Inclusion Criteria:
1. Provision of signed and dated, written informed consent prior to any study specific
procedures, sampling and analysis. If a patient declines to participate in any
voluntary exploratory research of the study, there will be no loss of benefit to the
patient and she will not be excluded from other aspects of the study. 2. Women aged at least 18 years. 3. The patient has a biopsy-confirmed diagnosis of recurrent, unresectable, locally
advanced, or metastatic AR+ TNBC. 1. AR+ assessed locally and defined as ≥1% of cells staining on IHC of last
recurrent/metastatic breast cancer specimen. 2. Local biopsy confirmation of last recurrent/metastatic site with positive IHC
for ER and/or PR in ≤10% of cells and negative for HER2 per ASCO/CAP-guidelines. 3. Prior invasive (metastatic) breast cancer with positive IHC for ER and/or PR in
>10% of cells is allowed, provided the last biopsy of recurrent/metastatic
disease has positive IHC for ER and/or PR in ≤10% of cells. 4. Prior invasive (metastatic) HER2-positive breast cancer per ASCO/CAP-guidelines
is not allowed. 5. The patient has measurable disease per RECIST 1.1 or evaluable bone-only
disease with lytic or mixed component that is progressive as evidenced on
pre-treatment baseline imaging. 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 with no
deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks. 5. The patient must have had prior treatment with at least 1 prior cytostatic regimen
in advanced setting setting unless treatment with a cytostatic regimen is
contraindicated as judged by Investigator. There is no upper limit for prior
treatment lines in advanced setting.
- - Patients with 1-10% cells with positive IHC for ER in the last
recurrent/metastatic site must be treated with at least one line of endocrine
therapy in advanced setting.
- - Patients with known germline BRCA1/2 pathogenic variants should have received
previous treatment with PARP inhibitors in the early/locally advanced or
metastatic setting, unless contraindicated.
- - Prior treatment with palbociclib or ribociclib is allowed, provided at least 6
months have elapsed between last administration and start of study treatment.
6. Patients must have recovered (Common Terminology Criteria for Adverse Events [CTCAE]
Grade ≤1) from the acute effects of prior anticancer treatment except for residual
Grade 2 alopecia, anemia or peripheral neuropathy prior to randomization. A washout
period of at least 21 days is required between last chemotherapy dose and first dose
of study drug (provided the patient did not receive radiotherapy).
7. Patients who received radiotherapy must have completed and fully recovered from the
acute effects of radiotherapy. A washout period of at least 14 days is required
between end of radiotherapy and randomization.
8. In females of child-bearing potential, a negative serum or urine pregnancy test
within 7 days prior to starting treatment is required. Women of child-bearing
potential must agree to use a highly effective method of contraception prior to
study entry, for the duration of study participation (in addition to the
LHRH-agonist), and for 3 weeks following completion of abemaciclib and for 130 days
following completion of bicalutamide.
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., has
had menses at any time in the preceding 12 consecutive months).
Exclusion Criteria:
1. Treatment with any of the following:
a. Any experimental treatment in a clinical trial within the last 30 days or 5
half-lives, whichever is longer, prior to randomization.
b) Currently enrolled in any other type of medical research (for example: medical
device) judged by the sponsor not to be scientifically or medically compatible with
this study.
c. Any other chemotherapy, immunotherapy or anticancer agents within 21 days of the
first dose of study treatment d. Treatment with palbociclib or ribociclib within 6
months of the first dose of study treatment e. Any prior exposure to abemaciclib f.
Any prior exposure to anti-androgen therapy (bicalutamide, abiraterone, and/or
enzalutamide)
2. Major surgery (excluding placement of vascular access) within 4 weeks of the first
dose of study treatment. 3. Spinal cord compression, leptomeningeal carcinomatosis, or brain metastases
- - unless
asymptomatic, treated, stable at baseline imaging and not requiring corticosteroids
>10 mg prednisolone daily (or equivalent) for at least 2 weeks prior to start of
study treatment.
4. Concurrent use of endocrine therapy (tamoxifen, anastrozole, letrozole, exemestane,
oral contraceptive pills)
5. 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).
6. 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.
7. 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 (eg, 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, hypokalemia, 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. Known left ventricular ejection fraction (LVEF) below lower limit of normal for
site. 8. Prior history of DVT/PE or embolic stroke, unless currently on therapeutic
anticoagulation. 9. 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/dL (Patients may receive 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 per local institutional practice); confirmation of
creatinine clearance is only required when creatinine is > 1.5 times ULN. 8. Known proteinuria 3+ on dipstick analysis or >500mg/24 hours. 9. Sodium or potassium outside normal reference range for site. Grade 1
abnormality of sodium and potassium (as defined by CTCAE v5.0) can be included
if judged clinically not significant by the investigator, based on the
participant's clinical context and comorbidities.
10. 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. 11. Severely impaired lung function defined as spirometry and DLCO that is less than or
equal to 50% of the normal predicted value and/or 02 saturation that is 89% or less
at rest on room air and/or serious /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).
12. Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN. 13. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product, or previous significant bowel resection that would
preclude adequate absorption of abemaciclib and/or bicalutamide. 14. Patients with an active bleeding diathesis. 15. 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.
16. History of hypersensitivity or allergic reaction to abemacliclib, bicalutamide or
goserelin, or drugs with a similar chemical structure or class. 17. 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. 18. Co-administration with strong CYP3A4 inducers (e.g., phenytoin, rifampin,
carbamazepine, St John's Wort, bosentan, efavirenz, etravirine, modafinil, and
nafcillin) or strong CYP3A4 inhibitors (e.g., clarithromycin, indinavir,
itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir,
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and
voriconazole). See Appendix 4 for complete list.
19. Other invasive malignancies within the past 3 years except for adequately treated
carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
20. Female patients who are pregnant or breast feeding/lactating, or females of
reproductive potential who are not using effective birth control methods. Hormonal
contraceptives are not acceptable as a method of contraception.
21. Patients with hereditary problems of galactose intolerance, total lactase
deficiency, or glucose-galactose malabsorption
