Combination of Abemaciclib and Endocrine Therapy in Hormone Receptor Positive HER2 Negative Locally Advanced or Metastatic Breast Cancer With Focus on Digital Side Effect Management

Inclusion Criteria:

Patients will be included in the trial only if they meet all the following criteria:

1. Have given written informed consent prior to any trial-specific procedures

2. Are reliable, willing to be available for the duration of the trial and are willingto follow trial procedures

3. Are female and aged ≥ 18 years

4. Diagnosis of hormone receptor positive (HR+), HER2- breast cancer. Although notrequired as a protocol procedure, metastatic disease should be considered for biopsywhenever possible to reassess HR and HER2 status if clinically indicated.

5. To fulfill the requirement for HR+ disease, a breast cancer must express, byimmunohistochemistry (IHC), at least one of the hormone receptors (estrogen receptor [ER], progesterone receptor [PgR]) as defined in the relevant American Society ofClinical Oncology (ASCO)/College of American Pathologists (CAP) Guidelines (Hammondet al. 2010).

6. To fulfill the requirement of HER2- disease, a breast cancer must not demonstrate,at initial diagnosis or upon subsequent biopsy, overexpression of HER2 by either IHCor in-situ hybridization (ISH) as defined in the relevant ASCO/CAP guidelines (Wolffet al. 2013).

7. Have locally advanced recurrent disease not amenable to resection or radiationtherapy with curative intent or metastatic disease

8. Indication for endocrine based therapy in the metastatic setting

9. Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology Group (ECOG) scale

10. If central nervous system (CNS) metastases are known these have to be stable (radiotherapy finished for more than 14 days ago, no required steroid medicationwith more than 4 mg Dexamethasone per day)

11. Pre- and postmenopausal patients are allowed. Postmenopausal is defined as no mensesfor 12 months without an alternative medical cause. Women of Childbearing Potential (WOCBP, defined as not postmenopausal and not surgically or congenitally sterile)whose male partners are potentially fertile (e.g. no vasectomy) must use highlyeffective contraception methods for the duration of the trial and for at least 3weeks after last dose of drugs used in the trial.Women of childbearing potentialmust use highly effective contraception methods for two years after the last dose offulvestrant. Highly effective birth control methods that results in a failure rateof less than 1% per year include combined (estrogen and progestogen containing)hormonal contraception associated with inhibition of ovulation (oral, intravaginal,transdermal), progestogen-only hormonal contraception associated with inhibition ofovulation (oral, injectable, implantable), intrauterine device, intrauterinehormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner.Sexual abstinence is only considered a highly effective method if defined asrefraining from heterosexual intercourse in the defined period. The reliability ofsexual abstinence needs to be evaluated in relation to the duration of the trial andthe preferred and usual lifestyle of the patient.

12. No prior therapy for metastatic disease (except for first line endocrine therapy formaximal 3 months prior to start of abemaciclib therapy and if no progress occurredbefore study entry)

13. Previous adjuvant endocrine therapy and (neo)adjuvant chemotherapy is allowed

14. Patients who received chemotherapy must have recovered (Common Terminology Criteriafor Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy exceptfor residual alopecia or ≤ Grade 2 peripheral neuropathy prior to registration. Awashout period of at least 21 days is required between last chemotherapy dose andregistration (provided the patient did not receive radiotherapy).

15. Patients who received radiotherapy must have completed and fully recovered from theacute effects of radiotherapy. A washout period of at least 14 days is requiredbetween end of radiotherapy and registration.

16. One of the following as defined by the RECIST v1. 1 (see Attachment 15.5):

17. Measurable disease. At least one measurable lesion assessable using standardtechniques by Response Evaluation Criteria In Solid Tumors Version 1.1 (RECISTv1.1). Tumor evaluation according to RECIST version 1.1 (based on localassessment) has to be performed within 28 days before trial registration.

18. Nonmeasurable bone-only disease (must be evaluable, but not necessarilymeasurable by RECIST). Nonmeasurable bone-only disease may include any of thefollowing: blastic bone lesion, lytic bone lesions without a measurable softtissue component, or mixed lytic-blastic bone lesions without a measurable softtissue component.

19. The patient has adequate bone marrow and organ function evidenced by the followinglaboratory results: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, Platelet count ≥ 100 × 109/L, Hemoglobin ≥ 8 g/dL, alanine aminotransferase (ALT) and aspartateaminotransferase (AST) ≤ 2.0 × ULN (≤ 3 x ULN in case of liver metastases), TotalBilirubin ≤ 1.5 × ULN (with Gilbert's syndrome max. 2 x ULN), Serum Creatinine ≤ 2.0mg/dl or 177µmol/L, Coagulation: International Normalized Ratio (INR) ≤ 1,5

20. The patient is able to swallow oral medications

21. Willingness to use the provided CANKADO digital health application to report sideeffects and patient reported outcomes (The use of the CANKADO app is not mandatoryfor study participation, but is strongly recommended)

22. Negative pregnancy test before trial registration for women of child-bearingpotential and highly effective contraception if the risk of conception exists and anegative serum pregnancy test within 7 days after the first dose of trial treatment.Pregnancy tests should be performed in premenopausal patients according to localstandard

Exclusion Criteria:

Patients will be included in the trial only if they meet none of the following criteria:

1. Visceral crisis or life expectancy < 6 months

2. History of hypersensitivity reactions attributed to Abemaciclib or to othercomponents of drug formulation

3. Prior treatment with chemotherapy in the metastatic setting or endocrine therapy inthe metastatic setting (except for first line endocrine therapy in metastatic orlocally advanced disease for maximal 3 months prior to start of abemaciclib therapyand if no progress occurred before study entry)

4. Patient not eligible for endocrine based therapy

5. Any concurrent severe, uncontrolled systemic disease, social or psychiatriccondition that might interfere with the planned treatment and with the patient'sadherence to the protocol

6. The patient has serious and/or uncontrolled preexisting medical condition(s) that,in the judgment of the investigator, would preclude participation in this trial (forexample, interstitial lung disease, severe dyspnea at rest or requiring oxygentherapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min],history of major surgical resection involving the stomach or small bowel, orpreexisting Crohn's disease or ulcerative colitis or a preexisting chronic conditionresulting in baseline Grade 2 or higher diarrhea).

7. Prior treatment with a CDK4/6 inhibitor for metastatic or locally advanced disease (first-line treatment with a CDK 4/6 inhibitor (Ribociclib/Palbociclib) in themetastatic setting is allowed only if terminated due to toxicity after max 3 monthsand no progression occurred before study entry. Prior treatment with a CDK 4/6inhibitor in the neo-/adjuvant setting is allowed.)

9. Treatment with any other investigational agents within four weeks or 5half-lives prior to trial registration, whichever is longer

10. The patient has a personal history of any of the following conditions: syncope ofcardiovascular etiology, ventricular arrhythmia of pathological origin (including,but not limited to, ventricular tachycardia and ventricular fibrillation), or suddencardiac arrest.

11. Females who are pregnant or lactating

12. Legal incapacity or limited legal capacity

13. History of any other cancer (except non-melanoma skin cancer or carcinoma in-situ ofthe cervix), unless in complete remission with no therapy for a minimum of 3 years.

14. The patient has active systemic bacterial infection (requiring intravenous [IV]antibiotics at time of initiating trial treatment), fungal infection, or detectableviral infection (such as known human immunodeficiency virus positivity or with knownactive hepatitis B or C [for example, hepatitis B surface antigen positive].Screening is not required for enrollment.

15. Prior systemic anti-cancer therapy within the last 21 days prior to start of trialtreatment except for first-line endocrine therapy in metastatic or locally advanceddisease (see above)

16. Radiotherapy within the last 14 days prior to registration

17. Patient has had major surgery within 14 days prior to trial registration.