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GBG93_PADMA Protocol Amendment 1_V9_2018-07-05_Synopsis_EN 1

SYNOPSIS OF PROTOCOL AMENDMENT 1

Study title A RANDOMIZED, OPEN-LABEL, MULTI-CENTER PHASE IV STUDY EVALUATING PALBOCICLIB PLUS ENDOCRINE TREATMENT VERSUS A CHEMOTHERAPY-BASED TREATMENT STRATEGY IN PATIENTS WITH HORMONE RECEPTOR POSITIVE / HER2 NEGATIVE METASTATIC BREAST CANCER IN A REAL WORLD SETTING (PADMA study).

Study code GBG 93

EudraCT number 2016-004482-89

Sponsor GBG Forschungs GmbH, Neu-Isenburg, Germany

Development phase Randomized phase IV low intervention study

Background Despite multiple guidelines recommend endocrine therapy as initial first-line treatment in estrogen receptor (ER) positive / HER2 negative metastatic breast cancer (MBC) for the majority of patients in Europe up to 50% of ER positive / HER2 negative metastatic breast cancer patients receive chemotherapy (CT) in this setting.1,2,3,4,5

In a retrospective chart review performed by physicians in five European countries, 111 of 355 patients (31%) received first-line CT. Only 7% of patients received 2 lines of endocrine therapy.4

Consistent with this recent report, results of a Market Research conducted in 2015 in France, Germany, Spain and Italy revealed a first-line CT use of 36% (Italy) up to 47% (Germany). Physicians considered that the most appropriate MBC patients to receive CT are those with a rapidly growing tumor, multiple visceral metastases and/or a heavy tumor burden. The main reasons for oncologists in these well developed and funded European countries to prescribe CT in first-line MBC are to treat disease that is thought to present as extensive disease and to progress faster and/or because this treatment plan allows for rapid tumor shrinkage desired by patients and physicians.5

Currently there is no modern prospective trial directly comparing endocrine therapy with chemotherapy in patients with initial diagnosis of hormone receptor (HR) positive MBC available in the literature. A meta-analysis of several randomized clinical trials comparing chemotherapy alone with endocrine therapy alone in patients with MBC found no difference in overall survival (OS) outcome.


In addition, there was no significant difference seen in survival at 12 months (OR 1.03, 95% CI 0.74, 1.43) or 24 months (OR 0.92, 95% CI 0.68, 1.25). Specifically in this Cochrane review, a pooled analysis of eight trials has shown superiority of chemotherapy in response rates, but the two largest trials demonstrated the opposite and there was a very significant heterogeneity in trial population. The trials included in this meta-analysis were generally old (published between 1963 and 1995) and small (median 70 participants).6 The chemotherapy regimens used in these trials were reasonably conventional, although taxanes were not included. Endocrine therapies did not include aromatase inhibitors or fulvestrant, which are currently the most frequently used endocrine agents in this setting.

Several retrospective studies and analyses address the value of chemotherapy versus endocrine therapy as initial therapy for ER positive MBC.

Most recently, retrospectively obtained real-world evidence showed that, for patients with HR positive MBC matched for age, tumor phenotype, number and sites of metastases, clinical outcome was not influenced by treatment strategy (HT vs. CT). There was no statistically significant difference in progress-free survival (PFS) for patients treated with HT vs. CT, although numerical difference was noted (8.8 vs. 12.6 months; HR 0.83, 95% CI 0.66-1.04, P=0.11) and no statistically significant difference in OS (HR 0.86, 95% CI 0.66-1.14, P=0.30) in patients treated with HT vs. CT.7

A real-world evaluation of 482 patients diagnosed with HR positive / HER2 negative MBC between 2007-2009 evaluated initial systemic treatment choices and subsequent patient outcome. First-line CT was associated with a worse clinical outcome compared with first-line HT (PFS 5.3 months [95% CI 4.2, 6.2] vs. 13.3 months [95% CI 11.3, 15.5]; OS 16.1 months [95% CI 13.7-19.7] vs. 36.9 months [95% CI 30.6-43.9]). Prognostic factors were not matched in this analysis and patients receiving first-line chemotherapy were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastases compared with those receiving HT. After adjustment for prognostic factors, first-line chemotherapy was associated with a somewhat worse PFS and OS, however not reaching statistical significance.8

Retrospective chart review of 139 postmenopausal women with HR positive / HER2 negative MBC initiating first-line HT or CT demonstrated equivalence in OS between HT and CT arms. The median OS was 35.5 months (95% CI, 22.7-41.2 months) for patients on first-line ET mono-therapy and 22.2 months (95% CI, 13.6-25.9 months) for those on first-line CT (P=0.021). Adjusting for baseline characteristics however, the OS between first-line ET


mono-therapy and CT was not significantly different.9

Meanwhile new targeted treatment options for the combination with ET have been developed amongst them mTOR inhibitors and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors.

Dysregulation of the cell cycle is one of the hallmarks of cancer. The CDKs are a large family of serine/threonine kinases that have a crucial role in regulating cell cycle progression. Once they are activated by their catalytic partners, the cyclines, they promote cell cycle progression in normal and malignant cells. The CDK4/6 and their partner D-type cyclines control transition from G1 to S phase of the cell cycle by phosphorylating the retinoblastoma protein.10

Strong preclinical evidence has been demonstrated for a synergistic growth inhibitory effect of CDK4/6 inhibition with anti-estrogens in hormone receptor positive breast cancer cell lines. Palbociclib, an oral small molecule inhibitor of CDK4/6 has been shown to significantly prolong progression free survival (from 10.2 to 20.2 months) in postmenopausal women with metastatic hormone receptor positive / HER2 negative breast cancer when added to letrozole in the randomized phase II study PALOMA-1.10,11 Treatment was well tolerated with mostly grade 1-2 adverse events with the exception of grade 3 neutropenia. The subsequent PALOMA-2 study confirmed the efficacy by prolonging PFS from 14.5 to 24.8 months (HR 0.58 [0.46- 0.72], p<0.00001).

PALOMA-3 showed an increase in PFS with fulvestrant plus palbociclib vs. fulvestrant alone.12 The PFS analysis after 8.9 months follow-up demonstrated an increase from 4.6 to 9.5 months in any line (HR 0.46, 95% CI 0.36-0.59, p<0.0001). About 20% of the patients were treated in the first line setting. The HR in this setting was 0.55 with an increase from 5.4 to 9.5 months in an endocrine resistant population (data on file). Palbociclib and other CDK4/6 inhibitors are currently evaluated in various disease settings including phase III trials in metastatic breast cancer.

The phase II FIRST study showed an improved PFS with fulvestrant 500mg vs. of 24 months vs. 13 months with anastrozole, which translated into an improved overall survival benefit of 54.1 months vs. 48.4 months.13 It might therefore be that in first-line metastatic breast cancer fulvestrant is a valid option in addition to aromatase inhibitor (AI) and tamoxifen. The confirmatory double-blind, placebo-controlled randomized phase III FALCON study also demonstrated a significant increase in PFS by using fulvestrant 500mg instead of AI in first-line untreated MBC.14

Based on the scientific and clinical rationale outlined above and the aim to perform a study with a high degree of relevance for


current clinical practice, this study will be a pragmatic, patient-centered randomized low-intervention clinical trial. It will compare two treatment strategies that are commonly used options in real-world practice: a combination of palbociclib with endocrine therapy vs. a pre-planned chemotherapy strategy with or without ET maintenance until treatment failure.

Rationale Endocrine therapy is the recommended option for ER positive / HER2 negative MBC patients as first-line therapy in the majority of patients except those with rapidly progressing, life-threatening disease, also known as visceral crisis.1,2,15 With the novel CDK4/6 inhibitors in addition to either an AI or fulvestrant the treatment landscape is changing rapidly. However, the data comparing endocrine therapy alone with chemotherapy are scarce and less convincing. Since palbociclib improves the efficacy of endocrine therapy alone by about 50%, the hypothesis is that palbociclib + endocrine therapy is superior to mono-chemotherapy of physician´s choice with or without ET maintenance therapy in time to treatment failure. However, due to rigid inclusion and exclusion criteria, limited number of treatment options, and strictly prescribed monitoring intervals the majority of clinical trials are done in an “artificial environment” and often do not mirror real world situation. Therefore, this trial is planned as so called low intervention real world trial.

The goal of the study is to show that palbociclib + ET shows a significant improvement in time-to-treatment failure (TTF) over chemotherapy regimen (mono-chemotherapy with or without ET maintenance therapy). This would provide level 1 evidence from real world that palbociclib + ET is the first choice in MBC patients needing first-line therapy not only compared to ET but also compared to CT with or without ET maintenance therapy.

In addition, we assume that PRO as measured by FACT-B and a composite endpoint of well-being and healthcare utilization will be improved with palbociclib + ET vs. CT regimen.

In real world, the majority of patients receive chemotherapy in this setting to obtain a quick response. Although it has not been proven that a quick response achievement will translate into a patients benefit (e.g., longer TTF). Therefore, a pre-planned analysis will investigate the association of response by month 3 and patient benefit (measured by TTF).

Primary objective To compare the time-to-treatment failure (TTF) for patients randomized to receive pre-defined chemotherapy treatment strategy versus those randomized to receive palbociclib and endocrine therapy.

Secondary objectives

To compare progression free survival (PFS) between treatment arms.


To compare time to first subsequent treatment (TFST).

To compare time to first subsequent chemotherapy (TFSCT).

To compare time to second subsequent treatment regimen (TSST).

To compare the overall survival between treatment arms 36 months after the first patient was randomized.

To compare patient well-being and health care utilization by daily monitoring treatment impact (DMTI) including content with Quality of Life (QoL) and degree of bother by side-effects, number and duration of phone calls, and patient visits to investigator sites.

To compare patient reported outcomes, measured by FACT-B.

To compare time-to-deterioration in Trial Outcome Index-Physical/Functional/Breast (TOI-PFB derived from FACT-B).

To compare safety and tolerability between the two arms.

To compare treatment compliance between the two arms.

Exploratory objectives To compare time to response as assessed by the investigator

To compare duration of first subsequent treatment (DFST).

To investigate association between investigator-assessed response by month 3 after randomization and patient benefit (measured by TTF).

Translational objectives

To evaluate biomarkers in FFPE (e.g., cyclines, RB expression, p27, p16, CCNE1 expression) in metastatic tissue predicting response to CDK inhibition.

To evaluate ctDNA at start of therapy, throughout treatment and at EOT.

To asses the correlation of exploratory biomarkers which will come-up during the study with response (i.e. mutations by targeted next generation sequencing [NGS]) and to assess specific mutations at baseline (e.g., PIK3CA, ESR1).

Study design and treatment

This is a prospective, randomized, open-label, multi-center, controlled phase IV low intervention trial to test whether endocrine treatment with palbociclib is better than mono-chemotherapy +/- endocrine maintenance therapy as per treating physician´s choice as first-line therapy in MBC. Patients will be randomized in a 1:1 ratio to receive either endocrine treatment with palbociclib or chemotherapy with or without endocrine maintenance therapy.

Stratification factors for randomization will be:

hormone resistant (relapse on or within 12 months of end of adjuvant endocrine therapy) versus hormone sensitive (relapse beyond 12 months after end of endocrine therapy or de-novo metastatic HR positive / HER2 negative breast cancer),


symptomatic (as defined per investigator) vs. asymptomatic (as defined by investigator).

In both study arms, treatment will be given until disease progression, unacceptable toxicity, or withdrawal of consent of the patient or change of initial treatment plan (either approximately six chemotherapy cycles followed by maintenance endocrine therapy or chemotherapy until disease progression).

Key considerations about the study design a. Target population: Pre-and postmenopausal patients with

HR positive, HER2-negative MBC, with symptomatic or asymptomatic metastases in which mono-chemotherapy (with or without endocrine maintenance therapy) deemed to be an appropriate option by the physician.

b. Primary efficacy endpoint is time-to-treatment failure (TTF) defined as time from randomization to discontinuation of treatment due to disease progression, treatment toxicity, patient’s preference, or death.

Inclusion criteria Patients will be eligible for study participation only if they comply with the following criteria:

1. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, willingness and ability to complete collection of data via wearable device and study mobile must be obtained and documented according to the local regulatory requirements.

2. Female or male patients.

3. Age ≥ 18 years old.

4. Metastatic invasive hormone receptor positive and HER2 negative breast cancer (histologically confirmed).

5. Patients who in the opinion of the treating physician are candidates suitable for randomization for mono-chemotherapy treatment, that has either an approved label in Europe and/or is supported by guidelines for the treatment of first-line advanced BC, which are based on evidence on safety and efficacy in this setting.

6. Symptomatic or asymptomatic metastatic breast cancer.

7. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 4.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).

8. Life-expectancy > 6 months.

9. For female patients: The patients need to be either A) of non-childbearing potential (documented postmenopausal or post hysterectomy) B) childbearing potential with negative serum or


urinary pregnancy test (in this case patients need to use highly effective non-hormonal contraceptive methods).

Exclusion criteria 1. Indication for poly-chemotherapy or single-agent endocrine therapy only or bevacizumab.

2. Asymptomatic oligometastases of the bone as the only site of metastatic disease.

3. Uncontrolled/untreated central nervous system lesions.

4. Patients who received treatment for metastatic/relapsed breast cancer.

5. Inadequate organ function as per physician’s assessment immediate prior to randomization.

6. Treatment with preparations containing St. John´s Wort within the last 7 days prior to randomization and/or concurrent use.

7. Known severe hypersensitivity reactions to compounds or excipients similar to palbociclib, planned chemotherapy or planned endocrine therapy.

8. Existing contraindication against the use of palbociclib, planned chemotherapy or planned endocrine therapy.

9. Patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency, and glucose-galactose malabsorption.

10. Female patients: pregnancy or lactation at the time of randomization or intention to become pregnant during the study and up to six months after treatment. Male patients: Intention to beget a child during the study and up to six months after treatment.

Investigational products

Palbociclib 125mg / 100mg / 75mg hard capsules on Days 1-21 q28.

Non-investigational products

Chemotherapy Physician´s choice mono-chemotherapy (capecitabine, epirubicin, paclitaxel or vinorelbine i.v.) having either an approved label in the respective countries and/or is supported by guidelines for the treatment of first-line MBC.

Endocrine therapy - In combination with palbociclib Aromatase inhibitors (exemestane or letrozole) or

fulvestrant as per label in the respective countries.

- As maintenance therapy after chemotherapy Tamoxifen, aromatase inhibitors (exemestane or letrozole) or fulvestrant as per label in the respective countries.

Primary endpoint Time-to-treatment failure (TTF) is defined as time from rando-mization to discontinuation of treatment due to disease progression, treatment toxicity, patient’s preference, or death.


Secondary endpoints Progression free survival is defined as the time from rando-mization to first progression as assessed by the investigator or death, whichever occurs first.

Time to first subsequent treatment (TFST) is defined as the time from randomization to start of first subsequent anti-cancer treatment or death.

Time to first subsequent chemotherapy (TFSCT) is defined as the time from randomization to start of first subsequent anticancer chemotherapy or death.

Time to second subsequent treatment regimen (TSST) is defined as the time from randomization to start of second subsequent treatment regimen or death.

Overall survival is defined as the time from randomization to death due to any reason.

Safety and tolerability. Safety by toxicity grades is defined by the NCI CTCAE version 4.0.

Treatment compliance defined as treatment reductions, delays or permanent discontinuation of treatment. The reason for termination includes aspects of efficacy (i.e. termination due to tumor relapse), safety (i.e. termination due to adverse events) and compliance (i.e. termination due to patient's withdrawal of consent).

Patient reported breast cancer specific quality of life.

Time to deterioration (TTD) in TOI-PFB (FACT-B) is defined as an increase of 5 or more score points from baseline.

Content with QoL and degree of bother by side-effects measured by two daily FACT-derived questions on a 5-point scale for level of agreement

Number and duration of phone calls, and patients visits to investigator sites.

Exploratory endpoints Time-to-response is defined as the time from randomization in first-line MBC treatment to response as assessed by the investigator (response, no response, not evaluable).

Duration of first subsequent treatment (DFST) is defined as the time from start to discontinuation of first subsequent anti-cancer treatment regimen.

Association between response and time-to-treatment failure.

Translational endpoints

Correlation of explorative biomarkers on time to event endpoint i.e. PFS and OS.

Correlation of ESR1 mutation with the effectiveness of endocrine therapy AI vs. non-AI and ET based therapy vs. chemotherapy.

Predefined and other exploratory analyses will be performed to identify possible relationships between biomarkers and


drug activity. The aim is to identify potential predictive parameters.

Sample size calculation The sample size for this study is determined based on the analysis of the primary endpoint time-to-treatment failure (TTF) with the following assumptions:

Time to TTF follows an exponential distribution.

Median TTF for patients receiving pre-defined chemotherapy treatment strategy is 10 months.

Risk reduction by 33% (a hazard ratio of 0.667) or an improvement by 50% corresponding to a median TTF of 15 months with palbociclib and endocrine treatment.

A total of 191 events are required to achieve 80% power to detect a hazard ratio (HR) of 0.667 in favor of palbociclib and endocrine therapy using a two-sided, log-rank test at a significance level of 0.05.

Assuming a 10% drop-out rate on either treatment arm and a non-uniform enrolment rate of 30 patients per month at the peak, it was estimated that 260 patients will need to be randomized. The total enrolment period is estimated to be 16 months with a follow-up for about 20 months after the last patient is enrolled.

In the final analysis a closed test procedure will be used to test for superiority of palbociclib and endocrine therapy first. If superiority cannot be shown, according to CPMP/EWP/482/99 (EMA, 2000) the objective can be downgraded to non-inferiority if the non-inferiority margin is pre-specified. The palbociclib and endocrine therapy arm will be considered as non-inferior to the pre-defined chemotherapy treatment strategy arm, if the 95% CI for the HR lies completely below 1.176 (corresponding to a median TTF of 10 months in pre-defined chemotherapy treatment arm and of 8.5 months in palbociclib and endocrine therapy arm).

Statistical methods

A modifed intent-to-treat (mITT) analysis will be conducted for all patients randomized in the study who have received at least one dose of study medication.

Primary efficacy analyses Primary efficacy endpoint is time-to-treatment failure (TTF) defined as time from randomization to discontinuation of treatment due to disease progression, treatment toxicity, patient’s preference, or death.

Specification of treatment failures Treatment failure will not include:

Chemotherapy arm extending the CT treatment compared to the initial

treatment plan in case of good tolerability or if the


investigator considers continuation of treatment to be in the patient’s best interest.

change of endocrine maintenance therapy within class of aromatase inhibitors (exemestane or letrozole).

Palbociclib + ET arm change of ET within class of aromatase inhibitors

(exemestane or letrozole).

Treatment failure will include: premature discontinuation of one of the treatment arms due

to disease progression, treatment toxicity, patient’s preference, or death.

switch from palbociclib + ET arm to CT arm or vice versa due to any reason.

loss of patient during study treatment in one of the treatment arms (i.e. patient does not visit center anymore and cannot be contacted).

Chemotherapy arm change from one mono-CT agent to another (as this is

considered a change of the antitumor effect). change of endocrine maintenance therapy from one class

to another (as this is considered a change of the antitumor effect; classes are: aromatase inhibitors (AI), fulvestrant +/- GnRH analogue, and tamoxifen).

use of any of the prohibited anticancer medications (including poly-chemotherapy).

use of radiotherapy, which was not indicated prior to start of randomization, or surgery indicated by the underlying MBC.

Palbociclib + ET arm change of ET from one class to another (as this is

considered a change of the antitumor effect; classes are AI, fulvestrant +/-GnRH analogue).

use of any of the prohibited anticancer medications. use of radiotherapy, which was not indicated prior to

start randomization, or surgery indicated by the underlying MBC.

The primary objective is to compare TTF for patients randomized to receive pre-defined chemotherapy treatment strategy versus those randomized to receive palbociclib and endocrine therapy.

The primary efficacy analysis for TTF will be the comparison between treatment arms in the mITT population with a two-sided log rank test at the overall significance level of 0.05.

Hypothesis testing Let hCT be the hazard rate in the arm with pre-defined chemo-therapy treatment strategy and hPalboET the hazard rate in the arm with palbociclib and endocrine therapy. The null and


alternative hypothesis can be formulated as follows:

H0: hCT = hPalboET there is no treatment difference in hazard rates.

H1: hCT ≠ hPalboET there is a treatment difference in hazard rates.

The null hypotheses will be tested using a two-sided log rank test.

In addition, TTF curve will be estimated in each treatment arm using the Kaplan-Meier method. The median event time and corresponding two-sided 95% confidence interval for the median will be provided for TTF. The HR and its 95% confidence interval will be estimated using Cox proportional hazards regression model.

A closed test procedure will be used to test for superiority of palbociclib and endocrine therapy first. If superiority cannot be shown, according to CPMP/EWP/482/99 (EMA, 2000) the objective can be downgraded to non-inferiority if the non-inferiority margin is pre-specified. The palbociclib and endocrine therapy arm will be considered as non-inferior to the pre-defined chemotherapy treatment strategy arm, if the 95% CI for the HR lies completely below 1.176 (corresponding to a median TTF of 10 months in pre-defined chemotherapy treatment strategy arm and of 8.5 months in palbociclib and endocrine therapy arm).

Secondary efficacy analyses Time-to-event curves will be estimated using the Kaplan-Meier method and compared between the two arms with a two-sided logrank test. The final OS analysis will be conducted approximately after 36 months of first patient randomized. Univariate and multivariate Cox-proportional hazards model will be used to adjust hazard ratios for stratification factors and the above defined covariates.

Subgroup analysis will be performed in the groups defined by the stratification factors using the same methods as for the analysis of the primary endpoint. The significance level for all tests is set to two-sided alpha = 0.05.

No adjustments for multiple comparisons will be made.

Safety and compliance Safety, tolerability, and treatment compliance: the number and percentage of patients whose treatment had to be reduced, delayed or permanently stopped will be summarized for each treatment arm, Reasons for dose modification, delay and premature termination will be categorized according to the main reason and will be presented in frequency tables. Treatment arms will be compared regarding the occurrence of any adverse events (AE) (grade 1-5), low grade AE (grade 1-2), and high grade AE


(grade 3-5) using Fisher’s exact test. No adjustments for multiple comparisons will be made.

PRO analyses For each treatment group and at each time point, the number

and percentage of patients who completed these instruments will be summarized, as will the reasons for non-completion of these questionnaires. An instrument is considered completed if at least one item was answered by the patient.

For each of the FACT-B scales, the results will be summarized using descriptive statistics for each treatment group at each time point. Results based on the observed values as well as changes from baseline where both within group and between group differences will be displayed. For each of the scales, statistical comparison between the two treatment groups will be based on a longitudinal repeated measures analysis using a mixed effects model. No adjustments for multiple comparisons will be made.

Time-to-deterioration (TTD) analyses will be performed for the TOI-PFB (FACT-B) using survival analysis methods. For the TOI-PFB a 5 –point from baseline has been established as being clinically meaningful and will be defined as deterioration. A two-sided Wald test will be used to compare TTD between the two treatment arms. TTD associated with each treatment arm will be summarized using the Kaplan-Meier method and displayed graphically. The Cox proportional hazards model will be used to compute the treatment HR and the corresponding 95% CI.

Analysis of patient’s well-being and healthcare utilization (DMTI) Two daily FACT-derived questions on content with Quality of Life (QoL) and degree of bother by side-effects will be summarized using descriptive statistics for each treatment group at each week. This will be done based on the observed values as well as changes from baseline where both within group and between group differences will be displayed. For each of the two questions, statistical comparison between the two treatment groups will be based on a longitudinal repeated measures analysis using a mixed effects model. No adjustments for multiple comparisons will be made. The assessments on the first 3 days of each cycle will be used to derive an average by item. For the two items a change from baseline of 0.2 to 0.3 can be considered clinically meaningful.

Derived healthcare utilization endpoints (phone calls to investigator site, and outpatient investigator site visits, hospitalizations) will be normalized to per patient per month and summarized using descriptive statistics (mean, median, standard


deviation, minimum, and maximum), for each treatment arm at each time point. This will be done based on the observed values as well as changes from baseline where both within group and between group differences will be displayed. For each of the endpoints, statistical comparison between the two treatment groups will be based on a longitudinal repeated measures analysis using a mixed effects model. Since healthcare utilization endpoints are based on counts, underlying distributions such as Poisson or negative binomial will be chosen based on pre-specified model fit criteria. No adjustments for multiple comparisons will be made.

Analysis of exploratory endpoints

Analysis of time-to-response will be performed comparable to the survival analyses described in the secondary endpoints. The objective of the analysis is exploratory and descriptive in nature. DFST and the association between response (complete response or partial response versus stable disease) and TTF will be analysed in a way to control for immortal time bias (details will be given in the Statistical Analysis Plan).

Stratification factors Randomization will be stratified using block randomization on the basis of the following stratification factors:

hormone resistant (relapse on or within 12 months of end of adjuvant endocrine therapy and no therapy for metastatic disease) vs. hormone sensitive (relapse beyond 12 months after end of endocrine therapy or de-novo metastatic HR positive / HER2 negative breast cancer).

symptomatic (defined as per investigator) vs. asymptomatic (as defined by investigator).

Number of sites It is planned to conduct the study within approximately 130 sites overall of which 50-80 sites in Germany and in additional other countries.

Enrollment period Approximately 16 months (Q-I 2018 - Q-III 2019).

Study duration Approximately 36 months.

Follow-up period 20 months after Last Patient In.


Figure 1: Study Design

Figure 2: Overview Key Efficacy Endpoints


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