A Phase I and Pharmacologic Evaluation of the DNA Intercalator CI-958 in Patients with Advanced Solid Tumors1 - Clinical Cancer Research
Page content transcription
If your browser does not render page correctly, please read the page content below
Vol. 6, 3885–3894, October 2000 Clinical Cancer Research 3885 A Phase I and Pharmacologic Evaluation of the DNA Intercalator CI-958 in Patients with Advanced Solid Tumors1 E. Claire Dees, Lloyd R. Whitfield, chemotherapy. Pharmacokinetic analysis of plasma and William R. Grove, Sue Rummel, urine concentration-time data from each patient was per- formed. At the recommended Phase II dose of 700 mg/m2, Louise B. Grochow, and Ross C. Donehower2 mean CI-958 clearance was 370 ml/min/m2, mean AUC was Johns Hopkins Oncology Center, Baltimore Maryland 21287 33800 ng䡠h/ml, and mean terminal half-life (t1/2) was 15.5 [E. C. D., L. B. G., R. C. D.], and Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company, Ann Arbor, days. The clearance was similar at all doses, and plasma Michigan 48105 [L. R. W., W. R. G., S. R.] CI-958 AUC increased proportionally with dose, consistent with linear pharmacokinetics. The percentage reduction in absolute neutrophil count from baseline was well predicted ABSTRACT by AUC using a simple Emax model. The pharmacokineti- 5-[(2-Aminoethyl)amino]-2-[2-(diethylamino)ethyl]-2H- cally guided dose escalation saved five to six dose levels in benzothiopyrano[4,3,2-cd]-indazol-8-ol trihydrochloride reaching the maximum tolerated dose compared with a (CI-958) is the most active member of a new class of DNA standard dose escalation scheme. This may represent the intercalating compounds, the benzothiopyranoindazoles. Be- most successful application to date of this dose escalation cause of its broad spectrum and high degree of activity as technique. well as a favorable toxicity profile in preclinical models, CI-958 was chosen for further development. The Phase I INTRODUCTION study described here was undertaken to determine the tox- DNA intercalating agents, including anthracyclines such as icity profile, maximum tolerated dose, and pharmacokinet- doxorubicin, have been used for many years in the treatment of ics of CI-958 given as an i.v. infusion every 21 days. Adult patients with cancer. However, prolonged treatment with many patients with advanced refractory solid tumors who had of these compounds can result in cardiotoxicity (1). The search adequate renal, hepatic, and hematological function, life for agents that provide therapeutic benefits with less toxicity led expectancy, and performance status were eligible for this to the development of a new class of intercalating agents, the study. Written informed consent was obtained from all pa- BTPIs.3 The BTPI agents differ structurally from the anthra- tients. Patients received a 1- or 2-h infusion of CI-958 at pyrazoles in that they contain a sulfur in place of the carbonyl in 21-day intervals. The starting dose was 5.2 mg/m2, and at the center ring. This modification may lessen the cardiotoxic least three patients were evaluated at each dose level before potential of this class of compounds by reducing the possibility proceeding to a new dose level. A pharmacokinetically for the semiquinone free radical generation thought to be in- guided dose escalation design was used until reaching a volved in anthracycline-induced cardiotoxicity. predetermined target area under the plasma concentration The most active member of the BTPI class, with respect to versus time curve (AUC), after which a modified Fibonacci both degree and spectrum of anticancer activity, is CI-958 (Fig. scheme was used. Forty-four patients (21 men and 23 wom- 1). CI-958 is a stable, synthetic, highly water-soluble drug. en; median age, 59 years) received 162 courses of CI-958. Preclinical data for CI-958 demonstrated marked antitumor ac- Neutropenia and hepatorenal toxicity were the dose-limiting tivity against a broad range of murine and human tumors in- toxicities, which defined the maximum tolerated dose of cluding leukemia, melanoma, lung, colon, and breast cancer CI-958 to be 875 mg/m2 when given as a 2-h infusion every (murine tumor models included P388, L1210, B16, M5076, as 21 days. There were no tumor responses. Two patients had well as mammary 16c, 17, 13c, 25, colon 36, 11a, and Ridgeway stable disease for >250 days. The recommended Phase II and Glasgow osteosarcoma; human tumor xenografts included dose is 560 mg/m2 for patients with significant prior chem- MX-1 mammary carcinoma and LOX melanoma). In general, its otherapy and 700 mg/m2 for patients with minimal prior activity resembles that of doxorubicin with superiority in some systems including one mammary and two colon murine tumor models. When compared with mitoxantrone, amsacrine, and the anthrapyrazoles, CI-958 has a broader spectrum and higher Received 11/15/99; revised 6/14/00; accepted 6/23/00. degree of activity against a panel of murine carcinoma and 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 3 Supported by Parke-Davis Pharmaceutical Research Division of The abbreviations used are: BTPI, benzothiopyranoindazole; CI-958, Warner-Lambert Company, Ann Arbor, Michigan. 5-[(2-aminoethyl)amino]-2-[2-(diethylamino)ethyl]-2H-benzothio- 2 To whom requests for reprints should be addressed, at Professor of pyrano[4,3,2-cd]-indazol-8-ol trihydrochloride; PGDE, pharmacokinet- Oncology and Medicine, Johns Hopkins University School of Medicine, ically guided dose escalation; AUC, area under the plasma concentration Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, versus time curve; D5W, 5% dextrose in water; BUN, blood urea MD 21287. Phone: (410) 955-8838; Fax: (410) 955-0125; E-mail: nitrogen; MTD, maximum tolerated dose; HPLC, high-performance email@example.com. liquid chromatography; ANC, absolute neutrophil count. Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
3886 Phase I and Pharmacologic Study of CI-958 dose escalation design was first proposed in 1986; it is based on the concept that interspecies differences in drug metabolism, elimination, and binding are largely responsible for interspecies differences in toxicity. Therefore, the AUC at the mouse LD10 may better approximate the AUC at human MTD than the mouse LD10 approximates the human MTD. The PGDE design uses real-time pharmacokinetic analysis and comparison with preclinical models and targets dose escalation to reach an AUC Fig. 1 Chemical structure of CI-958. equivalent to that seen at the murine LD10 within three to four steps. Prior attempts to use PGDE have been hampered by insensitive assays, interspecies differences in metabolism or human tumor xenografts.4 In addition, in vitro studies with target cell sensitivity, and interpatient variability in clearance. multidrug-resistant tumor lines have shown that CI-958 is less cross-resistant than other intercalating agents such as doxorubi- PATIENTS AND METHODS cin (2). Furthermore, development of acquired resistance to Patient Selection CI-958 is rare in human breast cancer cell lines that rapidly Patients with refractory solid tumors were recruited from develop resistance to doxorubicin and mitoxantrone.4 the Johns Hopkins Oncology Center Outpatient Department. Similar to doxorubicin and mitoxantrone, CI-958 is a potent Eligibility criteria included: (a) life expectancy of at least 12 inhibitor of nucleic acid synthesis, suppressing RNA and DNA weeks; (b) a Zubrod performance status score of two or better synthesis to an equal extent. Tight DNA binding via intercalation (7); (c) age 18 years or older and not pregnant or breast feeding; between the base pairs is the proposed mechanism of action. This (d) ability to give informed consent; (e) no more than one prior binding is thought to lead ultimately to breakage of the DNA, regimen containing an anthracycline-like compound and prior resulting in cell death. Like doxorubicin, CI-958 produces both cumulative doses no greater than 300 mg/m2 of doxorubicin or single- and double-strand protein-associated DNA breaks that un- 125 mg/m2 of mitoxantrone; (f) adequate renal (serum creatinine dergo repair very slowly. However, in vitro studies show that less than 2 ⫻ upper limit of normal or 24 h creatinine clearance unlike doxorubicin and most other quinone or quinone-derived ⬎60 ml/min), hepatic (serum bilirubin less than 1.5 ⫻ upper antitumor agents, CI-958 demonstrates little potential to generate limit of normal), and hematological function (granulocyte count superoxide radicals (3). Preclinical toxicology studies showed that ⬎1500/mm3 and platelet count ⬎100,000/mm3); and (g) no CI-958 produced fewer cardiac lesions in rats than did doxorubicin. history of myocardial infarction, angina, cardiomyopathy, or The dose-limiting toxicity of CI-958 in rats was myelosuppres- ventricular arrhythmia. Additionally, patients must not have had sion.4 Because of its broad spectrum and high degree of activity as chemotherapy or radiation therapy within the 3 weeks prior to well as a favorable toxicity profile, CI-958 was chosen for further enrollment and must have fully recovered from the toxic effects development. The Phase I study described here was undertaken to of previous regimens. The clinical trial described was carried determine the toxicity profile, maximum tolerated dose, and phar- out with approval from the institutional review board. Written macokinetics of CI-958 given as an i.v. infusion every 21 days in informed consent was obtained from all patients prior to study patients with refractory solid tumors. entry according to institutional and federal guidelines. Over the past decade, there has been increasing interest in the development of new Phase I trial designs that minimize the Treatment Protocol number of patients receiving biologically inactive doses of the Study Design. In this dose escalation study, CI-958 was Phase I agents without greatly increasing the risks of toxicity. administered as an i.v. infusion every 3 weeks. The starting dose For example, Simon et al. (4) used mathematical models based was 5.2 mg/m2, which corresponds to one-tenth of the mouse on data from 20 Phase I trials to evaluate four novel dose LD10 from preclinical single-dose toxicity studies.5 At least 3 escalation designs. Their analysis suggests that accelerated ti- patients were treated and evaluated at each dose level. Escala- tration designs using rapid interpatient dose escalation will tion to the next dose level was permitted only after 2 of the 3 effectively reduce the number of patients who are undertreated patients treated at each level had been monitored for a minimum and speed the completion of Phase I trials without significantly of 3 weeks and the third patient a minimum of 2 weeks. Results compromising safety (4). O’Quigley et al. (5) proposed the of the pharmacokinetics from all 3 patients were obtained prior continual reassessment method, which uses clinicians’ estimates to proceeding to the next dose level. of the dose range which may be toxic. Dose escalation is rapid Dose Escalation Scheme. The dose escalation scheme with toxicity evaluations of each cohort determining the dose of used in this trial was based on the concept proposed by Collins the next cohort (5). The PGDE design used in the present study et al. (6). This PGDE scheme targets an AUC equal to the is an example of a novel trial design that has been proposed to murine AUC at the LD10 and proceeds in three stages (Table 1). lessen the number of patients treated at inactive dose levels and In stage 1, the median CI-958 AUC in patients was determined shorten the time required to complete the Phase I trial (6). This at the starting dose. The first escalation step used the geometric 4 J. Bender and G. Courtland, CI-958 Investigator’s Brochure (May 5 1990, revised 1994), unpublished. M. J. Graziano, unpublished data. Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
Clinical Cancer Research 3887 Table 1 Dose escalation schema Stage 1 Starting dose: dose Level 1 ⫽ 5.2 mg/m 2 Mouse AUC at LD10 ⫽ 7980 ng䡠h/ml Dose level 2 ⫽ 共max ⫽ threefold兲 冑 Mouse AUC at LD10 Human AUC at Dose Level 1 ⫻ 5.2 mg/m2 Stage 2 Dose levels 3 . . . n ⫽ 2⫻ previous dose level until: a) CI-958 AUC in humans ⫽ 40% mouse AUC at LD10 ⫽ 3192 ng䡠h/ml or b) two of three patients at a dose level exhibit grade 2 toxicity Stage 3 Dose levels N⫹: a) No toxicity: modified Fibonacci b) Grade 2 toxicity: 1.33⫻ previous dose mean method. By this method, the calculated dose for the second preceding dose level. Patients who had not recovered by day 21 had dose level was equal to the starting dose multiplied by the square subsequent therapy delayed weekly until recovery. root of the ratio of the AUC in mice at the LD10 to the median AUC Pretreatment and Follow-Up Evaluations. Complete his- in humans at the entry dose level (obtained from the three patients tory, physical examination, assessment of performance status, rou- at the first dose level). If the calculated dose for level 2 represented tine laboratory studies, electrocardiogram, and measurement of a ⬎3-fold increase above level 1, dose level 2 was limited to a sentinel tumor lesions were conducted for each patient within 7 3-fold increase. In stage 2, if the median CI-958 AUC in humans at days prior to first treatment. While on study, patients were followed dose level 2 was ⬍40% of the murine AUC at the LD10, then dose weekly with complete blood count and differential, serum electro- levels 3 and higher were determined by the extended-factors-of- lytes, and serum chemistry profile (bilirubin, aspartate aminotrans- two method and were each equal to a 100% increase above the ferase, alanine aminotransferase, alkaline phosphatase, BUN, and preceding dose level until either: (a) the median CI-958 AUC in creatinine). A complete physical examination was repeated prior to patients had reached 40% of the murine AUC at the LD10; or (b) each course of treatment. Toxicity was evaluated for each dose two of the three patients treated at a dose level experienced grade level and each course of therapy and was monitored on an ongoing 2 drug-attributable adverse events. In stage 3 of this dose escalation basis. Appropriate radiographic and laboratory studies were per- design, if the target 40% AUC was reached without grade 2 formed as necessary to follow the disease response to treatment. toxicity, then dose escalation continued using the modified Fi- Measurements of sentinel lesions were reported every 3 weeks for bonacci schema. If grade 2 toxicity was seen, then subsequent lesions detected by palpation or chest X-ray or every 9 weeks for doses were only 1.33 times the previous dose level. lesions, followed by CT scans. Drug Administration. CI-958 was supplied as a lyoph- In this study, dose-limiting toxicity was defined as a gran- ilized powder in 50- or 250-mg vials. Vials containing 50 mg of ulocyte nadir ⬍500/mm3, a platelet count nadir ⬍50,000/mm3, drug were reconstituted with 5 ml of sodium phosphate buffer grade 3 or 4 nonhematological toxicity, or grade 2 neurological, and diluted in D5W. The CI-958 contained in the 250-mg vials renal, or cardiac toxicity. The MTD was defined as that dose was formulated to contain a buffer system, eliminating the need level of CI-958 that produced dose-limiting toxicity in at least for a separate buffer solution, and was reconstituted in sterile two patients treated at that dose level. When the MTD had been water for injection. Upon reconstitution, doses of CI-958 were determined, additional patients were treated at the level below initially diluted into 100 ml of D5W and administered over a the MTD to better define the recommended Phase II dose. period of 1 h. When local venous irritation became a problem, doses were diluted to a total volume of 400 ml in D5W and Pharmacokinetics infused over a period of 2 h. Sample Collection. Venous blood samples (5 ml) were Retreatment. Retreatment occurred every 21 days pro- collected prior to and 0.25, 0.5, 1 (end of infusion), 1.25, 1.5, vided the patient had not experienced dose-limiting toxicity and 1.75, 2, 2.5, 4, 6, 8, 12, 24, 32, 48, 72, 96, 120, 144, 168, 336, had fully recovered from the previous course. Dose escalations and 504 h after the start of the infusion. When infusion length were permitted in individual patients at the completion of at least was changed from 1 to 2 h, the 0.25, 0.5, 1.25, 1.5, and 1.75 time two 3-week courses if the prior course of treatment did not result in points were omitted. To anticoagulate and enhance plasma sta- any unacceptable toxicity or tumor progression, if all eligibility bility of CI-958, samples were immediately transferred to plastic criteria continued to be met, and if patients previously untreated centrifuge tubes to which 0.45 M citrate buffer (pH 5.0) con- with CI-958 had already been evaluated at the higher dose. Dose taining 40 mg/ml ascorbic acid had been added (25 l/ml reductions for subsequent courses in individual patients were based blood). Samples were gently mixed and centrifuged as soon as on toxicity. If a patient experienced grade 4 hematological or grade possible, and plasma obtained was rapidly frozen. Because 3– 4 nonhematological toxicity, the next dose was reduced to the CI-958 undergoes photodecomposition, plasma samples were Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
3888 Phase I and Pharmacologic Study of CI-958 kept from light. Urine excreted in the first 24 h after CI-958 Table 2 Patient characteristics administration was collected in opaque bottles in three intervals No. of patients of 8 h each. Thereafter, urine was collected in 24-h intervals for Total no. of patients 44 the subsequent 168 h. Gender (male:female) 21:23 Analysis. Both RIA and HPLC methods were initially Age (yr) used to measure the concentration of CI-958 in plasma and urine Median 59 samples. Plasma CI-958 concentration-time data obtained from Range 36–77 Performance status the RIA method was higher than that determined using HPLC, 0 20 suggesting that the CI-958 and its metabolites were quantified 1 22 simultaneously by RIA. Therefore, the pharmacokinetic results 2 2 reported are those obtained using the HPLC data. The pharma- Primary tumor type codynamic relationship between AUC and toxicity correlated Colon 18 Lung (Non-small cell) 9 equally well when AUC was determined by RIA or HPLC, Breast 3 suggesting that no information was lost by using HPLC. Plasma Ovarian 3 and urine samples were assayed for CI-958 concentration at Rectal 2 BAS Analytics (West Lafayette, IN) according to a validated Othera 9 Prior therapy HPLC method using electrochemical detection.6 Chemotherapy 41 Briefly, the method included solid-phase extraction of Radiotherapy 23 plasma samples on Bond-Elut C2 cartridges from which CI-958 Both 20 was eluted with 0.1% ethylenediamine eluting solvent. The a Other primary tumor: one patient each with esophagus, head and eluent was dried, and the residue was reconstituted in 0.5– 4.0 neck, intra-abdominal, oral cavity, pancreas, prostate, urinary bladder, ml of the mobile phase, depending on the estimated plasma vertebra, vulva. concentration. A 100-l aliquot was injected on the HPLC system. Chromatographic separation was performed on a DuPont Zorbax Rx 4.6 ⫻ 250 mm C-8 column at 40°C. The mobile phase consisted of a mixture of methanol/n-propyl alco- Total plasma clearance was calculated as dose/AUC(0-⬁). Vol- hol (2:1 for plasma analysis and 1:1 for urine analysis) and ume of distribution at steady state was calculated as [Dose ⫻ buffer (0.07 M citrate buffer for plasma analysis and 0.7 M citrate AUC(0-⬁)/AUC(0-⬁)2 ⫺ ((Dose ⫻ T)/2 ⫻ AUC(0-⬁))], where T is buffer for urine analysis). The mobile phase was run isocrati- the duration of the constant rate i.v. infusion. To determine cally at 1.5 ml/min. Peaks of interest were detected electrochem- whether a relationship exists between CI-958 exposure and ically at an applied potential of ⫹525 mV (plasma) and ⫹400 toxicity, the percent reduction in ANC was plotted versus AUC, mV (urine). CI-958 concentrations were quantitated by the peak and the data were fit with a simple Emax model (9) using height ratio method using PD-112451 as the internal standard. PCNONLIN 4.0 (SCI Software, Lexington, KY) and WinNonlin System reproducibility expressed as relative SD (%) of the peak 1.1 (Scientific Consulting, Inc., Apex, NC). height ratios was determined using pooled human plasma ex- tracts. The reproducibility of the HPLC system (%RSD) was RESULTS 1.6, 0.7, and 1.7% for CI-958 concentrations of 5.0, 100, and Forty-four patients received 162 courses of CI-958. The 1000 ng/ml. Assay precision and accuracy were determined by patient characteristics and demographics are displayed in Table analyzing three quality control pools in triplicate over three 2. Eleven dose levels were evaluated (as listed in Table 3). Dose separate days. Assay precision expressed as relative SD (%) of level 1 was set at 5.2 mg/m2, corresponding to one-tenth of the the assayed concentrations was 4.7, 6.2, and 3.6% for quality murine LD10. Dose level 2 was limited to 3-fold dose level 1 controls containing 5, 500, and 5000 ng/ml CI-958, respectively. because the dose determined by the geometric mean calculation CI-958 pharmacokinetic parameter values were calculated (17 mg/m2) exceeded the defined limit (15.6 mg/m2). Dose after each dose administered using noncompartmental methods. levels 3 and 4 were reached by doubling the preceding dose Length of infusion times and samples collection times varied in level, because the AUC values obtained at dose levels 2 and 3 each patient, and hence, actual collection and infusion times did not reach the target AUC value of 3192 ng䡠h/ml (40% of the were used in the analysis. AUC was determined by Lagrange murine AUC at the LD10). At dose level 4, the target AUC was polynomial interpolation (8). The apparent elimination-rate con- reached, using both HPLC and RIA methodology. Therefore, stant was estimated as the absolute value of the slope of a linear dose levels 5–9 were escalations based on the modified Fi- regression of natural logarithm (ln) of plasma CI-958 concen- bonacci scheme. The last two dose levels used smaller incre- tration against time during the terminal phase of the plasma ments based on the degree of neutropenia observed at level 9. concentration-time profile. The terminal elimination phase was The number of courses of treatment per patient ranged determined by visual inspection. Apparent elimination half-life from 1 to 29. Thirty-six patients (82%) received more than one was calculated as ln (2) divided by the elimination rate constant. course, and 8 patients (18%) received five or more courses. Four patients were escalated to higher dose levels for subsequent courses, and 4 patients were dose reduced. All patients were evaluable for toxicity. Patients were withdrawn from the study 6 Data on file at Parke-Davis Pharmaceutical Research, Division of because of progressive disease (38 patients; 86%), death within Warner-Lambert, Ann Arbor, MI 48105. 30 days of last dose (3 patients; 7%; all described in detail Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
Clinical Cancer Research 3889 Table 3 Hematological toxicity (worst toxicity per course) Neutropenia Thrombocytopenia Dose ANC nadir (mm ) 3 Max WHO toxicity grade 3 Platelet nadir (mm /1000) Max WHO toxicity grade level No. of No. of 2 mg/m patients courses Median Range 0 1 2 3 4 Median Range 0 1 2 3 4 5.2 3 9 5246 3808–7161 9 206 149–341 9 15.6 4 13a 2925 1887–6083 11 1 218 161–334 13 31.2 3 8 5038 3500–7221 8 395 179–535 8 62.4 3 7 4160 3036–8034 7 267 210–411 7 125 4 12 4068 1508–6438 10 2 256 146–393 12 200 4 16 4059 1575–5874 13 3 269 126–361 16 300 5 20 2746 1344–4081 18 1 1 195 110–302 20 425 7 28 1397 176–12070 6 6 14 1 1 115 82–365 21 7 560 8 18 1037 108–3256 4 6 5 3 205 110–317 18 700 9 21b 1013 210–6364 2 3 5 5 6 193 22–340 17 1 1 1 1 875 6 9 912 200–2436 1 1 2 3 2 184 16–271 7 1 1 a ANC available only for 12 courses. b ANC not available for one course where WBC nadir ⬍500. below), occurrence of adverse events (2 patients; 5%), or refusal (20%) experienced anemia of any grade. Three of these were of further treatment (1 patient). considered to have treatment-associated anemia. One patient at Hematological Toxicity. Severity of neutropenia was 700 mg/m2 and 1 patient at 875 mg/m2 had grade 1 anemia. One dose related. Median ANC nadir and maximum toxicity grade patient treated at 700 mg/m2 had grade 3 anemia. per course are listed by dose level in Table 3. Neutropenia was Nonhematological Toxicity. The most common treat- dose limiting (grade 4) in 1 of 7 patients at 425 mg/m2 (1 of 28 ment-associated, nonhematological toxicities were nausea courses), 2 of 8 patients (3 of 18 courses) treated at 560 mg/m2, and/or vomiting, asthenia, fever, chills, diarrhea, injection site 4 of 9 patients (6 of 21 courses) treated at 700 mg/m2, and 2 of symptoms (inflammation, reaction, edema, or pain), phlebitis, 6 patients treated at 875 mg/m2. Neutrophil count nadirs oc- and vasodilation. Table 4 shows the distribution of these toxic- curred at a median of 14 days (range, 8 –23 days), and the ities by dose level and toxicity grade. Dose levels 1–5 (5.2–125 median day of recovery (ANC ⱖ1500/mm3) was 22 days mg/m2) are not depicted because no toxicity greater than grade (range, 12–29) after dosing. One of the two patients mentioned 1 was observed at these dose levels. As shown, most of the above with dose-limiting neutropenia at 560 mg/m2 had also had toxicities seen at doses 200 mg/m2 and above were mild or dose-limiting neutropenia at 700 mg/m2 and had required dose moderate. One patient treated with 560 mg/m2 had grade 3 reduction. Similarly, one of the patients with dose-limiting injection site symptoms. One patient treated at 700 mg/m2 had neutropenia at 700 mg/m2 had been treated previously at 875 grade 3 fever on the day of infusion. Two patients had grade 4 mg/m2 and had required dose reduction for dose-limiting neu- nausea and vomiting at doses of 560 and 875 mg/m2. tropenia. Infusion of CI-958 through peripheral veins caused local Two patients developed serious adverse events related to reactions characterized by phlebitis, induration, erythema, or their neutropenia. One patient treated with 700 mg/m2 CI-958 pain. These problems were temporarily alleviated by increasing developed neutropenia, fever, and sepsis. She was hospitalized the volume of D5W infused with each dose and lengthening the and begun on antibiotics. Two days later, the antibiotics were infusion duration from 1 to 2 h. However, as the dose levels discontinued according to the wishes of the patient and her increased, local venous intolerance was again encountered. Use family. The patient died 2 days later. Another patient required of central venous catheters successfully prevented these prob- hospitalization for febrile neutropenia after her second course of lems. CI-958 (875 mg/m2). She was treated with broad spectrum i.v. One case of CI-958 extravasation occurred. The patient did antibiotics. All cultures were negative; no infection was de- not complain of local discomfort during the infusion but there- tected. Her neutropenia resolved, and she was discharged. Both after developed ulceration at the site of the injection. This of these serious adverse effects were considered related to reaction developed slowly over a period of several weeks, CI-958. eventually resulting in several small areas of necrosis and was In general, thrombocytopenia was infrequent and mild. In very slow to heal. A subsequent treatment in the opposite hand total, 6 patients experienced thrombocytopenia of any grade. caused an exacerbation at the initial reaction site. Thrombocytopenia appeared to be dose related. Median platelet A variety of acute reactions were reported during infusions nadir and maximum toxicity grade per course are listed by dose of CI-958, characterized by flushing, urticaria, pruritis, and level in Table 3. Two patients treated at 700 mg/m2 developed hyperesthesia, particularly of the head and neck region. These grade 3 or 4 thrombocytopenia. One patient developed grade 3 reactions were dose related and appeared to be related to the rate and grade 4 thrombocytopenia after each of 2 courses of CI-958 of infusion. On several occasions, infusions were either slowed at 875 mg/m2. Thus, thrombocytopenia was dose limiting in 1 of or temporarily interrupted, the reactions subsided, and the infu- 8 patients at 700 mg/m2and 1 of 6 patients at 875 mg/m2. sions were resumed to completion. Reactions occurred sporad- Treatment-associated anemia was infrequent. Nine patients ically, sometimes during the initial treatment (7 patients) and Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
3890 Phase I and Pharmacologic Study of CI-958 Table 4 Nonhematological toxicity Dose No. of Toxicity Nausea/ Injection levela pts grade vomiting Asthenia Fever site sx Diarrhea Chills Phlebitis Vasodilation 200 4 1 2 1 3 2 1 3 4 300 5 1 1 5 1 2 1 3 4 425 7 1 3 2 2 1 2 2 3 1 3 4 560 8 1 3 1 2 1 2 1 2 3 1 4 1 700 9 1 4 3 3 4 1 2 2 3 3 1 4 875 6 1 2 2 2 5 1 2 2 1 1 3 4 1 a Dose levels 1–5 are not depicted because no toxicity greater than grade 1 was observed at those dose levels. sometimes occurring only after multiple courses were given (4 enced atrial fibrillation, pericardial effusion, and shortness of patients). Reactions generally were self-limited and often did breath on day 1 after treatment with CI-958 at 875 mg/m2. He not recur on subsequent exposure. was treated with digoxin and quinidine gluconate, and the atrial In addition to the common nonhematological toxicities fibrillation resolved. The atrial fibrillation was thought possibly discussed above, two patients experienced dose-limiting renal or attributable to CI-958. hepatorenal toxicity associated with CI-958 treatment at 875 Pharmacokinetic Results. Pharmacokinetic sampling mg/m2. One patient, who had mildly elevated creatinine sec- was performed on 38 patients. Individual plasma CI-958 con- ondary to prior cisplatin and etoposide chemotherapy, was noted centration-time profiles exhibited a multiexponential decline at to have acute renal failure on day 8 after the second course of the end of infusion. Concentration-time curves were character- CI-958 treatment at 875 mg/m2. His baseline BUN and creati- ized by secondary peaks occurring throughout the distribution nine prior to course 1 were 26 and 1.9 mg/dl, respectively. Prior and elimination phases. A representative example, the concen- to course 2, his BUN and creatinine were 31 and 1.8 mg/dl, tration-time curve from patient 33 who received 700 mg/m2, is respectively. He developed severe nausea, vomiting, and de- shown in Fig. 2. Mean CI-958 pharmacokinetic parameters are creased oral intake after his second treatment. BUN and creat- summarized in Table 5. Plasma CI-958 AUC increased propor- inine rose to 130 and 14 mg/dl on day 10. The patient was tionally with dose (Fig. 3). However, there was considerable hospitalized with acidosis and uremia and treated with hemodi- interindividual variability, which resulted in similar AUC values alysis. He subsequently required mechanical ventilation and in individuals treated with widely differing doses of CI-958. At pressor support. He died on day 12 without recovery of his renal doses where biological activity was observed (dose ⱖ200 mg/ function. Another patient treated with CI-958 at 875 mg/m2 m2), 2–11% of the AUC was contributed by the extrapolation required hospitalization for acute renal insufficiency (48 mg/dl from the last sample to ⬁. The clearance values were similar at BUN and 2.5 mg/dl creatinine) and abnormal liver function tests all doses, consistent with linear pharmacokinetics of CI-958 (6.4 mg/dl peak bilirubin, ⬎2400 IU/l transaminases) after her (Fig. 4). Concentrations in the terminal elimination phase in first course of therapy. She was treated with aggressive support- many patients were near the limit of quantitation and exhibited ive care and recovered. No other patients experienced elevations secondary peaks. Therefore, the elimination half-life values in creatinine over 1.5 times normal (grade 1). Four other patients reported may be underestimated and should be interpreted with had transient mild to moderate transaminitis during treatment caution. The cumulative amount of unchanged CI-958 excreted that resolved to baseline. in urine of each individual was ⬍10% of dose, indicating that Patients were carefully monitored for any signs of cardio- urinary excretion of CI-958 is a minor elimination pathway. toxicity. No clinically significant electrocardiogram changes Pharmacodynamic Results. Two patients experienced were noted after treatment with CI-958 at any dose level. No dose-limiting renal or renal/hepatic toxicity associated with CI- patients developed signs or symptoms of cardiomyopathy after 958 treatment as discussed above. Plasma CI-958 AUC values treatment with this agent. One patient with lung cancer experi- for these patients during the first course of therapy were twice Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
Clinical Cancer Research 3891 Fig. 2 Representative concentration-time curve (inset, detail of first 72 h). Table 5 Mean CI-958 pharmacokinetic parameters after single i.v. infusion of CI-958a Dose (mg/m2) n AUC (0-tldc) AUC (0-⬁) CL CLnr CLcr Vdss t1/2 5.2 3 362 567 288 281 85.4 659 3.2 (208.2) (459.8) (262.6) (257.2) (11.8) (488.3) (3.2) 15.6 3 730 1070 281 275 49.5 1880 4.8 (303.0) (431.2) (139.1) (133.9) (10.4) (819.7) (1.9) 31.2 3 1360 1760 332 NC 79.2 1570 3.9 (394.4) (814.9) (123.2) (13.5) (367.4) (2.4) 62.4 3 3300 3550 273 NC 74.8 1070 4.6 (762.3) (837.8) (128.0) (28.0) (446.2) (2.2) 125 3 7870 8140 366 360 53.2 1270 3.0 (4824.3) (4875.9) (297.9) (294.8) (48.9) (582.9) (1.6) 200 3 8370 9240 346 335 71.1 2970 13.5 (1891.6) (2032.8) (70.6) (68.0) (7.8) (2004.8) (2.8) 300 3 21200 22900 238 230 53.7 1850 4.3 (6360.0) (8289.8) (73.1) (69.7) (11.4) (762.2) (1.4) 425 3 18600 19500 405 391 86.4 2270 8.6 (1488.0) (2047.5) (83.4) (70.4) (39.3) (497.1) (2.6) 560 6 26000 28500 338 323 79.0 2760 12.0 (5044.0) (6070.5) (54.8) (58.1) (17.3) (1669.8) (8.0) 700 4 30200 33800 370 351 195 3170 15.5 (5587.0) (11018.8) (102.9) (82.5) (56.0) (2754.7) (16.0) 875 4 51800 53100 307 296 265 980 5.5 (20150.2) (20124.9) (116.0) (113.1) (64.4) (715.4) (3.1) a Values represent mean (SD). AUC(0-tldc), area under the plasma concentration-time curve from time zero to last detectable concentration (ng䡠h/ml); AUC(0-⬁), area under the plasma concentration-time curve from time zero to infinity (ng䡠h/ml); CL, total plasma clearance (ml/min/m2); CLnr, nonrenal clearance (ml/min/m2); CLcr, estimated creatinine clearance; Vdss, volume of distribution at steady state (liters/m2); t1/2, apparent elimination half-life (days); NC, not calculated. those of other patients treated with 875 mg/m2 dose of CI-958 patients received 5 or more courses of therapy. One patient with (Fig. 3). Therefore, it would appear that these toxicities may breast cancer remained on study for 29 courses (609 days), and have resulted from higher systemic exposure to CI-958. Plasma one patient with colon cancer remained on study with stable CI-958 AUC values also predicted the reduction in ANC. How- pulmonary disease for 12 courses (252 days). ever, AUC was no more effective in predicting neutropenia than was dose. The relationships between percent reduction in ANC from baseline versus plasma CI-958 AUC values and CI-958 DISCUSSION dose are depicted in Figs. 5 and 6. The dose-limiting toxicities of CI-958 were neutropenia Tumor Response. There were no tumor responses after and renal or hepatorenal toxicity. Grade 4 neutropenia was dose treatment with CI-958. However, patients were permitted to related (Fig. 6), with four episodes at doses below 700 mg/m2 remain on treatment as long as their disease was stable. Eight and eight episodes at doses of 700 mg/m2 and above. The only Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
3892 Phase I and Pharmacologic Study of CI-958 Fig. 3 Relationship between plasma CI-958 AUC(0-⬁) and dose. The solid line represents the linear regression equation: AUC(0-⬁) ⫽ 54 ⫻ Dose ⫹ 176. Fig. 4 Relationship between total CI- 958 clearance and dose. two episodes of nonhematological dose-limiting toxicity occurred accurate estimation of the cardiotoxicity of this compound can at 875 mg/m2. The MTD of CI-958 was determined to be 875 only be made after further testing. mg/m2, based on the renal and liver toxicity, as well as the dose- CI-958 has shown marked antitumor activity in preclinical limiting myelosuppression encountered at this dose. The preceding models. Although assessing efficacy was not the primary end point dose level, 700 mg/m2, was well-tolerated by patients who had not of the present study, no tumor responses were seen. However, eight been heavily exposed to prior chemotherapy and is the recom- patients received five or more courses, and two patients had pro- mended Phase II starting dose for those patients. In heavily pre- longed periods of stable disease. Preliminary Phase II evaluation of treated patients, 560 mg/m2 is the recommended Phase II dose. CI-958 at the doses recommended above has been carried out. In a The BTPI class of compounds, and CI-958 in particular, pilot Phase II study in patients with hormone refractory prostate was developed in part because of structural changes hypothe- cancer, CI-958 was given at a dose of 700 mg/m2 over 2 h every 3 sized to make these agents less cardiotoxic than anthracyclines. weeks. Six of 30 patients with elevated prostate-specific antigen In this Phase I study, one patient treated at the MTD developed had response ⱖ50% reduction from baseline. Two of 11 patients atrial fibrillation in the setting of advanced lung cancer. No with measurable disease responded (10). Another Phase II study other patients experienced any electrocardiogram abnormalities has evaluated CI-958 in 15 patients with colorectal cancer and did or other evidence of cardiotoxicity. Although preclinical models not find this dose and schedule to be effective (11). suggest that CI-958 may be less cardiotoxic than doxorubicin,4 PGDE has been proposed as a potentially safer and faster Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
Clinical Cancer Research 3893 Fig. 5 Relationship between percentage reduction in ANC from baseline and plasma CI-958 AUC(0-⬁). The curve shown is the fit of the data to a simple Emax model: % reduction in ANC ⫽ [122 ⫻ AUC(0-⬁)]/22439 ⫹ AUC(0-⬁), r2 ⫽ 0.88. Fig. 6 Relationship between percentage reduction in ANC from baseline and CI- 958 dose. The curve shown represents the data fit to a simple Emax model: percent- age reduction in ANC ⫽ [158 ⫻ dose]/722 ⫹ dose, r2 ⫽ 0.89. dose escalation method. Its utility in many situations was con- preclinical and clinical testing, or limitations of the assay in firmed by retrospective analysis of results from a number of accurately measuring concentrations at both the LD10 and one- Phase I trials (6). However, there are a number of situations in tenth LD10 doses (6, 12). which this dose escalation technique cannot be used effectively. These caveats to the use of PGDE have been borne out by For example, PGDE cannot be used effectively if there are prior use of this technique in clinical trials. For example, a interspecies differences in target cell sensitivity or schedule number of retrospective reviews of the experience with antime- dependence or differences in metabolism or plasma protein tabolites have shown that many of these compounds are not binding that may not be accurately reflected by measuring total amenable to PGDE trial design because of profound interspecies plasma levels of parent drug. Additionally, there are a number of differences in target cell enzyme properties (6, 13). By contrast, technical factors that may limit the applicability of this tech- the anthracyclines appear to be a class of drugs for which the nique, such as differences in the mode of drug delivery between AUC is generally a much better predictor of toxicity than dose, Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
3894 Phase I and Pharmacologic Study of CI-958 and thus this class should be amenable to successful use of REFERENCES PGDE. However, the prospective use of PGDE in a Phase I trial 1. Doroshow, J. H. Anthracyclines. In: B. A. Chabner and D. L. Longo of the new anthracycline 4⬘-iodo-4⬘-deoxydoxorubicin was lim- (eds.) Cancer Chemotherapy and Biotherapy, pp. 409 – 434. Philadel- ited by unexpected interspecies differences in the metabolism of phia: Lippincott-Raven, 1996. 4⬘-iodo-4⬘-deoxydoxorubicin. Near the end of the trial, when the 2. Steinkampf, R. N., Sebolt-Leopold, J., and Klohs, W. D. Character- target for escalation was redefined as the sum of the concentra- ization of drug resistance to the benzothiopyranoindazole, CI-958. Proc. Am. Assoc. Cancer Res., 35: A2019, 1994. tion of both the parent drug and the active metabolite, PGDE 3. Fry, D. W., and Besserer, J. A. Biochemical pharmacology and could be used. However, the number of dose escalation steps DNA-drug interactions by CI-958, a new antitumor intercalator derived was only one fewer than the modified Fibonacci plan because from a series of substituted 2[H]-1-benzothiopyrano[4,3,2-cd]indazoles. PGDE could only be used late in the trial (14). Mol. Pharmacol., 33: 84 –92, 1988. Several prior Phase I trials of anthrapyrazoles have attempted 4. Simon, R., Freidlin, B., Rubenstein, L., Arbuck, S. G., Collins, J., PGDE with varying results. For example, wide interpatient varia- and Christian, M. C. Accelerated titration designs for Phase I clinical bility in AUC made application of PGDE impossible in a Phase I trials in oncology. J. Natl. Cancer Inst., 89: 1138 –1147, 1997. trial of the anthrapyrazole CI-941 (15). In a Phase I trial of the 5. O’Quigley, J., Pepe, M., and Fisher, L. Continual reassessment anthrapyrazole, piroxantrone, administered as a 1-h infusion every method: a practical design for Phase I clinical trials in cancer. Biomet- rics, 46: 33– 48, 1990. 3 weeks to patients with advanced cancer at our institution (16), the 6. Collins, J. M., Zaharko, D. S., Dedrick, R. L., and Chabner, B. A. usefulness of PGDE was limited by a relatively insensitive assay, Potential roles for preclinical pharmacology in Phase I clinical trials. rapid plasma clearance not anticipated by the sampling scheme, and Cancer Treat. Rep., 70: 73– 80, 1986. close proximity of the AUC at the starting dose to the target AUC, 7. Zubrod, C. G., Schneiderman, M., Frei, E., Brindley, C., Gold, G. L., where Fibonacci escalation should begin. Because of these limita- et al. Appraisal of methods for the study of chemotherapy of cancer in tions, there was no reduction in number of dose escalation steps man: comparative therapeutic trial of nitrogen mustard and triethylene from that required with a Fibonacci approach. In a similar Phase I thiophosphoramide. J. Chron. Dis., 11: 7–33, 1960. trial of piroxantrone conducted at a different institution, utilization 8. Rocci, M. L., Jr., and Jusko, W. J. LAGRAN program for area and of PGDE was also hampered by assay insensitivity and interspecies moments in pharmacokinetic analysis. Comp. Prog. Biomed., 16: 203– 216, 1983. differences in clearance such that the first dose escalation steps had 9. Holford, N. H. G., and Sheiner, L. B. Understanding the dose-effect to be made empirically. Despite these problems, this study required relationship: clinical application of pharmacokinetic-pharmacodynamic 6 –9 fewer patients than would have been needed to reach the MTD models. Clin. Pharmacokinet., 6: 429 – 453, 1981. using the Fibonacci approach (17). 10. Woolley, P. V., Freiha, F. S., Smith, D. C., Carlson, L., Hofacker, Interspecies differences in pharmacokinetics may also have J., Quinn, N., Grove, W., and Trump, D. L. A Phase II trial of CI-958 influenced the accuracy of PGDE in the present study. The AUC at in patients with hormone-refractory prostate cancer. Cancer Chemother. the human MTD was 6.6 times higher than the AUC at the murine Pharmacol., 44: 511–517, 1999. LD10, not identical as hypothesized. Thus, even when compared by 11. Shields, A. F., Philip, P. A., LoRusso, P. M., Ferris, A. M., and Zalupski, M. M. Phase II study of CI-958 in colorectal cancer. Cancer AUC instead of dose, the mouse overpredicted human toxicity. The Chemother. Pharmacol, 43: 162–164, 1999. cause of this disparity is unclear but may be explained in part by 12. EORTC Pharmacokinetics and Metabolism Group. Pharmacokinet- interspecies differences in plasma protein binding or pharmacoki- ically guided dose escalation in Phase I clinical trials. Commentary and netics such as higher clearance rates and larger volume of distri- proposed guidelines. Eur. J. Cancer Clin Oncol, 23: 1083–1087, 1987. bution in humans compared with mice (18). Nonetheless, this study 13. Reichelova, V., Juliusson, G., Spasokoukotskaja, T., Eriksson, S., represents the most successful use of PGDE to date. and Liliemark, J. Interspecies differences in the kinetic properties of The PGDE design used in the present study proved to be an deoxycytidine kinase elucidate the poor utility of a Phase I pharmaco- effective and efficient method for reaching the MTD of CI-958. logically directed dose-escalation concept for 2-chloro-2-deoxyade- nosine. Cancer Chemother. Pharmacol., 36: 524 –529, 1995. The MTD obtained in patients (875 mg/m2) was 168-fold 14. Gianni, L., Vigano, L., Surbone, A., Ballinari, D., Casali, P., greater than the starting dose (5.2 mg/m2), which had been Tarella, C., Collins, J. M., and Bonadonna, G. Pharmacology and calculated based on preclinical toxicology data. Only 11 dose clinical toxicity of 4⬘-iodo-4⬘-deoxydoxorubicin: an example of success- levels were needed to reach the MTD by using the PGDE ful application of pharmacokinetics to dose escalation in Phase I trials. design. Using the modified Fibonacci method, dose level 11 J. Natl. Cancer Inst., 82: 469 – 477, 1990. would be only 38 times greater than the starting dose, and an 15. Graham, M. A., Newell, D. R., Foster, B. J., Gumbrell, L. A., Jenns, additional 5– 6 dose levels (15–18 patients) would have been K. E., and Calvert, A. H. Clinical pharmacokinetics of the anthrapyrazole CI-941: factors compromising the implementation of a pharmacokinetically required to reach the MTD of 875 mg/m2. Therefore, using the guided dose escalation scheme. Cancer Res., 52: 603– 609, 1992. PGDE approach substantially decreased the total number of 16. Hantel, A., Donehower, R. C., Rowinsky, E. K., Vance, E., Clarke, patients studied and the length of time required for this study. Of B. V., McGuire, W. P., Ettinger, D. S., Noe, D. A., and Grochow, L. B. note, the 3-fold escalation for the first step in this study is, to our Phase I study and pharmacodynamics of piraxantrone (NSC 349174), a knowledge, the largest increment reported in any Phase I cancer new anthrapyrazole. Cancer Res., 50: 3284 –3288, 1990. chemotherapy trial, regardless of design. Importantly, because 17. Ames, M. M., Loprinzi, C. L., Collins, J. C., van Haelst-Pisani, C., of the rapid early escalation, the savings in patient resources Richardson, R. L., Ribin, J., and Moertel, C. G. Phase I and clinical occurred at early dose levels that were the least likely to be pharmacological evaluation of pirazatrone hydrochloride (oxantrazole). Cancer Res., 50: 3905–3909, 1990. effective. This may represent the most successful use of PGDE 18. Whitfield, L. R., Grove, W., Kowal, C., Rowinsky, E. K., Grochow, to date. However, the future application of this method remains L. B., and Donehower, R. C. Pharmacologically guided dose escalation in doubt as a result of the overall experience to date and the of CI-958 in phase I clinical testing. Proc. Am. Assoc. Cancer Res., 33: emergence of other accelerated titration designs. 3162a, 1992. Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
A Phase I and Pharmacologic Evaluation of the DNA Intercalator CI-958 in Patients with Advanced Solid Tumors E. Claire Dees, Lloyd R. Whitfield, William R. Grove, et al. Clin Cancer Res 2000;6:3885-3894. Updated version Access the most recent version of this article at: http://clincancerres.aacrjournals.org/content/6/10/3885 Cited articles This article cites 15 articles, 4 of which you can access for free at: http://clincancerres.aacrjournals.org/content/6/10/3885.full#ref-list-1 E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at firstname.lastname@example.org. Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/6/10/3885. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site. Downloaded from clincancerres.aacrjournals.org on March 15, 2021. © 2000 American Association for Cancer Research.
You can also read