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Phase II Study of CT-2103 in Patients With Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma

From the Memorial Sloan-Kettering Cancer Center, New York, NY; Gynecology Oncology Associates, Newport Beach, CA; Pacific Gynecology Specialists; Virginia Mason Medical Center; Swedish Medical Center and Cancer Institute; Cell Therapeutics, Inc, Seattle, WA; and Southwest Regional Cancer Center, Austin, TX

Address reprint requests to Paul Sabbatini, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; e-mail: sabbatip{at}mskcc.org

	ABSTRACT

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PURPOSE: To evaluate the safety and efficacy of CT-2103, a novel conjugate of paclitaxel and poly-L-glutamic acid, in heavily pretreated patients with recurrent ovarian, fallopian tube, or peritoneal cancer.

PATIENTS AND METHODS: Ninety-nine patients with measurable disease received intravenous CT-2103 at 175 mg/m² of conjugated paclitaxel over 10 minutes every 3 weeks without routine premedications. Platinum-sensitive (n = 42) and platinum-refractory or platinum-resistant patients (n = 57) were enrolled. Thirty-nine patients (39%) had received one or two prior regimens, and 60 patients (61%) had received between three and 12 regimens.

RESULTS: In 99 patients, the median number of cycles was three (range, one to 14 cycles). The response rate (RR) for all patients was 10% (10 of 99 patients), with median time to disease progression (TTP) of 2 months. The RR (partial response) in platinum-sensitive and platinum-resistant patients was 14% (six of 42 patients) and 7% (four of 57 patients), respectively. In patients with only one or two prior regimens, the RR in platinum-sensitive and platinum-resistant patients was 28% (five of 18 patients) and 10% (two of 21 patients), with a median TTP of 4 and 2 months, respectively. Grade 2 (15 patients) or 3 (15 patients) neuropathy was reported in 30 patients (30%). Grade 2 hypersensitivity occurred in eight patients (8%) who were subsequently treated with premedications; one patient had grade 3 hypersensitivity and was removed. Grade 2 alopecia was absent.

CONCLUSION: CT-2103 is active in patients with recurrent ovarian cancer. Neurotoxicity in these heavily pretreated patients was more frequent than predicted from phase I trials. Further study to define toxicity and efficacy in patients with less prior therapy is ongoing.

	INTRODUCTION

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Initial response rates for patients with ovarian cancer exceed 70% for modern chemotherapy with a platinum and taxane combination.¹ Despite initial responses, the majority of patients experience relapse, with a median disease-free interval of 18 to 24 months. Data from multiple agents in the second-line setting show response rates of approximately 20% to 35% in patients with platinum-sensitive disease (relapse > 6 months from initial platinum therapy) or 8% to 15% for patient with platinum-resistant disease (relapse within 6 months from initial platinum treatment).^2-4 Cumulative toxicities, such as neutropenia, thrombocytopenia, and neuropathy, may preclude the continued use of many of these agents. The schedule of administration and other side effects, such as alopecia, nausea, obstipation, and hypersensitivity reactions, also affect one's ability to tolerate more therapy.

CT-2103 [poly-L-glutamic acid paclitaxel] is paclitaxel covalently linked at the 2'-hydroxyl group through an ester bond to a carboxylate of a long-chain polymer of L-glutamic acid, a naturally occurring amino acid.⁵ The average molecular weight of CT-2103 is 80,000 da, and it contains 37% paclitaxel by weight. The postulated benefits of polymeric drug conjugates include the following: (1) enhanced solubility of hydrophobic drugs, thus obviating the need for toxic solubilizing agents such as Cremaphor EL (Sigma, St Louis, MO), resulting in shorter infusion times and eliminating one factor responsible for hypersensitivity reactions; (2) selective concentration in tumor tissue owing to the enhanced permeability of tumor vasculature to macromolecules and their retention in the tumor tissue as a result of the lack of lymphatic drainage; (3) minimized toxicity to normal tissues because of the exclusion of large macromolecules from normal tissue interstitium; and (4) the ability to decrease MDR1 gene-encoded resistance by releasing paclitaxel at intracellular sites less accessible to membrane-bound pumps.^6,7 Preclinical models of CT-2103 support these postulates, showing enhanced tumor uptake compared that of with standard paclitaxel.⁸ In a preclinical study, mice bearing OCA-1 ovarian carcinoma (mean size, 500 µL) were tumor free after a single intravenous dose equivalent to 160 mg of conjugated paclitaxel/kg.⁹ Preclinical pharmacokinetic studies confirm that the amount of free paclitaxel in plasma is markedly reduced when conjugated paclitaxel is compared with standard paclitaxel, although conjugated paclitaxel has a prolonged tissue half-life.⁸ CT-2103 is administered as a 10-minute infusion every 3 weeks. Phase I studies in humans using single-agent CT-2103 suggest a maximum-tolerated dose of 235 mg/m² (data on file, Cell Therapeutics, Inc, Seattle, WA).

The purpose of this multi-institution phase II study was to evaluate the toxicity, response rate, and time to disease progression (TTP) in women with recurrent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma treated with CT-2103. To date, this represents the first reported phase II trial of CT-2103 in this patient population.

	PATIENTS AND METHODS

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Eligibility Criteria
Eligible patients had histologic confirmation of epithelial ovarian, primary peritoneal, or fallopian tube cancer; measurable baseline disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST); progressive disease, defined as radiographic progression or a doubling in CA-125 from upper limits of normal or from nadir; and two or fewer prior chemotherapy regimens or platinum/taxane-refractory or platinum/taxane-resistant disease as defined by progression on or within 6 months of one of these agents (with any number of prior regimens). A midstudy assessment showed a preponderance of platinum-sensitive patients, so eligibility was limited to allow only patients with two or more prior regimens to increase accrual of platinum- and taxane-resistant patients. Other requirements included Karnofsky performance status 70%; adequate organ function, defined as absolute neutrophil count 1,500/µL, platelet count 100,000/µL, total bilirubin and serum creatinine 1.5 times institutional upper limit of normal, and AST and alkaline phosphatase 2.5 times institutional upper limit of normal; and no childbearing potential.

Patients were excluded from the study if they had neuropathy grade 3 or immunotherapy, chemotherapy, or any investigational drug during the 4 weeks before study entry. Patients were also excluded if they had any uncontrolled cardiac, pulmonary, metabolic, renal, or gastrointestinal conditions, infectious diseases, immune deficiency, or a history that, in the opinion of the investigator, placed the patient at an unacceptable risk for participation in the study.

All patients provided written informed consent. The protocol was approved by the respective institutional review boards and was reviewed annually.

Treatment Plan
CT-2103 was administered as an intravenous infusion (approximately 10 minutes) at a dose of 175 mg/m² on day 1 of each 3-week cycle. Treatment cycles were repeated every 3 weeks until disease progression, the occurrence of unacceptable toxicity, two cycles after documentation of complete response, death, or completion of 14 cycles. Premedications, including antiemetics, were not routinely given. In the event of hypersensitivity, subsequent cycles were administered using standard premedications for paclitaxel, typically consisting of dexamethasone, diphenhydramine, and ranitidine.¹⁰

Dose Adjustments
Dose adjustments were required for the following toxicities: drug-related grade 4 neutropenia lasting at least 5 days or of any duration when associated with a grade 3 infection; drug-related febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection with absolute neutrophil count < 1.0 x 10⁹/L); grade 3 thrombocytopenia with platelet nadir of less than 25 x 10⁹/L, or grade 3 or 4 nonhematologic toxicity (excluding nausea and vomiting of all grades, if adequately controlled by antiemetics), or progression of preexisting neurotoxicity. For patients requiring dose reduction, the dose of CT-2103 was reduced to 135 mg/m² at the next treatment cycle. If the toxicity recurred, a final dose reduction to 90 mg/m² was allowed at the following cycle. If the dose was reduced, the same dose was used for subsequent cycles. If toxicity recurred after the second reduction in dose, the patient was withdrawn from the study. Hematopoietic growth factors could be used as part of treatment of neutropenia with infection (followed by dose reduction at next cycle) but were not used prophylactically.

Evaluation During Study
Pretreatment evaluations included the following: history and physical examination, Karnofsky performance status assessment, CBC count with differential and platelet count, biochemical profile, ECG, computed tomography (CT) or magnetic resonance imaging scan of the abdomen and pelvis, and documentation of tumor measurements using RECIST.

During treatment, CBCs were performed weekly. History, physical examinations, and assessment of toxicities were performed before each cycle of treatment. Biochemical profiles and serum CA-125 assessments were performed approximately every 3 weeks. CT scans were repeated after every third cycle to assess response. All patients with complete response (CR), partial response (PR), or stable disease (SD) subsequently underwent CT scans approximately every 9 weeks until there was evidence of disease progression. At the discretion of the treating physician, CT scans were permitted to be performed earlier than required by protocol. If such a scan showed progression of disease, the date of that scan was used as the date of disease progression in the analysis. Treatment toxicities were graded by the National Cancer Institute Common Toxicity Criteria, version 2.0.

Response Criteria
To be considered assessable for response, a patient must have received at least one cycle. Responses were assessed by CT or magnetic resonance imaging scans. RECIST was used to determine best overall response.¹¹ Best response was defined as the greatest response achieved by a patient (thus, each patient had a single best response: CR, PR, SD, or progressive disease [PD]), and the date of best response was the date that best response was first detected. CR was defined as disappearance of all measurable and nonmeasurable lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of measurable lesions, taking as a reference the baseline sum of the longest diameters of the measurable lesions. PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as a reference the smallest sum longest diameter recorded since treatment started, or the appearance of new lesions. Progression could also be determined at the discretion of the treating physician by demonstrating surgically defined progression (if surgery was clinically indicated) or by symptomatic deterioration. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD and lasting at least until the first assessment (approximately > 8 weeks). The date of progression of disease was the date that progression was first detected. Patients were categorized as platinum-sensitive if they experienced recurrence 6 months from prior platinum regimen or platinum-refractory or platinum-resistant if progression occurred on or within 6 months of receiving prior platinum therapy. Patients were categorized as taxane-sensitive or taxane-resistant using a similar definition.

Statistical Considerations
All treated patients (N = 99) were included in the analysis. A sample size of 99 produces a significance level (probability of falsely declaring that the regimen warrants further study when the true response rate 10%) of .05 and power (probability of correctly declaring that the regimen warrants further study when the true response rate is at least 25%) of 0.53.

The patient characteristics, response evaluation, and toxicity assessment were evaluated using descriptive statistics and 95% CIs for response rates. TTP was analyzed using the method of Kaplan and Meier.¹² TTP was calculated from the time of first treatment until documented progression or death from any cause. Patients alive without disease progression were censored at the date of last contact.

	RESULTS

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Patient Characteristics
One hundred patients were enrolled onto the study, and 99 received at least one cycle of chemotherapy. Twenty-six patients received only one or two cycles because of rapid disease progression. Patient characteristics are listed in Table 1. The median age of the patients was 57 years (range, 29 to 89 years). Fifty-seven patients (58%) were categorized as platinum-refractory or platinum-resistant; 42 patients (42%) were categorized as platinum-sensitive. Sixty patients (61%) received three or more prior regimens, with 31 patients (31%) having received five or more prior regimens, defining a heavily treated population at study entry. Performance status was 70 in 9% of the patients entering the study. A total of 380 cycles of therapy were administered to 99 patients, with 36 patients receiving between four and 14 treatments. The median number of cycles administered was three (range, one to 14 cycles).

View larger version (13K): [in this window] [in a new window]   Fig 1. Time to progression. Plat-Res/Ref, platinum-resistant/refractory; Plat-Sens, platinum-sensitive.

	DISCUSSION

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The response rate of patients with recurrent ovarian cancer treated with standard paclitaxel (as well as other chemotherapeutic agents) varies widely depending on the proportion of patients in the study population who received prior paclitaxel as part of their first-line treatment, those who responded to initial taxane-based therapy, those who are platinum-sensitive, the duration of the treatment-free interval, the number of prior regimens, and the schedule of paclitaxel administration.^4,13-16 Furthermore, retrospective analyses of data have also shown that response to paclitaxel chemotherapy for patients with recurrent disease is related to tumor bulk (being worse for those with > 5 cm disease) and performance status.¹⁷

Standard paclitaxel response rates of 37% are seen in patients who are taxane-naïve.¹³ Response rates as high as 44% have been reported in patients who had a CR or PR to prior primary taxane therapy and who also had a prolonged treatment-free interval without intervening therapy.¹⁴ More heavily pretreated patients typically have lower response rates of approximately 22%, as seen in the original phase II trials.¹⁵ Response rates as low as 20% and 6.7% have been reported in the phase III setting in patients with platinum-sensitive and platinum-resistant disease.⁴ Finally, an objective response rate of 4% was seen in an extraordinarily heavily pretreated cohort on the initial National Cancer Center Referral Protocol despite patients being taxane-naïve.¹⁶

Increasing the number of prior therapies has a significant inverse effect on response rate. This was clearly shown in a phase III study by Gore et al,¹⁸ which compared paclitaxel to topotecan using a cross-over follow-up design. The response rate to paclitaxel in third-line patients declined from 13.2% to 10.2% in patients who had received two prior regimens. Similar results were observed with topotecan, as response rates declined from 20.5% in patients in first relapse to 13.1% in patients in second relapse. Thus the homogeneity and the characteristics of a given population are important considerations that frame the response rate and TTP observed with any given agent. This observation has led cooperative groups to test new agents in homogeneous populations limited to patients who have received only one or two prior regimens and in whom the sensitivity to prior platinum therapy can be well defined.

The patients in this study were heavily pretreated: 60 (61%) of 99 patients received between three and 12 prior treatment regimens before entering the study, as compared with one or two prior regimens in the majority of phase II studies available for comparison. The median number of sites of tumor was four (range, one to 11 sites). As expected, the response rates in our study are higher in patients with two or fewer prior regimens having platinum-sensitive disease (28%) or platinum-resistant disease (10%) as compared with those with more than two prior regimens (4% and 6%, respectively). These response rates in patients limited to two or fewer prior regimens are comparable to those reported for paclitaxel in randomized studies in this patient population.^4,18

A cohort of patients with SD of modest duration as the best response has also been reported with standard paclitaxel in many prior studies and, in fact, dominated some of the initial studies in very heavily pretreated patients.¹⁶ Markman et al¹⁹ reported an SD rate of 41% for minimally pretreated patients who had initially responded to platinum/taxane-based therapy. In a comparable subset of patients, our study with CT-2103 demonstrated an SD rate of 40% in patients with platinum-sensitive disease and 26% in patients with platinum-resistant disease.

In a preclinical study by Li et al,⁹ conjugated paclitaxel showed activity against a taxane-resistant SKOV3 ovarian cancer cell line, thus providing the rationale for evaluating this subset. In our study, the response rate in a clinically defined taxane-resistant population was 2%, showing no significant clinical activity in this population. Ongoing and future studies of CT-2103 in patients with ovarian carcinoma will investigate the agent in patients for whom standard taxane responses are expected.

Several nontaxane agents are available for use in the setting of recurrent ovarian cancer. Data from multiple phase II and III studies show response rates for these agents of approximately 20% to 35% in patients with platinum-sensitive disease.^2-4 The platinum-resistant population generally shows response rates to nontaxane agents in the 10% to 20% range and a median progression-free survival (PFS) in the 9 to 12 weeks range. Again, most of these studies limited eligibility to patients with two or fewer prior regimens. Response rates to topotecan (20.5%),⁴ liposomal doxorubicin (12.3%; median PFS, 9.1 weeks),² gemcitabine (19%),²⁰ vinorelbine (15%),²¹ and irinotecan (17.2%; median PFS, 11.2 weeks)²² are all within this range.

In relation to other nontaxane agents, the response rate of CT-2103 of 28% in platinum-sensitive patients with one or two prior regimens is in line with that seen in studies of other agents, as described above, with similar eligibility characteristics. If one includes all patients in this study with platinum-sensitive disease, recognizing that 60% of patients have three or more prior regimens, the response rate of 14% is difficult to interpret in the context of platinum-sensitive studies with fewer regimens. In the CT-2103 study, the response rate in platinum-resistant patients overall was 7%. In patients limited to one or two prior regimens, the response rate was 10%. Ten of the 19 platinum-resistant patients with PR (one patient) of SD (nine patients) had clinically defined standard taxane resistance.

Standard paclitaxel administration is associated with a wide variety of adverse events, depending on the patient population. A recent randomized study of recurrent disease comparing paclitaxel administered weekly versus every 3 weeks showed grade 3 or 4 neutropenia in 45 (45%) of 101 patients, grade 2 neuropathy (29%), alopecia (79%), and arthralgia (8%).²³ Treatment delay or dose reduction was required in 9% (nine of 99 patients) and 7% (seven of 99 patients), respectively, of patients receiving CT-2103 at 175 mg/m² over a 10-minute infusion. Grade 3 or 4 neutropenia occurred in 15 and nine patients, respectively; no febrile neutropenia occurred, and grade 3 anemia was seen in six patients. Most hematologic toxicity was asymptomatic and compares similarly to the hematologic toxicity reported for standard paclitaxel on a 3-week schedule.^24,25 Granulocyte colony-stimulating factor was not routinely administered. The favorable hematologic profile persisted despite the fact that these patients were at higher risk for symptomatic hematologic toxicity by virtue of their heavy prior treatment histories.²⁶ Recognizing that 27% of patients entered the study with alopecia, only seven additional patients (9%) experienced hair thinning, with no significant alopecia. This is an important advantage in this population with chronic disease.

The frequency and severity of paclitaxel hypersensitivity reactions have been well characterized.^27,28 The initial reported incidence of 16% to 40% grade 3/4 has been reduced to 2% to 3% with standard premedications, typically consisting of dexamethasone, diphenhydramine, and an H₂ antagonist such as ranitidine. The need for routine premedications adds time to treatment and often is the cause of other acute effects (insomnia, restlessness or fatigue, hyperglycemia), as well as effects seen with longer-term use, such as weight gain, fluid retention, and osteoporosis. The majority of hypersensitivity reactions to paclitaxel have been thought to be due to a nonimmunologically mediated response to Cremophor EL base (polyoxyethylated castor oil), which is not found in the CT-2103 conjugate and may explain the lower incidence of hypersensitivity reactions without the routine use of premedications.²⁷ In our study, grade 1 and 2 hypersensitivity reactions occurred in 13% patients (13 of 99). Nine of these patients received more cycles, and all but one of these were successfully re-treated with premedications. A grade 3 hypersensitivity reaction occurred in one patient (1%; this patient did not receive premedication). The patient was not rechallenged and was removed from the study. Patients with hypersensitivity reactions to prior taxanes were not excluded from the study, but these patients are not identified, so it is not known if such patients are at higher risk. It is also noted that of our grade 2 hypersensitivity reactions, all occurred during or at the end of the infusion, making prolonged periods of observation unnecessary. It is important to have appropriate medications available to treat hypersensitivity reactions should they occur, and patients should be observed during the short infusion time. The incidence of hypersensitivity will need to be monitored, particularly as clinical trials with CT-2103 proceed in taxane-naïve patients, to determine whether routine premedications should be considered.

The overall incidence of grade 2 and 3 neuropathy using CT-2103 at 175 mg/m² every 21 days in this heavily treated patient population was 30% (15% with grade 2 neuropathy and 15% with grade 3 neuropathy). Of the patients with grade 3 neuropathy, 12 had received five or more cycles of CT-2103. Eight of these patients were discontinued from study because of neurotoxicity, whereas seven patients were managed with dose reduction or delay and ultimately were removed for disease progression. The incidence of clinically relevant neurotoxicity is more frequent in this study than was predicted from either preclinical models or from pharmacokinetic studies of phase I trials, which demonstrated a low plasma concentration of free paclitaxel. Multiple factors may be contributing to this finding, either singly or in combination. First, it is possible that the low but sustained unconjugated paclitaxel exposure is sufficient to promote the development or worsening of neuropathy in heavily pretreated patients. Second, there may be a clinical contribution from the conjugate. In animal studies, focal nerve fiber degeneration was sporadically seen in spinal cord and peripheral nerve sections that were similar to that seen with nonconjugated paclitaxel in published studies. The clinical relevance of this finding is unknown (data on file, Cell Therapeutics Inc, Seattle, WA). Third, many of the initial phase I studies evaluating dose and schedule included nonovarian cancer patients (hence, with little or no prior taxane exposure). The incidence of neurotoxicity will be further characterized in ongoing studies in patients with ovarian cancer limited to the third-line setting.

In summary, this initial phase II experience shows that CT-2103 has activity in heavily pretreated patients with ovarian cancer. Advantages included the short infusion duration (10 minutes), the absence of routine premedication use, and the absence of grade 2 or worse alopecia. Clinically relevant neurotoxicity at this dose and schedule was higher than predicted from previous phase I studies. Further study to define efficacy and characterize toxicity in patients with less prior therapy is ongoing. These results will be important in defining the role of CT-2103 in the series of alternatives to standard paclitaxel for patients with ovarian cancer that are currently under development.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Amy J. Eisenfeld, Cell Therapeutics. Stock Ownership: Amy J. Eisenfeld, Cell Therapeutics. Honoraria: Paul Sabbatini, Cell Therapeutics. Research Funding: Paul Sabbatini, Cell Therapeutics; John V. Brown, Cell Therapeutics; William A. Peters, Cell Therapeutics; Andrew Jacobs, Cell Therapeutics; Aminder Mehdi, Cell Therapeutics.

	NOTES

 
Supported by Cell Therapeutics Inc, Seattle, WA, and by National Institutes of Health Ovarian Cancer grant No. CA-52477-10.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted December 9, 2003; accepted September 7, 2004.

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