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ANTICANCER RESEARCH 35: 4521-4526 (2015)

The Safety of Pegylated Liposomal Plus Irinotecan in Recurrent Patients: A Phase I Trial

DAISUKE MIYAHARA1*, TAEKO UEDA2*, TAKAHIRO KATSUDA1, MIYAKO MAEHARA1, SATOSHI FUKAGAWA1, KOHEI MIYATA1, SUNG OUK NAM1, HARUHIKO KONDO1 and SHINGO MIYAMOTO1

1Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; 2Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

Abstract. Aim: The study was designed to evaluate the safety improved survival in patients with epithelial ovarian of combined with pegylated liposomal cancers (2, 3). Previous reports indicate that 50-70% of doxorubicin (PLD) and irinotecan (CPT-11) in patients with advanced ovarian cancer patients will relapse within 2 years recurrent ovarian cancer. Patients and Methods: Six patients after the completion of first-line therapy (4, 5). Therefore, with platinum-resistant and -pretreated ovarian cancer new effective chemotherapeutic regimens for ovarian cancer were enrolled in the study based on the traditional 3-plus-3 remain to be studied. design. PLD was administered intravenously on day 1 and Ovarian cancer prognosis is dependent on the progression- CPT-11 on days 1 and 8 of each 28-day course. Initial doses free survival (6, 7). Progression-free survival is defined as the were 30 mg/m2 PLD and 50 mg/m2 CPT-11. Results: time to tumor progression from the completion of first-line Hematotoxicity was the principal toxicity (1 patient developed chemotherapy (8). The patients who relapse after 12 months grade 3 and 2 developed grade 3 leukocytopenia); from the last day of first-line chemotherapy indicate good hand-foot syndrome was not observed. Furthermore, 1 patient response for platinum plus taxane based-chemotherapy (6, 7). achieved complete response, whereas 2 patients achieved In contrast, platinum plus taxane-based chemotherapy often partial response. Conclusion: The combined PLD and CPT- fails to demonstrate curative effect for patients who relapse 11 regimen was well-tolerated indicating its potential clinical within the first 12 months after completion of first-line benefit for ovarian cancer patients. chemotherapy (6, 7). The administration of single-agent therapy with pegylated liposomal doxorubicin (PLD), In Japan, there is an increase in the number of patients with irinotecan (CPT-11), or was ovarian cancer every year. Each year, approximately 9,000 recommended for treating platinum-resistant ovarian cancer people contract ovarian cancer and approximately 5,000 patients according to the guidelines of the Japanese Society of people die of the disease (referred from GLOBOCAN Gynecologic Oncology in 2010 (8-11). However, single-agent 2012, http://globocan.iarc.fr/Default.aspx). Ovarian cancer therapy has not been proven to be effective in treating is frequently diagnosed in the advanced stages because of recurrent ovarian cancer as curative chemotherapy. Therefore, the limitations of its subjective symptoms (1). an effective combination is required for Cytoreductive surgery and the introduction of platinum plus patients who develop recurrent ovarian cancer within 12 taxane-based chemotherapy in the past decade have months after completion of platinum plus taxane-based chemotherapy. A new combined chemotherapeutic regimen that improves the prognosis of ovarian cancer patients who relapse within *These Authors contributed equally to this study. 12 months of completing platinum plus taxane-based chemotherapy needs to be established. Combination therapy Correspondence to: Shingo Miyamoto, MD, Ph.D., Department of with PLD and CPT-11 has been regarded as a desirable Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, strategy of ovarian cancer therapy as its adverse events show 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Tel: +81 no overlap. However, the safe dosage for this regimen is yet 928011011, Fax: +81 928654114, e-mail: [email protected] unresolved. We designed this Phase I study to determine the Key Words: ovarian cancer, safety, phase I trial, pegylated liposomal recommended dose for combined PLD and CPT-11 doxorubicin, irinotecan. chemotherapy in patients with recurrent ovarian cancer.

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Patients and Methods Table I. Dose escalation schema.

Study design. This Phase I, open-label, dose-finding study was Dose level PLD CPT-11 conducted at the Fukuoka University Hospital, Fukuoka, Japan Level-1 25 mg/m2 (day 1) 50 mg/m2 (day 1, 8) ( number: 10-9-06(10-059)). Six eligible patients were Level 1 30 mg/m2 (day 1) 50 mg/m2 (day 1, 8) enrolled and treated using the 3-plus-3 design. The protocol used in Level 2 30 mg/m2 (day 1) 60 mg/m2 (day 1, 8) this study was approved by the local ethics committee of Fukuoka University Hospital. PLD, Pegylated liposomal doxorubicin; CPT-11, irinotecan.

Eligibility criteria. The eligibility criteria were as follows: (i) age ranging from 20 to 75 years; (ii) histologically-diagnosed epithelial ovarian cancer, peritoneal cancer and fallopian tube cancer that had relapsed within 12 months from the last day of prior first- or second- Definition of dose-limiting toxicity. DLT was assessed according to the line chemotherapy (having completed >3 courses with platinum and common toxicity criteria of the National Cancer Institute (version 3.0, taxane-based agents); (iii) performance status (PS) of 0-1 on the Japanese version issued by the Japan Clinical Oncology Group Study) Eastern Cooperative Oncology Group scale; (iv) no serious organ and defined as follows: (i) grade 4 neutropenia or leucopenia lasting dysfunction (i.e. hemoglobin level >10.0 g/dl, leukocyte count for 5 days or more; (ii) grade 3 or more febrile neutropenia lasting for >3,000-12,000/mm3, count >1,500/mm3, platelet count 5 days or more with fever (body temperature ≥38˚C); (iii) grade 3 or >75,000/mm3, adequate hepatic function (transaminase or alkaline more thrombocytopenia; (iv) grade 3 or more non-hematological phosphatase level <2.5 times the normal upper limit and total toxicity (except for anorexia or nausea or epilation or anaphylaxis bilirubin level lower than the normal upper limit), adequate renal symptoms); and (v) treatment delay of greater than 4 weeks as a result function (serum creatinine level <1.5 times the normal upper limit) of toxicity. and cardiac function (ejection fraction <25% and changes within normal parameters on electrocardiography or asymptomatic with no Evaluation and assessment. Physical examination, performance status need for treatment)); and (v) informed consent. assessment, complete blood cell counts, chemistry profile, electrolyte assessment, chest radiography, electrocardiography and computed Exclusion criteria. The exclusion criteria were as follows: (i) tomography (CT) of the abdomen were performed prior to study complications that would adversely affect this study; (ii) active initiation. Physical examination, PS assessment and clinical laboratory concomitant malignancy; (iii) ascites, pleural effusion or pericardial tests were repeated weekly. fluid requiring effusion; (iv) history of myocardial infarction or heart In this study, we defined the first end-point as appearance of DLT. failure within 90 days or current unstable angina; (v) a condition or Although determination of tumor response was not a secondary brain metastases requiring medical treatment; (vi) bowel obstruction; endpoint of this study, patients with measurable or assessable disease (vii) watery stool or ; (viii) interstitial pneumonia or were evaluated to determine the efficacy of chemotherapy according to pulmonary fibrosis; (ix) history of bone marrow transplantation or the Response Evaluation Criteria in Solid Tumors (RECIST), version hematopoietic stem cell transplantation; (x) history of treatment with 1.1. In order to conduct these assessments, CT was performed in PLD or CPT-11; (xi) participation in other clinical study within 30 patients with measurable disease within 4 weeks of initiating treatment days; (xii) hypersensitivity to constituents in CPT-11 or PLD; (xiii) and after 2 cycles of treatment. Patients categorized as complete or pregnancy or lactation; (xiv) identified genetic polymorphism of partial response (CR or PR) were re-evaluated after 1 month. UGT1A1; and (xv) contraindication for participation reported by the physician in charge for any other reason. Results

Protocol. PLD was administered intravenously on day 1 and CPT-11 Patients’ characteristics. This study was initiated in May 2011 was administered intravenously on days 1 and 15. One course of and continued until administration of Level 2 dosage was chemotherapy lasted 28 days and patients received 6 courses at the accomplished in 3 patients or after occurrence of DLT in 2 maximum. patients. The patients’ clinical profiles are shown in Table II. Five patients were diagnosed with ovarian cancer and 1 patient Method for dose escalation. The method for dose escalation is had peritoneal cancer. The median age was 51.6 (range=40-63) summarized in Table I. The initial dose for PLD was fixed at 30 mg/m2 for Level 1 and Level 2. If dose-limiting toxicity (DLT) years. Five patients had a performance status of 0 and 1 patient appeared, the PLD dose was de-escalated to 25 mg/m2 (Level -1). had PS 1. Upon histological examination, 3 patients had serous The initial dose for CPT-11 was 50 mg/m2 (Level 1 and Level -1), adenocarcinoma, 1 had endometrioid adenocarcinoma and 1 which escalated to 60 mg/m2 (Level 2) in a stepwise fashion had clear cell adenocarcinoma. The total number of treatment (Table I). Briefly, if a group of 3 patients received the determined courses was 38 (22 cycles at Level 1, 14 cycles at Level 2) and dose for Level 1, the dose was increased to the next level. the median of treatment courses was 6 (range=2-11). Five However, if DLT was observed in 1 of the 3 patients at the same ovarian cancer patients were assessed using the International level, 3 additional patients were treated at the same dose level and, if there was no observable DLT in at least 3 of the total 6 patients, Federation of Gynecology and Obstetrics (FIGO) staging the dose was increased to the next level. If DLT was observed in 2 guidelines. Prior treatments included first-line and of 6 patients at any level, the lower dose level was judged to be the paclitaxel therapy (CP) in 3 patients, second-line CP in 2 recommended dose. patients and -plus-carboplatin therapy in 1 patient.

4522 Miyahara et al: Phase I Study of PLD plus CPT-11 for Ovarian Cancer

Table II. Clinical characteristics of enrolled patients.

Case Age Cancer subtype FIGO stage Previous Treatment period of Performance (Histology) chemotherapy PLD + CPT-11 (months) status

1 54 OVCA (EAC) IIb TC 3 0 2 40 OVCA (SAC) IIIc TC 5 0 3 63 PC (SAC) NA TC 10 0 4 58 OVCA (SAC) IIIc DP 1 0 5 50 OVCA (EMC) IIc TC 1 0 6 46 OVCA (CCC) Ic TC 1 1

OVCA, Ovarian cancer; PC, peritoneal cancer; EAC, endometrioid adenocarcinoma; SAC, serous cyst adenocarcinoma; CCC, clear cell carcinoma; TC, paclitaxel and carboplatin chemotherapy; DC, docetaxel and carboplatin chemotherapy.

Disease-free intervals upon study initiation were 1 month in 3 Table III. Summary of common drug-related adverse events occurred patients, 3 months in 1 patient, 5 months in 1 patient and 10 during treatment with PLD and CPT-11. months in 1 patient. Adverse event Level 1 Level 2

Treatment and assessment of adverse events. Three patients Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 were enrolled for treatment with Level 1 dose and no DLT appeared (Table III). Alopecia was observed in all patients Diarrhea (grade 2 in 2 patients and grade 1 in 1 patient). Other common Constipation G2 G2 Nausea G2 G1 G1 G1 G1 adverse events were anemia (grade 1 in 2 patients), nausea G2 G1 (grade 1 and grade 2 in each patient) and stomatitis (grade 1 in Stomatitis G1 G1 2 patients). General fatigue G1 Based on the results of treatment with Level 1 dosage of Palpitation G1 PLD and CPT-11, we progressed to treatment with Level 2 Headache G1 Dysgeusia G1 dosage. As observed for treatment with Level 1 dosage, all Alopecia G2 G2 G1 G2 G2 G2 patients showed grade 2 alopecia. Moreover, nausea (grade 1 Hand-foot syndrome in all patients), leukocytopenia and neutropenia (grade 2 in 2 Leukocytopenia G2 G2 G3 G2 patients and grade 3 in one patient) were observed in all Neutropenia G3 G2 G3 G2 patients. Other common adverse events were anemia (grade 1 Anemia G1 G1 G1 G1 Thrombocytopenia in 2 patients) and headache (grade 1 in 2 patients). Hand-foot syndrome was not observed in any patient during the entire G, Grade. treatment course. These findings indicate that combination therapy with PLD and CPT-11 was safe at Level 2 doses, as DLT was not observed in the study. Table IV. Assessment of clinical efficacy of PLD and CPT-11 chemotherapy. Assessment of anti-tumor effect. Based on the RECIST criteria, 5 out of 6 patients enrolled in this study had measurable Efficacy of chemotherapy Patients metastatic lesions. One out of the 5 enrolled patients was rated Complete response Case 6 as CR (case 6) and 2 patients rated as PR by CT conducted Partial response Case 2 and 4 after the second cycle of this study. One patient showed stable Stable disease Case 5 disease (SD) and 1 patient showed progressive disease (PD) Progressive disease Case 1 (Table IV). One patient (case 3), who did not have measurable lesion, was diagnosed with relapse and the serum cancer Response rate 60%. antigen (CA)125 level was used to determine the patient’s response to treatment. In this case, serum CA125 levels decreased to reference values after the fourth cycle of PLD plus bilateral pelvic and para-aortic lymph node dissection up to the CPT-11 treatment (Figure 1A). In the case of a 46-year-old left renal vein, as well as total omentectomy. Pathological gravida 3, para 2 woman who achieved CR, the patient evaluation showed clear cell adenocarcinoma indicating a stage underwent total hysterectomy, bilateral salpingo-oophorectomy, Ic(b) ovarian cancer (FIGO 2008). The patient received six

4523 ANTICANCER RESEARCH 35: 4521-4526 (2015)

Figure 1. Clinical course of 2 cases during PLD + CPT-11 therapy. A: Progress in serum CA125 levels of case 3. Gray arrows and numbers indicate the respective treatment cycle of PLD + CPT-11 therapy. B, C: Computed tomography of case 6 before first cycle (B) and after sixth cycle (C) of PLD + CPT-11 therapy. White arrow indicates the measurable metastatic region in right obturator lymph node.

cycles of chemotherapy with paclitaxel (175 mg/m2) and event above grade 3, observed in 2 out of 6 patients. Grade 1 or carboplatin (area under curve (AUC) 5), administered every 3 2 alopecia was observed in all 6 patients. In addition, weeks. One month later, cranial CT showed a pelvic recurrent evaluation of these cases with the RECIST criteria indicated mass, right obturator lymph node and para-aortic lymph node. that one patient achieved CR, whereas 2 patients achieved PR. The patient was administered 3 cycles of chemotherapy with Based on these lines of evidence, the combined PLD and CPT-11 (Level 2 dose). All lesions disappeared after chemotherapeutic regimen of PLD and CPT-11 is safe and 3 cycles of chemotherapy with PLD and CPT-11; the patient potentially effective in patients with recurrent ovarian cancer was assessed to have achieved CR and underwent 6 cycles of when administered within 12 months of completing prior chemotherapy in all (Figure 1B and 1C). Thereafter, the patient platinum and taxane-based chemotherapy. has been free from relapse for 33 months. The administration of 50 mg/m2 PLD often elicits severe adverse events, including myelosuppression, stomatitis, hand- Discussion foot syndrome, tongue inflammation and alopecia (12). Moreover, the administration of 100 mg/m2 CTP-11 may In this Phase I trial, we determined the recommended dose for induce severe adverse events, including myelosuppression, combination therapy with PLD and CPT-11 in patients with diarrhea, intestinal inflammation and alopecia (10). The recurrent ovarian cancer. Neutropenia was the only adverse aforementioned severe adverse events, which often present

4524 Miyahara et al: Phase I Study of PLD plus CPT-11 for Ovarian Cancer during treatment with either PLD (50 mg/m2) or CPT-11 3 Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL and Montz (100 mg/m2) alone, were not observed in the study. As FJ: Survival effect of maximal cytoreductive surgery for advanced myelosuppression and alopecia occur during the administration ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 20: 1248-59, 2002. of both PLD and CPT-11, most patients developed 4 International Collaborative Ovarian Neoplasm Group: Paclitaxel myelosuppression and alopecia in this study. However, most of plus carboplatin versus standard chemotherapy with either single- these adverse events were either grade 1 or 2. With respect to agent carboplatin, or , doxorubicin, and adverse events, each dose of PLD and CPT-11 is currently in women with ovarian cancer: the ICON3 randomised trial. Lancet regarded acceptable for the chemotherapeutic regimen in 360: 505-515, 2002. patients with recurrent ovarian cancer. 5 Ledermann JA and Kristeleit RS: Optimal treatment for relapsing In addition, several clinical trials that focused on the ovarian cancer.Ann Oncol 21(Suppl 7): vii218-222, 2010. 6 Colombo N and Gore M: Treatment of recurrent ovarian cancer efficacy of combination therapy with PLD were undertaken relapsing 6-12 months post platinum-based chemotherapy. Crit Rev with the aim of reducing adverse events. The CALYPSO Oncol Hematol 64: 129-138, 2007. study, a representative Phase III clinical trial of PLD 7 Blackledge G, Lawton F, Redman C and Kelly K: Response of combination therapy, demonstrated that combination therapy patients in phase II studies of chemotherapy in ovarian cancer: with carboplatin (AUC 5) and PLD (30 mg/m2) (CD) had implications for patient treatment and the design of phase II trials. comparable efficacy to that of a regimen with carboplatin and Br J Cancer 59: 650-653, 1989. paclitaxel (CP) in patients with highly platinum-sensitive 8 Dancey JE, Dodd LE, Ford R, Kaplan R, Mooney M, Rubinstein recurrent ovarian cancer (13). In this study, the median L, Schwartz LH, Shankar L and Therasse P: Recommendations for the assessment of progression in randomised cancer treatment progression-free survival and overall survival were 12.0 trials. Eur J Cancer 45: 281-289, 2009. months for the CD regimen and 12.3 for CP [hazard ratio 9 Ferrandina G, Ludovisi M, Lorusso D, Pignata S, Breda E, (HR)=1.05 (95% confidence interval (CI)=0.79-1.40); p=0.73 Savarese A, Del Medico P, Scaltriti L, Katsaros D, Priolo D and for superiority] and median overall survival was 40.2 months Scambia G: Phase III trial of gemcitabine compared with pegylated for CD and 43.9 for CP [HR=1.18 (95% CI=0.85-1.63); liposomal doxorubicin in progressive or recurrent ovarian cancer. J p=0.33 for superiority]. Overall response rates of CD and CP Clin Oncol 26: 890-896, 2008. were 42% and 38%, respectively (p=0.46). Moreover, a 10 Matsumoto K, Katsumata N, Yamanaka Y, Yonemori K, Kohno T, Shimizu C, Andoh M and Fujiwara Y: The safety and efficacy of response rate of 28% was observed for the combined regimen the weekly dosing of irinotecan for platinum- and -resistant of PLD and in patients with recurrent ovarian epithelial ovarian cancer. Gynecol Oncol 100: 412-416, 2006. cancer (14). A response rate of 30% was also observed for 11 Markman M, Hall J, Spitz D, Weiner S, Carson L, Van Le L and the combined regimen of adriamycin and CPT-11 in patients Baker M: Phase II trial of weekly single-agent paclitaxel in with recurrent ovarian cancer (15). With the recommended platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol 20: dosage, in this study, of PLD (30 mg/m2) and CPT-11 2365-2369, 2002. (60 mg/m2), the response rate was 50% and median 12 Muggia FM, Hainsworth JD, Jeffers S, Miller P, Groshen S, Tan M, Roman L, Uziely B, Muderspach L, Garcia A, Burnett A, Greco progression-free survival was 7.2 months. Two patients are FA, Morrow CP, Paradiso LJ and Liang LJ: Phase II study of alive beyond 2 years and median overall survival for the liposomal doxorubicin in refractory ovarian cancer: antitumor remaining 4 patients was 16.4 months. Based on these results, activity and toxicity modification by liposomal encapsulation. J a combined regimen with PLD and CPT-11, administered as Clin Oncol 15: 987-993, 1997. second-line chemotherapy, would enable improvements in the 13 Mahner S, Meier W, du Bois A, Brown C, Lorusso D, Dell'Anna T, prognosis of ovarian cancer. Cretin J, Havsteen H, Bessette P, Zeimet AG, Vergote I, Vasey P, In conclusion, we demonstrated that the combined regimen Pujade-Lauraine E, Gladieff L and Ferrero A: Carboplatin and versus of PLD (30 mg/m2) and CPT-11 (60 mg/m2) was safe and pegylated liposomal doxorubicin carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: Results from a potentially effective for patients with recurrent ovarian cancer. subset analysis of the CALYPSO phase III trial. Eur J Cancer 51: Further studies, involving larger cohort sizes, are necessary to 352-358, 2015. determine whether the combination of PLD and CPT-11 can 14 Verhaar-Langereis M, Karakus A, van Eijkeren M, Voest E and improve prognosis. Witteveen E: Phase II study of the combination of pegylated liposomal doxorubicin and topotecan in platinum-resistant ovarian References cancer. Int J Gynecol Cancer 16: 65-70, 2006. 15 Nishimura S, Tsuda H, Hashiguchi Y, Kokawa K, Nishimura R, 1 Heintz AP, Odicino F, Maisonneuve P, Quinn MA, Benedet JL, Ishiko O, Kamiura S, Hasegawa K and Umesaki N: Phase II study Creasman WT, Ngan HY, Pecorelli S and Beller U: Carcinoma of of irinotecan plus doxorubicin for early recurrent or platinum- the ovary. FIGO 26th Annual report on the results of treatment in refractory ovarian cancer: interim analysis. Int J Gynecol Cancer gynecological cancer. Int J Gynaecol Obstet 95(Suppl 1): S161- 17: 159-163, 2007. 192, 2006. Received April 3, 2015 2 Hoskins WJ: Surgical staging and cytoreductive surgery of Revised May 7, 2015 epithelial ovarian cancer. Cancer 71(4 Suppl): 1534-1540, 1993. Accepted May 8, 2015

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