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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Twenty-nine patients were treated with DENSPM using a dosing schedule of once daily for 5 days. Doses ranged from 25 mg/m2/day to 231 mg/m2/day.
Results: The dose-limiting toxicity was determined to be gastrointestinal including asthenia, abdominal cramps, diarrhea, and nausea. The maximal tolerated dose was 185 mg/m2/day for 5 days. At drug dosages for which it was possible to estimate, serum half-life ranged from 0.5 to 3.7 h without apparent dose dependence. Maximal serum concentrations increased with dosage. However, the increase was greater than the proportional increase of the administered dose. There were no objective disease responses observed during the Phase I trial.
Conclusions: The results of the Phase I clinical trial suggest that DENSPM can safely be administered to patients with minimal toxicity. Furthermore, the observed dose-limiting toxicity is unique to DENSPM, thus underscoring the potential for DENSPM to be a suitable agent for chemotherapy in combination with agents possessing different spectrums of toxicities.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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DENSPM, also known as N1,N11-bis(ethyl)norspermine (BENSpm), is a homologue of the spermine analogue DESpm, a prototypical spermine analogue initially evaluated in preclinical studies. Both compounds have shown antitumor activity in numerous human tumor models including lung and melanoma (7 , 9 , 10 , 13 , 14 , 17 , 19) . In human melanoma xenografts, DENSPM was shown to have greater antitumor activity with less associated toxicity compared with DESpm (13) . In addition, in this model system, DENSPM is a more potent inducer of SSAT activity and, therefore, polyamine catabolism than DESpm (9) . Additional studies using the human melanoma xenografts model showed that DENSPM had equivalent antitumor activity when given on two treatment schedules (10) . These treatment schedules included DENSPM given at equivalent daily dose (120 mg/kg/day) divided into three times a day for 6 days versus once daily for 6 days. In addition, similar antitumor activity with DENSPM was achieved when the dose was reduced to one-third the daily dose (40 mg/kg/day) and given once a day for 6 days. Toxicity, as determined by changes in body weight, was minimal in all treatment groups. On the basis of these studies, our Phase I trial was designed using a once-daily dosing schedule for 5 days.
The bis(ethyl)polyamine analogues have been extensively studied in human lung cancer cells in vitro (17 , 19 , 20) . These studies have shown that the growth of both NSCLC and SCLC cell lines are inhibited. Their activity, however, in NSCLC lines is associated with cytotoxicity and a net loss of cell number compared with only small to moderate growth inhibition in the SCLC lines. Both cell types exhibit down-regulation of the biosynthetic pathway enzymes, ODC and S-adenosylmethionine decarboxylase, and depletion of the natural polyamine pools. In the NSCLC lines, there is superinduction of SSAT (several hundred- to greater than a thousand-fold) compared with modest or no induction in the SCLC lines. This level of induction correlates with drug sensitivity in these cell lines (17 , 21 , 22) .
Initial toxicology studies were performed in the dog (23) using a once daily i.v. injection schedule of doses of 12.5, 25, 50, and 100 mg/kg. The first three doses were found to be well tolerated. However, the highest dose produced labored breathing, convulsive movements, and death. Using this regimen, there were no discernable end organ toxicities. The dose-limiting toxicity was determined to be hypotension; however, the hypotension was decreased by a slow infusion protocol. Subsequent toxicology studies were performed in dogs by SunPharm Corp. (SunPharm written supplement to Pre-IND submission) using dogs that were treated at 18, 40, and 60 mg/kg/day doses, equally divided and administered three times daily for 6 days. At the 40-mg/kg/day dose, dogs experienced lethargy and anorexia, which resolved 4 days after completion of therapy. These dogs also had black, tarry diarrhea, which resolved 3 days posttreatment. One dog treated at this dose level underwent endoscopy revealing mucosal abnormalities (erythema, edema, friability, and an indistinct vascular pattern) in the pyloric channel, duodenal bulb, and duodenum. Repeat endoscopy 24 days later revealed no abnormalities. In the dog treated at 60 mg/kg/day, treatment was discontinued after the first dose on day 4 secondary to toxicity (lethargy, diarrhea, vomiting, and extreme debilitation). Endoscopic evaluation of this animal on day 5 revealed mucositis in the stomach, duodenum, and rectum. No myelosuppression was observed.
Phase I clinical testing of DENSPM has included testing of other treatment schedules at different institutions. Creaven et al. (24) , from the RPCI, have reported the results of a Phase I study carried out at their institution using twice-daily 1-h i.v. infusions for 5 days with repeat courses every 28 days. They initiated the DENSPM dose at 25 mg/m2/day (12.5 mg/m2/dose). Escalation to doses of 83 and 125 mg/m2/day resulted in toxicity characterized by headache, nausea, vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia in three patients, symptoms consistent with CNS toxicity. After identification of this toxicity profile on this treatment schedule, our clinical protocol was modified to include a normal brain MRI for participation in this study (this amendment was added after the fifth patient was entered on our study).
This study summarizes a Phase I study and pharmacokinetic analysis of DENSPM in patients with NSCLC completed at the Johns Hopkins Oncology Center. The objectives of this study were: (a) to determine the maximally tolerated dose of DENSPM administered daily for 5 consecutive days every 21 days; (b) to describe and quantitate the toxicities of DENSPM administered on this schedule; (c) to evaluate the clinical pharmacology of this agent and to seek pharmacodynamic correlates; and (d) to see preliminary evidence of therapeutic activity in patients with advanced NSCLC.
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PATIENTS AND METHODS |
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2 (ambulatory and capable of self-care; Ref. 25
). Patients also had to have a life expectancy that would enable them to complete at least two courses of therapy. Patients with recent major surgery (within 14 days) and large-field radiation therapy or chemotherapy in the last 28 days (or 6 weeks if the previous chemotherapeutic regimen included nitrosoureas or mitomycin C) were ineligible for enrollment. Patients could not receive concurrent radiotherapy, alternative chemotherapy, radiotherapy, or immunotherapy while on this study. Patients had to have adequate bone marrow reserve (WBCs, >4000 µ1; platelets, >100,000/µ1) and hepatic (bilirubin, 1.5 mg/dl) and renal function (creatinine, 1.5 mg/dl). No active infectious processes could be present. The patients were required to have no medical problems unrelated to the malignancy that would interfere with full compliance during the study or would expose them to undue risk. Pregnant women were excluded, and adequate birth control measures were required for all patients with childbearing potential during the course of the study. Patients could not have any CNS abnormalities noted on MRI scans. All of the patients had to sign informed, written consent. The Joint Committee on Clinical Investigation of the Johns Hopkins University, School of Medicine, approved conduct of the trial.
Dosage and Drug Administration.
DENSPM for this Phase I trial was supplied by the SunPharm Corporation (Jacksonville, FL). The drug was administered as a once-daily i.v. infusion over 15 min for 5 consecutive days and was repeated every 21 days. The drug was obtained in lyophilized form, reconstituted in Sodium Chloride Injection, USP, and stored at room temperature for a maximum of 8 h. The desired dose was further diluted in 50 ml of normal saline for infusion. The drug was administered in the Outpatient Oncology Clinic.
Treatment Plan.
The initial dose level for DENSPM was 25 mg/m2/day. Dose escalations to 50, 60, 75, 94, 118, 148, 185, and 230 mg/m2/day were planned providing there were no dose-limiting toxicities observed in the three patients treated at the previous dose level. Dose escalations occurred after three patients had completed one course of treatment and no dose-limiting toxicities were observed for 16 days after the third patient’s first course of therapy. At the 185 mg/m2/day dose level, three additional DENSPM naïve patients were added to the cohort. These additional patients were followed through at least two courses before any additional dose escalations occurred. Dose escalations within individual patients were not permitted.
The MTD was defined as the highest safely tolerated dose. This was one dosage level below the dose that caused consistent (two or more episodes in at least two of six patients), defined toxicity that was reversible and did not subject the patients to excessive risk or discomfort. Common toxicity criteria were used and the dose-limiting toxicities were defined as any grade 3 or 4 toxicity.
If at any dose level, one instance of any grade 3 or 4 toxicity occurred, three additional patients were treated at that dose. If no additional patients experienced any grade 3 or 4 toxicity, dose escalation was allowed. If two or more instances of any grade 3 or 4 toxicity occurred in two patients, further entry at that dose level was terminated. If these toxicities occurred in patients treated at a lower dose than the current dose level, additional DENSPM naïve patients were added at the current levels for a total of at least six patients. These patients were followed for at least two courses before further escalation was attempted. If two or more episodes of any grade 3 or 4 toxicity occurred at this dose level, then the MTD was declared for the dose level that preceded the original episodes of toxicity. A minimum of six patients were treated at the MTD for at least two courses.
Dose modifications for an individual patient’s subsequent treatment were based on the patient’s nadir counts and the worst-grade nonhematological toxicity during the previous course. Dose modifications of 75% of the previous dose were made for grade 3 toxicity and 50% of the previous dose for grade 4 toxicity. Disease response was formally evaluated after every second 3-week cycle; however, the patients were taken off study if obvious tumor progression or unacceptable toxicity occurred at any time during the study. Patients could also request removal from the study at any time.
An antidiarrheal agent such as loperamide was promptly administered to patients who developed gastrointestinal adverse side effects such as diarrhea or abdominal cramping before completion of the 5-day treatment. The 5-day course of therapy was continued only if the patient’s symptoms were ameliorated by the antidiarrheal therapy. Prophylactic treatment for diarrhea was not permitted.
Study Parameters.
Pretreatment patient evaluation included a complete history and physical including a detailed neurological examination, weight, and performance status. Laboratory and radiographic studies included hemogram, clinical chemistries, urinalysis, electrocardiogram (EKG), chest X-ray, and brain MRI scan. Additional appropriate radiographic studies were done to document measurable disease. Evaluation during the study included a weekly hemogram and clinical chemistries. In addition, before each cycle, urinalysis and a physical examination were done, and weight and performance status documented. Tumor measurements were done after every second course of therapy as deemed appropriate. All of the patients had a detailed neurological examination after every three courses of treatment and at the time of development of any neurological symptoms while on study. Toxicities were noted at each dosage level and during each course of therapy. Hematological toxicities were noted as the lowest observed WBC or platelet count. Blood and/or platelet transfusions were documented. Renal and hepatic toxicities were reported as changes noted on clinical chemistries in blood urea nitrogen (BUN), creatinine, aspartate aminotransferase, alanine aminotransferase, bilirubin, or alkaline phosphatase during a course of therapy.
Pharmacokinetic Methods.
Heparinized blood samples were obtained pretreatment; 5 and 10 min after the start of infusion; just before the end of infusion; and at 2, 5, 10, 15, and 30 min and 1, 2, 4, 8, and 24 h postinfusion on day 1. Samples for days 2–5 were obtained pretreatment and just before the end of infusion. The blood samples were placed immediately on ice and centrifuged at 2500 x g at 4°C for 5 min. The plasma was stored at -20°C until analysis. Plasma samples were analyzed for DENSPM using a validated electron capture, gas chromatographic (GC) assay. Internal standard (diethlyhomospermine) was added to samples before derivatization (60°C for 2 h) with pentafluoroproprionic anhydride. Subsequent isolation of derivatized compounds with chromatographic separation on an Rtx-170 L capillary column with a temperature gradient has proven suitable for routine quantitation of DENSPM at concentrations ranging from 5 to 500 ng/ml using 0.1-ml aliquots of plasma. No interfering peaks were observed during validation. Mean recoveries of DENSPM and internal standard were 82.9 and 90.8%, respectively, with percentage RSD of less than 15%. Assay precision, based on replicate quality controls, was within 7% with an absolute accuracy of 2.7%.
DENSPM pharmacokinetic parameter values were calculated for each subject using noncompartmental analysis of concentration-time data. Nominal sample collection times were used for pharmacokinetic analysis. Maximal concentrations (Cmax) and times for these to occur (tmax) were recorded as observed. Plasma half-life (t1/2) was determined using the slope of the log-linear terminal phase of elimination. Areas under concentration-time profile assessed to time of the last detectable concentration (AUC0-tldc) and extrapolated to infinity (AUC0-inf) were estimated using the linear trapezoidal rule. Clearance (Cl) was determined as dose divided by AUC0-inf.
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RESULTS |
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were treated with DENSPM for a total of 83 complete courses through eight dose levels (Table 2)
. Of the incomplete courses, one patient at the 60-mg/m2/day dose died during the first course (day 11) secondary to his underlying disease. The three additional incomplete courses occurred at the highest dose levels of 185 and 231 mg/m2/day. One patient who received 185 mg/m2/day (of the six treated at this dose level) was unable to complete her second course of therapy because of gastrointestinal toxicity. The one patient treated at the highest level of 231mg/m2/day completed only two partial courses of therapy as well, because of gastrointestinal toxicity. The median number of complete courses of DENSPM/patient was three (range, 1–8).
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Toxicities.
There were no significant (grade 3 or 4) toxicities seen at the first seven dose levels, 25 to 148 mg/m2/day (Table 3)
. At the 185 mg/m2/day dose, one of six patients experienced grade 3 and 4 toxicities consisting of asthenia, abdominal cramps, diarrhea, and nausea. The patient had associated grade 2 vomiting, dehydration, and fatigue. Onset of these symptoms occurred on days 2 and 3 of her first course. The patient had complete resolution of these toxicities after 5 days except for her nausea, which resolved after 9 days. The drug was reintroduced without time delay or dose reduction for a second course. The patient received 1 day of therapy during her second course and experienced a recurrence of grade 3 and 4 gastrointestinal symptoms as described above. She was removed from the study 10 days into her second course. Both episodes were severe enough to warrant hospitalization for symptomatic and supportive care.
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One patient treated at 185 mg/m2/day developed a grade 2 elevation in creatinine during his fourth course, which recurred during his fifth course. He was discontinued from the study after his fifth course because of renal toxicity. Neurological toxicities were mild and consisted of two episodes of grade 1 facial numbness at doses 148 and 185 mg/m2 /day. There was no grade 3 or 4 drug-related hematological toxicities noted at any of the dose levels. Four episodes of grade 1 neutropenia were noted in three patients. In one patient (treated at 148 mg/m2/day), grade 1 neutropenia occurred in both of the courses given, whereas the other two patients had the occurrence in one of two or of seven courses given at 148 and 60 mg/m2/day dose levels, respectively. Grade 1 anemia was seen in three patients who were treated at the 60- and 75-mg/m2/day dose levels. There were two episodes of grade 1 thrombocytopenia in one patient treated at 118 mg/m2/day.
Antitumor Activity.
No objective partial or complete responses were noted. Two of the patients who opted not to continue therapy were noted to have stable disease after four and seven cycles of therapy as discussed above. In addition, the patient who discontinued therapy secondary to renal toxicity after five courses had stable disease at that time. The majority of patients, 83% (24 of 29), had evidence of progressive disease.
Pharmacokinetics.
Maximal (mean values) observed plasma concentrations (Cmax) of DENSPM increased more than proportionally with increasing dose (Table 4)
. There was a 9.2-fold increase in dose, whereas Cmax values demonstrated a 34.1-fold increase, with values ranging from 302 to 10,292 ng/ml. Half-life (t1/2) values at doses below 118 mg/m2/day were poorly estimated because of the rapid decline in plasma concentration and the resulting paucity of data. Therefore, values measured only for this dose and above were reported and used to calculate area under the curve (AUC), clearance (Cl), and volume of distribution at steady state (Vdss). t1/2 values at these dose levels ranged from 0.5 to 3.7 h without apparent dose dependence. With a 1.95-fold increase in dose, there was a 2.45-fold increase in plasma DENSPM AUC0-inf values. Plasma DENSPM clearance ranged from 524 to 928 ml/min/m2. The volume of distribution at steady state ranged from 6.71 to 40.8 liters/m2.
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DISCUSSION |
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Preclinical data with polyamine analogues have demonstrated antitumor activity in diverse tumor types, and animal studies have demonstrated antitumor activity with doses that produce minimal toxicity (8 , 13 , 14) . This Phase I study demonstrates that DENSPM can be safely administered to patients with a once-daily infusion schedule. The toxicity profile of this agent given at this schedule is primarily gastrointestinal, and no significant hematological or CNS toxicity was seen. DENSPM given as a once-daily infusion was generally well tolerated, with no grade 3 or 4 toxicities seen for the first seven doses evaluated. The predominant drug-related grade 3 and 4 toxicities apparent at the two highest doses evaluated were gastrointestinal. Symptoms of nausea, vomiting, and diarrhea were severe enough to warrant hospitalization in both of the patients who manifested these toxicities. One in six patients treated at the 185-mg/m2/day dose experienced recurrent gastrointestinal toxicities requiring discontinuation of the drug. Only one person was treated at the highest dose, and she tolerated only 2 days and 3 days of therapy, respectively, for each of the two partial courses given. No additional patients were treated at this dose, and the MTD was determined to be 185 mg/m2/day.
This toxicity profile is consistent with the toxicology studies done in the dog. Treatment at high dose levels in these animals resulted in gastrointestinal toxicity with associated diarrhea, melenic stools, anorexia, and lethargy. Endoscopic evaluation in a subset of animals revealed mucosal abnormalities consistent with DENSPM-induced mucositis/enteritis. The one abdominal CT scan done in our patient who was treated at the highest dose was suggestive of extensive mucosal damage with bowel-wall thickening and ulceration. Previous abdominal CT scan and follow-up abdominal MRI in this patient were negative for these changes, which suggests that drug-induced gastrointestinal mucosal damage was reversible after discontinuation of the drug. No endoscopic studies were available to document the extent and type of mucosal damage. It would be informative if imaging and endoscopic studies were performed to further evaluate gastrointestinal toxicities of DENSPM in Phase II studies.
The Phase I study done at the RPCI (24) used DENSPM at comparable total daily doses but administered the drug using a 1-hour infusion twice daily. That study was terminated because of apparent severe CNS toxicity in 3 of 15 patients treated. The CNS symptoms developed the week after completion of DENSPM administration. MRI evaluation in these patients demonstrated new lesions consistent with infarct or encephalitis (in one patient) and not new or progressive metastatic disease. One patient died secondary to pulmonary embolism; pathological evaluation of his brain gave no evidence of metastatic disease, infarct, or other abnormality, but his MRI had shown multiple bilateral cerebellar lesions consistent with infarcts. In the other two patients, partial and full recovery occurred over a period of weeks. After identification of this toxicity profile on this treatment schedule, our clinical protocol was modified to include a normal brain MRI for participation in our study. Therefore, the majority of our patients (24 of 29) did not have evidence of occult CNS disease as determined by MRI scans. Although it is impossible to conclude definitively that occult CNS disease did not contribute to this toxicity profile, the clinical scenarios, imaging studies, and autopsy results from RPCI support the possibility of a direct CNS toxic effect by DENSPM or a metabolite given at these doses by twice-daily 1-h infusions. In our study, once-daily infusion of DENSPM at comparable doses did not result in similar CNS toxicity. The lack of significant CNS toxicity seen in our study may be secondary to the exclusion of patients with occult CNS disease. However, differences in peak DENSPM concentrations or other pharmacokinetic parameters may also play a role in whether patients manifest DENSPM-induced CNS toxicity. Additional clarification of whether DENSPM induces CNS toxicity should be available when the drug is tested in additional patients with multiple tumor types in Phase II studies.
Pharmacokinetic studies with DENSPM were done in dogs (34) . Rapid i.v. bolus injection of the drug resulted in a rapid distribution phase of 0.067 h and a t[l/2] of 1.213 h. Volume of distribution was small at 0.216 liter/kg. Approximately 50% of the drug was excreted unchanged in the urine within the first 4 h after treatment. Infusion times of 10 and 15 min were also evaluated with resultant t[l/2] of 1.225 and 1.128 h, respectively. Pharmacokinetic data in human studies are available from our Phase I study, and limited data are available from the RPCI study. In our study, no parent compound was detectable in the urine. This most likely reflects a species difference rather than a technical problem with the assay because similar results are obtained in studies with primates.6 The disproportionate increase in plasma concentration with increasing dose may be attributable to saturation of the specific polyamine transporter used by DENSPM to enter the cells. Similarly, the short DENSPM half-life is not caused by rapid renal excretion nor, apparently, by rapid metabolism. Thus, the short half-life of DENSPM prevents accumulation of the drug in plasma and, at the same time, suggests tissue accumulation and retention under this dosing schedule. However, actual tissue half-life and possible tissue accumulation of DENSPM were not assessed in this study.
This Phase I study demonstrated that DENSPM could be safely administered as a once-daily infusion. The MTD was 185 mg/m2/day. Although no objective evidence of tumor response was seen in this small patient population, three patients had stable disease throughout several courses of therapy. The promising preclinical data, demonstrating antitumor activity of this compound in lung cancer model systems as well as its manageable toxicity profile seen with once-daily dosing, warrant its investigation in Phase II studies. Phase II studies have been initiated using this dosing schedule with a dose of 160 mg/m2/day in multiple tumor types. In addition, its lack of significant hematological toxicity makes it an attractive drug to test in combination with other cytotoxic chemotherapeutic agents.
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FOOTNOTES |
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1 Supported by the SunPharm Corporation and NIH Grants CA58184 and CA51085. 
2 Present address: Northwest Georgia Oncology Center, 55 Whitcher Street, Suite 300, Marietta, GA 30060.
3 Present address: Novartis Pharmaceuticals Corporation, Clinical Pharmacology, 59 Route 10, East Hanover, NJ 07936.
4 To whom requests for reprints should be addressed, at The Johns Hopkins Oncology Center, 1650 Orleans Street, CRB 551, Baltimore, MD 21231. Phone: (410) 955-8580; Fax: (410) 614-9884; E-mail: rcasero{at}jhmi.edu
5 The abbreviations used are: ODC, ornithine decarboxylase; SSAT, spermidine/spermine N1-acetyltransferase; DENSPM, N1,N11-diethylnorspermine; DESpm, N1,N12-diethylspermine; SCLC, small cell lung cancer; NSCLC, non-SCLC; MRI, magnetic resonance imaging; CNS, central nervous system; MTD, maximal tolerated dose; RSD, relative SD; CT, computed tomography; RPCI, Roswell Park Cancer Institute.
6 Unpublished data, communicated by S. Olson, Warner-Lambert/Parke-Davis.
Received 10/29/01; revised 12/11/01; accepted 12/18/01.
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