A Phase I and Pharmacologic Evaluation of the DNA Intercalator CI-958 in Patients with Advanced Solid Tumors1 - Clinical Cancer Research

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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
[1]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-[1]benzothio-
  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
rdonehow@jhmi.edu.                                                      liquid chromatography; ANC, absolute neutrophil count.

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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

       J. Bender and G. Courtland, CI-958 Investigator’s Brochure (May
     1990, revised 1994), unpublished.                                         M. J. Graziano, unpublished data.

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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
                                    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

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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
       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

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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
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
        ANC available only for 12 courses.
        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

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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
        300            5            1            1                                      5             1
                                    2                          1
        425            7            1            3             2                        2                                                    1
                                    2                                      2            3                         1
        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
        875            6            1            2             2           2            5                         1                          2
                                    2            1                                                                                           1
                                    4            1
             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

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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
    (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)
       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

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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
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,

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3894 Phase I and Pharmacologic Study of CI-958

     and thus this class should be amenable to successful use of               REFERENCES
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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.

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