Am JClin Oncol (CCT) 14(Suppl. 2): S36—S39, 1991.
`
`© 1991 Raven Press, Ltd., New York
`
`European Early Phase II Dose-Finding Study
`of Droloxifene in Advanced Breast Cancer
`
`J. Bellmunt, M.D., and L. Solé, M.D.
`
`Preliminary results from clinical phase II studies with dro-
`loxifene demonstrated eflicacy and good tolerability. One
`hundred ninety-six female, postmenopausal patients with
`advanced breast cancer were treated with 20, 40, or 100 mg
`ofdroloxifene daily. Exclusion criteria were as follows: nega-
`tive ER/PR status, tamoxifen treatment within the preced-
`ing three months, chemotherapy within the preceding three
`weeks, and performance grade of four. Seventeen percent of
`the patients treated with 20 mg daily responded to treat-
`ment, exhibiting complete or partial responses according to
`World Health Organization criteria. In the 40-mg group,
`30% responded and in the 100-mg group, 31% responded.
`Adverse symptoms generally were mild.
`Key Words: Droloxifene—Advanced breast cancer—Dose
`finding.
`
`From the Department of Medical Oncology, Hospital Vall d’He-
`bron, Barcelona, Spain.
`Address correspondence and reprint requests to Dr. J. Bellmunt
`at Department of Medical Oncology, Hospital Vall d’Hebron, P.
`Valle de Hebron s/n, E-08021 Barcelona, Spain.
`Note: The following investigators participated in the phase II de-
`velopment studies: Austria: R. Kolb and G. Reiner (Vienna); Bel-
`gium: M. Beauduin (Haine St. Paul), E. Salamon (Namur); Ger-
`many: L.M. Ahlemann (Lfidenscheid), J. Ammon (Aachen), R.
`Balas (Seigen), G. Bastert (Heidelberg), G.P. Breitbach (Homburg),
`H.G. Beger (Ulm), M. Brandtner (Wetzlar), K. Brunnert (Osna—
`briick), L. Heilmann (Rfisselsheim), F. Janieke (Mfinchen), R.
`Kreienberg (Mainz), G. Kieninger (Stuttgart), A.C. Mayr, U. Riihl
`and S. Tanneberger (Berlin), K.H. Renner (Hannover), D. Ross-
`mann (Bad Kreuznach), R. Souchon (Hagen); Norway: 0. Mella
`(Bergen), C. Gundersen and N. Raabe (Oslo), S. Kvinnsland
`(Trondheim), E. Wist (Tromso); Spain: L.A. Solé/J. Bellmunt/S.
`Morales (Barcelona).
`
`S36
`
`The data presented in this paper were obtained
`from a variety of European clinical dose-finding stud-
`ies designed as part of the phase 11 development of
`droloxifene. The studies were performed in collabora-
`tion, between investigators in several European coun—
`tries (see Note).
`
`PATIENT SELECTION AND METHODS
`
`Two types of studies are included in this article.
`The majority of the data comes from open dose-
`finding studies in which either one, two, or all three
`of the three possible dosage levels were investigated
`in each center. The rest of the data come from
`
`_
`
`droloxifene-treated patients from open, comparative
`studies with droloxifene versus other systemic treat-
`ment. In all of these studies, treatments were assigned
`in an alternating fashion, rather than by random allo-
`cation.
`
`All studies included postmenopausal women with
`advanced breast cancer and positive or unknown hor-
`mone receptor levels. Patients with negative hormone
`receptors, who had received tamoxifen therapy dur-
`ing the last three months, chemotherapy during the
`last three weeks, or who had poor performance status,
`grade four (1), were excluded. Patients were treated
`with 20, 40, or 100 mg of droloxifene once daily until
`disease progression. Treatment could also be stopped
`for medical or personal reasons. No other systemic
`tumor active treatment was allowed. Radiotherapy
`could be applied, provided not all target lesions were
`irradiated.
`
`Tumor measurements were obtained by means of
`ultrasound examinations, radiographs, radionuclide
`scans, or computer tomography—radionuclide scans
`could not be used for measurements alone but had to
`
`be interpreted together with appropriate radiographs.
`Target lesions had to be staged by the same technical
`method at each visit. Response was assessed accord-
`ing to World Health Organization (WHO)/Union In—
`ternationale Contre le Cancer (UICC) criteria ( l ). The
`
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`

`

`EUROPEAN DOSE FINDING STUDY
`
`S37
`
`data obtained were thoroughly validated against hos-
`pital records; for example, all tumor measurements
`were checked against original sources. Data not yet
`verified in this way have been omitted from this colla-
`tion. A total of 196 patients were treated as part of the
`trials described above. For a patient to be regarded as
`evaluable for efficacy, it was required that the inclu-
`sion criteria be fulfilled, that the protocol be properly
`adhered to, and that full tumor assessments be ob-
`tained. Data from 18 of the patients were, therefore,
`excluded because of protocol violations or insuffi-
`cient data. Of the remaining 178 patients, 44 received
`20 mg of droloxifene daily, 53 received 40 mg daily,
`and 81 received 100 mg. The entire group of 178 pa-
`tients is included in describing tolerability. In report-
`ing toxicity, all reported symptoms as collected in
`checklist questionnaires were included regardless of
`causality. Fifty-four of the 178 patients could not be
`evaluated for efficacy because of inadequate tumor
`assessment. Therefore, 124 patients were evaluable
`for efficacy. Thirty patients received 20 mg daily, 33
`patients received 40 mg daily, and 61 patients re-
`ceived 100 mg daily.
`
`RESULTS
`
`The median age for the 178 patients was 64 years,
`ranging from 34 to 87 years. In the 20 mg group the
`median age was 68 years, in the 40 mg group, 61
`years, and in the 100 mg group, 64 years. There is no
`difference among the three groups according to this
`parameter. Only 32% of the patients had positive hor-
`mone receptors in the primary tumor, and 9% in the
`secondary tumor. Three percent had negative recep-
`tors in the primary tumor and <1% negative in the
`secondary tumor. No patients had negative receptors
`in both primary and secondary tumors. It appears
`that the receptor state for the majority of the patients,
`65%, was unknown for the primary tumor. For the
`secondary tumor, this proportion was ~91%. The
`three dosage groups were similar with regard to recep-
`tor status. Eighty-one percent of patients had a dis-
`ease-free interval
`longer than 2 years. The mean
`ranged from 46.4 months in the lOO—mg treatment
`group to 51.3 months in the 20—mg group.
`Bone, soft tissue, and lung metastases were the
`most frequently occurring metastatic sites. Fifty-eight
`percent of all the patients had bone metastases, 34%
`had soft tissue metastases, and 31% had lung metas-
`tases. At least one-half of the patients presented with
`metastases at more than one location. Nineteen per-
`cent of patients had metastatic pleural effusions. Me-
`tastases in liver and peripheral lymph nodes were each
`present in 10%. Locations that were less frequently
`involved were the mediastinal lymph nodes in 6% of
`
`the patients, the central nervous system in 5% of the
`patients, and malignant ascites, which were reported
`in 1% of patients. In summary, the patients studied
`had extensive metastatic involvement with metas-
`tases that often respond poorly to hormonal therapy.
`Only 32% of the patients had not received any
`previous therapy, 28% had received one previous
`course of treatment, 19% had received two previous
`treatments, 14% had received three, and 7% had re-
`ceived four to six. Thus, many of these patients were
`intensively treated prior to study entry. The patients
`may be unevenly distributed with regard to previous
`therapy in the different dosage groups. It is, however,
`not possible to show whether or not this may influ-
`ence treatment results. With regard to type of
`previous therapy, 30% received both previous endo-
`crine- and chemotherapy, 19% received previous en-
`docrine treatment only, and 20% of the patients re—
`ceived only previous chemotherapy.
`The mean duration of droloxifene treatment was
`8.3 months in the 20-mg group, 8.9 months in the
`40-mg group, and 11.6 months in the 100-mg group.
`These figures represent all the 178 evaluable patients.
`The 44 patients still receiving treatment are included.
`All patients are included, even those who were not
`evaluable for efficacy. This means that early dropouts
`as well as patients with early progression are included,
`and this, of course, will shorten the mean duration of
`treatment. The duration of treatment ranged from <2
`weeks to 39.4 months in the 20-mg group, 41.9
`months in the 40—mg group, and 31.5 months in the
`lOO-mg group.
`In reporting efficacy, only those patients in whom
`proper tumor assessments were carried out are in-
`
`cluded. This group comprises 124 patients. The num—
`ber of responding patients—complete and partial—
`were 5 in the 20—mg group (17%), 10 in the 40-mg
`group (30%) and 19 in the 100—mg group (31%). One
`of 33 (3%) in the 40-mg group and 6 of61 (10%) in the
`lOO-mg group obtained complete responses. Re-
`sponses by site showed 14 of 69 (20%) in bone, and 6
`of 22 (27%) in patients with pleural effusion. In four,
`the effusion completely disappeared and two further
`patients had a marked decrease. In one patient with
`ascites, the ascites completely disappeared.
`Adverse symptoms are shown in Table 1. As one
`patient may have reported a symptom several times
`during the trial and in different grades of severity,
`only the most severe report is shown. This means that
`if a patient, for example, reported mild nausea several
`times during the treatment and moderate nausea
`once, the patient contributes to this diagram with
`moderate nausea only. No dose relations are promi-
`nent, though vomiting may be less frequent in the
`
`Am JCIin Onco/ (CCU, Vol. 14, Suppl. 2, 1991
`
`AstraZeneca Exhibit 2061 p. 2
`
`

`

`538
`
`BELLMUNT AND SOLE
`
`TABLE 1. Adverse symptoms with droloxifene
`____________________.—_——————————-—
`
`1
`
`2
`(20 mg group, n = 44)
`
`3
`
`Severity level“
`
`1
`
`2
`(40 mg group, n = 53)
`
`3
`
`1
`
`2
`(100 mg group, n = 81)
`
`3
`
`Symptom
`
`Gastrointestinal
`Nausea
`Gastrointestinal pain
`Headache
`Dizziness
`Lassitude
`Flush
`Vomiting
`Vaginal bleeding
`Pulmonary toxicity
`Neurotoxicity
`Depression
`Skin allergy
`Renal toxicity
`Hepatotoxicity
`Hypercalcemia
`Hot flushes
`Euphoria
`Thromb./Phlebit.
`Edema
`Lymphedema
`Weight gain
`Eye disorders
`Joint pain
`Anorexia
`Other
`
`3
`5
`1
`4
`7
`5
`5
`2
`3
`—
`—
`2
`~—
`1
`—
`1
`2
`—
`——
`1
`—
`3
`1
`2
`5
`5
`
`Ilel||l|||l|||l||l-*l|-‘l|-‘-*
`
`4
`5
`6
`4
`5
`6
`2
`4
`—
`_
`__
`1
`1
`._
`——
`1
`—
`1
`—
`4
`1
`6
`——
`1
`2
`3
`
`4
`4
`—
`1
`2
`5
`1
`3
`1
`1
`_.
`1
`—
`1
`—
`1
`3
`_
`—
`4
`3
`1
`—
`3
`7
`5
`
`2
`2
`—
`1
`—
`——
`1
`1
`—
`—
`_
`1
`—
`._
`1
`1
`—
`_
`——
`1
`—
`—
`—-
`——
`2
`3
`
`8
`9
`5
`3
`4
`9
`6
`8
`1
`3
`5
`6
`2
`_
`2
`1
`11
`_.
`1
`3
`1
`1 0
`2
`2
`4
`1 0
`
`4
`7
`1
`3
`3
`1
`3
`4
`1
`—
`3
`5
`1
`1
`—
`—
`7
`_
`1
`2
`——
`1
`—
`1
`—
`1 2
`
`'
`
`2
`1
`1
`—
`1
`1
`—
`2
`1
`1
`__
`—
`—
`__
`1
`1
`—
`-
`2
`—
`—
`—
`1
`1
`2
`2
`
`
`
`
`
`#m-n|—tmm||o>||—L||_.||—am4>m—Lromh
`
`
`
`
`
`‘ Severity 1 = mild, 2 = moderate, 3 = severe.
`
`20-mg group than in the two other groups and possi-
`bly hot flushes with more than 20% in the 100-mg
`group. Severe symptoms occurred in <5% of the pa-
`tients in each treatment group. The most common
`adverse symptoms in all groups were nausea 22%, gas-
`trointestinal discomfort 18%, lassitude 17%, hot
`flushes 15%, vomiting 15%, dizziness 14%, and an-
`orexia 13%. The largest proportion of these reports
`were of mild symptoms. Other symptoms reported in
`smaller proportions of the patients included depres-
`sion, weight gain,
`lymphoedema, hypercalcemia,
`joint pain, and skin rash.
`During these trials, 18 serious adverse events were
`noted, in most cases by source evaluation. In nine of
`the cases, droloxifene was eliminated as a possible
`cause. The remainder included three instances of hy-
`percalcemia, two of which were successfully treated
`and one that was associated with a fatal outcome.
`However, it could not be established if this patient
`could possibly have died from a suspected brain me-
`tastasis. In two patients, leucocytopenia was reported.
`Thrombophlebitis followed by pulmonary embolism
`wasseen in one patient. Severe dizziness, psychologi-
`cally provoked disturbances of the autonomic ner-
`vous system, and deep venous thrombosis have been
`reported, each for one patient.
`
`Am JClin Oncol (CCT), Vol. 14, Suppl, 2, 1991
`
`DISCUSSION
`
`In these studies, response rates of 17% in patients
`receiving 20 mg daily, 30% in those receiving 40 mg,
`and 31% in those receiving 100 mg daily were ob-
`tained. We regard the results as most satisfactory for a
`collection of patients in such relatively poor condi-
`tion. In general, we had the impression that the re-
`sponse to droloxifene was quite rapid and perhaps oc-
`curred sooner than we might normally expect from
`hormonal therapy. A further 36—40% disease stabili-
`zations were obtained. This means that only 31—33%
`of patients in the two best groups, 40 and 100 mg, and
`43% in the 20-mg group, had progressive disease while
`receiving droloxifene.
`Not many studies exist with a patient population so
`extensively pretreated as ours, as 68% of our patients
`had been pretreated and of those, 40% had had more
`than one pretreatment. However, one study that ob-
`tained some results with tamoxifen under similar 7
`study conditions was published by Muss and co-
`workers in 1985 (2). The patient population of that
`study differed in some aspects from ours: only 35% of
`the patients had been pretreated, and 66% of the pa-
`tients had positive receptor state; the rest had un-
`known receptor state. With this population of pa-
`
`AstraZeneca Exhibit 2061 p. 3
`
`

`

`EUROPEAN DOSE FINDING STUDY
`
`S39
`
`the same
`tients with relatively better prognosis,
`response rate was obtained as in our 40- and lOO-mg
`group, namely 31%. An additional 30% obtained dis-
`ease stabilization. A quantitative comparison of side-
`effect profile between droloxifene and tamoxifen can-
`not really be done outside the frame of a comparative,
`randomized study. However, qualitatively, the pro-
`files of the two drugs are comparable. Gastrointestinal
`disturbances, hot flushes and tumor flare are the most
`common symptoms with tamoxifen, according to the
`product description (3).
`On the basis of comparison of two independent
`studies, no firm conclusion can be drawn. However, it
`seems likely that in other studies with patients of bet-
`ter prognosis, the treatment results with droloxifene
`
`will be even better than those presented here. These
`favorable response rates in combination with the
`good tolerability we have observed with droloxi-
`fene, bring positive expectations
`for upcoming
`reports.
`(E
`
`REFERENCES
`
`1. Hayward JL, Carbone PP, Heuson J-C, Kumaoka S, Segalofl" A,
`Rubens RD. Assessment of response to therapy in advanced
`breast cancer. Eur J Cancer 1977;13:89—94.
`2. Muss HB, Paschold FH, Black WR, et a1. Megestrol acetate vs
`tamoxifen in advanced breast cancer: a phase III trial of the
`Piedmont Oncology Association (POA). Semin Oncol 1985;
`12(suppl):55—6 l.
`3. Nolvadex in the treatment of breast cancer. Macclesfield, En-
`glandleI Pharmaceuticals, June 1989.
`
`Am J Clin Oncol {CCT}, Vol. 14, Suppl. 2, 1991
`
`AstraZeneca Exhibit 2061 p. 4
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