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© 2000 American Society for Clinical Oncology Phase I Dose-Finding and Pharmacokinetic Study of Paclitaxel and Carboplatin With Oral Valspodar in Patients With Advanced Solid TumorsFrom the Princess Margaret Hospital, Ontario Cancer Institute; Toronto Sunnybrook Regional Cancer Center, University of Toronto, Toronto, Ontario, Canada; Department of Medicine and School of Medicine, Greenebaum Cancer Center, University of Maryland, Baltimore, MD; Department of Medicine, Washington University School of Medicine, St Louis, MO; Tumor Institute of Swedish Hospital Medical Center, Seattle, WA; and Novartis Pharmaceuticals, Hanover, NJ. Address reprint requests to Amit Oza, Princess Margaret Hospital, 610 University Ave, 5th Floor, Room 206, Toronto, Ontario, Canada M5G 2M9; email amit.oza{at}uhn.on.ca
PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function. PATIENTS AND METHODS: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m2 and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg·min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-naïve patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg·min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1.
RESULTS: Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic transaminase elevations were DLTs. In previously treated patients, no DLTs occurred at the first dose level (paclitaxel 54 mg/m2 and carboplatin AUC 6 mg·min/mL). However, one of 12, two of six, two of four, four of 11, and two of five patients experienced DLTs at doses of paclitaxel (mg/m2)/carboplatin AUC (mg·min/mL) of 67.5/6, 81/6, 94.5/6, 67.5/7.5, and 67.5/9, respectively. In chemotherapy-naïve patients, one of 17 developed DLT at paclitaxel 81 mg/m2 and carboplatin AUC 6 mg/mL·min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was CONCLUSION: The recommended phase II dose in chemotherapy-naïve patients is paclitaxel 81 mg/m2, carboplatin AUC 6 mg·min/mL, and valspodar 5 mg/kg every 6 hours. In previously treated patients, the recommended phase II dose is paclitaxel 67.5 mg/m2, carboplatin AUC 6 mg·min/mL, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study.
RESISTANCE IN MANY tumors is mediated by a 170-kd cell surface glycoprotein known as P-glycoprotein (P-gp), encoded for by the mdr1 gene.1 The mdr1 gene is differentially expressed in a variety of tissues, including the apical surface of secretory epithelium of the jejunum and colon, bile canaliculi, proximal tubular epithelium of kidney, and pancreas.2 The function of P-gp in tumor cells seems to be that of an efflux pump with the ability to expel agents, including various anticancer drugs, from tumor cells. Increased expression of P-gp may occur constitutively in intrinsically chemotherapy-resistant tumors (ie, renal cell and colon) or in other tumors after exposure to antineoplastic agents.3-5 Although resistance may occur as a result of exposure to a single anticancer drug, the pump is of a nonspecific nature and can transport a range of chemically unrelated agents. This phenomenon, termed multidrug resistance (MDR) and involves naturally occurring agents including anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, actinomycin D, and mitomycin.6-8 The presence of P-gp has been shown to be an independent, poor prognostic factor in several hematologic, lymphoid, and solid tumor malignancies; thus, reversal of P-gp function may potentially serve as a target for overcoming drug resistance.2,9-11 A number of pharmacologic agents have the ability to interfere with P-gp function. These agents include calcium channel antagonists, calmodulin antagonists, noncytotoxic anthracycline and vinca alkaloid analogues, corticosteroid and hormonal analogues, hydrophobic cationic compounds, and cyclosporines.12,13 Some of these agents have demonstrated the ability to modulate MDR activity in clinical trials; however, their utility has been limited by the serious toxicity accompanying the high plasma concentrations required for MDR modulation.14-16 Second-generation agents with more favorable therapeutic ratios have been developed to reverse P-gp function, and one of the most effective of these agents is valspodar.17,18 Valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) (Fig 1) is a highly lipophilic, oral, semisynthetic, nonimmunosuppressive cyclosporine D analog that can modulate MDR activity with low toxicity in vitro and in vivo.17-19 Valspodar has a high binding affinity for P-gp at concentrations that can readily be achieved in blood, and it has been shown to occupy the P-gp molecule for longer durations than does cyclosporine (CsA).20,21 Unlike CsA, which binds to both P-gp and cyclophilin, the latter accounting for its immunosuppressive effects, valspodar binds only to P-gp. In toxicology studies, valspodar is not immunosuppressive, nephrotoxic, or cytotoxic. Valspodar has been shown in in vitro models to be approximately 10-fold more potent than CsA in its ability to inhibit P-gp. Cell viability studies suggest that MDR reversal in highly resistant cell lines can be achieved at valspodar concentrations of 1,000 to 2,000 ng/mL.18,22-24 Valspodar completely reversed resistance of MDR-CHO, MDR-P388, and MDR-LoVo cells to four different anticancer drugs (vincristine, doxorubicin, daunorubicin, and etoposide) at concentrations ranging from 31.6 ng/mL to 1,000 ng/mL.18,22,25 Valspodar has no effect in sensitizing MDR-negative resistant cell lines or in altering sensitivities of resistant cell lines to anticancer drugs, such as platinum analogues, that are not known to be substrates for P-gp.23 In vivo studies using MDR-P388 (murine monocytic leukemia cell line) tumor-bearing mice showed two- to three-fold increases in survival times when valspodar doses of 25 to 50 mg/kg orally were used to pretreat animals 4 hours before receiving doxorubicin intraperitoneally compared with doxorubicin alone. Oral paclitaxel, when administered to mice at a dose of 10 mg/kg along with 50 mg/kg of oral valspodar, showed a 10-fold increase in area under the plasma concentration versus time curve (AUC) compared with controls that received the same dose of paclitaxel alone. Furthermore, the oral bioavailability of paclitaxel was increased 10-fold by the concomitant administration of valspodar.26 Phase I/II studies of valspodar in combination with a wide range of anticancer drugs that are P-gp substrates have shown the ability to achieve safe and consistent blood concentrations of valspodar that are above the in vitro threshold for MDR reversal.18,27,28
Valspodar affects the pharmacokinetics (PKs) of anticancer drugs that are P-gp substrates. In phase I studies, the mean decreases in clearance of doxorubicin and etoposide were 29% to 33% and 40%, respectively. The most likely explanation for this is inhibition by valspodar of the physiologic function of P-gp in the distribution and elimination of these agents.29-33 Therefore, cytotoxic drugs that are substrates for P-gp require dose reduction when administered concurrently with valspodar. In phase I trials of valspodar in combination with 3- and 24-hour paclitaxel, the recommended phase II dose of paclitaxel was 70 mg/m2, representing a 60% dose reduction from the commonly used 175 mg/m2 dose of paclitaxel.34,35 Data available on 61 patients with advanced solid tumors treated with valspodar at 5 mg/kg four times daily demonstrated that reversible ataxia and dysmetria, suggestive of possible cerebellar dysfunction, were common side effects and were the DLTs. Sixty-seven percent of patients experienced grade 1 or 2 reversible ataxia, whereas an additional 8% experienced reversible grade 3 ataxia. The ataxia was maximal several hours after oral dosing, thus suggesting a peak concentration effect.36 Although the etiology of the ataxia is unknown, it is hypothesized that this may be the result of P-gp inhibition at the blood-brain barrier. Reversible hyperbilirubinemia, though not dose-limiting, was also a frequent occurrence and was felt to be caused by the inhibition of P-gp in cells lining the bile canaliculi.34,35,37–40 Paclitaxel and carboplatin combinations are frequently used to the treat solid tumors. Although myelosuppression is the dose-limiting toxicity (DLT) for both agents, the combination is made possible by the greater degree of neutropenia seen with paclitaxel compared with the greater degree of thrombocytopenia seen with carboplatin.41 The differing mechanisms of action of the two agents suggests the possibility of relative non–cross-resistance and associated increased response rates over those seen with either single agent. We chose to study the combination of paclitaxel and carboplatin with valspodar in a phase I trial of patients with advanced solid tumors. The primary objective was to characterize the maximum-tolerated dose (MTD) and DLT in the following two populations of patients: (1) patients previously treated with one or two standard chemotherapy regimens and (2) chemotherapy-naïve patients at a fixed carboplatin AUC of 6 mg·min/mL. The secondary objectives were to examine the PK and pharmacodynamics (PDs) of paclitaxel and carboplatin when administered with valspodar and to describe the antitumor activity of the combination.
Eligibility Patients with solid tumors refractory to conventional chemotherapy or for whom no effective therapy existed, were eligible for this study. Patients were required to have at least one nonirradiated site of disease (or progressive disease since completion of radiation therapy) or an elevated tumor marker. Patients entered onto stage I of the study could have had up to a maximum of two prior chemotherapy regimens. Patients entered onto stage II of the study were required to be chemotherapy-naïve. Eligibility criteria included the following: age  18 years old; Eastern Cooperative Oncology Group performance status  2 (ambulatory and capable of self-care); and ability to give written informed consent before study entry.
Patients were excluded from study participation for any of the following reasons: investigational therapy within 30 days of study entry; radiation therapy within 4 weeks of treatment; major surgery within 2 weeks; known metastases to the brain or leptomeninges; concurrent severe and/or uncontrolled medical disease; impairment of gastrointestinal function that might significantly alter absorption of valspodar (ie, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or previous small bowel resection); a history of chronic active hepatitis or cirrhosis; known seropositivity for human immunodeficiency virus; impairment of hepatic, renal, or hematologic function (ALT > 2.5 times normal, bilirubin
Patients being considered for stage I of the study were ineligible if any of the following were present: chemotherapy less than 4 weeks before study entry; prior treatment with an MDR reversal agent; history of grade 3/4 paclitaxel-related cardiac conduction abnormality or peripheral neuropathy; and prior radiation to
Dosage and Dose Escalation
Stage II.
Once the MTD for paclitaxel was found in previously treated patients during stage I, the plan was to escalate the dose further in increments of 13.5 mg/m2 in previously untreated patients using a fixed carboplatin AUC of 6 mg/mL·min and maintaining the dose of valspodar at 5 mg/kg orally every 6 hours for 12 doses. Once the MTD was reached for stage II, the previous dose level was designated as the recommended dose for phase II trials in chemotherapy-naïve patients and expanded to
Treatment cycles were repeated every 3 weeks up to a maximum of six cycles unless there was disease progression or unacceptable toxicity. At the end of six cycles, patients achieving a complete response, partial response, or stable disease were given the option of further treatment at the discretion of the investigator. Toxicity was graded according to the National Cancer Institute common toxicity criteria. Cerebellar toxicity was graded according to the schema listed in Table 1. A minimum of three patients were treated at each dose level. Three more patients were added if one of the first three patients experienced DLT. The dose was escalated in the next cohort if none of three or one of six patients experienced DLT. The MTD was defined by the presence of DLT in two of three or two of six patients. DLT was defined as at least one of the following: ANC < 500/µL for longer than 7 days or associated with fever; ANC < 1,500/µL for more than 2 weeks beyond the scheduled start date of the second cycle; platelet count < 25,000/µL; platelet count < 100,000/µL for more than 2 weeks beyond the scheduled start date of the second cycle; nonhematologic toxicity
The dose of valspodar was held for cerebellar toxicity of grade 3 occurring before paclitaxel administration until the toxicity resolved to grade 2. Subsequently, the entire 12 doses of valspodar were restarted at 4 mg/kg/dose. If cerebellar toxicity of grade 3 occurred after the paclitaxel infusion had been initiated, valspodar was discontinued until the toxicity improved to grade 2. In subsequent cycles, the dose of valspodar was reduced to 4 mg/kg/dose. If at the end of cycle total bilirubin was 1.5 times the institutional upper normal limit, the next cycle was to be delayed up to 2 weeks until resolution. Lack of resolution within this time frame required discontinuation from study. For dose-limiting thrombocytopenia, the carboplatin dose was decreased by one dose level in subsequent cycles. Dose-limiting neutropenia required a one-level dose reduction in the agent that was being dose-escalated.
Drug Administration
Pretreatment Assessment and Follow-Up Studies
PK Analysis
Paclitaxel PK Analysis Blood samples were drawn into heparinized tubes and centrifuged at 2,200 rpm for 10 minutes, and the plasma was immediately frozen at -20°C until required. Once all samples were collected from a patient, plasma samples were extracted and analyzed following a modified procedure of Jamis-Dow et al44; 25 µL of internal standard (50 mmol/L) was added to each 1-mL plasma sample. Samples were applied to pretreated (1 mL methanol followed by 1 mL deionized water) CLEAN-UP (United Chemical Technologies Inc, Bristol, PA). Columns were washed with 3 mL of deionized water and eluted into glass tubes with two sequential 1-mL aliquots of methanol. Samples were dried under vacuum on medium heat and reconstituted with 200 mL of mobile phase. Spiked human plasma controls along with quality assurance/quality control samples provided through Sandoz Research Institute (East Hanover, NJ) were extracted at the same time as patient samples. HPLC conditions consisted of an isocratic mobile phase of acetonitrile/deionized water (v/v, 40/60) flowing at a rate of 1 mL/min and monitored at 227 nm. Reverse phase chromatography using a Hypersyl ODS 5-µm analytic column (Scientific Products & Equipment, Concord, ON, Canada) and preceded by a C18 guard column (Waters Canada, Mississauga, ON, Canada) was used to separate paclitaxel and the internal standard. One hundred µL was injected onto the HPLC. The assay was linear for paclitaxel between the range of 10 to 2,000 ng/mL.
A three-compartment nonlinear model45 was fit to the paclitaxel plasma concentration data using Bayesian estimation.46 The duration of time that plasma paclitaxel (T) was
Carboplatin PK Analysis
The 0- to 24-hour carboplatin AUC was estimated using the method described by Ghazal-Aswad et al,48 as follows:
PD Analysis
Fifty-eight patients from five centers received a total of 186 courses of treatment. The range of diagnoses and summary of patient characteristics are listed in Table 2. Twenty-eight of the 41 previously treated patients had received prior chemotherapy with an agent known to be a substrate for P-gp. All patients were assessable for toxicity and PK analysis. One patient who received the first dose of paclitaxel over 24 hours after experiencing a major hypersensitivity reaction when paclitaxel was administered at the 3-hour infusion rate was assessable for toxicity but excluded from dose-escalation decisions. Table 3 lists the number of patients, the median number of courses, and occurrence of DLT per dose level.
Hematologic Toxicity The principal DLT of the combination of valspodar, paclitaxel, and carboplatin was myelosuppression, particularly neutropenia. Table 4 lists the number of patients and courses associated with grades 3 (500/µL ANC < 1,000/µL) and 4 (ANC < 500/µL) neutropenia, febrile neutropenia, and combined grades 3 and 4 thrombocytopenia (platelet count < 50,000/µL). The median ANC nadir ranged from 100 to 1,500/µL across the dose levels. Treatment delays because of incomplete recovery of counts ranged from 7 to 27 days and were required in only 24 (13%) of 186 courses. Febrile neutropenia was observed in 11 of 186 courses and occurred in the first cycle for six patients, with five episodes meeting the criteria for DLT. All patients recovered with broad-spectrum IV antibiotics with the exception of one patient (dose level 6) who died from overwhelming Gram-negative sepsis on day 15 of cycle 1. Of the 17 chemotherapy-naïve patients who received 56 of 186 courses on this trial, two experienced febrile neutropenia during course 1; however, only one patient was deemed to have had a DLT. One of the episodes of febrile neutropenia in the chemotherapy-naïve cohort was ineligible for assessment of DLT because it occurred in the patient who received paclitaxel over 24 hours after experiencing a major hypersensitivity reaction during the first 5 minutes of her planned 3-hour paclitaxel infusion. Of the remaining 41 patients (130 cycles) who had received prior chemotherapy, four experienced DLT consisting of febrile neutropenia.
Of the 130 courses delivered to 41 patients who had received prior therapy, seven courses (5%) were associated with grade 3 or 4 thrombocytopenia, whereas 21 courses (16%) were associated with thrombocytopenia of at least grade 2 severity. Nadirs occurred in cycle 1 on eight episodes, with the median nadir on day 12 and recovery to pretreatment levels by days 9 to 28. The majority of episodes of thrombocytopenia, however, occurred after repeated cycles of treatment. There was no serious thrombocytopenia-related bleeding. One episode of thrombocytopenia met the criteria for DLT, occurring in a 55-year-old man (cohort 7) with carcinoma of unknown primary origin who had received prior therapy with cisplatin, etoposide, and bleomycin. This patient developed pancytopenia, with a platelet nadir of 6,000/µL on day 6 after course 1, and recovered his counts to 34,000/µL by day 12 and 49,000/µL by day 20. The patient had a concomitant ANC nadir of 300/µL on day 12, with recovery to 2,200/µL by day 20. Also in cohort 7 was a second patient with carcinoma of unknown primary who had received four cycles of etoposide and cisplatin and eight cycles of etoposide and carboplatin in the past and went on to receive a total of six courses of treatment on study. This patient developed grade 2 thrombocytopenia after course 1, 2, 3, and 4 and grade 3 thrombocytopenia after course 5. He required a prolonged treatment delay of greater than 5 weeks after courses 4 and 5 to allow for recovery of platelet counts. Of the chemotherapy-naïve patients, only one patient developed grade 3 thrombocytopenia on day 15 of course 3, with a platelet nadir of 40,000/µL and recovery to grade 2 by day 20. Three courses in chemotherapy-naïve patients were complicated by grade 2 thrombocytopenia, all occurring beyond cycle 2.
Nonhematologic Toxicity
There were seven deaths on study. One death (a patient on dose level 6 with overwhelming Gram-negative sepsis) was treatment-related. Three episodes of sudden death occurred within 16 days of course 1. All were thought to be clinically consistent with pulmonary embolism; however, no autopsies could be obtained. One patient with small-cell carcinoma of the lung presented on day 8 of course 1 with hemodynamic collapse. A chest x-ray performed during the cardiac arrest revealed massive amounts of air within the arterial system, suggestive of a broncho-arterial fistula. A 52-year-old man with carcinoma of unknown primary origin died of a massive gastrointestinal bleed on day 18 of course 1 after operative repair of a humeral fracture. At 5 weeks after course 2 of treatment, a 45-year-old woman with metastatic ovarian cancer died from a massive cerebrovascular accident.
Antitumor Activity The MTD for previously treated patients was paclitaxel 67.5 mg/m2, carboplatin AUC 7.5 mg/mL·min, and valspodar 5 mg/kg. The prior cohort (paclitaxel 67.5 mg/m2, carboplatin AUC 6 mg/mL·min, and valspodar of 5 mg/kg) was defined as the recommended phase II dose. Cohort 5 (paclitaxel 81 mg/m2, carboplatin AUC 6 mg/mL·min, and valspodar 5 mg/kg) was designated as the final MTD cohort (and recommended phase II dose) for chemotherapy-naïve patients and expanded without further dose escalation of paclitaxel, given the occurrence of two DLTs, including one death, in previously treated patients at dose level 4 (paclitaxel 94.5 mg/m2, carboplatin AUC 6 mg/mL·min, and valspodar 5 mg/kg).
PK Results
The paclitaxel AUC and T 0.05 µmol/L for all patients versus dose are illustrated in Fig 2A and 2B, respectively. Within each dose level, there was a large interindividual variation for both drug exposure parameters.
The paclitaxel AUC at the 81 mg/m2 dose level with valspodar and carboplatin (n = 15; 7.07 ± 2.45 µmol/L·h) approached that of published reports of single-agent paclitaxel at 105 mg/m2 (9.23 ± 0.66 µmol/L·h).50 Similarly, the AUC at the 94.5 mg/m2 dose level (n = 3; 13.12 ± 2.04 µmol/L·h) corresponded to published reports of single-agent paclitaxel at 135 mg/m2 (range, 9.5 to 13.7 µmol/L·h).50-53 Nonlinearity between AUC and dose, as previously described for paclitaxel either as a single agent or in combination with either carboplatin or valspodar, was difficult to assess given the wide interpatient variability.45,51,52,54,55 There seemed to be some deviation of the AUC at the highest dose level above the line of proportionality (Fig 2), but only few patients were entered onto this cohort.
There was a marked prolongation of the terminal phase of paclitaxel elimination as denoted by an increase in T
Paclitaxel PDs.
Complete PK and PD data were obtained from 46 patients. There was a poor correlation, regardless of model, between paclitaxel AUC or T
Carboplatin PKs. The estimated carboplatin AUC, obtained in 38 patients, is plotted against target AUC in Fig 4. The distribution of estimated AUCs is evenly distributed above and below the line of equivalence. Patients who should have received a target AUC of 6 mg·min/mL (n = 24) received a mean AUC of 6.1 mg·min/mL (SD = 1.4 mg·min/mL); a target AUC of 7.5 mg·min/mL (n = 9) corresponded to a mean AUC of 8 mg·min/mL (SD = 1.9 mg·min/mL); and a target AUC of 9 mg·min/mL (n = 5) corresponded to a mean AUC of 9.74 mg·min/mL (SD = 2.0 mg·min/mL). The mean prediction error for the estimated carboplatin AUC was -4%, the absolute mean error was 18.8%, and the root mean square error was 1.67%, indicating an unbiased model with reasonable precision.
Carboplatin PDs. PD analysis of hematologic toxicity (percentage decrease of platelets and ANC at the nadir) and target carboplatin AUC was performed for 47 patients. Regardless of the model assessed, there was a poor correlation. The estimated carboplatin AUC and haematologic toxicity was available in 34 patients. No PD model adequately described the relationship between percentage change in ANC and the estimated carboplatin AUC; the sigmoid Emax model: r2 = 0.33, EC50 = 1.9 mg·min/mL (95% confidence interval, 0.78 to 3.03 mg·min/mL). Similarly, no PD model adequately described the relationship between estimated AUC and percentage decrease nadir platelet count (Fig 5). Of all the models assessed, the sigmoid Emax model provided the best, albeit still weak, fit: r2 = 0.35, EC50 = 7.8 mg·min/mL (95% confidence interval, 6.6 to 9.0 mg·min/mL). Studies of single-agent carboplatin had demonstrated an AUC50 for the sigmoid Emax model in the range of 3.2 to 4.0 mg·min/mL.42,54,56 Because of the interpatient variability and hence wide confidence limit of the EC50 estimate, a platelet-sparing effect of the regimen could not be identified.
Drug resistance, either intrinsic or acquired, is a frequently encountered problem in the failure of antineoplastic agents. P-gp, an efflux pump that extrudes hydrophobic cytotoxic drugs from cancer cells, plays a key role in MDR. The presence of MDR has been correlated with poor outcome in acute myeloid leukemia, non-Hodgkin’s lymphoma, acute lymphoblastic leukemia, and multiple myeloma.2,9-11 The MDR phenotype can be reversed by the nonimmunosuppressive cyclosporine D analog valspodar through its binding and competitive inhibition of P-gp. Valspodar is approximately 10 times more potent than cyclosporine in reversing MDR, has a high binding affinity for P-gp in vitro at concentrations that can be achieved in vivo, and is tolerated without significant adverse effects.18,20,21 This study evaluated the feasibility of combining valspodar with paclitaxel and carboplatin. The dose of valspodar was fixed at 5 mg/kg orally every 6 hours for 12 doses (day 0 to 2). This was based on prior phase I trials with this agent that demonstrated the ability to achieve biologically relevant serum concentrations at this dose, a tolerable spectrum of side effects, adequate oral bioavailability, and a half-life of 6 hours after oral administration.33,40 To allow for its administration with carboplatin, we chose a starting paclitaxel dose of 54 mg/m2, which was 25% below the recommended phase II dose of single-agent paclitaxel when combined with valspodar.26 The primary objective of this trial was to establish an MTD for valspodar, paclitaxel, and carboplatin in both previously treated and previously untreated patients. The rationale for establishing an MTD in chemo-naïve patients using a fixed carboplatin AUC of 6 mg·min/mL was to direct future phase II/III trials toward first-line therapy of ovarian cancer. Data from prior studies have not demonstrated additional benefit with higher doses of carboplatin in this patient population.57 Valspodar combined with paclitaxel and carboplatin is a tolerable regimen in patients with advanced solid tumors. There were nine responses (one complete response and eight partial responses) and 28 patients with stable disease. For chemotherapy-naïve patients, the MTD and recommended phase II dose of paclitaxel is 81 mg/m2, carboplatin AUC of 6 mg/mL·min, and valspodar of 5 mg/kg. For previously treated patients, the MTD of paclitaxel is 67.5 mg/m2, carboplatin AUC of 6 mg/mL·min, and valspodar of 5 mg/kg. Consistently observed side effects attributable to valspodar include reversible ataxia and hyperbilirubinemia. The addition of valspodar to paclitaxel and carboplatin resulted in a 54% to 61% reduction in the MTD of paclitaxel, while having no effect on carboplatin dose. This is similar to observations made by others in prior trials using valspodar as an MDR modulator.40 The pharmacologic mechanism whereby valspodar affects paclitaxel dosing is by reducing its clearance and prolonging the duration that the concentration of paclitaxel is above 0.05 µmol/L. Valspodar increases the effect of paclitaxel as demonstrated by the observation that the MTD for paclitaxel occurs at a lower dose. The carboplatin AUC is not affected by the addition of paclitaxel or valspodar. The altered paclitaxel PKs is most likely because of valspodar rather than the influence of carboplatin. Studies of carboplatin in combination with paclitaxel, regardless of sequence, have not revealed an altered disposition or elimination of the latter, relative to historical data.52,54,55,58,59
The effect of valspodar on paclitaxel pharmacology has been studied in 10 patients treated first with paclitaxel alone and then in the subsequent course with a dose reduction combined with valspodar.51 Valspodar was found to produce a small increase in peak plasma levels and AUC as an effect of the dose reduction, but there was a marked increase in the terminal phase of paclitaxel clearance, with T The impact of valspodar on paclitaxel PKs may be at several levels, including bile canalicular membrane P-gp. In rats, valspodar has been shown to reduce bile flow rate and the biliary excretion of bile acids and glutathione in a dose-dependent manner.60 Cremophor EL, a known MDR modulator, in the isolated perfused rat liver has also been shown to reduce biliary paclitaxel excretion by approximately 50%.61 Studies in MDR knockout mice have also shown that P-gp mediates the direct excretion of paclitaxel from the systemic circulation into the intestinal lumen.62 An alternative mechanism may be the inhibition of hepatic microsomal cytochrome P450-3A4, converting paclitaxel to its 3-hydroxyl phenyl metabolite.63 Plasma levels of valspodar achieved by therapeutic doses approach the Ki for this interaction.64
The previously reported relationship between T
The influence of carboplatin on paclitaxel PDs without valspodar is conflicting. In the study reported by Huizing et al,55 patients with stage III or IV ovarian cancer received paclitaxel (125 to 250 mg/m2) over 3 hours, followed by carboplatin (300 to 600 mg/m2). The neutropenia was more severe than would be expected from paclitaxel alone using T Carboplatin PK data are available in 34 patients from course 1, with target AUCs ranging from 6 to 9 mg·min/mL. The limited sampling model of Ghazal-Aswad for carboplatin AUC estimation demonstrated a mean difference of +8.1% (SD = 5.1%) relative to the target AUC, without significant bias or imprecision. The creatinine clearance was determined from the serum creatinine using the Jeliffe method and then introduced into the Calvert formula.42,43 Studies calculating creatinine clearance by the Cockcroft-Gault and Jeliffe formulas have found that these methods underpredict the glomerular filtration rate.43,58,65,66 This leads to an underestimation of the dose required to achieve the target carboplatin AUC and hence a lower than expected actual AUC. This discrepancy can be explained by the methodologies used to determine the serum or plasma creatinine.67 In the study reported here, the estimated mean AUC was higher than the target value. The limited sampling model of Ghazal-Aswad has been assessed for carboplatin combined with either paclitaxel or high-dose cyclophosphamide/thiotepa. The predicted mean AUC was 4.4 mg·min/mL (SD = 1.2 mg·min/mL) compared with the measured AUC of 4.1 mg·min/mL (SD = 1.0 mg·min/mL). The model showed slight bias (mean prediction error = 6.5%) and was imprecise (root mean square error = 20.65%).68 The relationship between percentage decrease in platelet count and estimated carboplatin AUC in this study was poorly described by various PD models. Combination studies of carboplatin and paclitaxel without valspodar reported that the sigmoidal Emax model best described the relationship, with the AUC50 ranging from 5.2 to 5.7 mg·min/mL.54,55 Comparisons to single-agent carboplatin have demonstrated an AUC50 of 3.642 to 4 mg·min/mL.56 The platelet-sparing effect induced by paclitaxel in these combination studies was not apparent in the study reported here given the significant variability in the extent of the observed thrombocytopenia. Any affect of valspodar on this effect could not be elucidated for this reason. Resistance to cytotoxic agents may be intrinsic or acquired. There are several forms of MDR identified in tumors, including elevated levels of P-gp and the MDR-associated protein Mrp1, both members of the ATP-binding cassette (ABC) transmembrane protein family.69 Lung resistance protein and atypical MDR (mediated through altered expression of topoisomerase II) have also been implicated in MDR.70-73 The recently identified ABC gene BCRP/MXR/ABCP may also contribute to resistance to drugs such as doxorubicin, mitoxantrone, and topotecan, which is independent of P-gp or Mrp1.69 The relative contributions of each mechanism of MDR in clinical tumors is complex, and there are likely many unidentified or poorly understood mechanisms that have yet to be elucidated. A limitation in the clinical development of MDR inhibitors is that they may unmask new drug resistance mechanisms. It is likely, however, that fewer mechanisms of resistance would be operative in the early stages of tumor growth and development. This provides the rationale for examining the use of P-gp modulation in combination with cytotoxic agents in previously untreated patients. The combination of paclitaxel 80 mg/m2, carboplatin AUC 6 mg·min/mL, and valspodar 5 mg/kg is currently being compared with standard therapy (paclitaxel 175 mg/m2 and carboplatin AUC 6 mg·min/mL) in a front-line phase III trial of advanced ovarian cancer.
Presented in part at the Thirty-Third Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
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ABSTRACT
INTRODUCTION
