Breast Cancer Research and Treatment, 5, 3214326 (1985)
`© 1985 Martinus Nijhoff Publishers, Boston. Printed in the Netherlands
`
`Oral medroxyprogesterone acetate in the treatment of metastatic breast cancer
`
`Gabriel N. Hortobagyi, Aman U. Buzdar, Debra Frye, Hwee-Yong Yap, Verena Hug, Kavitha Pinna—
`maneni, Giuseppe Fraschini, H.C. Halvorson & George R. Blumenschein
`Medical Breast Section, Division of Medicine, The University of Texas M.D. Anderson Hospital and Tumor
`Institute, Houston, Texas
`
`Keywords: medroxyprogesterone acetate, metastatic breast cancer, side effects, survival
`
`Summary
`
`Thirty-nine evaluable, postmenopausal patients with metastatic breast carcinoma were treated with
`medroxyprogesterone acetate administered orally at daily doses of 800 mg/day in 29 patients and 400 mg/day
`in 10 patients. One patient experienced a complete remission and 16 had partial remissions for an objective
`remission rate of 44%. There was no apparent difference in response between the two dose levels. Median
`remission duration was 8 months, and median survival for the whole group is expected to exceed 18 months.
`Increased appetite (66%) and weight gain (97%) were the most common side effects, followed by fluid
`retention, muscle cramps, and increased blood pressure. Performance status improved and white blood cell
`and platelet counts increased in the majority of patients. Medroxyprogesterone acetate is an effective
`hormonal agent in the treatment of metastatic breast cancer.
`
`Endocrine therapy is effective in patients with re-
`current or metastatic breast cancer (1); 20% to 40%
`of unselected patients respond to some form of
`hormonal manipulation. The presence of steroid
`hormonal receptors, specifically estrogen and pro-
`gesterone receptors, within the tumor correlates
`
`with a 50% to 60% response rate to hormonal
`therapy. Conversely, receptor-negative tumors are
`unlikely to respond to these agents (2). Medroxy—
`progesterone acetate, a synthetic steroid molecule
`endowed with a specific progestational action, is
`one hormonal agent that has been demonstrated to
`be effective against breast cancer (3). It can be
`administered both orally and intramuscularly (4)
`Early experience with low dose (40 to 260 mg/day)
`medroxyprogesterone acetate given orally pro-
`
`duced objective responses in up to 25% of patients.
`When administered parenterally at doses of 500 to
`1,500 mg/day, this drug brought about responses in
`up to 40% of treated patients, with responses last-
`ing between 7 and 13 months. Intramuscular ad-
`
`ministration has been complicated by significant
`local reactions, such as sterile abscesses, in 16% to
`
`60% of patients (5,6). In addition, daily intra—
`muscular administration is inconvenient. In this
`
`study, we evaluated the therapeutic efficacy of oral
`administration of meroxyprogesterone acetate in
`high doses in patients with advanced breast cancer.
`
`Address for offprints: Gabriel N. Hortobagyi, MD, M.D. Anderson Hospital and Tumor Institute at Houston, 6723 Bertner Avenue,
`Houston, Texas 77030.
`
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`
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`322
`
`GN Hortobagyi el al.
`
`Materials and methods
`
`Patients who had histologically documented breast
`cancer and clearly measurable disease, who were
`one or more years postmenopausal, and whose
`performance status was $3 (Zubrod scale) were
`eligible for
`this
`study. Patients with known
`estrogen receptor-negative tumor or those who had
`
`received prior progestational therapy were not eli—
`gible. Also excluded were patients with other con-
`current or past malignancies, central nervous sys—
`tem metastases, or extensive liver metastases.
`
`Medroxyprogesterone acetate, 800 mg/day, was
`administered orally in four divided doses. The drug
`was provided in 50 mg tablets. To decrease side
`effects, after the initial six months of therapy, the
`maintenance dose of medroxyprogesterone acetate
`was decreased to 400 mg/day. Subsequently, the
`last 10 patients entered in this study were started at
`400 mg/day.
`An adequate trial was defined as 12 weeks of
`therapy unless clear-cut evidence of significant pro-
`gressive disease was detected before that date.
`Evaluation included a complete history and
`physical examination, complete blood count, bio-
`chemical
`survey (SMA 12), plasma carcino-
`embryonic antigen level, and the appropriate
`x-rays and scans to determine and measure the
`extent of metastatic disease. These assessments
`
`were made prior to initiation of therapy and re-
`peated monthly for the first 3 months and every 2
`months thereafter.
`
`The disappearance of all measurable lesions and
`complete recalcification of osteolytic lesions with—
`out the appearance of new lesions was considered a
`complete response. A partial response was defined
`as a 50% to 99% decrease in the sum of the prod—
`
`ucts of the two largest perpendicular diameters of
`all measurable lesions and partial recalcification of
`osteolytic lesions. Stable disease was defined as a
`decrease of less than 50% or an increase of less than
`
`25 % in the original measurements of all lesions for
`
`a period in excess of 8 weeks. Progressive disease
`was considered an increase in tumor burden of
`
`greater than 25% or the appearance of any new
`lesions. Time to progression was measured from
`the initiation of therapy until the time of relapse or
`
`last contact. Survival time was measured from the
`
`initiation of treatment until death or the last follow—
`
`times were plotted using the
`up visit. Survival
`Kaplan and Meier method (7), and the modified
`Wilcoxon test (8) was used to test the differences
`between pairs of curves for statistical significance.
`
`Results
`
`Forty—two patients seen between February 1981
`and October 1982 were selected for the trial. One
`
`was considered ineligible because of a history of
`soft tissue sarcoma. Two were inevaluable for re-
`
`sponse due to inadequate trial. All patients were
`assessable for toxicity. The pretreatment charac-
`teristics of the 41 eligible patients included the fol-
`lowing. Thirty-nine patients were female and 2
`were male. The median age was 62 years (range 32
`to 80). The disease-free interval was <12 months in
`4 patients, 12 to 36 months in 20, and >36 months in
`17. Thirty—six patients were Caucasian, 4 were
`black and 1 was Mexican'American. Twenty-nine
`
`(71%) patients had a performance status between 0
`and 1, 9 (22%) had a performance status of 2, and 3
`had a performance status of 3. Other pretreatment
`characteristics are shown in Table 1.
`
`Of the 39 evaluable patients, complete remission
`was achieved in 1 (3%), partial remission in 16
`(41%), 14 had stable disease, and 9 (23%) con—
`tinued to have clear-cut progressive disease. Four
`patients included in the stable category achieved
`objective responses that did not meet the criteria
`for a partial remission. The overall major objective
`response rate was 44%. Of 30 patients treated at
`800 mg/day, 11 (37%) had a complete or partial
`response. Six of the 9 patients (67%) treated from
`the beginning at 400 mg/day achieved a partial re-
`sponse. The difference between these two re-
`sponse rates is not statistically significant. Univari-
`ate analysis was performed to search for correla-
`tions between response to medroxyprogesterone
`acetate and standard prognostic factors (Table 2).
`Response rates were higher in patients over 60
`years old, those with soft tissue or osseous domi-
`nant disease, those who achieved responses with
`
`prior hormone therapy, and those with estrogen
`
`
`
`
`
`AstraZeneca Exhibit 2145 p. 2
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`

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`Table 1. Pretreatment characteristics.
`
`
`Time To Progression
`
`
`
`No. of patients ("/o)
`
`Oral medroxyprogesterone acetate
`
`323
`
`Eligible patients
`Performance status (Zubrod)
`0
`1
`2
`3
`Number of sites
`
`1
`2
`23
`Dominant site of disease
`
`41
`
`11
`18
`9
`3
`
`20
`11
`10
`
`(27)
`(44)
`(22)
`( 7)
`
`(49)
`(27)
`(24)
`
`7
`19
`15
`
`20
`21
`
`Soft tissue
`Osseous
`Visceral
`Estrogen receptor
`Positive
`Not done
`Progesterone receptor
`(10)
`4
`Positive
`( 5)
`2
`Negative
`
`
`35Not done (85)
`
`(17)
`(46)
`(37)
`
`(49)
`(51)
`
`and/or progesterone receptor-positive tumors.
`One 68—year-old male patient with an estrogen re-
`ceptor-positive, progesterone receptor-unknown
`tumor achieved a partial remission on this regimen,
`while the other patient, a 47-year-old male, with a
`borderline estrogen receptor, progesterone recep-
`tor-negative tumor did not respond. The median
`time to progression for all patients was 7 months
`(range 1 to 23+), for responders 8 months (range 4
`to 23+), and for nonresponders 5 months (range 1
`to 17) (P = 0.003) (Figure 1). Median survival has
`not been reached. but this interval is estimated to
`
`be in excess of 18 months for the whole group.
`In 19 patients (16 treated with 800 mg/day and 3
`with 400 mg/day) there was clear-cut improvement
`of at least 1 point in performance status rating.
`Twenty-seven (66%) had a noticeable increase in
`appetite. In 29 patients the white blood cell count
`increased more than 2,000/mm3. These hema—
`
`tologic changes occurred within the first month
`after initiation of treatment.
`
`The toxicities that occurred in these patients are
`listed in table 3. The most common side effect was
`
`excessive weight gain with or without fluid reten-
`
`
`
`ProportionFreeFromProgression
`
`80
`
`Fail
`Total
`
`17
`12
`o Responders
`
`22
`19
`Nonresponders
`
`Non—failure
`
`p-0.003
`
`60
`
`40
`
`20
`
`
`
`0
`
`6
`
`12
`Months
`
`18
`
`24
`
`Fig. I. Progression-free curves for responders and nonrespon-
`ders.
`
`tion. While it occurred at both dose levels, an
`
`increase of more than 20 lbs took place only in
`patients receiving 800 mg/day of the drug and was a
`gradual process over many months. This side effect
`was also analyzed relative to body weight: weight
`increase of 5% or less was observed in 40% of
`
`patients, a 6—10% increase in 25% of patients, and
`a greater than 10% weight increase in 35% of them.
`The median weight gain for the entire group was
`6% and the maximal increase observed was 30%.
`
`Only patients treated with 800 mg/day of medrox-
`yprogesterone acetate had weight gains exceeding
`10% of their body weight. Thirteen patients had
`mild hypertension (11 treated at 800 mg/day and 2
`
`treated at 400 mg/day), and 3 others required anti—
`hypertensive medical treatment. Congestive heart
`failure developed in 4 patients, probably as a result
`of fluid retention. Treatment with medroxyproges-
`terone acetate was discontinued in 3 of them, and
`
`their cardiac funtion returned to normal. In 1 pa-
`tient diuretics resulted in improved cardiac func—
`tion, while medroxyprogesterone acetate, 400 mg/
`day, was continued.
`Ten patients experienced mild to moderate fa—
`
`
`
`
`
`AstraZeneca Exhibit 2145 p. 3
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`324
`
`GN Hortobagyi et a].
`
`Table 2. Analysis of response by prognostic factors
`
`
`No. of patients
`No. of responses
`(%)
`
`
`Age (years)
`560
`>60
`Disease—free interval
`
`<12 months
`12—36 months
`>36 months
`N0. of sites
`
`1—2
`23
`Dominant site
`
`Soft tissue
`Bone
`Visceral
`Performance status
`
`16
`23
`
`4
`19
`16
`
`30
`9
`
`7
`18
`14
`
`6
`11
`
`3
`7
`7
`
`12
`5
`
`4
`9
`4
`
`(38)
`(48)
`
`(75)
`(37)
`(44)
`
`(40)
`(55)
`
`(57)
`(50)
`(29)
`
`(P1
`2
`3
`Prior hormonal therapy
`Response
`No response
`Prior chemotherapy
`Yes
`No
`Estrogen receptor
`Positive
`Unknown
`Progesterone receptor
`(67)
`2
`3
`Positive
`( 0)
`—
`1
`Negative
`(43)
`15
`35
`Unknown
`
`
`(45)
`(29)
`(67)
`
`(54)
`(25)
`
`(44)
`(43)
`
`(53)
`(35)
`
`29
`7
`3
`
`26
`4
`
`25
`14
`
`19
`20
`
`13
`2
`2
`
`14
`1
`
`11
`6
`
`10
`7
`
`
`
`The differences observed in response rate were not statistically significant. The p value calculated for the differences in response rate
`according to dominant site of disease was 0.07_
`
`tigue (8 treated at 800 mg/day and 2 at 400 mg/day).
`One patient who was treated with 800 mg/day of
`the drug for 7 months developed a severe Cushing—
`oid syndrome and congestive heart failure. Two
`patients treated with 800 mg/day developed nonfa-
`tal pulmonary embolism during treatment. One
`patient treated at 400 mg/day developed moder-
`ately severe vaginal bleeding which precluded con—
`tinuation of therapy after the first month.
`
`Discussion
`
`Medroxyprogesterone acetate given at
`
`the two
`
`dose levels used in this study consistently produced
`objective responses in patients with metastatic
`breast cancer. Only 10 patients were treated at the
`lower dose, but no apparent difference in the re—
`sponse rate was observed between the two dose
`schedules; however, at the higher dose the inci-
`dence and severity of side effects, especially weight
`gain, were increased. The therapeutic results
`achieved with the oral administration of medroxy-
`progesterone acetate are similar to those obtained
`with parenteral administration (4), and the re-
`sponse rate is also in keeping with reports of other
`investigators who have prescribed similar doses of
`orally administered medroxyprogesterone acetate
`
`
`
`AstraZeneca Exhibit 2145 p. 4
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`

`

`Table 31 Toxicity.
`
`
`
`
` No. of patients (%)
`
`Oral medroxyprogesterone acetate
`
`325
`
`Common side effects
`Increased appetite
`Weight gain (lbs)
`0—10
`11—20
`21—30
`>30
`Weight gain (% body weight)
`< 5%
`“0%
`11—20%
`>20%
`Fluid retention
`Mild
`Moderate
`Severe
`Muscle cramps
`Increased blood pressure
`Increased perspiration
`Fatigue (mild)
`Nervousness
`Tremor
`Facial fullness
`
`21
`8
`6
`5
`
`9
`2
`4
`
`27
`40
`
`16
`10
`8
`6
`15
`
`17
`16
`14
`10
`9
`7
`9
`
`(51)
`(20)
`(15)
`(12)
`
`(66)
`(97)
`
`(40)
`(25)
`(20)
`(15)
`(37)
`
`(22)
`( 5)
`(10).. =
`
`,
`
`(41)
`(39),.
`(34)
`(24)
`(22)
`(17)
`(22)
`
`Uncommon side effects
`(10)
`4
`Hair loss (slight)
`(10)
`4
`Vaginal bleeding
`(10)
`4
`Headache
`(10)
`4
`Hot flashes
`(10)
`4
`Irritability
`( 7)
`3
`Insomnia
`( 7)
`3
`Facial hair
`(10)
`4
`Congestive heart failure
`( 5)
`2
`Pulmonary embolism
`( 2)
`1
`Thrombophlebitis
`( 2)
`1
`Cushingoid syndrome
`( 2)
`1
`Hypercalcemia
`( 2)
`1
`Diabetes
`
`
`
`therapy (500 to 1,500 mg/day). Though doses of at
`least 400 mg/day appear to be more effective than
`low doses of the drug (20 to 400 mg/day),
`it
`is
`unclear whether doses in excess of 500 mg/day pro—
`duce an additional therapeutic benefit (4). It ap-
`pears, however, that the higher doses are associ-
`ated with more toxicity by either route of admin—
`istration.
`
`Several other favorable biological effects were
`observed during this study. Increased appetite and
`
`weight gain occurred in a few patients who experi-
`enced anorexia and weight loss as a result of pre-
`vious cytotoxic therapies. Increased white blood
`cell and platelet counts suggested that the combina-
`tion of medroxyprogesterone acetate and chemo-
`therapy may be an aid in decreasing the myelosup-
`pressive toxicity of the latter form of therapy.
`Indeed, some investigators have reported that
`medroxyprogesterone acetate reduces toxicity of
`combination chemotherapy (11).
`
`
`
`
`
`AstraZeneca Exhibit 2145 p. 5
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`326
`
`GN Hortobagyi 6t al.
`
`Based on these results, we suggest that medroxy—
`progesterone acetate administered orally at a dose
`of 400 mg/day is an effective and well tolerated
`form of treatment. Clinical trials using this agent
`may be desirable in assessing its efficacy in com—
`bination with other regimens for metastatic cancer
`as well as its ability to reduce the side effects of
`combination chemotherapy.
`Diet supervision prior to and during therapy with
`medroxyprogesterone acetate is recommended to
`control food intake and to reduce the severity of
`weight gain, thus improving the tolerance to this
`drug.
`
`Acknowledgments
`
`Supported by a grant from The Upjohn Company,
`Kalamazoo. Medroxyprogesterone acetate (Pro-
`vera®) was kindly supplied by The Upjohn Com-
`pany.
`The authors wish to thank Joan Trammell for her
`
`assistance in the preparation of this manuscript.
`
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`
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`AstraZeneca Exhibit 2145 p. 6
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