limiting hematological toxicity and dose-limiting emesis.

Per protocol, a PLD dose of 40 mg/m2 was identified as the suggested MTD when administered in combination with carboplatin at a dose of AUC 6 and an additional 12 patients were treated at this dose. Of these 12 patients, four experienced toxicity meeting the definition of a DLT used in the dose-finding phase (Table 3).


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  		Table 3. Toxicity fulfilling the criteria of DLT

 
In the dose-finding phase I part of the study, DLT resulted in treatment discontinuation before cycle 4 in six patients; two additional patients discontinued after the third course (one at a PLD dose of 20 mg/m2, one at a PLD dose of 30 mg/m2, two at 40 mg/m2 and four at 50 mg/m2). The reasons for early discontinuation at the 40 mg/m2 dose were grade 3 neutropenia (one patient) and grade 3 emesis/abdominal pain (one patient). Further grade 3/4 toxicities were observed in 12 patients during the phase II portion of the study at a PLD dose of 40 mg/m2 and included grade 4 neutropenia and grade 3 thrombocytopenia, both of short duration; and one patient experienced a deep vein thrombosis. Grade 3/4 non-hematological adverse events in patients treated at the MTD were nausea/vomiting, constipation, diarrhea, myalgia/arthralgia and pain (Table 4). No patient developed signs of cardiotoxicity.


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  		Table 4. Toxicity, per cent of courses (hematological toxicity) or patients (non-hematological toxicity) at PLD 40 mg/m2 plus carboplatin at AUC 6a (reported as the worst grade experienced)

 
A total of 11 patients were evaluable for response. One patient each at doses of 30 mg/m2 and 40 mg/m2 achieved a complete response and one at each of these doses achieved a partial response. An additional four patients were classified as having stable disease (no change) and three patients had progressive disease. Objective responses were seen in patients with epithelial ovarian cancer and endometrial cancer.


   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
References
 
PLD is a unique formulation of doxorubicin, with a prolonged circulation time, lower peak plasma concentrations of free drug, and four- to 11-fold higher tumor concentrations compared with the conventional formulation of doxorubicin [8Go, 9Go]. When administered as a single agent, PLD demonstrates equivalent efficacy versus paclitaxel [4Go] and superior efficacy versus topotecan [5Go, 6Go], regardless of platinum sensitivity, as second-line therapy in advanced ovarian cancer. Most women enrolled in our study (42%) had ovarian cancer and had received prior chemotherapy (53%), including treatment with a platinum compound (42%).

During phase I we established a MTD of PLD of 40 mg/m2 when combined with carboplatin at AUC 6. However, the MTD was not confirmed as written in the protocol in the extended phase, as the number of patients experiencing a DLT (n = 5; one in phase I and four in the confirmation cohort) exceeded the protocol-defined limit of four. However, the investigator attributed the case of thrombosis to the underlying disease, not to treatment.

At the MTD, most toxicity was grade 1 or 2. The most serious toxicities were hematological, with grade 3 or 4 neutropenia reported in 33% of courses and grade 3 or 4 leukopenia in 17% of course. Despite these hematological toxicities, there were no grade 3 or 4 infections. Grade 3/4 non-hematological toxicities were primarily gastrointestinal, with nausea/emesis, constipation and diarrhea each reported in 6% of patients. All reports of PPE were grade 1 (28% of patients). Although stomatitis/mucositis occurred in 55% of patients, most cases were grade 1 (44%). There were no reported cases of cardiotoxicity.

These data demonstrate the feasibility of administering PLD in combination with carboplatin to women with gynecologic malignancies. In addition to good tolerability, limited response data suggest promising activity. A regimen of PLD plus carboplatin might offer tolerability advantages compared with the commonly use platinum–taxane regimen. Additional research is required to determine the role of this new platinum doublet in the treatment of gynecologic malignancies.


   Acknowledgements
 
None of the authors declared any personal conflict of interest regarding the present study. However, Essex Pharma GmbH, the German branch of Schering-Plough, provided study medication and financial support for the study group infrastructure and for educational activities (information material, lectures, consultations).

Received for publication August 18, 2005. Revision received August 23, 2005. Accepted for publication September 5, 2005.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 References
 
1. ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer; the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361: 2099–2106.[CrossRef][Web of Science][Medline]

2. Pfisterer J, Plante M, Vergote I et al. Gemcitabine/carboplatin (GC) vs. carboplatin (C) in platinum sensitive recurrent ovarian cancer (OVCA). Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVAR, the NCIC CTG and the EORTC GCG. Proc Am Soc Clin Oncol 2004; 23: 449 (Abstr).

3. Guastalla JP, Pujade-Lauraine E, Weber B et al. Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian cancer. A multicenter GINECO phase II study. Ann Oncol 1998; 9: 37–43.[Abstract/Free Full Text]

4. O'Byrne KJ, Bliss P, Graham JD et al. A phase III study of Doxil/Caelyx versus paclitaxel in platinum-treated, taxane-naive relapsed ovarian cancer (abstract 808). Proc Am Soc Clin Oncol 2002; 21: 203a.

5. Gordon AN, Fleagle JT, Guthrie D et al. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus toptecan. J Clin Oncol 2001; 19: 3312–3322.[Abstract/Free Full Text]

6. Gordon AN, Tonda M, Sun S et al. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol 2004; 95: 7–8.

7. Calvert AH, Newell DR, Gumbrell LA et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748–1756.[Abstract]

8. Martin FJ, Gabizon A et al. Human pharmacokinetics of stealth liposomes containing doxorubicin. J Cell Biochem 1992; 16E (Suppl): 98.

9. Gabizon A. Liposomal anthracyclines. Hematol Oncol Clin North Am 1994; 8: 431–450.[Web of Science][Medline]


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