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© 2001 American Society for Clinical Oncology Phase II Study of Paclitaxel and Valspodar (PSC 833) in Refractory Ovarian Carcinoma: A Gynecologic Oncology Group StudyFrom the Department of Medicine, Washington University School of Medicine, St Louis, MO; Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo, NY; Department of Obstetrics and Gynecology, Indiana University Medical Center, Indianapolis, IN; Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences, Oklahoma City, OK; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland, OH; Medical Affairs-Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ; Department of Pathology, University of Arizona, Tucson, AZ; University of Mississippi School of Medicine, Jackson, MI; and Gynecologic Oncology Center, Mercy Medical Center, Baltimore, MD. Address reprint requests to GOG Administrative Office, 1234 Market St, Ste 1945, Philadelphia, PA 19107; email: fracasso{at}im.wustl.edu
PURPOSE: A phase II study was conducted to determine the efficacy of paclitaxel and valspodar (PSC 833) in patients with advanced epithelial ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D analogue that reverses P-glycoprotein–mediated multidrug resistance, in combination with paclitaxel might be active in paclitaxel-resistant and refractory ovarian cancer. PATIENTS AND METHODS: Patients received valspodar 5 mg/kg orally qid x 12 doses. Paclitaxel (70 mg/m2 intravenously for 3 hours) was administered on day 2, 2 hours after the fifth or sixth dose of valspodar. This treatment was repeated every 21 days. One blood sample was collected before the sixth dose of valspodar for the first three cycles to evaluate valspodar trough concentration. Tumor tissue was obtained from patients for immunohistochemical staining of P-glycoprotein.
RESULTS: Of 60 patients entered, 58 were assessable for response. There were five partial responses (8.6%; 90% confidence interval [CI], 3.8 to 20.0; median duration of response, 5.0 months [range, 1.9 to 10.5 months]). Median progression-free survival was 1.5 months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and cerebellar ataxia. The trough concentrations of valspodar were CONCLUSION: Valspodar in combination with paclitaxel has limited activity in patients with paclitaxel-resistant ovarian carcinoma. An international randomized clinical trial of paclitaxel and carboplatin with or without valspodar as first-line therapy in advanced ovarian cancer is underway.
EPITHELIAL OVARIAN carcinoma is the fifth most frequent cause of cancer in United States women and accounts for nearly 14,000 deaths per year in the United States.1 Most women present with advanced disease and are treated with cytoreductive surgery followed by platinum and paclitaxel combination chemotherapy. Although women with ovarian carcinoma initially respond to treatment, the majority experience tumor recurrence and eventually die because of recurrent and resistant disease.2 Therefore, therapeutic approaches to overcome drug resistance are essential for the effective treatment of women with ovarian carcinoma. The development of drug resistance to paclitaxel or other available agents used in the treatment of ovarian carcinoma may be compounded by the emergence of cross-resistance to multiple chemotherapeutic agents unrelated in structure and function to the original selective agent. This phenomenon, termed multidrug resistance (MDR), is caused by several different mechanisms. The most extensively characterized mechanism is that associated with overexpression of the MDR1 gene and its protein product, P-glycoprotein.3 P-glycoprotein is a 170-kd membrane glycoprotein that acts as an adenosine 5'-tripohsphate–dependent efflux pump in reducing the intracellular accumulation of paclitaxel, anthracyclines, vinca alkaloids, epipodophyllotoxins, dactinomycin, and other natural products.3 Despite rapid advances in understanding of the cellular and molecular biology of MDR1 in resistant animal and human cell lines, the role of P-glycoprotein in clinical drug resistance remains unclear. Studies have demonstrated increased P-glycoprotein expression in many human cancers, including ovarian cancer,4 and because of the potential importance of P-glycoprotein in clinical drug resistance, many investigators have focused on the pharmacologic reversal of this phenomenon. In particular, researchers have studied drugs that overcome MDR by inhibiting efflux and allowing chemotherapeutic agents to accumulate within resistant tumor cells in vitro and in vivo.5 These drugs include calcium channel blockers, calmodulin antagonists, local anesthetics, membrane active agents, steroids, hormonal agents, and cyclosporines.5 Valspodar (PSC 833), a nonimmunosuppressive analogue of cyclosporine D, is a potent agent that reverses MDR in the laboratory.6-12 A phase I trial to determine the maximum-tolerated dose and the dose-limiting toxicity of this drug with paclitaxel was completed at Stanford University and Washington University.13,14 When valspodar was administered at 20 mg/kg/d orally qid before, during, and after paclitaxel, the maximum-tolerated dose of paclitaxel administered as a continuous intravenous (IV) infusion for 3 hours was 70 mg/m2 (40% of 175 mg/m2). Pharmacokinetic studies demonstrated that at this reduced dose of paclitaxel, when administered with valspodar, paclitaxel drug exposure and degree of myelosuppression were comparable to that of patients who received 175 mg/m2 of paclitaxel alone. The current phase II study treated with paclitaxel and valspodar women who had had stable or progressive disease while receiving first-line paclitaxel and platinum or who had experienced disease recurrence within 6 months of receiving paclitaxel and platinum. It was postulated that if P-glycoprotein is important in drug resistance, then the combination of paclitaxel and valspodar may demonstrate activity in women who have paclitaxel-resistant disease.
Patients Sixty patients were entered onto this study between April 1996 and September 1996, and again between November 1996 and July 1997. All patients had histologically confirmed recurrent or persistent ovarian epithelial ovarian carcinoma. Patients must have had only one previous treatment consisting of a platinum compound and paclitaxel and must have progressed while on platinum and paclitaxel, had clinically measurable disease with a best response as stable after at least six courses of paclitaxel and platinum therapy, or experienced recurrent disease within 6 months of completion of that treatment.
Patients were required to be at least 18 years old and have measurable disease, a Gynecologic Oncology Group performance score of 0 to 2, and a life expectancy of at least 3 months. Laboratory criteria for eligibility included WBC count
Treatment Plan, Dose Modifications, and Response Evaluation
Paclitaxel dose escalation by 17.5 mg/m2 was permitted after a patient completed a course of treatment if the patient’s ANC and platelet nadirs in the previous course were Cerebellar dysfunction is the dose-limiting toxicity of valspodar when administered alone, and grade 3 and 4 cerebellar toxicity required dose modification of valspodar. In this study, grade 1 cerebellar toxicity was defined as a patient’s slight subjective sense of incoordination without difficulty in walking. Grade 2 toxicity was defined as a patient’s definite subjective incoordination in walking but ability to walk without assistance and, on examination, evidence of cerebellar dysfunction, such as broad-based gait, mild dysmetria, difficulty in walking heel-to-toe or difficulty with rapid alternating movements. Grade 3 toxicity was defined as the inability to walk without assistance and, on examination, a markedly abnormal gait and inability to walk heel-to-toe were noted. Grade 4 toxicity was defined as the inability to walk because of incoordination, even with assistance. If grade 3 or 4 cerebellar toxicity occurred before paclitaxel was administered, treatment was discontinued until the toxicity resolved. The patient was restarted at a 20% reduction in the dose of valspodar (4.0 mg/kg/dose) and received all 12 doses of valspodar at this reduced dose. If grade 3 or 4 cerebellar toxicity occurred after paclitaxel was administered, valspodar was discontinued until the toxicity resolved. Treatment with the reduced dose of valspodar (4.0 mg/kg/dose) was resumed at the dose number that the patient would have reached if the treatment course had continued without interruption. For example, if grade 3 ataxia occurred in a patient after the sixth dose and then resolved by the time the ninth dose would have been due, treatment resumed with the ninth dose and continued through the twelfth dose. The seventh and eighth doses were not administered. If grade 3 or 4 cerebellar toxicity recurred after valspodar dose reduction, the patient was removed from the study.
Patients were eligible to continue treatment until evidence of disease progression or adverse effects prohibited further therapy. Patient response to therapy was evaluated every two courses of therapy. Patients were assessable for toxicity if they received any therapy and assessable for response if one course of therapy was completed and their response was evaluated. The Gynecologic Oncology Group response criteria were defined as follows. A complete response was the disappearance of all measurable disease by physical examination and/or radiographic criteria for at least 4 weeks. A partial response was a reduction of
Laboratory Correlative Studies Tumor specimens or malignant fluid was requested when possible to perform P-glycoprotein immunohistochemical analysis. Although fresh tissue or malignant fluid was preferred, only paraffin blocks or stained slides were sent to T.M.G.’s laboratory for immunohistochemical studies. The tissue samples were assayed for P-glycoprotein using a method described previously.15,16 Briefly, sections were cut from the paraffin blocks into 3- to 4-µm sections and heated at 60°C for 45 minutes. The slides were deparaffinized using standard histological techniques. After deparaffinization, microwave antigen retrieval was performed using a citric buffer, pH 6.0. Then the slides were incubated at room temperature for 1 hour with the primary monoclonal antibody JSB-1 (Accurate Chemical & Scientific Corporation, Westbury, NY) at 1:20 dilution or with a negative control (phosphate-buffered saline with 2% bovine serum albumin). After the slides were incubated, they were run on the VMS automated immunostainer (Ventana Medical Systems, Inc, Tucson, AZ) using the diaminobenzidine technique as described previously.17 Then they were counterstained with methylene green and mounted. The presence of any immunostaining for P-glycoprotein expression was considered positive.
Statistical Considerations Overall survival, progression-free survival (PFS), and duration of patient response were assessed from the date of entry into the study. Survival was measured until the date of death (due to any cause), whereas PFS and response duration were terminated at the first occurrence of either disease progression or death. The product limit method was used to estimate the survival and PFS distributions.20
Patient Characteristics Sixty patients were entered into this trial. Two patients were considered ineligible: one patient had received no paclitaxel treatment in the previous 6 months and another had primary peritoneal disease. The characteristics of the 58 eligible patients are listed in Table 1. The patients’ median age was 55.6 years, and 60% of them had a Gynecologic Oncology Group performance score of 0. All patients had one prior chemotherapeutic regimen with platinum- and paclitaxel-based therapy. All had either persistent disease that was unresponsive to platinum and paclitaxel therapy or disease progression within 6 months of completing that therapy.
Treatment Fifty-six of the 58 eligible patients completed at least one entire course of paclitaxel and valspodar combined therapy. The two patients who did not complete at least one course of therapy were withdrawn from the study treatment before initiating any paclitaxel because of either moderate cerebellar toxicity or moderate neurologic toxicity with nausea attributable to valspodar. Nine additional patients stopped treatment after completing only their first course of therapy. Two of these patients died of neutropenic sepsis attributable to the study treatment, four demonstrated clinical progression of their disease, and three others experienced increasing general debilitation. No patient received G-CSF before the first course of therapy, but four patients initiated G-CSF after their first course of therapy. Of the 47 patients in whom a second course of treatment was initiated, the second course had to be delayed for more than 5 days in four patients (8.5%) because of depressed ANC. The paclitaxel dose for the second course of therapy was escalated to 87.5 mg/m2 in 18 patients (38.3%) and attenuated to 56 mg/m2 in four patients (8.5%). The number of patients escalated to 105 or 122.5 mg/m2 at each course is listed in Table 2.
A total of 189 paclitaxel and valspodar combined-treatment courses were initiated, with a median of two courses/patient (range, one to 14 courses). Table 2 lists the number of patients treated at each dose level of paclitaxel by course of treatment for the first eight courses of treatment. Three patients received more than eight courses of treatment.
Toxicity
Response Patients’ responses to treatment are listed in Table 4. Five patients (8.6%; 90% confidence interval [CI], 3.8 to 20.0%) had a partial response, with a median response duration of 5.0 months (range, 1.9 to 10.5 months). Fifteen patients (25.9%) had stable disease, and 36 patients (62.1%) experienced increasing disease, general debilitation, or death before their first clinical assessment. The median progression-free survival for all patients was 1.5 months (90% CI, 1.4 to 2.4). The median overall survival duration was 8.4 months (90% CI, 6.2 to 10.7). The product-limit estimates of the survivorship functions are displayed in Fig 1.
Laboratory Correlative Studies We obtained trough valspodar blood concentrations from 40 (69%) of the 58 patients during their first course of treatment. The trough valspodar concentrations were greater than 1,000 ng/mL in all but two patients (920 and 970 ng/mL). A valspodar concentration greater than 1,000 ng/mL is considered adequate to reverse P-glycoprotein–mediated resistance in vitro.8 The median valspodar concentration was 2,445 ng/mL, and the first and third quartiles were 1,880 and 3,105 ng/mL, respectively. Valspodar trough concentrations were also available from 35 (74%) of 47 patients who had a second course of treatment and from 18 (78%) of 23 patients who were administered a third course of treatment. The median valspodar concentrations obtained during these treatment courses were 2,870 and 2,975 ng/mL, respectively. A tissue specimen for immunohistochemical detection of P-glycoprotein was available from the initial diagnostic procedure (before any chemotherapy) in 28 patients and after first-line treatment (before treatment in this study) in five patients (see Table 5). Among the tissue specimens collected before any chemotherapy was begun, nine (32%) stained positive for P-glycoprotein. Among the five tissue specimens collected after first-line treatment and before treatment in this study, two (40%) stained positive for P-glycoprotein. All five patients who responded to treatment in this study had tissue specimens from the initial diagnostic procedure. None of these specimens stained positive for P-glycoprotein. Only one of the specimens from the two patients whose tissue specimens were obtained just before treatment in this study stained positive for P-glycoprotein.
In this phase II study, paclitaxel was used in combination with valspodar, a second-generation MDR-reversing agent, in women with recurrent, platinum-resistant ovarian carcinoma. The phase I studies of this combination revealed enhanced myelosuppression with the combination therapy of paclitaxel and valspodar.13,14,21 These phase I studies demonstrated that when paclitaxel was administered at a dose of 70 mg/m2 in combination with valspodar, the length of time that plasma paclitaxel concentration remained  0.05 µM (the pharmacokinetic parameter most relevant to neutropenia produced by paclitaxel therapy22) was similar to that observed when full-dose paclitaxel was administered without valspodar. Therefore, in this phase II study, women were treated with paclitaxel 70 mg/m2 and valspodar, and dose escalation of paclitaxel was implemented on the basis of nadir counts from the previous course. As in the phase I trials with this combination therapy, hematologic toxicity was the major adverse effect.13,14,21 Despite this side effect, many patients were able to continue dose escalation until paclitaxel was administered at 70% (or 122.5 mg/m2) of the single-agent paclitaxel dose. Cerebellar ataxia, a potential toxicity of valspodar, was observed but was seldom dose-limiting. Paresthesias of the hands and feet were observed, but whether this toxicity was secondary to paclitaxel alone or was exacerbated by the combination of paclitaxel and valspodar is unknown. Other nonhematologic toxicities were modest and, although possibly related to the study drug, were not dose-limiting. Paclitaxel was used in combination with valspodar with the goal of increasing the response rate in patients with recurrent ovarian cancer by reversing any contribution that P-glycoprotein might have in resistant disease. This trial demonstrated a partial response rate of only 8.6%, however, which is similar to the response rate (8%) observed by the New York Gynecologic Oncology Group (NYGOG).23 In the NYGOG trial, eligible women must have had a paclitaxel-based regimen and must have progressed while on this regimen or relapsed within 6 months of achieving a partial or complete response. Unlike the current trial, however, in the NYGOG trial, patients who had been pretreated heavily were allowed, and the median number of previous chemotherapy regimens was four. Interestingly, stable disease was noted in women with paclitaxel-resistant cancer. In the current trial, 25.9% of women demonstrated stable disease. Perhaps the response rate in this study was low because multiple mechanisms of drug resistance are responsible for disease recurrence in ovarian cancer.24-27 Paclitaxel resistance is thought to be related to decreased drug accumulation due to overexpression of P-glycoprotein and to altered cellular target (in this case, tubulin).28 Platinum resistance may be caused by enhanced detoxification of these agents by cytosolic sulfhydryl molecules (glutathione and glutathione S-transferases) and increased DNA repair mechanisms.28 Strategies for overcoming resistance by these various mechanisms are being investigated; the causal role of these mechanisms in the clinical setting of recurrent disease is unknown.29 In this phase II study, we were interested in the role of P-glycoprotein in patients with resistant, recurrent ovarian cancer. Many studies have demonstrated P-glycoprotein levels in clinical specimens from women with untreated ovarian cancer. A recent review reported that P-glycoprotein levels in women with untreated ovarian cancer are variable, with some studies reporting high levels of 65 to 100% and other studies reporting low levels of 0 to 35%.30 This variability in P-glycoprotein expression has been attributed to the different sensitivities of the detection methods. In particular, the polymerase chain reaction method detects very low levels of expression of MDR1, levels that may not be clinically significant. Among all studies, however, approximately one third of all untreated ovarian tumors are positive for P-glycoprotein overexpression, and our study supports this finding. Less information is available with regard to overexpression of P-glycoprotein in tumor specimens from women after treatment, although it seems to be similar in frequency.30 Given our low response rate and the limited number of tissue specimens obtained for P-glycoprotein immunohistochemical staining, we can make no statement about the presence or absence of P-glycoprotein and our patients’ responses to treatment. Recent in vitro studies suggest the possibility that MDR modulators such as valspodar may actually prevent the emergence of P-glycoprotein overexpression when administered to patients whose tumors do not overexpress P-glycoprotein.31,32 Beketic-Oreskovic et al31 demonstrated that the combination of valspodar and doxorubicin decreases the rate of mutation for drug resistance by nearly 10-fold and suppressed the activation of the MDR1 gene in sarcoma cells. Futscher et al32 have done similar work, using verapamil to suppress the emergence of P-glycoprotein-mediated MDR in myeloma cells that were exposed to doxorubicin. Together, these findings suggest that MDR modulators might prevent P-glycoprotein MDR from occurring. We performed a phase II study of paclitaxel in combination with the MDR-reversing agent valspodar in women with resistant and recurrent ovarian carcinoma. Although the response rates for both this trial and the NYGOG study are lower than expected, patients with paclitaxel-resistant and platinum-resistant tumors may not be the ideal population in whom to evaluate this agent. Perhaps initial treatment with valspodar in combination with paclitaxel and platinum chemotherapy might suppress the emergence of resistant tumor cells, thereby prolonging the time to disease progression and subsequent survival in patients with this disease. This strategy is presently being examined in the ongoing Novartis-sponsored international phase III study comparing the combination of paclitaxel, carboplatin, and valspodar with paclitaxel and carboplatin without valspodar in women with suboptimally debulked stage III or stage IV ovarian carcinoma.
The following Gynecologic Oncology Group institutions participated in this study: University of Alabama at Birmingham, Oregon Health Sciences University, Duke University Medical Center, Emory University Clinic, University of Southern California Medical Center at Los Angeles, University of Mississippi Medical Center, University of Washington Medical Center, Hospital of the University of Pennsylvania, Georgetown University Hospital, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Tufts New England Medical Center, Rush-Presbyterian-St Luke’s Medical Center, Cleveland Clinic Foundation, The Johns Hopkins Oncology Center, Pennsylvania Hospital, Washington University School of Medicine, Columbus Cancer Council, University of Massachusetts Medical Center, University of Oklahoma Health Sciences Center, University of Virginia Health Science Center, Tacoma General Hospital, Thomas Jefferson University Hospital, Case Western Reserve University, Tampa Bay Cancer Consortium, and Carolina Gynecologic Oncology.
Supported by National Cancer Institute grant no. CA 27469 from the Gynecologic Oncology Group Administrative Office, grant no. CA 37517 from the Gynecologic Oncology Group Statistical Office, a Clinical Oncology Career Development Award from the American Cancer Society to P.M.F., and the Novartis Pharmaceuticals Corporation. We thank the following individuals for their contribution to this study: Teresa J. Vietti, MD, and Shelagh M. Revell, RN, MHS, for editorial assistance; Gary J. Jones and Jane Chong, PharmD, of Novartis Pharmaceuticals Corporation, and Patricia A. Brehm, Kia Neff, and Bette L. Stonebraker of the Gynecologic Oncology Group for their work in protocol management and data collection and analyses; and Yvette M. Frutiger for technical assistance.
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Beketic-Oreskovic L, Duran GE, Chen G, et al: Decreased mutation rate for cellular resistance to doxorubicin and suppression of mdr1 gene activation by the cyclosporin PSC 833. J Natl Cancer Inst 87: 1593-1602, 1995 32. Futscher BW, Foley NE, Gleason-Guzman MC, et al: Verapamil suppresses the emergence of P-glycoprotein-mediated multi-drug resistance. Int J Cancer 66: 520-525, 1996[Medline] Submitted August 29, 2000; accepted March 26, 2001. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2.0 mg/dL, bilirubin 
