Cancer Chemother Pharmacol (1994) 33: 313 e 316
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`Cancer
`Chemotherapy and
`P harmacology
`© Springer‘Verlag 1994
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`Phase I trial of droloxifene in patients with metastatic breast cancer
`
`Aman U. Buzdarl, Shu Kaul, Gabriel N. Hortobagyil, Richard L. Theriaultl, Daniel Booserl,
`Frankie A. Holmesl, Ronald Waltersl, Irwin H. Krakoffl
`
`1 Department of Medical Oncology/Medical Breast Service, University of Texas MD. Anderson Cancer Center, Houston, TX 77030, USA
`2 Division of Medicine, University of Texas MD. Anderson Cancer Center, Houston, TX 77030, USA
`
`Received: 20 March l993/Accepted: 4 August 1993
`
`Abstract. Droloxifene (3-hydr0xytam0xifen) is a new,
`nonsteroidal antiestrogen. In comparison with tamoxifen, it
`has a 10— to 64—fold higher affinity for the estrogen receptor
`and has shown a lower estrogenic and higher antiestrogenic
`effect in experimental studies. The objective of this study
`was to determine the toxicity (and its reversibility) of
`droloxifene given at different doses to patients with ad-
`vanced metastatic breast cancer refractory to conventional
`endocrine therapy and chemotherapy. In this study, 30
`patients were treated in groups of 6 at 5 different doses
`(20, 40, 100, 200, and 300 mg) by mouth once a day. Toxic
`effects included hot flashes, nausea, and fatigue and were
`not dose-related. Toxicity did not require any dose reduc—
`tion or discontinuation of therapy. There was one episode
`of deep venous thrombosis and pulmonary embolism.
`There was no complete or partial response in this study, but
`four patients showed a minor response (13%). These data
`illustrate that this drug is well tolerated and needs to be
`further evaluated in phase II and III studies.
`
`Introduction
`
`Approximately 25%~60% of breast cancer patients have
`tumors that are estrogen (ER)- and progesterone receptor
`(PR)—positive. The response to endocrine therapy corre—
`lates with the quantity of receptors. The antiestrogen
`tamoxifen has antitumor activity in 50%—55% of patients
`with metastatic breast cancer and an ER-positive tumor but
`in less than 10% of those with ER—negative tumors [1—3].
`Tamoxifen accumulates in the organs, and after progres-
`
`This study was supported by a research grant from Fujisawa Phar—
`maceutical (USA)
`
`Correspondence to: Aman U. Buzdar, M.D., Department of Medical
`OncologY, BOX 56, MD. Anderson Cancer Center, 1515 Holcombe,
`Houston, TX 77030, USA
`
`sion of the disease, a washout period is needed prior to a
`change to other therapies [4].
`During the initial tamoxifen therapy, tumor flare occurs
`in 4%~13% of patients [5—8]. Although the mechanism of
`this tumor flare has not been elucidated, it is presumed that
`the estrogenicity of tamoxifen may play a significant role.
`Side effects such as thromboembolic complications, en-
`dometrial hyperplasia,
`endometn'al polyps,
`and en-
`dometrial carcinoma may possibly be explained by the
`estrogenicity of the drug [7—9]. In isolated cases, tamoxifen
`causes peliosis, hepatitis, icterus, and increases in liver
`enzyme levels [7, 8, 10, 11]. In a few cases, cataracts,
`corneal changes, or retinopathy have been reported, espe—
`cially in patients receiving higher doses over longer peri-
`ods [12-19]. In premenopausal patients, menstrual dis-
`orders and ovarian cysts have been observed [20].
`Although the overall frequency of these side effects is
`low, the search for an antiestrogen with a better thera-
`peutic index and better pharmacological characteristics is
`ongoing.
`is a new, non-
`Droloxifene, or 3—hydroxytamoxifen,
`steroidal antiestrogen. Preclinical in vitro and in vivo stud—
`ies have shown that this drug has the following advantages
`as compared with tamoxifen: a 10— to 64-fold higher affin—
`ity for the ER; lower estrogenic and higher antiestrogenic
`effects in rat uterus (better therapeutic index); greater inhi-
`bition 0f the growth of previously tested human ER-posi—
`tive breast cancer cells; more effective reduction of the
`S—phaSe fraction; and more effective stimulation of the
`estrogen—independent, growth factor—stimulated prolifera—
`tion of MCF-7 cells [21—24]. In addition, the drug blocks
`estrogen—activated c-myc expression more effectively than
`tamoxifen and induces a higher production of tumor
`growth factor B (TGF-B) in MCF—7 cells as well as lower
`growth of various experimental and transplanted tumors in
`animals more effectively (R3230, DMBA,T61) [23—25]. In
`contrast to tamoxifen, droloxifene itself is an active sub—
`stance; therefore, metabolic activation is of no importance.
`In comparative animal toxicity trials, droloxifene had been
`qualitatively and quantitatively better
`tolerated than
`tamoxifen [26, 27]. In contrast to tamoxifen, in experimen—
`
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`314
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`Table 2. Toxicity
`
`Toxic reactionsa
`
`Grade
`
`
`
`Table 1. Phase I study of droloxifene: patient’s characteristics
`
`Characteristics
`
`Number
`
`30
`
`1
`2
`3
`4
`
`
`tal systems, droloxifene does not induce hepatic carcinoma
`and has no carcinogenic effect.
`Droloxifene has been evaluated in a limited number of
`
`patients in phase l—ll studies in Eur0pe and Canada, and
`the response rates have been encouraging [28—32]. We
`designed this study to determine the drug’s toxicity (and its
`reversibility) at different doses in patients with advanced
`metastatic breast cancer.
`
`Patients and methods
`
`This phase I study included patients with metastatic breast cancer who
`had failed conventional endocrine therapies and chemotherapy options
`and met the following eligibility criteria: ew'dence of a response to one
`prior endocrine therapy or of an ER—positive tumor, an International
`Union Against Cancer (IUCC) performance status of $2, and a life
`expectancy of >3 months. Patients were required to have been off all
`previous chemotherapy or radiotherapy for 3 weeks prior to entering on
`this study and to have recovered from the toxic effects of the therapy.
`Adequate bone marrow function was defined as a peripheral absolute
`granulocyte count of >1,500/mm3 and a platelet count >100,000/mm3;
`adequate liver function, as a bilirubin value of S 1.5 mg/100 ml; and
`adequate renal function, as a creatinine level of 51.5 mg/100 ml.
`Patients with ER—negative tumors could be enrolled if they had pre-
`viously responded to endocrine therapy. Patients with brain metastases
`who were symptomatic after receiving irradiation to the brain, those with
`previous malignancies except for in situ carcinoma of the cervix or
`basal—cell carcinoma of the skin, and those with a history of retinopathy
`or recurrent thromboembolic episodes were excluded.
`In this study, six patients were evaluated at each dose level for acute
`and chronic toxicity. The drug was given orally once a day. After six
`patients had been entered at the first dose level and three patients had
`been observed for a minimum of 4 weeks and had no toxicity of greater
`than grade 2, additional patients were entered at the next dose level.
`We treated six patients on each planned dose level: 20, 40, 100, 200, and
`
`Results
`
`A total of 30 patients were entered, and 6 patients were
`studied at each dose level. As shown in Table l, the median
`age of the patients was 59 years (range, 31—75 years). The
`median performance status was 1 (range, 0—2), the median
`number of prior endocrine treatments was 3 (range, 1—5),
`and the median number of prior chemotherapy regimens
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`Total patients
`Age:
`Median
`< 50 years
`Z 50 years
`Dominant site of disease:
`Soft tissue
`Viscera
`Bone
`.
`M d
`e 1an performance status
`Estrogen receptor status:
`Positive
`Unknown
`Negative
`Prior Chemotherapy:
`None
`l
`2
`Z 3
`
`Prior endocrine therapy:
`l
`2
`Z3
`
`59 (range, 31 —75) years
`9
`21
`
`4 (13%)
`12 (40%)
`14 (47%)
`
`_
`1 (range, 0 2)
`
`23 (77%)
`3 (10%)
`4 (13%)
`
`6 (20%)
`10 (33%)
`5 (17%)
`9 (30%)
`
`12
`l
`4
`2
`5
`5
`3
`4
`0
`2
`1
`
`1
`
`6
`0
`1
`0
`0
`0
`0
`0
`1
`1
`0
`
`0
`
`1
`0
`O
`O
`0
`0
`0
`O
`2
`O
`O
`
`0
`
`EgtfaShes
`1g tsweats
`Nausea.
`Anorexra
`Headache
`Fatigue
`Dizziness
`Leg cramps
`Bone pain
`Constipation
`Diarrhea
`Transient
`skin rash
`Deep vein thrombosis and
`
`pulmonary embolus
`0
`0
`0
`1
`a Not d s - e1 t d
`0 e r a e
`
`0
`0
`0
`0
`0
`O
`0
`0
`0
`0
`0
`
`0
`
`-
`-
`.
`300 mg. All pat1ents were registered With our central data-management
`office. Each patient was informed regarding the investigational nature of
`this study, and a written informed consth was obtained prior to initiation
`(7%)
`2
`0f the therapy, in keeping with the institutional policy. Dose adjustment
`9 (30%)
`
`19 (63%) for individual patients was planned as follows: if the absolute granulo-
`cyte count was <500/mm3, the platelet count was <50,000/mm3, or
`>grade 2 nonhematological toxicity was observed, the dose was to be
`reduced by one level.
`Prior to entry on the study, each patient underwent a complete history
`and physical examination; documentation of all measurable disease,
`signs and symptoms of the disease, and performance status; a complete
`blood count (CBC) as well as a platelet and differential count; urinalysis;
`a systematic multiple analysis (SMA); a coagulation profile; and
`estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH),
`prolactin, and hormone-binding globin (SHBG) determinations. Patients
`were evaluated weekly with SMA, urinalysis, CBC, and platelet and
`differential counts for the initial 4 weeks. If the results were normal,
`these tests were repeated first at 2—week intervals and then at 4-week
`intervals. Coagulation profiles and hormonal measurements of estradiol,
`LH. FSH, prolactin, and SHBG were obtained at 2—week intervals for 6
`weeks and then at 8-week intervals. Changes in hormone levels and in the
`level of SHBG were evaluated using repeated measures and analysis of
`variance. A small number of cases were omitted from the analysis due to
`missing measurements, and changes in the estradiol level were not eval—
`uated because the measurement technique could not detect low levels.
`Because many patients were removed from study after 6 weeks of ther—
`apy due to progressive disease, few measurements were available beyond
`6 weeks; analyses were therefore limited to changes observed within the
`first 6 weeks of therapy. For purposes of presentation, the difference
`between week-0 and week-6 measurements for each of the hormones and
`SHBG at each dose were also considered. Tumor measurements were
`documented every 2 weeks for the first 6 weeks and then every 4 weeks.
`Appropriate radiology and radioisotope studies Were repeated after 4
`weeks and at 8 weeks of therapy or earlier to document response or
`progression of the disease.
`
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`

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`Table 3. Summary of hormonal measurement changes from 0 to 6 weeks with droloxifene therapy
`LH
`Prolactin
`SHBG
`
`
`
` Dose (mg) Estradiol
`
`FSH
`
`—12.3
`—3.0
`12.0
`20
`—8.0a
`—47.0
`17.0
`3.5
`29.0
`40
`—77.6
`—1.3
`—15.3
`6.6
`46.4
`100
`100.8
`—0.1
`3.9
`~20
`43.5
`200
`—5.8
`3.1
`—7.7
`0.1
`36.0
`300
`—5.6
`0
` 1.1—3.5 35.4
`—10.9
`0.8
`Totals
`
`
`
`
`
`315
`
`3 Entries represent the mean of the week-6 value minus the week-0 value
`
`was 2 (range, 1—5). The median duration of prior endocrine
`therapies was 29 months (range, 3—97 months), and the
`median duration of prior chemotherapy was 14 months
`(range, 2—30 months). The median duration of droloxifene
`therapy was 3 months (range, 1—16 months). All patients
`were off therapy at the time of this report.
`Toxic reactions included hot flashes, nausea, and fa~
`tigue. The grade of toxicity, shown in Table 2, was not
`dose-related. Toxicity was in no case severe enough to
`require dose reduction or discontinuation of therapy. There
`was one episode of deep venous thrombosis and pulmo-
`nary embolism, but no hematological, hepatic, or renal
`toxicity occurred. The data regarding estradiol, LH, FSH,
`prolactin, and SHBG are summarized in Table 3. With the
`exception of SHBG, there was no clear pattern of change
`over time at any of the dose levels examined. Testing for a
`time effect over the first 6 weeks (using measurements
`taken at 0, 2, 4, and 6 weeks) for SHBG indicated a statis-
`tically significant increase (P<0.01). No change in any of
`the other factors approached statistical significance.
`There was no complete or partial response in this study,
`but four patients showed a minor response (13%). For the
`patients who showed a minor response, the median time to
`progression from the initiation of therapy was 9 months
`(range, 8—12 months). In all, 16 patients showed no change
`in discase status for 22 months, and the median time to
`progression from the start of therapy was 4 months (range,
`2—16 months). Ten patients developed progressive disease
`within 1-3 months on the study.
`
`Discussion
`
`The objective of this study was to determine the safety of
`droloxifene at five different dose levels. Considering that
`this patient population was heavily treated, the treatment
`was well tolerated. Increasing the dose produced no evi-
`dence of increased toxicity. The major toxic reactions were
`hot flashes and nausea; these were mostly of grade 1 and
`did not result in discontinuation of the treatment in any
`patient. One patient experienced deep vein thrombosis.
`No complete or partial response was observed, but a
`few patients showed a minor response and a large number
`of patients had stabilization of their disease. In a phase I—II
`European trial, the drug showed significant antitumor ac—
`tivity when given at 20, 40, and 100 mg on a once—a—day
`schedule [30]. In this study there was suggestive evidence
`that a higher response rate occurred at 40 and 100 mg/day
`than at 20 mg/day, but this suggestion was inconsistent
`
`with the experience with tamoxifen, which had no dose-de—
`pendent antitumor activity.
`From European trial data, there is enough evidence of
`the significant antitumor activity of droloxifene. To see
`some antitumor activity in our heavily treated patient popu-
`lation was also encouraging and may suggest at least a
`partial lack of cross-resistance with other endocrine treat-
`ments. Phase II studies are needed to determine the role of
`
`droloxifene as a second-line therapy in patients treated
`with tamoxifen, and comparative trials are needed to deter-
`mine its antitumor and toxicity profile relative to that of
`other antiestrogens.
`
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