Abemaciclib in Combination With Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer

Inclusion Criteria:

• Provision of signed and dated, written informed consent prior to any study specificprocedures, sampling and analyses

• If a patient declines to participate in any voluntary exploratory researchand/or genetic component of the study, there will be no penalty or loss ofbenefit to the patient and he/she will not be excluded from other aspects ofthe study

• Women aged at least 18 years

• The patient has a biopsy-confirmed diagnosis of recurrent, unresectable, locallyadvanced, or metastatic HER2neu-negative breast cancer (including bone-onlymetastatic disease) o The patient must have had biopsy confirmation of a metastaticsite (with appropriate ER/PR/HER2neu IHC staining) o The patient has measurable or evaluable disease as evidenced on pre-treatmentbaseline CT chest, abdomen, and pelvis with bone scan OR PET/CT

• The patient has AR+ breast cancer (defined as > or equal to 1% staining onimmunohistochemistry of metastatic breast cancer specimen)

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 with nodeterioration over the previous 2 weeks and minimum life expectancy of 12 weeks

• If the patient has ER+ or PR+ (>1% on IHC) metastatic breast cancer: o patient must have had 1 prior line of endocrine therapy in the metastatic setting

• prior CDK4/6 inhibitor exposure allowed (abemaciclib. palbociclib, orribociclib)

• no more than 2 prior line of cytotoxic chemotherapy in the metastatic settingallowed

• If the patient has ER-,PR-, HER2- metastatic breast cancer ("triple-negative"): o The patient may have had up to 4 prior lines of chemotherapy in the metastaticsetting and at least 1 prior line of chemotherapy in the metastatic setting

• 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 randomization. Awashout period of at least 21 days is required between last chemotherapy dose andrandomization (provided the patient did not receive radiotherapy).

• 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 randomization.

• Post-menopausal status or receiving ovarian ablation with a GnRH agonist such asgoserelin or leuprolide. Postmenopausal status is defined by any one of thefollowing criteria:

• Prior bilateral oophorectomy.

• Age ≥ 60 years.

• Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy,tamoxifen, or ovarian suppression) and FSH, LH, and estradiol in thepostmenopausal range per local normal.

If the patient does not meet criteria for postmenopausal status but is receiving ovarian ablation therapy with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin or leuprolide, the patient is eligible for the study, provided that the GnRH agonist is started at least 2 weeks prior to C1D1 of study therapy.

• Negative serum pregnancy test within 7 days prior to starting treatment

• Women of child-bearing potential and men must agree to use a highly effective method of contraception prior to study entry, for the duration of study participation, and for 3 weeks following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately, as cases of pregnancy that occur during maternal exposures to abemaciclib should be reported. If a patient or spouse/partner is determined to be pregnant following abemaciclib initiation, she must discontinue treatment immediately. Data on fetal outcome and breast-feeding are to be collected for regulatory reporting and drug safety evaluation.

Note: Recommended methods of birth control are: The consistent use of an intrauterine device (IUD), Double barrier methods (Diaphragm with spermicidal gel or condoms with contraceptive foam), Sexual abstinence (no sexual intercourse) or Sterilization.

Men must agree to use a condom and not father a child or donate sperm for the duration of the study and for 90 days after completion of therapy.

A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., hashad menses at any time in the preceding 12 consecutive months).

Exclusion Criteria:

• Treatment with any of the following:

1. Any investigational agents or study drugs from a previous clinical study within 28 days of the first dose of study treatment

2. Any other chemotherapy, immunotherapy or anticancer agents within 21 days ofthe first dose of study treatment

3. Any prior exposure to anti-androgen therapy (bicalutamide, abiraterone, and/orenzalutamide)

• Major surgery (excluding placement of vascular access) within 4 weeks of the firstdose of study treatment

• Spinal cord compression, leptomeningeal carcinomatosis, or brain metastases - unlessasymptomatic, treated and stable and not requiring steroids for at least 2 weeksprior to start of study treatment

• Concurrent use of endocrine therapy (tamoxifen, anastrozole, letrozole, exemestane,oral contraceptive pills)

• As judged by the investigator, any evidence of severe or uncontrolled systemicdiseases, including active bleeding diatheses, or active infection includinghepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening forchronic conditions is not required.

• Any of the following cardiac criteria:

1. Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutiveelectrocardiograms (ECGs)

2. Any clinically important abnormalities in rhythm, conduction or morphology ofresting ECG (e.g., complete left bundle branch block, third degree heart block)

3. Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, abnormalities in serum electrolytes, congenitallong QT syndrome, family history of long QT syndrome or unexplained suddendeath under 40 years of age or any concomitant medication known to prolong theQT interval

4. Personal history of syncope of cardiovascular etiology, ventricular arrhythmia (of pathologic origin including, but not limited to, ventricular tachycardiaand ventricular fibrillation), or sudden cardiac arrest.

5. Experience of any of the following procedures or conditions in the preceding 6months: coronary artery bypass graft, angioplasty, vascular stent, myocardialinfarction, angina pectoris, congestive heart failure NYHA Grade 2 or greater

6. Uncontrolled hypotension - Systolic BP <90mmHg and/or diastolic BP <50mmHg

7. Left ventricular ejection fraction (LVEF) below lower limit of normal for site

• Prior history of DVT/PE or embolic stroke, unless currently on therapeuticanticoagulation

• Inadequate bone marrow reserve or organ function as demonstrated by any of thefollowing laboratory values:

1. Absolute neutrophil count < 1.5 x 109/L

2. Platelet count < 100 x 109/L

3. Hemoglobin < 8 g/L (Patients may receive erythrocyte transfusions to achievethis hemoglobin level at the discretion of the investigator. Initial treatmentmust not begin earlier than the day after the erythrocyte transfusion.)

4. Alanine aminotransferase > 3 times the upper limit of normal (ULN)

5. Aspartate aminotransferase > 3 times ULN

6. Total bilirubin > 1.5 times ULN (patients with Gilbert's syndrome with a totalbilirubin ≤2.0 times ULN and direct bilirubin within normal limits arepermitted)

7. Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation ofcreatinine clearance is only required when creatinine is > 1.5 times ULN

8. Proteinuria 3+ on dipstick analysis or >500mg/24 hours

9. Sodium or potassium outside normal reference range for site

• Liver disease such as cirrhosis, chronic active hepatitis, or chronic persistenthepatitis. Patients who are hepatitis B Core antibody IgG positive are allowed toparticipate if taking and compliant with daily oral hepatitis B prophylacticmedications

• The patient has serious and/or uncontrolled preexisting medical condition(s) that,in the judgment of the investigator, would preclude participation in this study (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).

• Severely impaired lung function as defined as spirometry and DLCO that is 50% of thenormal predicted value and/or 02 saturation that is 89% or less at rest on room air

• Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow the formulated product, or previous significant bowel resection that wouldpreclude adequate absorption abemaciclib or bicalutamide

• Patients with an active bleeding diathesis

• The patient has active systemic bacterial infection (requiring intravenous [IV]antibiotics at time of initiating study 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.

• History of hypersensitivity or allergic reaction to abemaciclib or bicalutamide, ordrugs with a similar chemical structure or class

• Judgment by the investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions andrequirements

• Co-administration with CYP3A4 inducers (e.g., phenytoin, rifampin, carbamazepine, StJohn's Wort, bosentan, efavirenz, etravirine, modafinil, and nafcillin), CYP3A4inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole,lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,telaprevir, telithromycin, verapamil, and voriconazole), and CYP3A4 substrates (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus,fentanyl, pimozide, quinidine, sirolimus and tacrolimus). See Appendix C forcomplete list.

• Other malignancies within the past 3 years except for adequately treated carcinomaof the cervix or basal or squamous cell carcinomas of the skin.

• Female patients who are pregnant or breast feeding/lactating, or adults ofreproductive potential who are not using effective birth control methods. If barriercontraceptives are being used, these must be continued throughout the trial by bothsexes. Hormonal contraceptives are not acceptable as a method of contraception.