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Phase III Study of Valspodar (PSC 833) Combined With Paclitaxel and Carboplatin Compared With Paclitaxel and Carboplatin Alone in Patients With Stage IV or Suboptimally Debulked Stage III Epithelial Ovarian Cancer or Primary Peritoneal Cancer

Catherine Lhommé, Florence Joly, Joan L. Walker, Andrea A. Lissoni, Maria O. Nicoletto, Gregory M. Manikhas, Mark M.O. Baekelandt, Alan N. Gordon, Paula M. Fracasso, William L. Mietlowski, Gary J. Jones, Margaret H. Dugan

From the Institut Gustave-Roussy, Villejuif Cedex; Centre François Baclesse, Caen, France; University of Oklahoma Health Science Center, Oklahoma City, OK; Ospedale S. Gerardo-III Clinica Ginecologia, Monza; Ospedale Civile-Oncologia-Padova, Padova, Italy; St. Petersburg City Oncologic Dispensary, St. Petersburg, Russia; Norwegian Radium Hospital, Oslo, Norway; Arizona Gynecologic Oncology, Phoenix, AZ; University of Virginia, Charlottesville, VA; and Novartis Pharmaceuticals Corporation, East Hanover, NJ

Corresponding author: Catherine Lhommé, MD, Institut Gustave-Roussy, Service de Gynécologie, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: lhomme{at}igr.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To compare the safety and efficacy of carboplatin and paclitaxel administered with or without the multidrug resistance modulator valspodar (PSC 833) in untreated patients with advanced ovarian or primary peritoneal cancer.

Patients and Methods Seven hundred sixty-two patients with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer were randomly assigned to receive either valspodar 5 mg/kg every 6 hours for 12 doses, paclitaxel 80 mg/m², and carboplatin area under the curve (AUC) 6 (PC-PSC; n = 381) or paclitaxel 175 mg/m² and carboplatin AUC 6 (PC; n = 381). Time to disease progression (TTP) was the primary end point. Secondary end points were overall survival time (OS), response rate (RR), safety, and tolerability.

Results With a median follow-up of 736 days (range, 1 to 2,280 days), the median TTP was 13.2 and 13.5 months in the PC-PSC and PC groups, respectively (P = .67); the median OS was 32 and 28.9 months, respectively (P = .94). The overall RR was higher in the PC group (41.5% v 33.6%; P = .02). Central and peripheral nervous system and GI toxicities were more common in the PC-PSC group. Ataxia occurred in 53.5% and 3.2% of PC-PSC–and PC-treated patients, respectively. Febrile neutropenia occurred more frequently in the PC-PSC group. More PC-PSC–treated patients discontinued therapy because of adverse events (AEs), experienced serious AEs, and required paclitaxel dose reductions.

Conclusion The addition of valspodar to PC did not improve TTP or OS and was more toxic compared with PC in untreated patients with advanced ovarian or primary peritoneal cancer.

	INTRODUCTION

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The standard first-line chemotherapy regimen for ovarian cancer is carboplatin and paclitaxel.¹ Despite improvements in survival times with the use of platinum agents combined with paclitaxel, most ovarian cancer patients experience relapse, and their prognosis remains poor.^1,2 Multidrug resistance (MDR), an anomaly whereby tumor cells possess intrinsic or acquired cross-resistance to a range of functionally and structurally unrelated antineoplastics, may contribute to low survival rates.^3-5 Many antineoplastics routinely associated with MDR (taxanes, vinca alkaloids, anthracyclines, epipodophyllotoxins, and topotecan) are used to treat ovarian cancer.^4-6 Drug resistance in cancer cells results from numerous metabolic or structural aberrations causing decreased drug uptake, increased drug efflux, a reduced ability of cells to undergo apoptosis, and/or improved repair of DNA damage caused by chemotherapy.² One mechanism of MDR to antineoplastics is the overexpression of P-glycoprotein (P-gp), an adenosine triphosphate–dependent membrane transporter that functions as an efflux pump, thereby decreasing intracellular concentrations of various antineoplastics.^4,5,7 Overexpression of P-gp in ovarian cancer cells is common and considered an unfavorable prognostic factor.^3,8,9

Pharmacologic inhibition of P-gp activity has been investigated as a means of reversing MDR.¹⁰ Agents that inhibit P-gp function include verapamil, cyclosporine A, tamoxifen, and some calmodulin antagonists.⁴ The high serum concentrations required by these agents to reverse MDR cause significant toxicities that limit the agents' therapeutic usefulness.^11,12 Valspodar (PSC 833), a nonimmunosuppressive analog of cyclosporine D and second-generation MDR modulator, is less toxic and 10- to 20-fold more active in vitro as a P-gp inhibitor than is cyclosporine A.^4,13

The results of phase I/II and II trials evaluating valspodar combined with cisplatin-doxorubicin or paclitaxel as salvage therapy for cisplatin-, anthracycline-, or paclitaxel-resistant ovarian cancer have demonstrated antitumor responses and acceptable toxicity.^7,14,15 In vitro data also suggest that MDR modulators, including valspodar, may suppress the activation of the MDR1 gene and prevent emergence of MDR cancer cells.¹⁶

The aim of this prospective, randomized, multicenter, phase III study was to evaluate the efficacy and tolerability of valspodar combined with paclitaxel and carboplatin as first-line chemotherapy in patients with advanced ovarian or primary peritoneal cancer.

	PATIENTS AND METHODS

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Study Objectives
Patients with stage IV or suboptimally debulked stage III epithelial ovarian or primary peritoneal cancer were randomly assigned to receive paclitaxel and carboplatin with (PC-PSC) or without (PC) valspodar as first line-chemotherapy. The primary objective was to determine the time to disease progression (TTP). Secondary objectives included determining the overall survival (OS), response rate (RR), and safety and tolerability of the two regimens.

Eligibility Criteria
Women ( 18 years) were eligible if they had histologically documented stage IV or suboptimally debulked (> 1 cm) stage III epithelial ovarian or primary peritoneal cancer. Patients were also required to (1) have a WHO performance status (PS) no higher than 2; (2) start chemotherapy within 6 weeks of initial surgery; and (3) have adequate laboratory values (absolute neutrophil count [ANC] 1,500/mm³; platelet count 100,000/mm³; serum creatinine level < 1.5x the upper limit of normal [ULN] or creatinine clearance > 50 mL/min; serum total bilirubin level less than 1.5x the ULN; and AST/ALT 2.5 times the ULN). Main exclusion criteria included (1) known brain or leptomeninges metastases; (2) concurrent severe and/or uncontrolled disease or impairment of GI function, which could significantly alter the absorption of valspodar; (3) history of another primary malignancy within 5 years; (4) any prior anticancer treatment; (5) more than grade 1 impairment of neurocerebellar function (National Cancer Institute [NCI] Expanded Common Toxicity Criteria [CTC], version 1¹⁷); or (6) hypersensitivity to the study medication or chemotherapy, including cyclosporine A and drugs formulated in polyoxyethylated castor oil. Medications known to alter cyclosporine A pharmacokinetics were prohibited.

Study Design and Treatment
In this international, prospective, randomized, open-label, phase III study, a stratified randomization scheme with institutional balancing placed patients into eight strata based on the following stratification factors: WHO PS (0 to 1 v 2), diameter of residual disease (< 5 cm or unknown v 5 cm), and the study center's intention to perform interval debulking (ID) in eligible patients (yes v no). Each investigator declared whether ID surgery would be performed in all eligible patients between the third and fourth cycles of chemotherapy before the first patient was randomly assigned. Patients eligible for ID surgery had stage III disease or stage IV disease with distant metastases measuring no larger than 1 cm and had undergone either complete or incomplete initial surgery with a subsequent decrease in tumor volume as assessed by radiographic studies and/or decreasing cancer antigen (CA-125) levels, or incomplete initial surgery and achieved a complete response (CR). Second-look laparotomy was prohibited during the study. All patients signed an institutional review board/ethics committee–approved consent form before enrollment. Patients were randomly assigned to receive up to six cycles of either PC-PSC or PC every 21 days. An additional three cycles were permitted in patients showing treatment benefit. Therapy was discontinued in patients experiencing disease progression (PD) or unacceptable toxicity.

In the PC-PSC group, valspodar 5 mg/kg, supplied as a microemulsion-based solution (Novartis Pharmaceuticals Corporation, East Hanover, NJ) was administered orally every 6 hours on an empty stomach, beginning on day 0 for 12 doses. The drug was diluted (at least 1:10) in a beverage other than grapefruit juice.

Valspodar prolongs the elimination and increases the area under the curve (AUC) of paclitaxel; therefore, a reduced paclitaxel dose was used in the PC-PSC group to provide equivalent paclitaxel exposure and toxicity between groups.^14,18 In the PC-PSC group on day 1, paclitaxel 80 mg/m² was administered by a 3-hour intravenous (IV) infusion between doses 5 and 7 of valspodar; paclitaxel 175 mg/m² IV was administered in the PC group on day 1. Paclitaxel doses were preceded by dexamethasone, an H₁ blocker (ie, diphenhydramine), and an H₂ blocker (ie, cimetidine). IV carboplatin (AUC 6, calculated using the Calvert formula¹⁹) was administered in both groups on day 1 over 30 to 60 minutes immediately after completion of paclitaxel. Creatinine clearance was determined before each treatment cycle using the Jelliffe method.²⁰ Prophylactic antiemetics were administered at the investigator's discretion.

Response and Toxicity Evaluation
Antitumor activity was assessed according to TTP (primary end point) and OS and RR (secondary end points). Tumor evaluations included assessments of all measurable, assessable, and nonassessable disease. Physical examinations were performed and CA-125 levels obtained after every cycle. All patients underwent computed tomography scanning or ultrasound examination of the abdomen and pelvis after every 3 cycles and/or at study discontinuation. All responses required radiographic confirmation 4 weeks after initial documentation. Postsurgical computed tomography scans were performed on patients who underwent ID surgery; these scans established a new baseline for future assessments. The Southwest Oncology Group Solid Tumor Response Criteria were used to define measurable, assessable, and nonassessable disease and the type of response (eg, CR).²¹ The US Food and Drug Administration allowed the use of confirmed rises of CA-125 levels and protocol-specified disease symptoms (ie, bowel obstruction, weight loss 10%, decreased PS, symptomatic ascites) as criteria for documenting PD in the absence of radiographic evidence (Appendix, online only).

Toxicity was graded using the NCI Expanded CTC, version 1.¹⁷ Because valspodar was associated with a high incidence of ataxia in phase II trials, a separate cerebellar toxicity grading system, which has been used previously to assess valspodar-induced cerebellar toxicity, was used.¹⁸ Protocol-specific treatment delays, dose reductions, or treatment withdrawals were required in patients experiencing significant neurologic, hepatic, hematologic, or other toxicities caused by study drugs (Appendix, online only).

Statistical Analysis
TTP was measured from the date of random assignment to the date of documented PD or the last date the patient was known to be progression free. Patients who were lost to follow-up were not considered failures, but were treated as censored observations at the date of loss to follow-up. Scheduled follow-up assessments were identical for both groups (Appendix, online only). OS was measured from the date of random assignment to the date of death or the last date the patient was known to be alive (censored observation). Randomly assigned patients who never received treatment were handled as censored observations at the date of random assignment. Assuming a PC:PC-PSC hazard ratio of 1.333—a ratio that corresponds to an increase in the median TTP from 18 months in the PC group to 24 months in the PC-PSC group—a sample size of 698 patients was required to obtain at least 385 treatment failures using a stratified two-tailed log-rank test at the .05 level of significance and a power of 0.8.²²

The intention-to-treat (ITT) patient population consisted of randomly assigned patients and was used in all efficacy analyses. TTP and OS distributions were estimated using the Kaplan-Meier method. Stratified log-rank tests were used to compare TTP and OS. The Cochran-Mantel-Haenszel test was used to analyze RRs in the ITT population. Safety was assessed by evaluating treatment-emergent adverse events (AEs) and identifying new or worsening laboratory abnormalities in all patients who received at least one dose of study treatment and had at least one postbaseline safety assessment. A data monitoring board performed three early safety reviews to determine whether patients receiving PC-PSC had an unacceptable safety profile relative to the PC treated patients requiring dose reduction or early termination of the study.

	RESULTS

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Patient Demographics
From November 1997 to October 1999, 762 patients were enrolled at 116 medical centers. All patients were included in the ITT analysis; 749 patients were included in the safety analysis (Fig 1). The treatment groups were generally well balanced according to known prognostic factors (Table 1) and according to age, race, weight, body-surface area, and other disease characteristics (data not shown).

View larger version (32K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CONSORT diagram. (a) Treatment discontinuations reported during treatment cycles 1 to 5; (b) included consent withdrawal, protocol violations, and other reasons for discontinuation; (c) performed in patients receiving at least one cycle of treatment (safety population); (d) performed in all randomly assigned patients (intent-to-treat population). PC, paclitaxel/carboplatin; PC-PSC, paclitaxel/carboplatin/valspodar; PD, progressive disease.

TTP and OS
Median TTP was similar between the PC-PSC and PC groups (13.2 v 13.5 months, respectively; P = .67; Table 2; Fig 2). In both groups, the manifestation of progression was similar and predominantly resulting from the development of a new tumor lesion (66.2% of all patients) or recurrence of a lesion (13.8% of all patients). With a median follow-up of 736 days (range, 1 to 2,280 days), median OS did not differ significantly between groups (PC-PSC, 32 months; PC, 28.9 months; P = .94; Table 2; Fig 3).

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimates of time to disease progression for patients receiving paclitaxel/carboplatin (PC) and patients receiving paclitaxel/carboplatin/valspodar (PC-PSC) using an intention-to-treat method. Hazard ratios greater than 1 favor the PC-PSC treatment group.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier estimates of overall survival (OS) rates in patients receiving paclitaxel/carboplatin (PC) and patients receiving paclitaxel/carboplatin/valspodar (PC-PSC) using an intention-to-treat method. The analysis for OS was performed on August 31, 2004. In the PC-PSC group, there were 112 patients alive, 250 deaths, and 19 patients lost to follow-up. In the PC group, there were 120 patients alive, 240 deaths, and 21 patients lost to follow-up.

CA-125 Levels
In a subgroup of 534 patients without PD, CA-125 levels were measured at the end of the third cycle.²³ A correlation between lower CA-125 levels and longer TTP or a higher 18-month survival rate was statistically significant (Table 3). The strength of these findings was demonstrated using a Cox proportional hazards model, which adjusted the results on the basis of baseline prognostic factors and time-dependent CA-125 levels.

View this table: [in this window] [in a new window]   Table 4. AEs Occurring in 10% of Patients and Significant Laboratory Value Abnormalities

The data monitoring board performed the three planned early safety analyses and confirmed a higher incidence and severity of some AEs in the PC-PSC group, but they deemed the increases to be insufficient to warrant early study termination or further reduction in the paclitaxel dose in the PC-PSC arm.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Previous studies have demonstrated that the addition of valspodar to standard chemotherapy regimens produces responses in heavily pretreated patients with refractory ovarian cancer.^3,14,15 Our phase III study of patients receiving paclitaxel and carboplatin as front-line chemotherapy for stage IV or suboptimally debulked stage III epithelial ovarian or primary peritoneal cancer, sought to demonstrate the ability of valspodar to prolong the TTP by possibly preventing the emergence of resistant tumor cells. Our results, however, did not show any improvements in TTP or OS.

The presence of other mechanisms of drug resistance in ovarian cancer cells may help explain the failure of valspodar to enhance antitumor responses to PC.^14,24,25 For example, resistance to paclitaxel, a standard component of ovarian cancer chemotherapy regimens, is probably related to both decreased drug accumulation caused by overexpression of P-gp and alterations in tubulin, the target molecule of paclitaxel.¹⁴ Because approximately one third of all untreated ovarian tumors test positive for P-gp overexpression, targeting P-gp overexpression as a means of overcoming paclitaxel resistance is logical.¹⁴ Despite this relatively high incidence of P-gp overexpression in ovarian cancer cells, the range of positivity for this disease characteristic is highly variable and may be attributed to the different sensitivities of P-gp detection methods.¹⁴ Analysis of tumor cells for P-gp overexpression was not part of the eligibility criteria for this trial; therefore, P-gp overexpression might have been low in our population, leading to limited activity of valspodar.

Another hypothesis is that MDR is not the principal mechanism of resistance in ovarian cancer. Cisplatin and carboplatin are the most active chemotherapy agents in the treatment of ovarian cancer.¹ Other mechanisms of resistance to platinum compounds, such as defects in the mismatch repair pathway, altered p53-induced apoptosis, enhanced drug inactivation, or increased DNA repair, may be involved.¹⁰ However, carboplatin dose reductions were similar in both groups, indicating that the carboplatin dosage did not account for the difference between the groups.

Conversely, differences in paclitaxel exposure may have contributed to the lack of clinical improvement in the PC-PSC group. More patients in the PC-PSC group required a paclitaxel dose reduction than did those receiving PC. The increased toxicity observed in the PC-PSC group is likely attributable to increased paclitaxel exposure caused by the pharmacokinetic interaction between paclitaxel and valspodar⁴; however, limited pharmacokinetic data obtained from 80 patients failed to show a significant difference between the groups (data not shown). Despite the uncertainty of whether patients in the PC-PSC group received adequate paclitaxel concentrations at their tumor sites, the role of paclitaxel dose and/or dose density in ovarian cancer has not been clearly established.^26,27

Despite the use of a reduced dose of paclitaxel, significantly more grade 3 and 4 AEs occurred with PC-PSC (P < .001 for both). Ataxia, a known toxicity of valspodar, was the most commonly reported neurotoxicity and occurred in significantly more PC-PSC–than PC-treated patients; 39 patients (69.6%) required reductions in their valspodar dose and 17 patients (30.4%) discontinued treatment because of ataxia in the PC-PSC group. The exact etiology of valspodar-induced ataxia, which is rapidly reversible on valspodar discontinuation, is unclear.¹⁸ One hypothesis includes blood-brain barrier P-gp inhibition; however, others suggest that valspodar-induced ataxia may not be directly related to P-gp inhibition because other P-gp inhibitors (ie, cyclosporine) do not cause ataxia and P-gp knockout mice are not ataxic.^18,28,29 However, inhibition of the blood-brain barrier P-gp may lead to increased CNS concentrations of P-gp substrates (ie, paclitaxel) and result in increased neurotoxicity.³⁰ The incidence of hematologic toxicities was relatively high in both groups; more patients receiving PC-PSC experienced febrile neutropenia and grade 4 thrombocytopenia (Table 4). More patients in the PC-PSC group discontinued treatment because of AEs (Fig 1), and/or experienced serious AEs, and/or required dose reductions of study medications.

In addition to analyzing our primary and secondary objectives, we measured antitumor activity in an unplanned analysis of CA-125 levels at the end of the third cycle.²³ Our results confirm those by Mogensen³¹ and suggest that determining the CA-125 level at the end of the third cycle may be a useful measure of antitumor activity for proof of concept in future phase I/II ovarian cancer trials.

Results of phase III trials evaluating valspodar combined with standard chemotherapy in patients with acute myelogenous leukemia have also been disappointing^32,33; these results combined with the results of our trial have led investigators to halt further clinical evaluations of valspodar. Future studies in patients with advanced ovarian cancer should target multiple resistance mechanisms as a means to enhance response and overcome drug resistance.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: William L. Mietlowski, Novartis Pharmaceuticals Corporation (C); Gary J. Jones, Novartis Pharmaceuticals Corporation (C); Margaret H Dugan, Novartis Pharmaceuticals Corporation (C) Consultant or Advisory Role: None Stock Ownership: William L. Mietlowski, Novartis Pharmaceuticals Corporation; Margaret H. Dugan, Novartis Pharmaceuticals Corporation Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Catherine Lhommé, Mark M.O. Baekelandt, Alan N. Gordon, William L. Mietlowski, Gary J. Jones

Administrative support: Gary J. Jones

Provision of study materials or patients: Catherine Lhommé, Florence Joly, Joan L. Walker, Andrea A. Lissoni, Maria O. Nicoletto, Gregory M. Manikhas, Mark M.O. Baekelandt, Alan N. Gordon, Paula M. Fracasso

Collection and assembly of data: Catherine Lhommé, Gary J. Jones, Margaret H. Dugan

Data analysis and interpretation: Catherine Lhommé, Florence Joly, Alan N. Gordon, William L. Mietlowski, Gary J. Jones, Margaret H. Dugan

Manuscript writing: Catherine Lhommé, Florence Joly, Alan N. Gordon, Gary J. Jones, Margaret H. Dugan

Final approval of manuscript: Catherine Lhommé, Florence Joly, Joan L. Walker, Andrea A. Lissoni, Maria O. Nicoletto, Gregory M. Manikhas, Mark M.O. Baekelandt, Alan N. Gordon, Paula M. Fracasso, William L. Mietlowski, Gary J. Jones, Margaret H. Dugan

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Post-Treatment Evaluations
Scheduled post-treatment evaluations (physical examination, performance status, and CA-125 levels) were identical between the groups. These evaluations were performed every 2 months for 2 years after each patient went off study. During years 3 and 4, these evaluations were performed every 3 and 4 months, respectively. After disease progression was documented, patients were followed for survival status every 4 months until death or loss to follow-up.

	ACKNOWLEDGMENTS

 
We thank Syntaxx Communications Inc (Suzanne Day, Laura Jung, and Lisa Holle, who provided manuscript development and medical writing services, and Alison Shore, who provided editorial services), with the support of Novartis Pharmaceuticals Corporation.

	NOTES

 
Supported by Novartis Oncology, East Hanover, NJ.

Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted October 23, 2007; accepted February 1, 2008.

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