A Phase I and Pharmacokinetic Study of Weekly Oxaliplatin Followed by Paclitaxel in Patients with Solid Tumors Ta Ni O S S

Cancer Therapy: Clinical

A Phase I and Pharmacokinetic Study of Weekly Oxaliplatin Followed by Paclitaxel in Patients with Solid Tumors Ta ni o s S . B e k a i i- S a a b , 1, 2 Jing Liu,3 Kenneth K. Chan,1, 3 Stanley P. Balcerzak,1Percy S. Ivy,4 MichaelR.Grever,1and Eric H. Kraut1

Abstract Purpose: Oxaliplatin and paclitaxel are widely used in treating solid tumors.We designed a phase I study with the purpose of determining the maximal tolerated dose and pharmacokinetic properties of weekly oxaliplatin followed by paclitaxel based on evidence suggesting that weekly administration of both drugs allows equivalent dose intensity with less neurotoxicity. Experimental Design:Twenty-three patients with advanced solid tumors were treated. Starting doses were 35 mg/m2 oxaliplatin followed by 45 mg/m2 paclitaxel weekly for 4 weeks every 6 weeks. Dose was escalated as follows: 45 mg/m2 oxaliplatin and 45 mg/m2 paclitaxel, 60 mg/m2 oxaliplatin and 45 mg/m2 paclitaxel, and 60 mg/m2 oxaliplatin and 60 mg/m2 paclitaxel. Pharmacokinetic studies were evaluated during the first course of therapy for oxaliplatin using population kinetics approach. Results: A total of 49 courses were administered.The dose-limiting toxicity was peripheral neuropathy with oxaliplatin and paclitaxel both at 60 mg/m2. There were three partial responses. There was evidence of pharmacokinetic interaction with a significant amount of total platinum (46.2-49.5%/24 h) eliminated in the urine in this group of patients, consistent with published data from others. The total body clearance values of plasma platinum and ultrafiltrable platinum were higher in this combination compared with corresponding values from our previous study with oxaliplatin only (P < 0.001). Conclusions: The recommended phase II dose of this combination is 60 mg/m2 oxaliplatin followed by 45 mg/m2 paclitaxel. Evidence of antitumor activity and acceptable toxicity with this combination and schedule warrants further investigation.We have obtained more definitive pharmacokinetic properties of oxaliplatin and confirmed its drug interaction with paclitaxel in the current sequence.

Oxaliplatin (trans-l-1,2-diaminocyclohexane oxalatoplati- are more effective in inhibiting DNA synthesis and are num) is a third-generation platinum derivative with a 1,2- more cytotoxic than those formed from cisplatin and diaminocyclohexane carrier ligand (1). Platinum compounds carboplatin. Mechanisms thought to be important in containing the 1,2-diaminocyclohexane ligand have antitu- resistance to cisplatin, such as alterations in mismatch repair mor activity in cell lines with acquired cisplatin resistance activity and ability of the replication complex to synthesize (2, 3) and lack the nephrotoxicity and significant myelosup- DNA past the sites of DNA damage, do not affect oxaliplatin pression associated with other platinum compounds (4, 5). activity (1, 7). Although its exact mechanism of action is not known, In preclinical studies, oxaliplatin showed a wide spectrum oxaliplatin like other platinum compounds forms DNA of activity against a variety of murine and human tumor cell adducts (6). These 1,2-diaminocyclohexane-platinum adducts lines, including L1210 murine leukemia and human colon, ovarian, and breast cancers (2, 3, 6). Additive or synergistic activity was seen in vitro when oxaliplatin was combined with

1 5-fluorouracil, CPT-11, and paclitaxel (8–10). Authors’ Affiliations: Division of Hematology and Oncology, Department of Phase I trials with oxaliplatin as a single agent using i.v. bolus Medicine, 2Department of Pharmacology, and 3Division of Pharmaceutics, College of Pharmacy,The Ohio State University, Columbus, Ohio; and 4Investigational Drug schedules given either weekly or every 3 weeks established that Branch, CancerTherapy Evaluation Program, National Cancer Institute, Bethesda, the major dose-limiting toxicity (DLT) was neurologic, man- Maryland ifested by a transient or persistent peripheral neuropathy Received 11/15/07; revised 1/23/08; accepted 2/18/08. enhanced by exposure to cold. The duration and intensity of Grant support: National Cancer Institute grant U01CA076576. The costs of publication of this article were defrayed in part by the payment of page the symptoms correlated with the cumulative dose of the drug charges. This article must therefore be hereby marked advertisement in accordance administered, and was typically reversible (11). with 18 U.S.C. Section 1734 solely to indicate this fact. Phase II studies of oxaliplatin as monotherapy have shown Requests for reprints: Eric H. Kraut,The Ohio State University, A434B Starling activity in both untreated and previously treated patients with Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-3161; Fax: 614-293-7529; E-mail: [email protected]. metastatic colorectal cancer with response rates of 18% and 10%, F 2008 American Association for Cancer Research. respectively (5, 8). Oxaliplatin has also been successfully doi:10.1158/1078-0432.CCR-07-4903 combined with other agents, such as 5-fluorouracil, gemcitabine,

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If one or more patients in this additional microtubules and stabilizing them against depolymerization group had a DLT, then this level was considered too toxic and the prior (9, 13). Cells treated with paclitaxel exhibit changes level was then evaluated further with the addition of three patients. If consistent with programmed cell death. Paclitaxel is highly no more than one of these six patients had a DLT, this level would be active in numerous preclinical tumor models and has shown considered the maximal tolerated dose. significant clinical activity in several human malignancies, We defined DLT as follows: (a) neutropenia (polymorphonuclear including ovarian cancer, non–small cell lung cancer, and <500/AL) and/or thrombocytopenia (platelets <25,000/AL), (b) irre- breast cancer (13, 14). versible grade 2 nonhematologic toxicity, (c) grade z3 nonhematologic We initiated a phase I and pharmacokinetic study of the toxicity including grade >3 nausea and/or vomiting occurring despite combination of weekly oxaliplatin and paclitaxel based on the maximal antiemetic therapy and grade >3 diarrhea that occurs despite patient compliance with loperamide, (d) grade >3 neuropathy that does following observations: (a) paclitaxel has been studied in vitro not resolve before the planned initiation of the next cycle of therapy, in combination and has shown synergism with platinum and (e) treatment delays of >3 wk. In addition, because of the potential compounds including oxaliplatin (8–10) and (b) paclitaxel is for both drugs to induce neurotoxicity, patients were carefully evaluated used extensively in combination with the other platinums before each treatment for neuropathy signs and symptoms by history (cisplatin and carboplatin) in ovarian, non–small cell lung, and physical examination. The grading of specific toxicities was done germ cell, and thyroid cancers with evidence of clinical using the National Cancer Institute Common Toxicity Criteria, except synergism (19–23). neuropathy grading was based on a scale developed specifically for The goal of this study was to attempt to deliver a more dose oxaliplatin by Sanofi. Paresthesia/dysesthesias of short duration that intense therapy by using a weekly dosing schedule in the hopes resolve and do not interfere with function were grade 1, those of improving efficacy without increasing toxicity. interfering with function but not activities of daily living were considered grade 2, those with pain or with functional impairment that interfered with activities of daily living were grade 3, and persistent Materials and Methods paresthesias/dyesthesias that were disabling or life threatening were grade 4. Patients. Patients entered on this study had to have the following: Evaluation. We did a pretreatment evaluation consisting of a histologically proven solid tumors for which no curative therapy was history and physical examination, including a thorough neurologic available; an age >18 y; life expectancy z12 wk; Eastern Cooperative evaluation, complete blood count, liver enzymes, and chemistry profile. Oncology Group performance status of 0 to 2; no concomitant We also did radiographic evaluation of tumor measurements, including chemotherapy, radiotherapy, or hormonal therapy; no prior treatment computed tomography scans before treatment and after every course. with oxaliplatin or paclitaxel; no more than two prior chemotherapy Response evaluation was done using the WHO (24) criteria for regimens; and no known brain metastases. Patients were required to evaluation of solid tumors. have adequate organ function with absolute neutrophil count of Correlative studies. We evaluated pharmacokinetic studies during z1,500/AL, platelets z100,000/AL, creatinine V1.4 mg/dL, aspartate the first course of therapy for oxaliplatin. Blood samples were collected aminotransferase and alanine aminotransferase V2.5 times the institu- at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 7, 9, 13, 24, 27, 39, 51, and 74 h from tional normal, and a normal bilirubin. Patients were excluded from the the beginning of oxaliplatin infusion. Each blood sample was study if they had evidence of peripheral neuropathy, history of allergy immediately centrifuged to separate plasma and plasma ultrafiltrate to platinum compounds, radiotherapy to >25% of the bone marrow, or using the ultrafiltration method (25–27). Briefly, plasma sample was documented HIV positivity. loaded onto an Amicon Centrifree Micropartition System (30,000 Da Because of the potential toxicity from chemotherapy, pregnant cutoff; Millipore Corp.), which was spun at 1,800 g at 4jC for women or women currently breast-feeding were also excluded. 10 min. Total platinum in plasma and plasma ultrafiltrate was mea- All patients signed an informed consent. The human investigations sured by a validated inductively coupled plasma-mass spectrometry were done after approval by our local institutional review board. The method (25). The pharmacokinetics of paclitaxel has been well studied protocol and informed consent received approval from The Ohio State in literature, and in our preclinical study (26), there was no indication University Biomedical Review Board and the National Cancer Institute. that it was altered in the presence of oxaliplatin. Therefore, in the Drug administration. Patients were treated at the Ohio State current study, paclitaxel levels were not measured. University General Clinical Research Center according to the following We fitted platinum concentration-time data using a computer guidelines and schedule. Oxaliplatin in 5% dextrose and water was software NONMEM (version 5; GloboMax) and analyzed the data with administered as a 2-h infusion followed immediately by paclitaxel in population pharmacokinetics approach with mixed-effect modeling 5% dextrose and water given over 1 h weekly for 4 wk with a 2-wk rest period (which defines one course of treatment). Oxaliplatin powder solution was reconstituted by adding 10 mL (for the 50 mg vials) or 20 mL (for the 100 mg vials) of water for injection or dextrose 5% in Table 1. Dose levels water, which yields a 5 mg/mL solution. The solution was then diluted n 2 2 in an infusion of 250 to 500 mL dextrose 5% in water. Patients received Dose level ( ) Oxaliplatin (mg/m ) Paclitaxel (mg/m ) 16 mg ondansetron, 20 mg decadron i.v., 20 mg famotidine i.v., and Level 1 (6) 35 45 50 mg benadryl i.v. before medication to prevent hypersensitivity Level 2 (3) 45 45 reactions to paclitaxel and reduce the risk of nausea and vomiting. Level 3 (7)* 60 45 Patients could receive weekly oxaliplatin and paclitaxel after their first Level 4 (7) 60 60 week of treatment as long as their granulocyte count was z1,500/AL, platelets z125,000/AL, no significant mucositis persisted, and pares- *Dose level 3 was determined to be the maximal tolerated dose. thesias or dysesthesias were grade V2.

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and tingling in both upper and lower extremities exacerbated N Table 2. Patient characteristics ( = 23) by exposure to cold. In one patient, the neuropathy clearly

n interfered with activities of daily living, although eventually resolving to a grade 1 after 2 months from stopping treatment. Sex Patients were then treated at the next lower dose level (level 3: M122 2 F1160 mg/m oxaliplatin and 45 mg/m paclitaxel) and tolerated Median age (range) 62 (34-76) the treatment well with only transient cold-induced neuropathy Performance status that rapidly resolved when patients were in their 2-week rest 04period. Other toxicities observed were generally mild and 116included nausea, vomiting and/or diarrhea, as well as other 23 Prior chemotherapy predictable toxicities. Myelosuppression was minimal with this 01drug combination with only one patient having a treatment 112delay due to grade 2 neutropenia. There were no grade z3 210hematologic toxicities observed (Tables 3 and 4). Tumor type Colorectal 14 Responses. Twenty-one patients were evaluable for response. Head and neck 1 Two patients were nonevaluable: one patient withdrew consent Other gastrointestinal* 2 andtheotherdiedfromcomplicationsrelatedtohis Neuroendocrine 1 malignancy before evaluation. There were three objective Prostate 1 responses observed in the 12 patients treated at the two highest Melanoma 1 Mesothelioma 1 dose levels (3 and 4). One patient with metastatic colon cancer Sarcoma 1 who was previously treated with two prior chemotherapy ACUP 1 regimens, including irinotecan, 5-fluorouracil, and bevacizu- mab, followed by capecitabine had a partial response at level 3 Abbreviation: ACUP, adenocarcinoma of unknown primary. that lasted for close to 20 months. Another patient with *Gastric (1) and bile duct (1). adenocarcinoma of unknown primary treated at dose level 3 achieved a partial response that lasted 9.5 months. His only prior therapy was chemoembolization. One other partial response lasted 6 months in a patient with recurrent rectal (28). Potential covariate effects (e.g., creatinine clearance, body weight, cancer at dose level 4. This patient received adjuvant and paclitaxel) on the total platinum distribution and clearance were also evaluated. The 24-h urine following the first dose was collected 5-fluorouracil, leucovorin, and levamisole followed by radia- from each patient. The total platinum in urine was also analyzed by the tion before her recurrence. There were also two other patients inductively coupled plasma-mass spectrometry method. with colon and gastric cancer with one prior therapy that experienced prolonged stabilization of their disease. Results Pharmacokinetics. The concentration-time profiles of total platinum in plasma and in plasma ultrafiltrate followed A total of 23 patients were entered on this study. Their biexponential decays and were well described by a two- characteristics are shown in Table 2. There were 12 females and compartment model with a zero-order infusion to and first- 11 males included with a median age of 62 years (range, order elimination from the central compartment (Fig. 1). The 34-76). Performance status with the majority of patients was 0 relevant pharmacokinetic variables as estimated are summa- to 1 with three patients having a performance status of 2. rized in Table 5. In the dose levels studied, the mean total Nineteen patients had at least one prior therapy. The group of plasma platinum concentrations at the end of oxaliplatin patients included had a diversity of tumor types, with the infusion (Cend) were 1.49 to 2.83 Ag/mL and the mean majority (14) having colorectal cancer. ultrafiltrable platinum concentration were 0.694 to 1.29 Ag/mL. Toxicities. A total of 49 courses were given to the 23 patients The mean areas under the concentration-time curves (AUC) of with a median of 2 per patient (range, 1-10). The major DLT total plasma platinum and ultrafiltrable platinum were 43.7 to was persistent peripheral neuropathy seen in two patients at 140.3 Agh/mL and 4.65 to 10.1 Agh/mL, respectively. The dose level 4 with oxaliplatin at 60 mg/m2 and paclitaxel at mean total body clearance (CL) of platinum was 0.694 L/h in 60 mg/m2. The neuropathy was characterized by persistent pain plasma and 7.76 L/h in plasma ultrafiltrate, respectively. The

Table 3. All grade 3/4 toxicities (except neurotoxicity)

Toxicity Dose level 1 Dose level 2 Dose level 3 Dose level 4 Total (n =6) (n =3) (n =7) (n =7) (N = 23) Fatigue 2 1 1 0 4 Diarrhea 1 1 0 1 3 Nausea 1 1 1 0 3 Constipation 0 1 1 0 2 Injection site reaction 1 0 0 1 2 Vomiting 0 0 1 0 1 Infection 0 0 0 1 1

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Table 4. Neurotoxicity (all grades)

Dose level 1 (n = 6) Dose level 2 (n = 3) Dose level 3 (n = 7) Dose level 4 (n =7) Neuropathy (motor) G1/2 0 0 2 1 G3/4 0 0 0 0 Neuropathy (sensory) G1/2 5 1 6 4 G3/4 0 0 0 2

mean steady-state volumes of distribution (Vss) of total plasma and 0.22 h, respectively, and the corresponding mean terminal platinum and ultrafiltrable platinum were 45.5 and 134 L, disposition half-lives (t1/2h) were 39.4 and 18.5 h, respectively. respectively. The mean initial disposition half-lives (t1/2a)of The ultrafiltrable platinum (free drug) showed a shorter total plasma platinum and ultrafiltrable platinum were 0.46 elimination half-life, a more rapid clearance, and a higher

Fig. 1. Concentration-time profiles of total platinum in plasma (A) and plasma ultrafiltrate (B) followed biexponential decays in patients receiving combination of oxaliplatin and paclitaxel at 35/45, 45/45, 60/45, and 60/60 mg/m2. Open symbols represent the observed data, and lines represent the model-predicted individual profiles using a two-compartment model.

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Table 5. Pharmacokinetic variables of total platinum in plasma, plasma ultrafiltrate, and 24-h urine elimination

Oxaliplatin/paclitaxel (mg/m2) 35/45 (n = 6) 45/45 (n = 3) 60/45 (n = 7) 60/60 (n =7)

Total platinum in plasma C end (Ag/mL)* 1.49 F 0.28 1.72 F 0.17 2.83 F 1.28 2.13 F 0.44 AUC0-1 (Agh/mL)* 43.7 F 14.4 54.8 F 1.8 140.3 F 26.22 63.2 F 13.9 CL (L/h)c,b 0.694 F 0.047 c,b V 1 (L) 10.5 F 1.3 c,b V 2 (L) 27.1 F 2.3 Q (L/h)c,b 13.8 F 1.9 b,x V ss (L) 45.5 F 4.9 b,x t 1/2a (h) 0.460 F 0.055 b,x t 1/2h (h) 39.4 F 0.9 Plasma ultrafiltrate C end (Ag/mL)* 0.694 F 0.146 1.21 F 0.33 1.29 F 0.53 0.940 F 0.196 AUC0-1 (Agh/mL)* 4.65 F 0.81 8.02 F 1.47 10.1 F 7.3 6.40 F 1.94 CL (L/h)c,b 7.76 F 0.92 c,b V 1 (L) 7.73 F 0.62 c,b V 2 (L) 94.3 F 9.9 Q (L/h)c,b 16.5 F 1.5 b,x V ss (L) 134 F 5 b,x t 1/2a (h) 0.219 F 0.011 b,x t 1/2h (h) 18.5 F 0.7 24-h urine elimination (% of dose) 47.9 F 14.4 49.5 F 5.4 46.7 F 4.34 46.2 F 20.6

NOTE: Data are presented as mean F SE. *Observed. cModel-estimated primary variables. bComposite variables for all doses (N = 23). xSecondary variables derived from the model.

volume of distribution than the total drug in plasma because of agent, where cumulative doses of 1,200 mg/m2 produced the extensive irreversible plasma protein binding of total significant functional impairment in 50% of patients (11). platinum derived from oxaliplatin. The substantial plasma Increasing the dose of paclitaxel from 45 to 60 mg/m2 in the protein binding of total platinum was also evidenced by the fact present regimen produced dose-limiting neurotoxicity in two that the AUC of ultrafiltrable platinum was only 8.8% of that of patients when paclitaxel alone given at 70 to 80 mg/m2/wk total plasma platinum. The mean 24-h urinary elimination of typically produces grade 1 to 2 sensory neurotoxicity (13, 14). total platinum was 46.2% to 49.5% in these groups of patients. Oxaliplatin, similar to other platinating agents, forms a variety of complexes with some active and some not (27, 32–36). Discussion It is generally accepted that protein-bound species are not important for activity (both antitumor activity and toxicity) We initiated this phase I study to evaluate the maximum but ultrafiltrable platinum species are. We used a sensitive and tolerated dose and pharmacokinetic profile of the combination specific inductively coupled plasma-mass spectrometry method of oxaliplatin and paclitaxel given on a weekly basis. We chose for measurement of the ultrafiltrable platinum species. this schedule due to the evidence that weekly administration of We did a population approach in the pharmacokinetic data paclitaxel or oxaliplatin might allow equivalent dose intensity analysis of oxaliplatin to examine any potential interactions with less toxicity, specifically neurotoxicity (29–31), an over- when combined with paclitaxel. A similar approach has been lapping toxicity of both agents that usually limits giving used for studying the clinical pharmacokinetics of carboplatin them in combination. We showed that this combination could (36). This approach has several advantages over the conven- be administered safely with dose intensity of oxaliplatin at tional approach of averaging individual pharmacokinetic 60 mg/m2 and paclitaxel at 45 mg/m2 weekly for 4 weeks every variables: (a) it better defines the values of population 6-week cycle with minimal hematologic and neurologic toxi- pharmacokinetic variables, (b) it provides a better estimation city. In addition, we showed some interesting activity with of the interpatient variability of these variables, and (c)it the combination, especially in refractory metastatic colorectal defines a quantitative relationship between the covariate effect cancer. The longest-lasting response was a partial response and pharmacokinetic variables (37). In this study, the lasting for 20 months in one patient with refractory colorectal intersubject variability was evaluated on CL (a dose-normalized cancer, a disease traditionally resistant to paclitaxel and where value) and the central (V1) and peripheral (V2) volumes of oxaliplatin has minimal activity as a single agent in the distribution, and the values were less than 50% and 30% for refractory setting. plasma and ultrafiltrable platinum, respectively. Some of the The relationship of neurologic toxicity to dose was especially variability was explained by the covariate effects. Covariate interesting. At the established maximal tolerated dose, minimal analysis indicated that individual’s CL of ultrafiltrable platinum neurologic complaints were seen, including one patient who significantly correlated with their creatinine clearance, suggest- received 10 courses with a cumulative dosage of 2,400 mg/m2. ing that glomerular filtration is a major pathway for ultra- This is in contrast to the experience with oxaliplatin as a single filtrable platinum clearance. This is evidenced by the significant

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amount of total platinum (46.2-49.5% in 24 h) eliminated in In another rat model, administration of taxanes before the urine in this groups of patients. These data are consistent platinums suggests further minimization of neurotoxicity when with the results from Takimoto et al. (27). compared with the reverse sequence (38). It has been shown We analyzed the data obtained from this study with the that administration of oxaliplatin alone, but not paclitaxel platinum concentration data from a phase II study with alone, induced both morphologic and nerve conduction oxaliplatin alone our group recently published (25). Although changes in dorsal root ganglion (39). When paclitaxel is given the AUC values reflect changes according to doses, their before oxaliplatin, the morphologic and nerve conduction comparison from these two studies was not apparent. abnormalities were lessened compared with oxaliplatin alone. Covariate analysis showed that the CL values of plasma All these data justify considering the administration of a taxane platinum and ultrafiltrable platinum were significantly higher before oxaliplatin, unlike what was done in our study. (increased f50%; P < 0.001) in this combination study In conclusion, the combination of oxaliplatin at 60 mg/m2 compared with the corresponding values obtained from the followed by paclitaxel at 45 mg/m2 given weekly for 4 weeks study by oxaliplatin alone (4.81 F 1.93 L/h; ref. 25). This every 6 weeks merits further testing in the phase II testing. As increase in CL values confirms previous observation in a shown, this combination has preliminary antitumor activity smaller population using a conventional pharmacokinetic coupled with a relative low rate of toxicity at the maximal analysis. More importantly, the current pharmacokinetic data tolerated dose and eventual reversibility of most of the herein provide a more statistically robust assessment of observed toxicities. We have obtained more definitive pharma- pharmacokinetic property of oxaliplatin when combined with cokinetic properties of oxaliplatin and confirmed its drug paclitaxel. The objective functions, which are measurements of interaction with paclitaxel in the current sequence. We also the statistical significance of covariate effects, also decreased in think that, based on the preclinical data that have now become this population (data not shown). In a more recent study, we available to us, it would be interesting to look at other more showed that the reverse sequence, with paclitaxel given first, novel taxanes, such as nanoparticles, or other effective could be more clinically favorable because it would prolong congeners, such as docetaxel (all free of Cremophor EL), in the residence of oxaliplatin in systemic circulation (26). This combination with oxaliplatin and compare the different longer residence of oxaliplatin, as with the use of the sequencing strategies in randomized clinical studies. platinum agent alone, may be due to a diminishing effect of Cremophor EL on oxaliplatin when a taxane is given earlier. Therefore, the alteration in the pharmacokinetics of oxalipla- Disclosure of Potential Conflicts of Interest tin is thought to be due mainly to the formulation vehicle Tanios Bekaii-Saab has received a research grant from Sanofi-Aventis. He is also Cremophor EL. on the Speaker Bureau of Sanofi Aventis.

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Tanios S. Bekaii-Saab, Jing Liu, Kenneth K. Chan, et al.

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