Journal of Clinical Oncology, Vol 17, Issue 7
(July), 1999: 2213
© 1999 American Society for Clinical Oncology
Phase I Clinical and Pharmacologic Study of 13-cis-Retinoic Acid, Interferon Alfa, and Paclitaxel in Patients With Prostate Cancer and Other Advanced Malignancies
R. S. DiPaola,
M. M. Rafi,
V. Vyas,
D. Toppmeyer,
E. Rubin,
J. Patel,
S. Goodin,
M. Medina,
P. Medina,
R. Zamek,
C. Zhang,
E. White,
E. Gupta,
W. N. Hait
From the Departments of Medicine and Pharmacology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School; The Cancer Institute of New Jersey; and Rutgers University College of Pharmacy, New Brunswick, NJ.
Address reprint requests to Robert S. DiPaola, MD, Division of Medical Oncology, The Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901; email dipaolrs{at}umdnj.edu
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ABSTRACT
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PURPOSE: Recent studies demonstrate that retinoids decrease expression of the anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and act synergistically with interferon alfa (IFN ) to inhibit tumor cell growth in vitro. A phase I trial of 13-cis-retinoic acid (CRA), IFN, and paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination. Pharmacodynamic studies were performed to determine whether CRA and IFN could modulate bcl-2 expression in vitro and in patients.
PATIENTS AND METHODS: Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFN and escalating doses of TAX. The effect of CRA/IFN on TAX pharmacokinetics was analyzed in both patients and human liver microsomes. The effect of CRA/IFN on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting.
RESULTS: CRA 1 mg/kg on days 1 to 4, IFN 6 MU/m2 subcutaneously on days 1 to 4, and TAX 175 mg/m2 onday 3 was well tolerated. Pharmacokinetic studies demonstrated that CRA/IFN caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-time curve values of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced conversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFN decreased bcl-2 expression in vitro and in PBMCs.
CONCLUSION: CRA/IFN and TAX is a well-tolerated regimen. CRA/IFN increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFN can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFN/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response.
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INTRODUCTION
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OVEREXPRESSION OF bcl-2 is common in many tumor cells and can increase cell viability although the abrogation of normal mechanisms of programmed cell death.1 bcl-2 prevents the release of cytochrome c from mitochondria, a pivotal event in the apoptotic pathway.1 Initial studies demonstrated an association between bcl-2 protein expression and chemotherapy resistance in non-Hodgkin's B-cell lymphomas.2 Additional studies demonstrated an association between bcl-2 expression with the emergence of androgen independent prostate cancer and chemotherapy resistance.3,4
Agents that downregulate bcl-2 expression may sensitize tumor cells to chemotherapy by decreasing the tumor cell threshold for apoptosis. Adam et al5 studied the use of phenylacetate and tamoxifen in MCF-7ras breast cancer cell lines and demonstrated apoptosis associated with bcl-2 downregulation. Haldar et al6,7 demonstrated restoration of apoptosis in resistant prostate cancer cell lines in associated with inactivation of bcl-2 through phosphorylation by antimicrotubular agents, including paclitaxel (TAX).
Retinoids reduce expression of bcl-2, induce apoptosis in tumor cell lines that overexpress bcl-2, and act synergistically with interferon alfa (IFN) to inhibit tumor cell growth.8,9 The effect of IFN alone on the expression of bcl-2 is less well understood because studies demonstrated that it can decrease the expression of bcl-2 in colorectal tumor cells and increase bcl-2 expression in chronic lymphocytic leukemia tumor cells.10,11 We previously demonstrated the clinical activity of 13-cis-retinoic acid (CRA) in combination with IFN in patients with prostate cancer, a tumor with high levels of bcl-2 expression.12 We now hypothesize that CRA/IFN will decrease the expression bcl-2 in prostate cancer cells in vitro and in patients, thereby enhancing the effect of TAX chemotherapy. The present study was designed to determine the safety and pharmacokinetics of TAX with CRA/IFN in patients and to determine whether CRA/IFN achieves plasma concentrations capable of altering bcl-2 expression in patient peripheral-blood mononuclear cells (PBMCs).
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PATIENTS AND METHODS
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Patients
Twenty-two patients with prostate cancer or other refractory malignancies were enrolled onto this phase I clinical trial. Eligibility criteria included histologically confirmed advanced cancer for which there was no standard treatment, an Eastern Cooperative Oncology Group (ECOG) performance status  2, and a life expectancy of at least 6 months. Requirements also included age  18 years, adequate bone marrow function (WBC count 3,500/µL and platelet count 100,000/µL), adequate renal function (serum creatinine level 1.5 mg/dL), and adequate hepatic function (bilirubin level 1.5 mg/dL). Patients could have received multiple prior chemotherapeutic regimens. All patients were required to give written informed consent, which was approved by the institutional review board of the Robert Wood Johnson Medical School and University Hospital.
Treatment Plan
Patients were initially treated with CRA 1 mg/kg/d orally every day and IFN 6 MU/m2 three times per week subcutaneously starting on day 1, with escalating doses of TAX that ranged from 100 mg/m2 (n = 3) to 135 mg/m2 (n = 3) on day 1 given for 3 hours every 21 days. After these initial two dose levels of TAX, the dosing schema was changed because of moderate toxicity from CRA and IFN ( grade 2 depression and fatigue). All patients at the 175-mg/m2 level (n = 16) received CRA 1 mg/kg/d orally and IFN 6 MU/m2/d subcutaneously on days 1 to 4 with TAX administered on day 3. Nine patients at the 175-mg/m2 dose level received an initial cycle of TAX chemotherapy alone to define intrapatient pharmacokinetics of TAX. Five of these nine patients underwent complete pharmacokinetic analysis in both the first and second cycle of therapy when treated with a first cycle of TAX 175 mg/m2 alone and second cycle of CRA, IFN, and TAX 175 mg/m2.
Response was followed clinically by measurable lesions and biochemically by prostate-specific antigen (PSA) in patients with metastatic prostate cancer. Clinical complete response was defined as the complete disappearance of all clinical signs of active disease. Partial response was defined as at least a 50% decrease in the sum of the products of the longest perpendicular lesion diameters. Stable disease was defined as a less than 25% increase in measurable lesions. Biochemical partial response in patients with prostate cancer was defined as a decrease in PSA of more than 50%. Biochemical stable disease was defined when PSA was decreased less than 50% and increased less than 25%.
Dose-Limiting Toxicity
Dose-limiting toxicity (DLT) was defined in the first cycle of combined therapy as any adverse response that required removal of the patient from the study, any National Cancer Institute grade 2 renal toxicity, or grade 3 or 4 nonhematologic toxicity. TAX was escalated to the next higher dose in three subsequent patients if these toxicities did not occur in the first cycle of therapy (defining a DLT). If one of three patients experienced a DLT at a given dose level, three more patients were accrued to the same dose level with a plan that the dose would be escalated in three subsequent patients if none of these additional patients suffered from a DLT. After one patient experienced a DLT at the 175-mg/m2 dose level, a total of 16 patients were treated at this level to establish the safety of this dosing as the recommended phase II dosing and for the assessment of bcl-2 in PBMCs. Dose was not escalated further because this dosing of TAX is a therapeutic single-agent dose in most malignancies.
Cell Lines, Cell Culture, and Reagents
DuPro-1 cells are hormone-refractory prostate cancer cells and were provided by Dr John Issacs.13 Cells were maintained at 37°C in an atmosphere of 5% CO2 in RPMI media supplemented with 10% fetal bovine serum, 50 units of penicillin and 50µg/mL streptomycin. Cells were routinely checked and were found to be free of contamination by mycoplasma and fungi. CRA and TAX used for laboratory studies were purchased from Sigma Chemical Company (St Louis, MO) and prepared in dimethyl sulfoxide and ethanol, respectively. IFN was purchased from Hoffman La Roche (IFN2a; Nutley, NJ) for laboratory studies and from Hoffman La Roche or Schering Plough Corp (IFN2b; Kenilworth, NJ) for clinical studies.
For pharmacokinetic studies, TAX was obtained from Hande Tech USA (Houston, TX), 6-alfa-hydroxytaxol (6-HT) was purchased from Gentest (Woburn, MA), and CRA, baccatin, and all other reagents for the microsomal incubation studies were purchased from Sigma. All organic solvents were of high-performance liquid chromatography (HPLC) grade and obtained from Fisher Scientific (Springfield, NJ).
Immunoblot Analysis of Cells in Culture and in Patient Mononuclear Cells
Tumor cells treated in culture with CRA (5 µmol/L) alone, IFN (1,000 U/mL) alone, and CRA (5 µmol/L)/IFN (1,000 U/mL) for 24, 48, 72, and 96 hours were lysed in ice-cold RIPA buffer with protease inhibitors, and equivalent amounts of protein from each sample were electrophoresed on 12% gel sodium dodecyl sulfate–polyacrylamide gel electrophoresis and transferred to nitrocellulose as previously described.14 Patient PBMCs were isolated before CRA/IFN administration on days 1 to 4 of therapy. Cells were centrifuged at 1,500 rpm for 20 minutes in CPT mononuclear cell isolation tubes (Becton Dickinson, Mountain View, CA), and the mononuclear cell layer was removed. PBMCs were lysed in RIPA buffer with protease inhibitors, subjected to sodium dodecyl sulfate–polyacrylamide gel electrophoresis, and transferred to nitrocellulose membranes. bcl-2 protein was detected from tumor cells or PBMCs with a monoclonal bcl-2 primary antibody (DAKO, Copenhagen, Denmark) and secondary goat anti-mouse horseradish peroxidase conjugated antibody (Bio-Rad Laboratories, Richmond, CA).
Pharmacokinetics
To determine the pharmacokinetics of TAX and its metabolite 6-HT, blood samples were obtained after the first and second cycle of therapy with TAX 175 mg/m2 alone and CRA/IFN combined with TAX 175 mg/m2, respectively. Samples were obtained before therapy and at 1, 2, 3, 4, 5, 6, 7, 9, 24, 48, and 72 hours after the initiation of the 3-hour TAX infusion. The resultant plasma samples were stored at –20°C and analyzed by HPLC within 1 week of collection. Plasma TAX and 6-HT concentrations were evaluated using a validated reverse-phase HPLC. Baccatin (internal standard) was added to 1 mL of plasma followed by extraction with 4 mL acetonitrile. The supernatant was evaporated to dryness, reconstituted with 200 µL of 50% acetonitrile in water, and injected onto a uBondapak C18 reverse-phase HPLC column (Waters Associates, Milford, MA). TAX and 6-HT were eluted using gradient conditions where the percentage of acetonitrile:water increased from 35:65 to 65:35 over 40 minutes. TAX and its metabolite underwent ultraviolet detection at a wavelength of 250 nM. The lower limit of quantitation for TAXand 6-HT were 11 nM and 0.25 nM, respectively. The interday and intraday variabilities for both TAX and 6-HT were less than 15%.
The plasma concentration-time profiles of TAX and 6-HT were analyzed by noncompartmental methods using WinNonlin (version 1.5; Apex, NC). The maximal plasma concentration and the time to obtain maximal plasma concentration were obtained from evaluation of the plasma concentration–versus-time data. The area under the plasma concentration–versus-time curve up to the last assessable concentration [AUC(T)] was calculated by the trapezoidal rule.15 The terminal half-life was calculated as the ratio of 0.693 and the slope of the terminal phase of the log-linear concentration-time profiles. AUC(T) was extrapolated to infinity by the summation of AUC(T) and the ratio of the last assessable concentration to the terminal slope. Clearance was determined as the ratio of the dose to AUC infinity.
In Vitro Microsomal Studies
Four human liver specimens were obtained through the Tissue Retrieval and Distribution Core Facility of the Cancer Institute of New Jersey, which has institutional review board approval for the use of discarded human tissues for research. The tissues were obtained during surgery immediately after organ resection, placed in cryogenic vials and snap-frozen in liquid nitrogen within 30 minutes after surgical removal, and stored at –70°C until analysis (within 2 weeks). Microsomes were prepared as previously described.16 Briefly, approximately 3 g of liver tissue was homogenized with 12 mL of homogenization buffer (0.154 mol/L potassium chloride and 50 mmol/L Tris hydrochloride) and centrifuged at 10,000 x g for 20 minutes. The supernatant was recentrifuged at 105,000 x g for 1 hour, and the microsomal pellet was washed in incubation buffer (0.1 mol/L potassium phosphate, pH 7.4). The protein concentration was determined by the method of Bradford.17 Simultaneous microsomal incubations of TAX and TAX plus CRA for each liver sample were performed. The microsomes (1 mg) were added to a 1-mL mixture that contained 20 mg/mL glucose 6-phosphate, 20 mg/mL nicotinamide adenine dinucleotide phosphate, 13.3 mg/mL magnesium chloride, 40 U/mL glucose 6-phosphate dehydrogenase in 5 mmol/L sodium citrate, and 0.1 mol/L potassium phosphate (pH 7.4). Aliquots were withdrawn over a period of 60 minutes and immediately added to acetonitrile to terminate the enzymatic reaction. HPLC analysis of the samples from each liver obtained from microsomal incubations with TAX or TAX plus CRA were performed within the same run. 6-HT formation rates were determined from the initial linear phase of plots of 6-HT concentrations as a function of time.
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RESULTS
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Patient Demographics
Twenty-two patients were entered onto the protocol and treated with 73 cycles of therapy. Patient demographics are listed in Table 1. The most commonly treated malignancy was hormone-refractory prostate cancer (n = 10). The median age was 59 years, and the Eastern Cooperative Oncology Group performance status was 1 for all patients. Half of the patients received prior chemotherapy. Patients were treated initially in cohorts of three at each dose level (100 mg/m2, 135 mg/m2, and 175 mg/m2). A total of 16 patients were treated at the 175-mg/m2 dose level to establish the safety of this dosing and for the assessment of bcl-2 in PBMCs.
Hematologic Toxicity
Hematologic grades 3 and 4 toxicities are shown in Table 2 for all cycles. No hematologic DLT was noted, as defined in the first cycle of combined therapy. Grade 4 neutropenia that lasted more than 5 days was observed after the third cycle in only one patient at the 175-mg/m2 dose. Grade 4 neutropenia of less than 5 days duration without fever occurred in one patient at the 100-mg/m2 dose level and four patients at the 175-mg/m2 level. One occurrence of grade 3 thrombocytopenia was observed, but no platelet transfusions were required during this study.
Nonhematologic Toxicity
Nonhematologic grades 3 and 4 toxicities for all cycles are listed in Table 3. Dose-limiting mucositis occurred in one of 16 patients at the 175-mg/m2 dose level after the first cycle of combined therapy. Although grade 1-2 fatigue and myalgia were common, only one patient experienced grade 3 fatigue after the second cycle of therapy, which required a 50% reduction in the dose of IFN. Severe diarrhea was also noted in two patients at the 175-mg/m2 level (one grade 3 and one grade 4 after the third cycle of therapy).
Responses
Ten patients received at least three cycles of combined therapy and were evaluated for response. One patient with metastatic cervical cancer achieved a partial response. A second patient with prostate cancer had a greater than 50% decrease in PSA that was maintained for more than 1 month. Two other patients with prostate cancer had stable disease defined by PSA at 3 months of therapy. Three other patients had stable disease after three cycles of therapy (one chondrosarcoma, one breast, and one thyroid).
Patient Pharmacokinetics
The alteration in intrapatient pharmacokinetics of TAX between cycle 1 (TAX alone) and cycle 2 (TAX with CRA/IFN) is summarized in Table 4. There were no substantial changes in maximal plasma concentration values obtained in cycles 1 and 2. However, there was a consistent decrease in clearance values in cycle 2 compared with cycle 1 (reduction range, 14% to 59%). There was a mean increase of 54% in the TAX half-life in cycle 2 compared with cycle 1. Profiles for 6-HT were obtained from two patients and showed 17% and 28% decrease in AUC(T) of the metabolite during cycle 2.
Liver Microsomal Studies
To determine whether CRA (a cytochrome P450 substrate) inhibited cytochrome P450 metabolism of TAX to 6-HT, the effect of CRA on 6-HT formation was assessed in human liver microsomes. As demonstrated in Fig 1, CRA reduced the 6-HT formation rates from TAX in human liver microsomes (n = 4). In the absence of CRA, the 6-HT formation rates were 36.8, 66.0, 34.3, and 63.2 pmol/min/mg protein, which decreased to 25.8, 25.3, 16.9, and 48.3 pmol/min/mg, respectively, in the presence of CRA.
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Fig 1. Effect of CRA on 6-HT formation in human liver microsomes. HPLC analysis of 6-HT is represented from samples obtained after treatment as a function of time. Human liver microsomes were incubated with TAX (•) or TAX plus CRA ( ). Data are represented as mean (SD) for four incubations.
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bcl-2 Protein Analysis
To determine whether CRA and/or IFN modulate expression of bcl-2 and to assess the time course of modulation, we measured bcl-2 by immunoblotting in tumor cells treated with CRA/IFN for 96 hours. As demonstrated in Fig 2, CRA or IFN alone had minimal effect on bcl-2 expression after 96 hours of therapy. The combination of CRA/IFN decreased bcl-2 expression in DuPro-1 cells, with the maximal effect occurring at 72 to 96 hours. To determine whether CRA/IFN was biologically active in patients and to develop a pharmacodynamic marker of CRA/IFN effect, we assessed PBMCs for expression of bcl-2 before and during treatment with CRA/IFN/TAX. As shown in Fig 3, bcl-2 levels decreased after treatment in four patients tested. The time course of the effect in patients (Fig 3) seemed similar to the effect of CRA/IFN on bcl-2 in cultured cells (Fig 2).
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DISCUSSION
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The combination CRA/IFN/TAX is well tolerated in patients with advanced malignancies. Clinical studies using CRA/IFN alone demonstrated the tolerability and activity of this combination in patients with cervical, squamous cell, prostate, and renal cell carcinoma.12,18-20 In our prior study, patients with early recurrence of prostate cancer were treated with 1 mg/kg/d of CRA and 3 MU of IFN three times per week throughout a 28-day cycle.12 Twenty-six percent of patients experienced a decrease in PSA (median decrease, 23%) and no grade 3 or 4 toxicities related to treatment. However, 14 of 30 patients experienced grade 1 to 2 fatigue and 28 of 30 grade 1 to 2 dry skin. Our current study also demonstrated grade 1 to 2 constitutional symptoms when CRA/IFN was administered throughout the treatment cycle in the 100-mg/m2 and 135-mg/m2 TAX dose levels. By limiting the CRA/IFN to a day-1-to-4 schedule at the 175-mg/m2 TAX dose level, less constitutional symptoms were observed.
CRA altered the pharmacokinetics of TAX, resulting in minimal (14%) to substantial (59%) decrease in TAX clearance (Table 4). The limited data obtained from two patients suggests that reduced 6-HT formation could be a cause of reduced TAX clearance in the presence of CRA. This hypothesis is supported by the in vitro metabolism data, which indicates reduced formation of 6-HT in the presence of CRA (Fig 1). These results were not surprising because hepatic metabolism has been identified as a major elimination pathway of TAX, with cytochrome P450 (CYP)2C8 and 3A4 being involved in the formation of the primary metabolite 6-HT; and retinoic acid is another CYP2C8 substrate.21-24 The clinical implications of the observed TAX-CRA interaction is unclear and could depend on the individual patient contribution of CYP2C8 in the clearance of TAX and the TAX dose administered.
The combination of CRA/IFN downregulated bcl-2 in DuPro-1 cells (Fig 2). Both CRA and IFN have been shown to independently decrease bcl-2 in cell culture and induce apoptosis.10,25 In contrast, the results by Jewell et al11 demonstrated that IFN alone increased bcl-2 in chronic lymphocytic leukemia cells. Our results demonstrated that the combination of CRA/IFN had a greater effect to reduce bcl-2 expression than either drug alone. Other studies that support the use of CRA/IFN have shown that the combination acts synergistically to inhibit tumor cell growth and seems to have some clinical activity in patients with advanced malignancies.9,12,18-20 Because TAX has been shown to induce bcl-2 phosphorylation, which may decrease bcl-2 function, the use of CRA/IFN to reduce bcl-2 expression along with TAX may exert a greater effect to overcome bcl-2 mediated tumor cell resistance. Further studies are warranted to determine the importance of CRA or IFN as modulators of bcl-2 in other cell lines and the effect of CRA and IFN on TAX-induced bcl-2 phosphorylation.6,7
CRA/IFN is capable of modulating bcl-2 in PBMCs in patients (Fig 3). The development of measurable markers of CRA/IFN biologic activity in patients with solid tumors has been difficult, although assessment in patients with leukemia has been demonstrated.26 Handa et al26 evaluated the effect of CRA and IFN in patients with chronic myelogenous leukemia by treating patients with a 3-day course of CRA/IFN. Treatment was associated with increased marrow apoptosis and suppression of bcl-2 in a minority of patients. Further studies with more patients are needed to compare the effects of CRA/IFN in PBMCs with the effect in tumor tissue and response to therapy.
In summary, the present study determined that it is safe to use CRA/IFN with TAX in patients with prostate cancer and advanced malignancy. We also found that CRA/IFN reaches biologically relevant plasma levels capable of altering bcl-2 expression in patients and developed an easily measurable marker of bcl-2 modulation in patients with solid tumors. Further studies are warranted to determine the response rate of CRA/IFN/TAX in phase II trials and correlate bcl-2 modulation in PBMCs to effects in tumor tissue and response.
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ACKNOWLEDGMENTS
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Supported in part by Bristol-Myers Squibb, Inc, Princeton, NJ, and by grants no. CA77135, CA80654, CA72720, and CA57142 from the National Cancer Institute, Bethesda, MD.
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Submitted January 5, 1999;
accepted February 26, 1999.
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TOP
ABSTRACT
INTRODUCTION
