Phase I feasibility trial of carboplatin, paclitaxel, and gemcitabine in patients with previously untreated epithelial ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study

Gynecologic Oncology 92 (2004) 93 – 100 www.elsevier.com/locate/ygyno

Phase I feasibility trial of carboplatin, paclitaxel, and gemcitabine in patients with previously untreated epithelial ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study Katherine Y. Look, a,* Michael A. Bookman, b Jessie Schol, b Thomas J. Herzog, c Thomas Rocereto, d and Jennifer Vinters e a

Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA b Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA c Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA d UMDNJ/Robert Wood Johnson Medical School Department of Obstetrics and Gynecology, Camden, NJ 08033, USA e Gynecologic Oncology Section, Indiana University School of Medicine, Indianapolis, IN 46202, USA Received 29 January 2003

Abstract Purpose. To determine the feasibility of administering a minimum of four cycles of carboplatin, paclitaxel, and gemcitabine (CPG) every 21 days without excessive dose modification or cycle delay in patients with previously untreated epithelial ovarian cancer or primary peritoneal cancer. Methods. Paclitaxel 175 mg/m2 was given over 3 h followed by carboplatin concentration time curve (AUC) 5 (day 1) and gemcitabine 1 g/m2 (days 1 and 8) in the first cohort. A second cohort received paclitaxel 135 mg/m2 over 3 h followed by carboplatin AUC 5 (day 1) and gemcitabine 800 mg/m2 (days 1 and 8). A maximum of eight cycles was administered. Results. Fourteen patients received 89 cycles during the first cohort. Seven patients experienced 19 hematologic dose-limiting events (DLEs) within the first four cycles, including grade 4 thrombocytopenia (n = 9), febrile neutropenia (n = 3), and omission of gemcitabine on day 8 (n = 7). This exceeded the threshold for nonfeasibility. In the second, less intense regimen, 36 patients were entered. Thirty-one evaluable patients received a total of 200 and median of 6 (range: 2 – 8) cycles. Thirteen of the thirty-one had 27 DLEs within the first four cycles including grade 4 thrombocytopenia (n = 5), prolonged grade 4 neutropenia (n = 2), febrile neutropenia (n = 2), and omission of day 8 gemcitabine (n = 18). There was one patient death secondary to a wound abscess and febrile neutropenia. Myelosuppression as expected was the dose-limiting toxicity. Conclusion. The schedule of paclitaxel 135 mg/m2 (day 1, 3 h), carboplatin AUC 5 (day 1), and gemcitabine 800 mg/m2 (days 1 and 8) is feasible, with an acceptable toxicity profile. D 2003 Elsevier Inc. All rights reserved. Keywords: CPG; Feasibility trial; Ovarian cancer

Introduction Improvements in response rate, time to progression, and median overall survival have been achieved with

* Corresponding author. Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, Indiana University School of Medicine, Room 437, 535 Barnhill Drive, Indianapolis, IN 46202. Fax: +1-317-274-4878. E-mail address: [email protected] (K.Y. Look). 0090-8258/$ - see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2003.09.019

combinations of platinum and paclitaxel for patients with advanced epithelial ovarian carcinoma [1,2]. Unfortunately, 5-year survival rates for patients with residual disease greater than 2 cm remain below 30% [1,2]. One potential strategy to improve the 5-year survival rates is to add a third active agent to the established platinum-based doublet. However, the addition of topotecan to cisplatin and paclitaxel has met with a degree of myelosuppression such that therapeutic doses of topotecan cannot be delivered without adding colony-stimulating factors [3]. Another potential triplet using carboplatin, paclitaxel, and

94

K.Y. Look et al. / Gynecologic Oncology 92 (2004) 93–100

oral etoposide was found to be feasible without cytokine support; however, several patients developed acute myeloid leukemia, making this triplet less attractive for frontline therapy [4]. The metabolite 2V2V-difluorodeoxycytidine 5V-triphosphate of gemcitabine [2V2V-difluorodeoxycytidine] inhibits ribonucleotide reductase and DNA synthesis [5]. In vitro assays utilizing the BG-1 ovarian cancer cell line have demonstrated exposure to gemcitabine at concentrations from 0.5 to 10 AM for 8 h is associated with chromatin condensation, membrane condensation, and formation of apoptotic bodies [6]. Prior trials utilizing single-agent gemcitabine at a dose schedule of 800 – 1250 mg/m2 weekly for three consecutive weeks followed by a 1-week treatment break have noted response rates of 13 – 19% in patients with epithelial ovarian carcinoma previously treated with platinum-based chemotherapy [7,8]. Synergistic cytotoxic activity has been demonstrated in ovarian cancer cell lines when gemcitabine was combined with platinum [9]. This has been attributed to impaired removal of platinum-DNA adducts because of gemcitabinemediated inhibition of DNA repair [9]. Thus, gemcitabine offers the opportunity to incorporate an active agent that could also enhance the efficacy of platinum, which remains the single most important cytotoxic agent utilized against advanced EOC. Gemcitabine and cisplatin combinations have led to 40 –45% response rates in patients with non-small cell lung cancer (NSCLC) [10]. Two trials have recently been reported which establish the therapeutic equivalency of carboplatin versus cisplatin in combination with paclitaxel for patients with advanced epithelial ovarian carcinoma [11,12]. The reduced non-hematologic toxicity of carboplatin is appealing, but it is partially offset by increased hematologic toxicity that limits dosing of other agents, with the exception of paclitaxel. Acceptable toxicity and encouraging activity has been reported in abstract form with the use of platinum, paclitaxel, and gemcitabine in both primary and salvage settings [13,14]. The current trial was designed to determine the feasibility of administering multiple cycles of carboplatin, paclitaxel, and gemcitabine (CGP) without excessive dose modification or cycle delay in patients with previously untreated epithelial ovarian or primary peritoneal carcinoma.

Materials and methods Eligibility criteria This study was developed by the Gynecologic Oncology Group (GOG) Phase I Subcommittee, and accrual was limited to member institutions of the GOG Phase I Working Group. Patients entered into the trial were required to have a GOG performance status of 0 – 2, histologically confirmed advanced Stage III –IV epithelial ovarian or primary peri-

toneal cancer. They were to have recovered from surgery, be without signs of infection, and have adequate bone marrow, renal and hepatic function as defined by: granulocytes z 1500/Al; platelets z 100,000/Al; creatinine V 1.5 mg%; bilirubin V 1.5  institutional normal; and SGOT and alkaline phosphatase V 3  institutional normal. Patients must have given written informed consent that fulfilled institutional, state, and federal regulations before entry into the trial. Patients with a prior malignancy who had been disease-free for at least 5 years and who had not received prior chemotherapy or radiotherapy were allowed onto the trial. Measurable disease was not required, although pretreatment CT scans were obtained to determine if there was measurable disease following initial cytoreductive surgery. Following baseline evaluation to verify eligibility and initiate treatment, patients were to receive a weekly CBC including differential and platelet count. If grade 4 neutropenia was documented, the CBC was to be obtained twice weekly until recovery to grade 3. Toxicity scoring was done by GOG Common Toxicity Criteria (CTC). Before each course, a history and physical examination, performance status, CBC with differential and platelet count, serum creatinine, bilirubin, SGOT, alkaline phosphatase, calcium, phosphorus, and magnesium were obtained. Chest radiographs, EKGs, urinalysis, and audiograms were repeated as clinically indicated. Patients with measurable disease on CT scan were to have a repeat scan every other course. Chemotherapy administration and dose modifications Patients were to receive paclitaxel as a 3-h intravenous infusion on day 1 after receiving a standard premedication regimen including 10 – 20 mg dexamethasone given po or iv, and intravenous H1 and H2 receptor antagonists to minimize anaphylactoid reactions. The dose of carboplatin was based on the area under the concentration time curve (AUC) using the Calvert formula with estimation of the glomerular filtration rate by the Jelliffe formula, based on age and serum creatinine [15]. Carboplatin at the target AUC was delivered intravenously over 30 min after the paclitaxel on day 1. Gemcitabine was then administered intravenously over 30 min on days 1 and 8. Carboplatin was utilized instead of cisplatin, as we intended to infuse the paclitaxel over 3 h and wished to minimize nephrotoxicity. Doses for the initial regimen were selected from preliminary data from patients with previously untreated lung cancer [16]. Due to the frequency of dose-limiting events (DLEs), a second regimen with reduced doses of paclitaxel and gemcitabine was added (Table 1). Dose and schedule modifications were as follows, using individual dose levels as indicated in Table 1. Initiation of a new cycle could be delayed a maximum of 2 weeks to allow for recovery of hematologic and nonhematologic toxicities to grade 1. Grade 3 peripheral

K.Y. Look et al. / Gynecologic Oncology 92 (2004) 93–100 Table 1 Dose levels and modificationsa

Regimen I

Regimen II

a

Starting Dose 1 Dose Level Starting Dose 1 Dose Level

95

Statistical considerations

Paclitaxel (over 3 h, day 1)

Carboplatin (30 min, day 1)

Gemcitabine (30 min, days 1 and 8) (mg/m2)

175 mg/m2

AUC 5

1000

135 mg/m2

AUC 4

1000 (day 1 only)

135 mg/m2

AUC 5

800

90 mg/m2

AUC 4

800 (day 1 only)

Doses for each agent modified individually as noted in text.

neuropathy required reduction of paclitaxel by one dose level and delay of the next cycle until recovery to grade 1. First occurrence of febrile neutropenia and/or prolonged (greater than 7 days) grade 4 neutropenia was managed with a one-level reduction in gemcitabine, without change to either carboplatin or paclitaxel. Recurrent febrile neutropenia and/or prolonged grade 4 neutropenia was managed with a one-level reduction in carboplatin and paclitaxel. To better evaluate cumulative toxicity, prophylactic G-CSF was not permitted unless the doses of carboplatin and paclitaxel had already been lowered one level. Patients with grade 4 thrombocytopenia or bleeding associated with thrombocytopenia in need of a platelet transfusion required a one dose level reduction of carboplatin without change to paclitaxel or gemcitabine, unless the carboplatin was already reduced to AUC 4. Gemcitabine on day 8 was omitted (without delay or dose modification) if the ANC was less than 500/mm3 (CTC grade 4). Patients were to receive a minimum of four and a maximum of eight courses of therapy, unless contraindicated by toxicity or disease progression. Patients with measurable disease were to have lesions measured in two perpendicular diameters and the product calculated as an estimate of lesion size. Standard GOG response criteria were applied as follows: complete response = disappearance of all measurable disease with no deterioration in performance status lasting at least 1 month; partial response = 50% or greater reduction in the sum of the products of all measurable lesions for at least 1 month without the appearance of any new lesions; increasing disease = 50% or greater increase in the product of any lesion documented within 2 months of study entry or the appearance of any new lesion. Patients with measurable disease by physical examination criteria were to have an assessment of lesion size before each course, whereas those with disease measurable only by CT scan were to be assessed every other course. After completion of chemotherapy, if a patient’s physical examination and CA125 was normal, she was considered to have achieved a complete clinical response.

The primary goal of this study was to assess the feasibility of delivering multiple cycles of CGP without excessive dose modifications or delays. Feasibility was defined according to the number of patients with specific dose-limiting events (DLEs) during the first four cycles. Patients were considered to have met the clinically relevant primary endpoint at the first occurrence of any DLE during the first four cycles. The primary endpoint was defined as the number of patients who suffered any DLE during the first four cycles. Study-specific DLEs included delay of day 1 for greater than 2 weeks, omission of day 8 gemcitabine due to grade 4 neutropenia on day 8, febrile neutropenia requiring hospitalization or intravenous antibiotics, prolonged (>7 days) grade 4 neutropenia, grade 4 thrombocytopenia, or grade 3 thrombocytopenia with utilization of platelet transfusion. The study design included entering evaluable patients in cohorts of 15, with an early stopping rule such that if DLEs were documented in five or more patients during the first four cycles, that regimen would be declared infeasible and modifications in starting dose would be considered. If fewer than 5/15 patients experienced DLEs, a second cohort of 15 patients would be accrued. At that point, if fewer than 4/30 patients experienced DLEs, the regimen would be declared feasible, whereas if more than 7 patients experienced DLEs, the regimen would be declared infeasible.

Results Regimen I This study was activated in August 1998 and the first stage of accrual on the first regimen was completed in March 1999. Characteristics of this first cohort of patients are summarized in Table 2. A total of 89 cycles was delivered with Regimen I, and seven patients were documented to have 19 DLEs within the first four cycles. The first DLE in these seven patients was as follows: febrile neutropenia (n = 3), grade 4 thrombocytopenia (n = 3), and day 8 gemcitabine held (n = 1). Therefore, in accordance with the study design, this dose and schedule of CGP was declared infeasible and closed to further accrual. The total of 19 DLEs in this regimen included: grade 4 thrombocytopenia (n = 9), febrile neutropenia (n = 3), and omission of day 8 gemcitabine due to ANC < 500 (n = 7). Patients without DLEs were allowed to continue treatment, with subsequent modifications, if required. The median number of cycles delivered per patient in the first cohort was eight (range: two to eight). The ANC and platelet nadirs for each cycle of therapy in this regimen are summarized in Tables 3 and 4, respectively. With Regimen I, day 8 gemcitabine was omitted at least once during the first four cycles in 5/

96

K.Y. Look et al. / Gynecologic Oncology 92 (2004) 93–100

Table 2 Patient characteristics Characteristic

Regimen II No. of patients

14 patients. Overall, day 8 gemcitabine was omitted in 17/ 89 (19.1%) cycles. Carboplatin AUC reductions were necessary in 5/14 patients within the first four cycles and 8/14 (57%) patients overall. Consequently, 19/89 (21.3%) cycles were administered with carboplatin reduced at AUC 4. Dose delays greater than 1 week (but less than 2 weeks) were required in 7/14 patients (50%).

Following analysis of DLEs from the first cohort treated with Regimen I, it was elected to reduce the dose of gemcitabine and paclitaxel to form the basis for Regimen II (Table 1). From October 1998 until April of 2000, 36 patients were entered into the second regimen using two stages of accrual. This included five patients who manifested anaphylactoid reactions following the first dose of paclitaxel. Although not dose-limiting according to the protocol criteria, this rendered the patients inevaluable for study-specific toxicity endpoints, and additional patients were accrued to complete each cohort; thus, 31 patients were evaluable for toxicity using Regimen II. Their characteristics are summarized in Table 2. A total of 200 cycles was delivered using this regimen with a median of 6 (range: 2– 8) per patient. There were 13 patients with 27 DLEs within the first four cycles using Regimen II. The first DLE in these 13 patients was as follows: febrile neutropenia (n = 2), grade 4 thrombocytopenia (n = 3), prolonged grade 4 ANC (n = 2), and day 8 gemcitabine held (n = 6). The 27 total DLEs within the first four cycles of this schedule included febrile neutropenia (n = 2), prolonged grade 4 neutropenia (n = 2), grade 4 thrombocytopenia (n = 5), and day 8 gemcitabine held (n = 18). Following a third cycle, one patient succumbed to sepsis complicated by febrile neutropenia, wound abscess, and grade 4 thrombocytopenia. The ANC and platelet nadirs for each round of therapy using this second regimen are summarized in Tables 3 and 4, respectively. Day 8 gemcitabine was omitted at least once during the first four cycles in 10 (32.%) patients, including 1/31 (3.2%) in whom day 8 gemcitabine was omitted during each of the first four cycles. These 10 patients had gemcitabine held a total of 18 times in the first four cycles. Overall, 38/200 courses (19%) required omission of day 8 dosing. Carboplatin dose reductions to AUC 4

Table 3 Neutropenia

Table 4 Thrombocytopenia

No. of courses delivered Total Median (range) Age Median (range) Performance status 0 1 Site Ovary Peritoneal Stage 3 4 Measurable disease No Yes Residual Optimal Suboptimal Histology Serous Endometrioid Mixed Grade N/A 1 2 3

Cycle

1 2 3 4 5 6 7 8 a

Regimen I (n = 14)

Regimen II (n = 31)

89 8 (2 – 8)

200 6 (2 – 8)

57 (34 – 82)

61 (35 – 73)

8 6

15 16

11 3

27 4

13 1

26 5

13 1

25 6

11 3

21 10

11 2 1

25 3 3

1 1 0 12

3 0 8 20

Regimen I

Regimen II

Cycle

No. of patients

Nadir median

Range (109/l)

No. of patients

Nadir median

Range (  109/l)

14a 14 13 11 10 10 9 8a

635 857 1410 700 1013 885 1022 1400

0 – 2200 70 – 2200 148 – 2100 200 – 4100 380 – 4700 260 – 4500 280 – 4500 247 – 6000

31 31 30b 28 26 25c 14 14d

740 588 600 690 599 568 645 481

173 – 4556 220 – 4928 230 – 2025 90 – 2910 100 – 1574 100 – 1160 86 – 3282 184 – 1508

Data represent 13/14 patients for cycle 1 and 7/8 patients for cycle 8. Data represent 29/30 patients. c Data represent 24/25 patients. d Data represent 10/14 patients. b

1 2 3 4 5 6 7 8

Regimen I

Regimen II

No. of patients

Nadir median

Range (109/l)

No. of patients

Nadir median

Range (109/l)

14a 14 13 11 10 10 9 8

89 86 105 67 70 75a 100 148

6 – 407 16 – 407 17 – 509 11 – 182 14 – 282 15 – 304 17 – 208 36 – 273

31 31 30b 28 26 25 14 14c

85 101 108 81 54 59 54 37

31 – 487 31 – 530 17 – 346 20 – 620 9 – 190 11 – 490 14 – 290 14 – 110

a Data represent 12/14 patients for cycle 1 and 9/10 patients for cycle 6 Regimen I. b Data represent 29 patients. c Data represent 10 patients.

K.Y. Look et al. / Gynecologic Oncology 92 (2004) 93–100

were necessary in 5/31 (16%) patients but only in 1/31 (3%) patients within the first four courses, and with only 10/200 (5%) cycles reduced overall. Dose delays greater than 1 week (but less than 2 weeks) were required in 12/ 31 (38.7%) patients including 6/31 (19.3%) during the first four cycles. Overall, 28/200 courses (14%) were delayed greater than 1 week. Paclitaxel dose reduction was not required in any of the 31 patients in the second cohort. Two stages of accrual were completed with only 13/31 patients experiencing DLEs within the first four cycles, including six patients in whom the only DLE was omission of gemcitabine on day 8 due to transient asymptomatic neutropenia. Therefore, complicated neutropenia and/or thrombocytopenia was only observed in 7/31 or 22.5% of patients during the first four cycles. Although the protocol design would have permitted an additional stage of accrual to better define the frequency of DLEs using Regimen II, it was felt that the occasional omission of gemcitabine on day 8 was of minor clinical consequence and the regimen was deemed feasible for phase III evaluation. As expected, the dose-limiting toxicity of this triplet combination was myelosuppression. Grade 4 neutropenia was seen in 71% and 67.7% of patients in Regimens I and II, respectively; however, grade 4 thrombocytopenia was less frequent, with 12.9% of patients in Regimen II versus 42.8% in Regimen I. Non-hematologic toxicity

Table 5 Adverse effects in the first four cycles Adverse effect

Grade 0

Regimen I (n = 14) Neutropenia Thrombocytopenia Fever Fatigue Diarrhea Nausea Stomatitis Peripheral neuropathy Myalgia Arthralgia

0 6 9 9 12 6 14 7 10 12

1 2 0 0 4 2 4 0 6 2 0

2 0 0 1 1 0 4 0 0 2 2

3 2 2 0 0 0 0 0 1 0 0

4 10 6 4 0 0 0 0 0 0 0

97

Table 6 Disease outcome Initial tumor status

Total enrolled Not evaluable Evaluable for progression Complete clinical response No recurrence Recur >6 months Recur <6 months Stable disease Progressive disease Not evaluated a

Measurable

Nonmeasurable

Total

7 0 7 3/7 1 0 2 2/7 2/7 0/7

38 1 37 24/37 15 6 3 4/37 4/37 5/37

45 1a 44 27/44 16 6 5 6/44 6/44 5/44

Death due to wound infection with abscess.

was generally mild and not dose-limiting in any patient, as can be seen in Table 5. Disease status As most patients in this trial did not have measurable disease nor undergo a second look, we chose to report the complete clinical response (CCR) rate as defined by a normal pelvic examination and normalization of CA125. Subsequently, patients who had achieved CCR were followed until disease recurrence was documented. Disease status is illustrated in Table 6. One patient was excluded from the response analysis due to a fatal wound infection after cycle 3. In addition, three patients were removed due to toxicity after three or fewer cycles and did not have formal response assessments, but are included in the analysis. Two additional patients were lost to follow-up before disease status assessment. Overall, 61.3% of patients achieved complete clinical response following cytoreductive surgery and chemotherapy. Thirty-six patients were assessable by CA125 criteria, 29 of which had their CA125 normalize by the end of the regimen. An additional five patients had decrements in CA125 but the value did not fall to normal. One patient had a rise in CA125 and another had a paradoxical response with a fall in CA125 but evidence of progression by CT scan criteria. The median progressionfree survival was 12 (range: 1.25 –41.2) months.

Discussion Regimen II (n = 31) Neutropenia Thrombocytopenia Fever Fatigue Diarrhea Nausea Stomatitis Peripheral neuropathy Myalgia Arthralgia

1 4 29 17 28 28 28 23 30 27

0 6 1 10 0 1 3 8 1 3

3 6 0 3 0 0 0 0 0 1

6 12 0 1 2 2 0 0 0 0

21 4a 1a 0 1 0 0 0 0 0

a One patient with grade 4 febrile neutropenia, wound abscess, and grade 4 thrombocytopenia (toxic death).

The current standard of cytoreductive surgery followed by chemotherapy with carboplatin and paclitaxel for patients with epithelial ovarian cancer has improved median survival times, when compared to platinum and cyclophosphamide. However, 5-year survival rates in suboptimally debulked patients remain less than 30% [1,2]. Newer cytotoxic agents such as gemcitabine, liposomal doxorubicin, topotecan, and VP-16 have demonstrated single-agent activity in a second line setting [7,17 – 19] and merit consideration for incorporation into front-line platinum-based therapy in an attempt to

98

K.Y. Look et al. / Gynecologic Oncology 92 (2004) 93–100

further improve median response duration and, ultimately, survival. The goal in this trial was to find an acceptable triplet regimen using gemcitabine, carboplatin, and paclitaxel that would not require cytokine administration or excessive dose modification. An expanded cohort phase I design was used to assess feasibility based on the number of patients who experienced at least one DLE. In this triplet combination, paclitaxel was administered over 3 h, which was found to be less myelosuppressive than a 24-h infusion [20]. Carboplatin, rather than cisplatin, was selected to avoid non-hematologic toxicity and potential alterations in renal clearance that could have an impact on toxicity of other agents [21,22]. However, carboplatin is more myelosuppressive than cisplatin and the AUC of 5 was selected to permit the addition of gemcitabine without the need for prophylactic hematopoietic growth factors [23]. The Jelliffe formula for estimating creatinine clearance was utilized in calculating the AUC dose, based on validated pharmacokinetic studies undertaken in a prior GOG trial of carboplatin and paclitaxel [21]. As expected, the dose-limiting toxicity of this triplet combination was myelosuppression, which is similar to the experience with other triplet combinations incorporating topotecan [3], oral etoposide [4], or doxorubicin [24]. Various schedules of carboplatin, paclitaxel, and gemcitabine (CPG) have been investigated in patients with nonsmall cell lung cancer (NSCLC) [16,25,26]. The schedules utilized and toxicity experienced in the NSCLC trials is outlined in Table 7. The dose and regimen employed in Regimen I of this GOG trial is similar to that of Hussein et al. [25] and Greco et al. [26] with the exception of the lower paclitaxel dose (175 mg/m2) and 3- versus 1-h infusion. Our combined incidence in the two cohorts of grade 4 thrombocytopenia (10/45, 22%) is similar to the earlier reports. The reduced incidence of neutropenia seen in Greco’s study might be attributable to the 1-h paclitaxel infusion, differential tolerance in lung cancer patients, impact of cytoreductive surgery in ovarian cancer patients, or alterations in carboplatin dose because of different methods of estimating

Table 7 Carboplatin, paclitaxel, gemcitabine triplet experience in NSCLCa Authors

Schedule (mg/m2)

Kelly et al. [16]

P175 – 200 day 1 carbo AUC 5 – 6 day 1 gemcitabine 600 mg – 1 g day 1, 8 rec 175, AUC = 5, gem 1000 Hussein et al. [25] P200 over 1 h day 1 carbo AUC 5 day 1 gemcitabine 1 g day 1, 8 Greco et al. [26]

a

P200 over 1 h day 1 carbo AUC 5 gemcitabine 1000

Non-small cell lung cancer.

Toxicity 40% grade 4 neutropenia 21% grade 4 thrombocytopenia

71% grade 4 neutropenia 42% grades 3 to 4 thrombocytopenia 21% platelet transfusion 1 death from nadir sepsis 14% grade 4 leukopenia 21% thrombocytopenia

glomerular filtration rate. In our first cohort, compared to Hussein’s schedule, there was a similar incidence of grade 4 thrombocytopenia (42.8%) and slightly higher incidence of grade 4 neutropenia (71%). However, the 28.5% incidence of febrile neutropenia documented in Regimen I, together with other DLEs, was judged unacceptable for taking that schedule forward for phase III evaluation. Therefore, accrual on Regimen I was terminated and Regimen II was initiated using a reduced dose of gemcitabine and paclitaxel while maintaining the dose of carboplatin. As expected, the addition of gemcitabine to carboplatin and paclitaxel increased the risk of myelosuppression when compared to that reported with carboplatin and paclitaxel as used in the GOG and AGO trials [11,12]; however, there was no increase in non-hematologic toxicity. For example, Ozols et al. reported a 12% incidence of grade 4 leukopenia and 5% incidence of grades 3 to 4 thrombocytopenia in the carboplatin and paclitaxel arm of GOG Protocol #158 [11], and the AGO reported a 14% incidence of grades 3 to 4 neutropenia and 4% incidence of grades 3 to 4 thrombocytopenia [12]. In contrast, with Regimen II of CGP, there was a 67% incidence of grade 4 neutropenia and 12.9% incidence of grade 4 thrombocytopenia. However, the absence of any grade 3 neurotoxicity and a 6.4% incidence of grade 2 or greater gastrointestinal toxicity is not greater than the 7 – 10% incidence of these two toxicities as seen in the carboplatin and paclitaxel arms of the AGO and GOG randomized trials [11,12]. Patients with NSCLC entered in trials using the carboplatin, paclitaxel, and gemcitabine triplet have experienced minimal ( < 5%) grade 4 gastrointestinal toxicity and 4– 8% grade 3 neurotoxicity [16,26]. Two groups have reported the feasibility and excellent activity (100% response rates) of CGP in patients with epithelial ovarian cancer, in both the primary [13] and salvage [14] settings. The dose schedule used in Regimen II of this GOG trial was associated with neutropenic fever in only 1% (2/200) of cycles with uncomplicated grade 4 neutropenia in 67% of patients, and grade 4 thrombocytopenia in 12.9% of patients, which compares favorably to the 75% grade 4 neutropenia and 43% grade 4 thrombocytopenia rates reported by Hansen et al. [13] using a higher dose of paclitaxel (175 mg/m2). Hansen updated the results seen in two earlier ovarian cancer trials with carboplatin, gemcitabine, and paclitaxel and noted 100% response rates in both, with a complete remission rate of 60% and a median time to progression of 16 months in one of the trials [27]. The European –Canadian trial did not find a statistically significant improvement in clinical outcomes with paclitaxel at 175 mg/m2 compared to 135 mg/m2 for management of recurrent disease [20]. Therefore, we feel that the paclitaxel dose of 135 mg/m2 used in Regimen II should not compromise clinical outcomes in patients with newly diagnosed epithelial ovarian cancer. The degree of myelosuppression seen with Regimen II of this trial is acceptable, without a requirement for hematopoietic growth factors, and with a favorable clin-

K.Y. Look et al. / Gynecologic Oncology 92 (2004) 93–100

ical response rate consistent with platinum-based chemotherapy. As such, the triplet regimen appears feasible for incorporation in a phase III trial without the need for additional (phase II) evaluation. It is recognized that the favorable performance status of patients in this trial may make the toxicities seen more tolerable than they might be in a ‘‘less selected’’ patient population that may be seen in the community. Other triplet combinations, such as regimens that incorporate topotecan, an inhibitor of topoisomerase-I, have proven more difficult to develop, due to excessive myelosuppression requiring cytokine support in spite of substantial dose attenuation of the individual components [3]. In addition, although a potential triplet combination that incorporates prolonged oral etoposide has been defined, the association with secondary leukemia and myelodysplasia has reduced the enthusiasm for utilization of etoposide in primary therapy of ovarian cancer [4]. Although Regimen II is tolerable and is now being evaluated as an arm of GOG protocol 182, it remains to be established if long-term clinical outcomes will be improved by adding a third agent, whether gemcitabine, topotecan, or liposomal doxorubicin, to the established platinum – paclitaxel doublet.

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

Acknowledgments This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517). The following Gynecologic Oncology Group member institutions participated in this study: University of Washington, University of Iowa Hospitals and Clinics, Indiana University Medical Center, The Cleveland Clinic Foundation, Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, Fox Chase Cancer Center, and Case Western Reserve University.

[14]

[15] [16]

[17]

[18]

[19]

References [1] McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 2000;334:1 – 6. [2] Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92:699 – 708. [3] Armstrong DK, O’Reilly S, Bookman M, et al. A phase I study of Topotecan (T), Cisplatin (C) and Paclitaxel (P) in newly diagnosed epithelial ovarian cancer: a Gynecologic Oncology Group (GOG 9602) study. Proc Am Soc Clin Oncol [Abstr# 1351] 1998;17:350. [4] Rose PG, Rodriguez M, Waggoner S, et al. Phase I study of paclitaxel, carboplatin and increasing days of prolonged oral etoposide in

[20]

[21]

[22]

[23]

99

ovarian, peritoneal, and tubal carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2000;18(16):2957 – 62. Huang C, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2V2Vdifluorodeoxycytidine on DNA synthesis. Cancer Res 1991; 51(22):6110 – 7. Cartee L, Kucera GL. Gemcitabine induced programmed cell death and activates protein kinase C in BG-1 human ovarian cancer cells. Cancer Chemother Pharmacol 1998;41:403 – 12. Lund B, Hansen OP, Theilade K, Hansen M, Neijt JP. Phase II study of gemcitabine (2V2Vdifluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 1994;86:1530 – 3. Shapiro JD, Millward MJ, Rischin D, et al. Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 1996;63:89 – 93. van Moorsel CJ, Pinedo HM, Veerman G, et al. Mechanisms of synergism between cisplatin and gemcitabine in ovarian and nonsmall cell lung cancer cell lines. Br J Cancer 1999;80(7):981 – 90. Ricci S, Antonuzzo A, Galli L, et al. A randomized study comparing two different schedules of administration of cisplatin in combination with gemcitabine in advanced non-small cell lung cancer. Cancer 2000;89(8):1714 – 9. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 2003;21(17):3194 – 200. DuBois A, Lueck HJ, Meier W, et al. Cisplatin/paclitaxel vs carboplatin/paclitaxel in ovarian cancer: update of an Arbeitgemeinschaft Gynaekologische Onkologie (AGO) study group trial. Proc Am Soc Clin Oncol [Abst# 1374] 1999;18:356. Hansen SW, Anderson H, Boman K, et al. Gemcitabine, Carboplatin, Paclitaxel (GCP) as first-line treatment of ovarian cancer FIGO stages IIB-IV. Proc Am Soc Clin Oncol [Abst# 1379] 1999;18:357. Geertsen P, Hansen M, Stroyer I, Hansen SW. Combination chemotherapy with platinum, paclitaxel and gemcitabine in patients with relapsed ovarian carcinoma. Proc Am Soc Clin Oncol [Abst# 1395] 1999;18:361. Jelliffe RW. Creatinine clearance: bedside estimate. Ann Intern Med 1973;79:604 – 5. Kelly K, Mikhaeel-Kamel N, Pan Z, Murphy J, Prindiville S, Bunn Jr PA. A phase I/II trial of paclitaxel, carboplatin, and gemcitabine in untreated patients with advanced non-small cell lung cancer. A University of Colorado Cancer Center study. Clin Cancer Res 2000; 6(9):3474 – 9. Creemers GJ, Bolis G, Gore M, et al. Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 1996;14(12):3056 – 61. Muggia FM, Hainsworth JD, Jeffers S, et al. Phase II study of liposomal doxorubicin in refractory ovary cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997;15(3):987 – 93. Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second line therapy for platinum resistant and platinum sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1998;16(2):405 – 10. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al. European-Canadian randomized trial of paclitaxel in replapsed ovarian cancer: high-dose versus low dose and long versus short duration. J Clin Oncol 1994;12(12):2654 – 66. Bookman MA, McGuire III WP, Kilpatrick D, et al. Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group. J Clin Oncol 1996;14(6):1895 – 902. Rowinsky EK, Gilbert M, McGuire WP, et al. Sequences of taxol and cisplatin: a phase I pharmacologic study. J Clin Oncol 1991;9(9): 1692 – 703. Jodrell DI, Egorin MJ, Cannetta RM, et al. Relationships between carboplatin exposure and tumor response toxicity in patients with ovarian cancer. J Clin Oncol 1992;10(4):520 – 8.

100

K.Y. Look et al. / Gynecologic Oncology 92 (2004) 93–100

[24] Fleming GF, Fowler JM, Waggoner SE, et al. Phase I trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubicin in advanced endometrial cancer and other gynecologic malignancies: a Gynecologic Oncology Group study. J Clin Oncol 2001;19(4):1021 – 9. [25] Hussein A, Birch R, Waller J, et al. Preliminary results of a randomized study comparing paclitaxel and carboplatin (PC) with or without

gemcitabine (G) in newly diagnosed non small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol [#1973] 2000;19:504 A. [26] Greco FA, Burris III HA, Hainsworth JD. Gemcitabine, paclitaxel and carboplatin for advanced non-small cell lung cancer. Oncology 2000;14(7):31 – 4. [27] Hansen SW. Gemcitabine, platinum, and paclitaxel regimens in patients with advanced ovarian carcinoma. Semin Oncol 2002;29:17 – 9.