Annals of Oncology Advance Access originally published online on March 8, 2006
Annals of Oncology 2006 17(5):860-865; doi:10.1093/annonc/mdl010
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© 2006 European Society for Medical Oncology
Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer
1 Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, Ohio, USA; 2 Sammons Baylor Cancer Center, Dallas, Texas, USA; 3 Novogen Ltd., North Ryde, New South Wales, Australia
* Correspondence to: Dr T. K. Choueiri, Department of Hematology and Medical Oncology, Taussig Cancer Center, The Cleveland Clinic Foundation, 9500 Euclid Avenue, R-35, Cleveland, OH 44195, USA. Tel: +1 216–444–2200; Fax: +1 216–444–9464; E-mail: choueit{at}ccf.org
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Abstract |
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Background: Phenoxodiol is a multi-pathway initiator of apoptosis with broad anti-tumor activity and high specificity for tumor cells. Its biochemical effects are particularly suited to reversal of chemo-resistance, and the drug is being developed as a chemo-sensitizer of standard chemotherapeutics in solid cancers. This phase I, single-center trial was conducted to test a continuous intravenous dosing regimen of phenoxodiol in patients with late-stage, solid tumors to determine toxicity, pharmacokinetics, and preliminary efficacy.
Methods: Phenoxodiol given by intravenous infusion continuously for 7 days on 14-day cycles was dose-escalated on an inter-patient basis at dosages of 0.65,1.3, 3.3, 20.0, and 27.0 mg/kg/day (three to four patients per stratum). Treatment cycles continued until disease progression. Toxicity was based on standard criteria; efficacy was based on changes in tumor burden (WHO); pharmacokinetic analysis was conducted on plasma samples at specified time points during treatment cycles.
Results: Nineteen heavily-pre-treated patients with solid tumors received a median of three cycles of treatment (range 1–13); two patients received 
12 cycles. No dose-limiting toxicities were encountered, with emesis and fatigue (one patient) and rash (one patient) the only significant toxicities. Stabilized disease was the best efficacy outcome, with one patient showing stable disease at 24 weeks. Pharmacokinetics suggested a linear relationship between dosage and mean steady-state plasma concentrations of phenoxodiol.
Conclusion: A 7-day continuous infusion of phenoxodiol given every 2 weeks is well tolerated up to a dose of 27.0 mg/kg/day
Key words: phase I trial, phenoxodiol, refractory cancer, toxicity, pharmacokinetics
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introduction |
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Phenoxodiol (2H-1-benzopyran-7–0, 3-(hydroxylphenyl) is a pharmacophore of the naturally-occurring plant isoflavone, genistein. These plant hormones regulate plant cycle kinetics and death and may have similar effects in animals [1
]. The anti-cancer effect of isoflavones was initially suggested by the observation of an inverse relationship between dietary isoflavone intake and cancer incidence [12]. Genistein is a pan inhibitor of tyrosine kinases in human tumor cells, and along with certain other members of the family of plant flavonoids such as quercetin and rohitukane (source of flavopiridol), exerts modest anti-cancer activity against a wide range of human and animal cancers including melanoma [2, 3], leukemias [4, 5], breast cancer [6, 7], gastrointestinal cancers [8], prostate cancer [9, 10] and other solid tumors [11]. Phenoxodiol is an analogue of genistein that delivers substantially greater anti-tumor potency and bioavailability [19, 20]. Although an active anti-tumor agent both in vitro and in vivo as a monotherapy, the drug is being developed in late-stage cancers as a chemo-sensitizer. In vitro, it shows a potent ability to restore sensitivity in tumor cells to platinum-based drugs and docetaxel where there is acquired resistance to such drugs [30, 31]. The underlying mechanism of action of this chemo-sensitizing effect is unclear, but may be associated with a reduction in sphingosine-1-phosphate (S-1-P) levels and an increased degradation of anti-apoptotic proteins [22], with increased levels of both being linked to drug resistance in tumor cells [20]. This study was conducted to evaluate the pharmacokinetics and safety of a continuous intravenous injection regimen. This regimen was selected because of the strategy of developing phenoxodiol as a chemo-sensitizer. The hypothesized mechanism of action of phenoxodiol in restoring drug sensitivity suggests that the effect would be enhanced by maximizing the duration of exposure of the tumor cell to phenoxodiol, such as would be delivered by continuous intravenous infusion.
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patient eligibility
Eligibility requirements included a histologically confirmed malignancy that was refractory to standard therapy. Other eligibility criteria included: age
18 years, an estimated life expectancy of at least 3 months, an ECOG performance scale 
2, adequate renal and hepatic function (serum creatinine 1.4 mg/dl, bilirubin <1.2 mg/dl, and serum transaminases levels 3 times the upper limit of normal (ULN) for the reference laboratory) and an adequate hematological function defined by platelet counts 100 x109/l, white cell counts (WBC) 3 x 109/l, hemoglobin (Hb) 10 g/dl (9 g/dl for females) and neutrophils count 1.5 x 109/l. Exclusion criteria included pregnant or currently lactating females, concurrent investigational study, active infection and active central nervous system (CNS) metastases.
Prior chemotherapy, hormonal therapy, immunotherapy or radiotherapy was allowed provided it had been completed at least four weeks before enrollment in the study. Patients with known CNS metastases must have received prior radiation therapy or surgery, and CNS metastatic disease must have been stable for at least four weeks prior to entry into the study.
All inclusion and exclusion criteria were assessed within 14 days and all hematological and biochemical studies were performed within 7 days prior to the initiation of therapy with phenoxodiol. All patients were required to give a written consent in accordance with the US Food and Drug Administration and institutional guidelines.
dose and treatment schedule
Phenoxodiol solution is 15 mg/ml phenoxodiol in 2-hydroxyypropyl-ß-cyclodextrin (HPßCD) in isotonic salt solution. The drug was supplied by Marshall Edwards, Inc.
Phenoxodiol was given by ambulatory CIV infusion via a CADD pump at an infusion rate of 0.1 ml per min (6 ml/h), using a central venous line, e.g. Portacath or a peripherally inserted central catheter (PICC). A 1 mg dose of warfarin was given daily for the duration of the study beginning from the time of insertion of the central venous line in situations where the treating investigator deemed it appropriate.
A treatment cycle is defined as continuous intravenous infusion (CIV) of phenoxodiol for 7 days followed by 7 days of rest (= total 14 days). The starting dose of 0.65 mg/kg/day was chosen, which was equivalent to one-tenth of the dose tolerated by rats without significant toxicity over 28 days CIV infusion. In this phase I design, three to six patients were treated at six different phenoxodiol levels: 0.65 mg/kg/day, 1.3 mg/kg/day, 2.2 mg/kg/day, 3.3 mg/kg/day, 20.0 mg/kg/day and 27.0 mg/kg/day in sequential cohorts. The six-fold dose escalation from 3.3 to 20 mg/kg/day was employed since another study with phenoxodiol found patients to be tolerant of levels up 25 mg/kg/day for 7 days without toxicities [27].
Dose liming toxicity (DLT) was defined as Grade 3 non-hematological toxicity or Grade 4 hematological toxicity using the National Cancer Institute Common Toxicity Criteria, version 2.0 (NCI CTC v.2.0) [28] during the first four weeks of treatment. If no DLTs were observed among the first cohort of three patients at each dose level, then the next set of three patients entered the study at the next highest dose. If two or more DLTs were observed, then the previous dose level was identified as the MTD. If one DLT was observed among the initial three patients, then an additional three patients would be entered. If none of the additional three patients experienced DLT, then the dose was escalated. The MTD was defined as the highest dose level, at which 1 out of three to six patients developed DLT.
patient evaluation
The safety of the treatment was assessed through daily adverse events assessments for the whole cycle period (days 1–14). Regular medical examinations including neurological examinations were performed on days 1, 8 and 14 during the first cycle and on days 8 and 14 during subsequent cycles. Electrocardiograms were performed on days 1, 8 and 14. Complete blood counts, serum chemistries (including liver enzymes, amylase, lipase, and bilirubin) and urinalyses were performed on days 1, 3, 6, 8, 10 and 14. An INR assessment was performed on day 1 and on day 10 (at the discretion of the investigator).
The WHO criteria [26] for assessment of response in patients with measurable disease were used in this study.
statistical methods
Due to the small sample size of each dose level (three to six patients) and difference in tumor types, only descriptive statistical analyses were performed. All patients who received at least one dose of study medication were included in the safety analysis. All observed toxicity was recorded according to organ system and grade, and analyzed for each cohort of patients. Likewise, all laboratory data were collected and analyzed for each cohort.
pharmacokinetic analysis
blood collection for pharmacokinetic analysis.
During the first cycle of treatment, blood was collected on days 1, 2, 3, 6, 8, 10 and 14 for pharmacokinetic analysis. On day 1, samples were collected immediately prior to the start of the infusion and then at 5, 10, 30, 60, 120, 240 and 480 min after infusion initiation. Single samples were collected on days 2, 3, 6, 10 and 14. On day 8, a sample was collected immediately prior to the discontinuation of infusion. During the additional treatment cycles, plasma samples for analysis were collected on day 1 (2 h after commencement of infusion), 3, 8, 10 and 14. Blood was collected in lithium heparin tubes. Blood was centrifuged, plasma collected, and stored at –20°C prior to analysis.
assay methods.
Plasma phenoxodiol assays were performed at Novogen Research Laboratories (Sydney, Australia). Total (conjugated + unconjugated) phenoxodiol levels were determined by dissolving plasma samples in acetonitrile and then analysing by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Unconjugated phenoxodiol (representing that phenoxodiol bound within the HPßCD carrier) were determined separately, and the amount of conjugated phenoxodiol then determined by subtracting the unconjugated phenoxodiol level from the total phenoxodiol level.
pharmacokinetic parameters.
Pharmacokinetic parameters (Tmax, Cmax and AUC0-t) were calculated using the Microsoft® Excel-based program PK Functions (Joel I. Usansky, PhD, Atul Desai, MS and Diane Tang-Liu, PhD, Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA 92606, USA), using a non-compartmental approach [29]. Css was defined as the concentration at steady state. Mean steady-state plasma concentrations of conjugated phenoxodiol were estimated by averaging the values from the first indication of steady state (time to Css) to the sample collected 5 min prior to the end of the infusion on day 8. The range of data used for each patient was determined by inspection of the individual plasma concentration-time curves. Total plasma clearance, Cl, was calculated by dividing the infusion rate by the average steady state concentration. Half-life was estimated by dividing time to Css by 5, as it takes five half-lives to reach steady state. Data manipulation and analyses were performed with Microsoft® Excel (Microsoft Corporation (2003) Seattle, WA) and GraphPad Prism statistical package (version 3.00 for Windows, GraphPad Software Incorporated, CA, USA).
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patient characteristics
Nineteen patients were enrolled in the study between July 10, 2001 and July 9, 2002. All patients were evaluable for toxicity and response to treatment. All the patients were treated at the Cleveland Clinic Foundation, Cleveland, Ohio. Patient characteristics are illustrated in Table 1. The median age was 57 years [Range: 38–80 years]. There were 11 males (57.9%) and eight females (42.1%) in the study. Colorectal cancer was the most prevalent malignancy (n = 5 patients; 26%). All patients had ECOG performance status of 0 (7 patients; 36.8%) or 1 (12 patients; 63.2%). Seventeen of 19 patients had received prior systemic therapy.
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treatment administered and toxicity
In total, patients received a median of three cycles of treatment (range, 1–13 cycles) as outlined in Table 2. Thirteen of 19 patients, (68.4%) completed at least three cycles of phenoxodiol including two patients in the highest dose cohort of 27 mg/kg/24 h (dose level VI). The most number of cycles of phenoxodiol administered was in the 1.3 and 2.2 mg/kg/24 h-dose cohorts with a total of 14 and 12 cycles, respectively. The maximum total phenoxodiol administered throughout the trial was 61557 mg in the 27-mg/kg/24 h-dose cohort (over three cycles). Two patients (thymic cancer, dose level 3 and renal cell cancer, dose level 2) received 12 and 14 cycles, respectively.
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The toxicity related to phenoxodiol was mild to moderate, with no DLT encountered during cycle 1. The most common drug-related toxicities were Grade 1–2 fatigue (9 of 19 patients, 47%), gastrointestinal toxicities including Grade 1–2 nausea (9 of 19 patients, 47%), Grade 1 diarrhea (6 of 19 patients, 32%) and Grade 1–2 emesis (four of 19 patients, 21%). Grade 1–2 cough was experienced by 15.8% of patients (three of 19 patients).
Grade III toxicities were uncommon and included emesis and fatigue in one patient (dose level III, cycle 2) and rash in another patient (dose level V, cycle 2). These were related to phenoxodiol, and resolved with follow up. No grade 4 toxicity was seen. No significant hematological toxicities (e.g. neutropenia, thrombocytopenia or anemia) were observed. Four patients (21.1%) were found to have tachycardia or T wave abnormalities on electrocardiogram assessment, which were felt to be unrelated to the study drug.
Nine (47.4%) patients experienced an increase in their ECOG PS over their period of participation in the trial. In this cohort of patients, seven withdrew because of disease progression and two withdrew because of adverse events not related to the study treatment.
tumor responses
No objective responses were seen. Fourteen of 19 patients treated (73.7%), stopped treatment because of progressive disease. At the last cycle assessed, one patient with metastatic renal cell carcinoma (dose level II), had stable disease for 12 cycles (6 months) of phenoxodiol. He was later withdrawn at cycle 14 due to a gram-negative bacteremia not related to the study drug.
pharmacokinetics
Mean pharmacokinetic parameter estimations for patients in each dosage level and for all patients are presented in Tables 3 and 4, respectively. Fourteen of 19 patients in the trial reached steady state concentration of conjugated phenoxodiol within 48 h (mean 53.14 h) of infusion initiation. The accumulation half-life was 10.63 h. An approximately linear relationship between dose level and mean steady state plasma concentrations of conjugated drug was demonstrated (Figure 1).
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Five patients did not reach steady state, exhibiting rising plasma concentrations over the 7-day infusion period. While steady state was not reached, the concentrations at final sampling point (day 8) did not appear to be significantly elevated compared to patients who did achieve steady state.
The clearance of conjugated phenoxodiol showed only slight variation between subjects and with a mean value of 0.026 l/kg/h. The potential accumulation of conjugated phenoxodiol over three treatment cycles was tested using concentrations at the day 8 sampling point (Figure 2). Values were dose-normalized to allow inclusion of most patients in the calculation. Data was included from patients who completed at least three cycles of treatment (11/19 patients). A repeated measures ANOVA test indicated no significant difference in mean values between the three cycles (F = 1.366, P = 0.2778).
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Phenoxodiol is a synthetic isoflavonoid with 1,2-diphenylpropane-ring structure (Figure 3). Naturally-occurring plant isoflavonoids have been found to regulate a wide variety of functions of mammalian cells, in many cases through undescribed genomic mechanisms. These agents have been described to act via modulation of signal transduction mechanisms [1
], interruption of cell cycle kinetics [6], inhibition of androgen and estrogen synthesis [13, 14], antioxidant activity [12], induction of apoptosis [15], inhibition of angiogenesis [16, 17], and promotion of cancer cell adhesion [18].
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The mechanisms responsible for the antineoplastic activity of phenoxodiol are only partially understood. Straszewski-Chavez et al. [21
] showed that X-linked inhibitor of apoptosis (XIAP), one of the most potent antiapoptotic proteins, protects first-trimester trophoblast cells from Fas-mediated apoptosis. In their study, phenoxodiol induced XIAP degradation and caused trophoblast cells to undergo apoptosis, as evidenced by the decrease in cell viability and activation of the caspaces cascade in the phenoxodiol-treated cells.
Kamsteeg et al. [22] showed that chemotherapy-resistant human ovarian cancer cells, isolated from ascitic fluids of ovarian cancer patients, undergo apoptosis following phenoxodiol treatment. FLICE inhibitory protein (FLIP) is an important antagonist of the proapoptotic Fas pathway competing with caspases for binding into the death-inducing signaling complex (DISC). Phenoxodiol was found in this study to induce FLIP downregulation and therefore activation of the caspases leading to the tumor cell death [22].
Constantinou et al. [23] showed that phenoxodiol also appears to selectively inhibit topoisomerase (topo) II in a dose-dependent manner by stabilizing the topo II-mediated cleavable complex.
Another signaling pathway primarily affected by phenoxodiol appears to be via the sphingomyelin pathway [20]. S-1-P levels are shown to be elevated in cancer cells in response to cisplatin-resistance [32].
Phenoxodiol specifically inhibits sphingosine kinase in tumor cells, leading to inhibition of production of S-1-P, and resulting in increased degradation of Akt and subsequent apoptosis [20].
The high specificity of phenoxodiol for cancer cells lies in the fact that the primary molecular target of phenoxodiol is a tumor-specific NADH oxidase (tNOX), an enzyme expressed only on tumor cells and a splice variant of the constitutive form of NADH oxidase (cNOX) that is present on non-tumor cells [33]. cNOX and tNOX regulate hydrogen excretion across the plasma membrane [34]. The selective targeting of tNOX by phenoxodiol is thought to explain the lack of known biological effects of phenoxodiol on non-tumor cells and its lack of toxicity in animals [20].
These preclinical studies [21–23, 32–33] demonstrate a variety of potential mechanisms for the action of phenoxodiol; studies either as monotherapy or in combination with standard anti-cancer drugs are suggested.
Clinical trials with phenoxodiol are predominantly phase I and early phase II studies. Recently, Rutherford et al. [24] enrolled 18 patients with platinum-refractory recurrent ovarian cancers that are resistant to 2 chemotherapy lines at 2 dose levels: 1 and 3 mg/kg given as weekly intravenous bolus on two consecutive days. The authors reported no severe toxicities related to phenoxodiol treatment. Twenty-five percent of patients had stable disease at 12 weeks, but no objective responses were seen. Compared with Rutherford et al. [24] our study used continuous intravenous infusion of phenoxodiol, which produces sustained plasma phenoxodiol levels. Toxicities were also minimal even at the highest tested dose (27 mg/kg) in our study. Similar to Rutherford et al. [24], we observed no objective responses. On the other hand, stable disease was only present in one patient with renal cell carcinoma (5%) in our study.
Kelly et al. [25] reported the interim results of a phase Ib/IIa study of oral phenoxodiol in patients with late-stage, hormone-refractory prostate cancer. Phenoxodiol was given orally every 8 h for 21 days in a 28-day-cycle. Five dose levels of phenoxodiol were used (20, 80, 200, 400 and 800 mg per dose) and 24 patients enrolled. The study found no major toxicities related to phenoxodiol treatment, with 37% of patients having stable disease without any objective response.
Joshua et al. [27] designed a phase I trial very similar to the current study. Phenoxodiol was given by continuous IV infusion for 7 days on a 14-day cycle. Seven dose levels were used in this trial at a range from 1.3 to 40 mg/kg/day. Twenty one patients were treated in this trial with melanoma being the most common malignancy (six patients, 28%). Grade 1 and 2 toxicities included mainly fatigue (21%), nausea (17%) and increased serum alkaline phosphatase (12%). Likewise, no severe toxicities were reported. The authors did not report objective responses among the treated patients.
The primary objective of this study was to determine the safety of phenoxodiol when administered by continuous intravenous infusion. Dose limiting toxicity was not identified in subjects treated up to a dosage of 27 mg/kg/24 h using a regimen of continuous infusion over seven consecutive days followed by 7 days without treatment. Dose escalation beyond 27 mg/kg/24 h was not pursued as this dosage represented the upper limit of the amount of drug that could practically be infused.
The common side effects in the current trial included fatigue, cough and gastrointestinal toxicities. All these side effects, however, were mild, and did not appear to be related to the dose level. Grade 3 toxicities occurred in two patients, both during cycle 2 of treatment (one patient with emesis and fatigue and another one with rash), but were readily reversible. It is possible that at least some of these toxicities are associated with the drug's carrier, hydroxypropyl-ß-cyclodextrin (HPßCD) [35].
Steady-state plasma levels of phenoxodiol were achieved in the majority of patients. A linear relationship between steady-state concentrations and the infusion rate was demonstrated, confirming the linear pharmacokinetic behavior of phenoxodiol in this dose range. No evidence of drug accumulation with repeated cycles was seen. The Cmax of conjugated phenoxodiol (60 µg/ml) at the highest dose of 27 mg/kg/24 h compares with an IC50 range across a range of tumor types of approximately 5–20 µg/ml [20].
No objective tumor responses were seen in this study, although we did see stabilization of disease in one patient (5%) with renal cell carcinoma at dose level II.
The results of this phase I study demonstrate that phenoxodiol is a well-tolerated agent with only mild toxicity. No dose limiting toxicity was seen, and repeated cycles of this agent were easily administered. Steady-state levels of phenoxodiol were related to dose level administered, with no accumulation being encountered. It is unclear if continuous infusion is required or even optimal for the administration of this agent. Rutherford et al. [24] has shown that intermittent IV bolus administration also is feasible, and with good evidence of efficacy and a high degree of safety. More recently, an oral dosage form of phenoxodiol has been developed and shown in late-stage prostate cancer patients to be without any toxicity or intolerances and to have significant anti-tumor activity in that tumor type [25].
In conclusion, this is the first phase I published trial of the novel agent phenoxodiol showing that 7-day continuous infusion regimen of this drug is well-tolerated with no dose limiting toxicity observed.
Received for publication November 30, 2005. Revision received January 12, 2006. Accepted for publication January 12, 2006.
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