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Clinical Cancer Research Vol. 8, 3100-3104, October 2002
© 2002 American Association for Cancer Research

Clinical Trials

Phase I and Pharmacokinetic Trial of the Proapoptotic Sulindac Analog CP-461 in Patients with Advanced Cancer1

Weijing Sun, James P. Stevenson, James M. Gallo, Maryann Redlinger, Daniel Haller, Kenneth Algazy, Bruce Giantonio, Hector Alila and Peter J. O’Dwyer2

University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104 [W. S., J. P. S., M. R., D. H., K. A., B. G., P. J. O.]; Cell Pathways Inc., Horsham, Pennsylvania 19044 [H. A.]; and Fox Chase Cancer Center, Philadelphia, Pennsylvania, 19111 [J. M. G.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CP-461 is a member of a class of novel proapoptotic drugs that specifically inhibit cyclic GMP phosphodiesterases but not cyclooxygenase-1 or -2. CP-461 inhibits the growth of a broad range of human tumor cell lines in vitro at micromolar concentrations and selectively induces apoptosis in cancer cell lines but not normal cells. Preclinical studies revealed good oral bioavailability and no toxicity in dogs and rats at single doses up to 500 mg/kg. In a Phase I trial, 21 patients with a range of solid tumors and good performance status received CP-461 p.o. twice daily for 28 consecutive days. Cycles were repeated without a treatment-free interval. CP-461 doses ranged from 100 to 800 mg/day. Therapy was well tolerated overall, and a maximum tolerated dose was not reached. Grade 3 asymptomatic aspartate aminotransferase/alanine aminotransferase elevation in 1 patient treated at 800 mg/day was the only dose-limiting toxicity. No hematologic toxicity was noted. Peak plasma concentrations occurred between 1 and 2 h after dosing, and doses above 200 mg/day exceeded the known in vitro EC50 (1–2 µM) for apoptosis in cancer cells. No drug was detectable after 24 h of administration, and the terminal half-life was 6.7 h. The area under the plasma concentration-time curve was dose-proportional from 200 to 800 mg/day. Four patients exhibited disease stability after two cycles of treatment. CP-461 is minimally toxic at doses up to 800 mg/day when administered p.o. on a twice-daily schedule.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Exisulind (sulindac sulfone), the oxidative metabolite of sulindac, is a member of a new class of compounds called selective apoptotic antineoplastic drugs (Fig. 1)Citation . Exisulind and its analogs induce apoptosis and inhibit growth of tumor cell lines of diverse origin (1, 2, 3) . The drug inhibits tumor growth in rodent xenograft models of colon, mammary, prostate, bladder, and lung carcinogenesis (4, 5, 6) . Exisulind is not a nonsteroidal anti-inflammatory drug because it has no COX-13 or COX-2 inhibitory activity (4) . In patients with familial adenomatous polyposis, the potential for exisulind as a chemopreventive agent has been suggested by decreases in polyp size and number after treatment (7) .



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  		Fig. 1. Structures of exisulind and the novel analog CP-461.

 
CP-461 (or its free base, CP-255) is a potent exisulind analog with broad antitumor activity, which selectively inhibits cell growth of a variety of epithelial and nonepithelial tumor cell lines (8) . Evidence has been presented that exisulind and CP-461 induce apoptosis through inhibition of 3', 5'-cGMP PDEs (cGMP-PDE2 and PDE5), which results in sustained elevated cellular cGMP concentrations, activation of protein kinase G, and proteasomal degradation of ß-catenin (8) . CP-461-induced apoptosis in both SW480 and HT-29 colon cancer cells was associated with cell growth inhibition. CP-461 is 50-fold more effective than exisulind in apoptosis induction (data on file, Cell Pathways, Inc). A recent study showed that CP-461 caused rapid and sustained activation of c-Jun NH2-terminal kinase 1, together with activation of the upstream stress-activated protein/extracellular signal-regulated kinase kinase 1 and mitogen-activated protein kinase kinase 1 kinase (9) . protein kinase G phosphorylation effects, including decreased raf kinase or inhibitor of nuclear factor-{kappa}B kinase ß inhibition, may also contribute to growth inhibition and relate to apoptosis induction (10 , 11) .

Preclinical studies revealed good oral bioavailability and no toxicity in dogs and rats at single doses up to 500 mg/kg. It was indicated that there were two phases of absorption of CP-461. The first peak of absorption is resulting from initially the upper gastrointestinal tract, and the second absorption peak arising from the lower gut or enterohepatic recirculation. The drug was not detectable at 48 h (data from the Investigational Brochure, Cell Pathways, Inc.). In the rat model, CP-461 inhibited formation of aberrant crypt foci, precursors to colonic tumors, induced by azoxymethane (a carcinogenesis inducer).

A Phase Ia study in 18 healthy volunteers was performed by using a crossover rising dose design for assessing the safety, tolerability, and pharmacokinetics of CP-461 (12) . The results showed that CP461 was safe, and no clinically significant adverse events were observed up to a dose level of 700 mg/day. Headache (n = 3), abdominal pain (n = 2), rash (n = 2), and somnolence (n = 2) were the main complaints. Only somnolence reached a grade 2 level of severity, and it resolved quickly without therapy. Doses >100 mg produced Cmax that exceeded those predicted to be necessary to achieve anticancer effects. Absorption was rapid, and Cmax was achieved by 0.5–2 h after oral administration. Peak concentrations and AUCs of CP-461 increased in a dose-dependent manner. The t1/2 ranged from 7 to 14 h.

In the current Phase I study, we have studied a range of doses of CP-461 in patients with cancer to characterize their safety, tolerability, and pharmacokinetics when administered p.o. on a twice-daily schedule. We show that p.o. administration of CP-461 is well tolerated on this schedule, and that the drug is rapidly absorbed. At doses >200 mg/day, plasma concentrations exceed those required to induce apoptosis in cancer cells in vitro.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Pharmaceutical Characteristics.
The chemical formula of CP-461 [(Z)-5-fluoro-2-methyl-(4-pyridylidene)-3-(N-bezyl)-indenylacetamide hydrochloride] is C25H22ClFN2O, and its molecular weight is 420.91 g/mol (Fig. 1)Citation .

Patient Population.
Patients eligible for this study had a histological diagnosis of a malignant solid tumor and had exhausted the standard therapeutic options for their disease or had a malignant disease for which no established therapy exists. They had adequate bone marrow (absolute granulocyte count >=1,500/mm3; platelet count >=100,000/mm3), liver (serum bilirubin <=1.5 mg/dl; serum aspartate aminotransferase and alanine aminotransferase <=5-fold the institutional upper limit of normal), and kidney (serum creatinine <=2.0 mg/dl) function. Patients had recovered from all of the toxicities of prior treatment, and had no prior chemotherapy or radiotherapy within 3 weeks of entry (6 weeks for drugs with delayed toxicity, such as nitrosoureas or mitomycin C). The study was approved by the Institutional Review Board of the University of Pennsylvania. Patients gave written informed consent in accordance with federal, state, and institutional guidelines before therapy.

Before therapy, a medical history, physical examination, complete blood count, biochemical profile, electrocardiogram, urinalysis, and chest X-ray were performed. Patients were monitored with complete blood counts and biochemical profiles once a week. Physical examination, as well as appropriate X-ray, scans, and other tests to assess the response of the patient disease were performed and repeated every other course.

Treatment Plan.
CP-461 was administered p.o. twice daily for 28 consecutive days. The starting dose of CP-461 was 100 mg/day (in two divided doses, 12 h apart). Doses were escalated in 100% increments to a target of 800 mg daily (Table 1)Citation , at which level it was expected that sustained plasma levels in excess of 1 µM could be maintained. Cycles were repeated without a treatment-free interval. There was no dose escalation in individual patients. The dose for subsequent cycles of treatment was determined by the toxicity experienced in the first course. Toxicity was graded using the Revised Common Toxicity Criteria version 2.0 (Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, 1988). Cohorts of at least 3 patients were treated at each dose level. Dose escalation proceeded if no patients had DLT. DLT was defined as at least one of the following: (a) absolute neutrophil count < 500/mm3 or platelet count < 50,000/mm3; (b) diarrhea > common toxicity criteria grade 3 despite loperamide support; and/or (c) nonhematologic toxicity >= grade 3. The MTD was defined as one dose level below the dose that induced DLT in more than one-third of patients (nausea, vomiting, and alopecia were not used in the assessment of MTD). Patients with stable disease or response to therapy were continued on the therapy. Responses were evaluated according to WHO criteria (13) .


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  		Table 1 Dose escalation schema

 
Pharmacokinetic Sample Acquisition and Handling.
Blood samples were obtained from patients 15 min before p.o. administration of CP-461, and then at 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 24 h after administration on days 1 and 28. At each time point, 7 ml of blood were drawn into a heparinized Vacutainer to obtain at least 2 ml of plasma. Within 15 min of collection, whole blood samples were centrifuged at 2000–3000 rpm for 10–20 min at 4°C. Plasma was transferred into polypropylene tubes and frozen at -70°C. Urine was collected in polystyrene containers for the intervals 0–8 h (in treatment area) and 8–24 h (outpatient). During each interval, the urine containers were kept sealed and on ice. At the end of each interval, the total urine volume and pH was recorded. A 20-ml aliquot of urine from each of the four collection intervals was transferred to polyethylene storage containers, and the appropriate labels were affixed to the tubes. The specimens were immediately frozen and stored at -70°C until analysis.

Pharmacokinetic Analysis Methods.
After solid-phase extraction samples were analyzed using a validated liquid diromatography/mass spectrometry/mass spectrometry assay by MDS-Pharma services (Sunnyvale, CA). Noncompartmental analysis was applied to individual CP-461 plasma concentration-time data on days 1 and 28 using the WinNonlin computer program that used linear-log trapezoidal numerical integration method (14) . The terminal elimination t1/2, and various measures of the AUC were calculated. On day 1, in which serial samples were available to 24 h after dosing, the AUC from time 0 to infinity (AUCinf), the AUC to the last measured time point (AUClast), and the AUC to the equivalent time point as that on day 28 (AUC D1 = D8) were calculated. On day 28, in which serial samples were collected for a maximum of 8 h after the dose, partial AUC values were determined and then compared with day 1 AUC values determined for an equivalent time period. The AUCinf values were not calculated from day 28, because the limited time period of measured plasma concentrations prevented an accurate estimate of the terminal elimination phase. The observed Tmax and Cmax values are reported on both days 1 and 28.

Statistical analyses of the pharmacokinetic parameters considered both dose-dependent and time-dependent effects. For dose-dependent behavior, the days 1 and 28 parameters can be analyzed independently, and consisted of performing an ANOVA on Tmax, Cmax, AUCinf (day 1), AUClast (day 28), and the terminal disposition rate constant with dose as the factor. This dose-dependent analysis was supplemented by using the same variables in linear regression analyses. Time-dependent characteristics of CP-461 pharmacokinetics were determined by comparing the day 1 and 28 equivalent AUC, Tmax, and Cmax values for the 11 patients in which complete data were available. The statistical program JMP was used for these analyses (15) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics.
The demographic characteristics of the patients entered on this study are shown (Table 2)Citation . Twenty-one patients were enrolled, all with good performance status, and a range of tumor types. A total of 38 courses of treatment were given, for a median of 2 courses per patient (range 1–4).


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  		Table 2 Patient characteristics

 
Toxicities.
Therapy was well tolerated overall, and a MTD was not defined. No hematologic toxicity was noted. A single occurrence of DLT was observed in 1 patient, who had grade 3 asymptomatic aspartate aminotransferase/alanine aminotransferase elevations in her first cycle treatment at dose level of 800 mg/day. The enzymes were recovered back to normal a week later. Other toxicities included grade 1/2 sensory neuropathy in 2 platinum-pretreated patients. In both, the neuropathy represented a reactivation or worsening of a pre-existing condition. Grade 1 alopecia occurred in 1 patient. It may be concluded that CP-461 is minimally toxic at doses up to 800 mg/day on this twice-daily schedule.

Pharmacokinetic Analysis.
Both Cmax and AUCinf values increased with increasing dose (Table 3)Citation . There was a greater than proportional increase in both Cmax and, in particular, AUCinf as dose was increased from 100 mg/day to 200 mg/day (Fig. 2)Citation . The lower values at the 100 mg dose level could reflect the inability to characterize the terminal elimination phase as these values were near the sensitivity limit. Alternatively, the low mean AUCinf value at 100 mg could indicate saturable presystemic elimination in which a threshold dose has to be reached to saturate drug metabolism before reaching dose proportionality. Approximate proportional changes occurred in Cmax values as the dose was increased from 200 mg to 800 mg; however, the mean AUCinf values showed more discordance with values at the 400 mg dose level being less than expected. At all of the dose levels the interpatient variability was substantial. Tmax (range, 1–2.3 h) and t1/2 (range, 4.6–7.9 h) values did not significantly differ on day 1 as a function of dose, consistent with linear or dose-independent pharmacokinetics.


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  		Table 3 CP-461 pharmacokinetic parameters from day 1

 


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  		Fig. 2. Plot of dose of CP-461 versus its area under the concentration-time curve.

 
Overall, the day 28 parameters show a more complex pattern than those on day 1 (Table 4)Citation . There were no significant changes in Tmax, Cmax, and equivalent AUC values on days 1 and 28 in the same patients. There was a trend toward higher Cmax and AUC values on day 28. This can in part be attributed to the nonzero CP-461 plasma concentrations at time 0 on day 28.


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  		Table 4 Comparative CP-461 pharmacokinetic parameters from days 1 and 28 in same patients

 
Response Evaluation.
At the level of 200 mg/day, 2 colorectal cancer patients treated previously had stable disease and finished four cycles of the treatment. One patient had systemic 5-fluorouracil/leucvorin along with endobronchial brachytherapy and cryotherapy for pulmonary metastases, followed by irinotecan. The second patient has received infusional 5-fluorouracil, tomudex with irinotecan, and oxaliplatin/5-fluorouracil/leucovorin for hepatic and pulmonary metastases. The respiratory symptoms of both patients were subjectively improved during the study. At the level of 800 mg/day, 2 patients were stable. One was a patient with squamous cell carcinoma of the parotid gland who had radiation therapy after surgical resection but no chemotherapy or radiation treatment for advanced disease. The other had colorectal cancer previously treated with 5-fluorouracial/leucovorin, irinotecan, and oxaliplatin; both had a total of 4 cycles of CP-461.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The induction of apoptosis (or programmed cell death) is thought to be one of the key targets for rational cancer treatment. Noncytotoxic approaches to apoptosis induction include inhibition of survival signaling pathways, activation of cell death receptors of the tumor necrosis factor family, and inhibition of COX-2 (16) . Sulindac is a nonsteroidal anti-inflammatory drug that binds to and inhibits COX-1 and -2, and has less well-characterized effects on other cellular proteins (11 , 17 , 18) . Exisulind (sulindac sulfone) is a metabolite of sulindac that has been evaluated for its effects on the development of rectal polyps in patients with familial adenomatous polyposis (19) . Sixteen of 18 patients had regression of small polyps. Histopathologic examination of the polyp biopsy specimens suggested that the exisulind-induced regression appeared to be associated with stimulation of mucous differentiation and increased levels of apoptosis in glandular epithelium. CP-461 is an analog of exisulind that is substantially more active in inducing apoptosis of tumor cells and in inhibiting cGMP-associated PDEs. It has been shown that the apoptosis induced by this class of compounds is p53-independent (20) .

This trial describes the administration of CP-461 to cancer patients at doses up to 800 mg/day. Mild neurological and sporadic hepatic toxicity were the major adverse effects. The goal of the trial was not to reach a MTD but to determine the safety of pharmacologically rational doses. The absence of meaningful toxicity supports the use of this dose for future combination studies or for Phase II trials of CP-461 as a single agent. The pharmacokinetic analysis demonstrated that Cmax and AUC values increased in an approximately linear fashion as the dose was increased from 200 to 800 mg. The mean values for AUCinf at 400 mg were less than expected compared with the 200 and 800 mg, but no evidence of saturable kinetics was observed at the highest dose level. At all of the dose levels the interpatient variability was substantial. The plasma concentration of CP-461 at doses >200 mg/day exceeded the concentration required for induction of tumor cells apoptosis in vitro. The pharmacokinetic results from this trial are consistent with the data from the study of healthy volunteers (12) . The t1/2 of 5–8 h supports this twice-daily schedule of p.o. administration.

No partial responses were observed in this trial, although stable disease was recorded in some 20% of the patients. Whether this was a consequence of drug administration is conjectural, and more extensive trials will be needed to determine whether selective induction of apoptosis can be induced in human cancers. With the safety of the drug at various doses established through the current trial, biological studies in selected patient populations may be initiated, either in patients with disease accessible to repeated biopsy or perhaps in some patients about to undergo surgical resection of their tumors. Preclinical data continue to elucidate the importance of apoptotic pathways, including the role of bcl-2 family proteins, in the mechanism of sulindac (20) . Other studies suggest a positive interaction of sulindac and exisulind with cisplatin, paclitaxel, and 13-cis-retinoic acid in vitro (21) . In non-small cell lung cancer and breast cancer cell lines the activity of exisulind and CP-461 was independent of the resistance phenotype of the tumor cell (21, 22, 23) . Phase I studies of CP-461 in combination with cytotoxic drugs are in progress.

In summary, CP-461 is well tolerated on a twice-daily schedule. Its linear pharmacokinetic profile with wide interpatient variability suggests that adaptive dosing strategies may be of value early in Phase II development, alone and in combination with chemotherapy.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by CA 16520 from the National Cancer Institute, NIH, and a grant from Cell Pathways, Inc. Back

2 To whom requests for reprints should be addressed, at University of Pennsylvania Cancer Center, 51 North 39th Street, MAB, Philadelphia, PA 19104. Back

3 The abbreviations used are: COX, cyclooxygenase; PDE, phosphodiesterase; cGMP, cyclic GMP; Cmax, peak plasma concentration; AUC, area under the plasma concentration-time curve; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; t1/2, half-life; Tmax, time of the maximum CP-461 plasma concentration. Back

Received 12/18/02; revised 5/30/02; accepted 6/ 4/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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