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

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 of the first dose of study treatment
• •3. Any prior exposure to anti-androgen therapy (bicalutamide, abiraterone, and/or enzalutamide)
• •Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment
• •Spinal cord compression, leptomeningeal carcinomatosis, or brain metastases - unless asymptomatic, treated and stable and not requiring steroids for at least 2 weeks prior 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 systemic diseases, including active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
• •Any of the following cardiac criteria:
• •1. Mean resting corrected QT interval (QTc) \> 470 msec obtained from 3 consecutive electrocardiograms (ECGs)
• •2. Any clinically important abnormalities in rhythm, conduction or morphology of resting 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 arrhythmic events such as heart failure, abnormalities in serum electrolytes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
• •4. Personal history of syncope of cardiovascular etiology, ventricular arrhythmia (of pathologic origin including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
• •5. Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, 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 therapeutic anticoagulation
• •Inadequate bone marrow reserve or organ function as demonstrated by any of the following 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 achieve this hemoglobin level at the discretion of the investigator. Initial treatment must 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 total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted)
• •7. Creatinine \>1.5 times ULN concurrent with creatinine clearance \< 50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine 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 persistent hepatitis. Patients who are hepatitis B Core antibody IgG positive are allowed to participate if taking and compliant with daily oral hepatitis B prophylactic medications
• •The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment \[e.g. estimated creatinine clearance \<30ml/min\], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
• •Severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal 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 to swallow the formulated product, or previous significant bowel resection that would preclude 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 detectable viral infection (such as known human immunodeficiency virus positivity or with known active 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, or drugs with a similar chemical structure or class
• •Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
• •Co-administration with CYP3A4 inducers (e.g., phenytoin, rifampin, carbamazepine, St John's Wort, bosentan, efavirenz, etravirine, modafinil, and nafcillin), CYP3A4 inhibitors (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 for complete list.
• •Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
• •Female patients who are pregnant or breast feeding/lactating, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a method of contraception.