Am J Clin 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 efficacy and good tolerability. One
`hundred ninety-six female, postmenopausal patients with
`advanced breast cancer were treated with 20, 40, or 100 mg
`ofdroloxifene daily. Exclusioncriteria were as follows: nega-
`tive ER/PR status, tamoxifen treatment within the preced-
`ing three months, chemotherapy within the preceding three
`weeks, and performancegrade of four. Seventeen percent of
`the patients treated with 20 mg daily respondedtotreat-
`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 symptomsgenerally 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 andreprint 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 JI de-
`velopmentstudies: Austria: R. Kolb and G. Reiner (Vienna); Bel-
`gium: M. Beauduin (Haine St. Paul), E. Salamon (Namur); Ger-
`many: L.M. Ahlemann (Liidenscheid), J. Ammon (Aachen), R.
`Balas (Seigen), G. Bastert (Heidelberg), G.P. Breitbach (Homburg),
`H.G. Beger (Uim), M. Brandtner (Wetzlar), K. Brunnert (Osna-
`briick), L. Heilmann (Riisselsheim), F. Janicke (Miinchen), 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: O. Mella
`(Bergen), C. Gundersen and N. Raabe (Oslo), S. Kvinnsland
`(Trondheim), E. Wist (Troms6); Spain: L.A. Solé/J. Bellmunt/S.
`Morales (Barcelona).
`
`S36
`
`The data presented in this paper were obtained
`from a variety of Europeanclinical dose-finding stud-
`ies designed as part of the phase II 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
`advancedbreast cancer and positive or unknown hor-
`monereceptorlevels. 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 performancestatus,
`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 notall 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 sametechnical
`method at each visit. Response was assessed accord-
`ing to World Health Organization (WHO)/UnionIn-
`ternationale Contre le Cancer (UICC)criteria (1). 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 againstoriginal sources. Data not yet
`verified in this way have been omitted from this colla-
`tion. A total of 196 patients weretreated 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 befulfilled, 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 mgof droloxifene daily, 53 received 40 mgdaily,
`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 groupthe
`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% ofthe patients had positive hor-
`monereceptors 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 receptorstate for the majorityofthe patients,
`65%, was unknown for the primary tumor. For the
`secondary tumor, this proportion was ~91%. The
`three dosage groupswere 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 100-mg treatment
`group to 51.3 monthsin the 20-mggroup.
`Bone, soft tissue, and lung metastases were the
`most frequently occurring metastaticsites. Fifty-eight
`percentofall the patients had bone metastases, 34%
`hadsoft tissue metastases, and 31% had lung metas-
`tases. At least one-half of the patients presented with
`metastases at more than onelocation. Nineteen per-
`cent of patients had metastatic pleural effusions. Me-
`tastases in liver and peripheral lymph nodes were each
`present in 10%. Locations that wereless frequently
`involved were the mediastinal lymph nodesin 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 hormonaltherapy.
`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. Thepatients
`may be unevenly distributed with regard to previous
`therapyin 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% ofthe 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 monthsin the 100-mg group.
`These figures representall the 178 evaluable patients.
`The 44 patientsstill receiving treatment are included.
`All patients are included, even those who were not
`evaluable for efficacy. This meansthat early dropouts
`as well as patients with early progression are included,
`andthis, 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
`monthsin the 40-mg group, and 31.5 monthsin the
`100-mg group.
`In reporting efficacy, only those patients in whom
`proper tumor assessments werecarried 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 of 61 (10%) in the
`100-mg group obtained complete responses. Re-
`sponses by site showed 14 of 69 (20%)in bone, and 6
`of 22 (27%)in patients with pleuraleffusion. 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 meansthat
`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 doserelations are promi-
`nent, though vomiting maybeless frequent in the
`
`Am J Clin Oncol (CCT), Vol. 14, Suppl. 2, 1991
`
`AstraZeneca Exhibit 2061 p. 2
`
`

`

`S38
`
`BELLMUNT AND SOLE
`
`TABLE 1. Adverse symptoms with droloxifene
`
`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./Phiebit.
`Edema
`Lymphedema
`Weight gain
`Eye disorders
`Joint pain
`Anorexia
`Other
`
`1
`
`aan=aw|=|Jva[afrv]|enaanaaae
`
`2
`(20 mg group, n = 44)
`
`3
`
`Plattithibbbtitbitbatiletic-
`
`Severity level*
`
`1
`
`2
`(40 mg group, n = 53)
`
`3
`
`1
`
`2
`(100 mg group, n = 81)
`
`3
`
`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
`1
`—
`1
`3
`1
`10
`2
`2
`4
`10
`
`4
`7
`1
`3
`3
`1
`3
`4
`1
`_
`3
`5
`1
`1
`—
`_
`7
`—
`1
`2
`_
`1
`—
`4
`—
`12
`
`-
`
`2
`1
`1
`—
`1
`1
`—
`2
`1
`1
`—
`—
`—
`—
`1
`1
`_
`—
`2
`—
`—
`_
`1
`1
`2
`2
`
`
`
`Ana|=nn|||{+[]4+]|,4%an2na5
`
`® 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 symptomsoccurred in <5% of the pa-
`tients in each treatment group. The most common
`adverse symptomsin 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 symptomsreported in
`smaller proportions of the patients included depres-
`sion, weight gain,
`lymphoedema, hypercalcemia,
`joint pain, and skin rash.
`During thesetrials, 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 wasreported.
`Thrombophlebitis followed by pulmonary embolism
`was.seen 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 J Clin Oncol (CCT), Vol. 14, Suppl. 2, 1991
`
`DISCUSSION
`
`In these studies, response rates of 17% in patients
`receiving 20 mgdaily, 30% in those receiving 40 mg,
`and 31% in those receiving 100 mg daily were ob-
`tained, Weregard theresults 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 perhapsoc-
`curred sooner than we might normally expect from
`hormonaltherapy. A further 36-40% disease stabili-
`zations were obtained. This meansthat only 31-33%
`ofpatients in the two best groups, 40 and 100 mg, and
`43% in the 20-mggroup,had progressive disease while
`receiving droloxifene.
`Not manystudies 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 _
`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% ofthe pa-
`tients had positive receptor state; the rest had un-
`knownreceptor state. With this population of pa-
`
`AstraZeneca Exhibit 2061 p. 3
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`

`

`EUROPEAN DOSE FINDING STUDY
`
`S39
`
`the same
`tients with relatively better prognosis,
`response rate was obtained as in our 40- and 100-mg
`group, namely 31%. An additional 30% obtained dis-
`ease stabilization. A quantitative comparison ofside-
`effect profile between droloxifene and tamoxifen can-
`notreally be done outside the frame ofacomparative,
`randomized study. However, qualitatively, the pro-
`files ofthe two drugs are comparable. Gastrointestinal
`disturbances, hot flushes and tumorflare are the most
`common symptomswith tamoxifen, according to the
`product description (3).
`On the basis of comparison of two independent
`studies, no firm conclusion can be drawn. However,it
`seemslikely that in other studies with patientsof 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.
`
`REFERENCES
`
`1. Hayward JL, Carbone PP, Heuson J-C, Kumaoka §S,Segaloff 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 al. Megestrol acetate vs
`tamoxifen in advanced breast cancer: a phase III trial of the
`Piedmont Oncology Association (POA). Semin Oncol 1985;
`12(suppl):55-61.
`3. Nolvadex in the treatment of breast cancer. Macclesfield, En-
`gland:ICI Pharmaceuticals, June 1989.
`
`Am J Clin Oncol (CCT), Vol. 14, Suppl. 2, 1991
`
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