Ribociclib and Bicalutamide in AR+ TNBC

OUTLINE: This is a multi-center study.

INVESTIGATIONAL TREATMENT:

- bicalutamide - 150mg po daily D1 - D28 (Cycle = 28 days)

- ribociclib po daily D1 - D21 of 28 day cycle

PHASE I SAFETY RUN-IN COHORT:

The maximum tolerated dose (MTD) of bicalutamide in combination with ribociclib will be
determined using a standard "3+3" design. The first cohort of 3 subjects will receive
ribociclib 400mg po daily D1 - D21 of a 28 day cycle (Dose Level 1). If no DLTs are
experienced then the next cohort of 3 subjects will receive ribociclib 400mg po daily D1 -
D28 of a 28 day cycle (Dose Level 2). If no DLTs are experienced then the next cohort of 3
subjects will receive ribociclib 600mg po daily D1 - D21 of a 28 day cycle (Dose Level 3). If
no DLTs are experienced on Dose Level 3, then 3 additional subjects should be treated at this
level before declaring MTD.

DLTs will be assessed within the first cycle (28 days).

PHASE II INVESTIGATIONAL TREATMENT:

- co-therapy bicalutamide 150mg po daily D1 - D28

- ribociclib po at the RP2D as determined in the Phase I Safety Run-In Cohort

Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 28 days prior
to registration

Life expectancy of > 12 weeks as determined by the treating physician.

Hematological:

- White blood cell (WBC) ≥4 × 10^9/L

- Absolute Neutrophil Count (ANC) ≥1.5 × 10^9/L

- Hemoglobin (Hb) ≥9 g/dL

- Platelets (Plt) ≥100 × 10^9/L

Renal:

- Creatinine ≤1.5 mg/dL OR

- Calculated creatinine clearance ≥50 ml/min using the Cockcroft-Gault formula

Hepatic:

- Bilirubin ≤upper limit of normal (ULN)*

- Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN if liver mets.

- Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN if liver mets. * For subjects with
Gilbert's syndrome, this will apply to direct bilirubin only.

Inclusion Criteria:

- Metastatic or unresectable AR+ triple-negative breast cancer (TNBC); AR positivity
assessed centrally and defined as immunohistochemical (IHC) staining of >0% of tumor
nuclei.

- Written informed consent and Health Insurance Portability and Accountability Act of
1996 (HIPAA) authorization for release of personal health information. NOTE: HIPAA
authorization may be included in the informed consent or obtained separately.

- One prior line of therapy is allowed.

- Age ≥ 18 years at the time of consent.

- Measurable disease according to RECIST 1.1 within 28 days prior to registration.

- No active central nervous system (CNS) metastatic disease. NOTE: Subjects with CNS
involvement must meet ALL of the following to be eligible:

- At least 28 days from prior definitive treatment of their CNS disease by surgical
resection, stereotactic body radiation therapy (SBRT) or whole brain radiation
treatment (WBRT) at the time of registration

- AND asymptomatic and off systemic corticosteroids and/or enzyme-inducing
anti-epileptic medications for brain metastases for >14 days prior to
registration.

- Prior cancer treatment must be completed at least 14 days prior to registration and
the subject must have recovered from all reversible acute toxic effects of the regimen
(other than alopecia) to ≤grade 1 or to baseline prior to initiation of that therapy.

- Screening rate-corrected QT interval (QTc) must be <450msec and a resting heart rate
of at least 50-90 bpm via a standard 12-lead ECG within 28 days prior to registration.

- Females of childbearing potential must have a negative serum pregnancy test within 7
days prior to registration. NOTE: Females are considered of child bearing potential
unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy), or they are naturally postmenopausal for at
least 12 consecutive months, or her male partner has had a vasectomy at least 6 months
prior to screening (The sterilized male partner must be her only sexual partner.).

- Females of childbearing potential and males must be willing to abstain from
heterosexual activity or must agree to use adequate contraception (hormonal or barrier
method) for the duration of study participation and for 3 weeks after discontinuation
of study treatment.

- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study.

- Able to swallow bicalutamide and ribociclib capsules/tablets.

Exclusion Criteria:

- No prior therapy with AR antagonists including but not limited to bicalutamide,
enzalutamide, abiraterone and orteronel.

- No prior therapy with any CDK 4/6 inhibitors.

- Active infection requiring systemic therapy.

- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).

- Known additional malignancy that is active and/or progressive requiring treatment;
exceptions include basal cell or squamous cell skin cancer, in situ cervical or
bladder cancer, or other cancer for which the subject has been disease-free for at
least three years.

- Treatment with any investigational drug within 14 days prior to registration or within
5 half-lives of the investigational product, whichever is longer.

- Subject who has received radiotherapy <14 days prior to registration, and who has not
recovered to grade 1 or better from related side effects of such therapy (exceptions
include alopecia).

- Subject has had major surgery within 14 days prior to registration or has not
recovered from major side effects of the surgery (tumor biopsy is not considered as
major surgery).

- Known hypersensitivity to any of the excipients of ribociclib or bicalutamide.

- Any impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

- Known history of HIV infection (testing not mandatory).

- Any concurrent severe and/or uncontrolled medical condition that would, in the
investigator's judgment, cause unacceptable safety risks, contraindicate subject
participation in the clinical study or compromise compliance with the protocol (e.g.
chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled
fungal, bacterial or viral infections, etc.).

- Subjects with any of the following conditions are excluded:

- Serious or non-healing wound, ulcer, or bone fracture.

- History of abdominal fistula, gastrointestinal perforation, or intra- abdominal
abscess within 28 days prior to registration.

- Any history of cerebrovascular accident (CVA) or transient ischemic attack within
12 months prior to registration.

- Any history of arterial or venous thrombosis/thromboembolic event, including
pulmonary embolism within the past 12 months prior to registration.

- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or
symptomatic pericarditis within 6 months prior to registration.

- Symptomatic congestive heart failure (New York Heart Association III-IV) or
documented cardiomyopathy with left ventricular ejection fraction (LVEF) <50% as
determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at
screening. MUGA/ ECHO to be performed within 28 days prior to registration.

- Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia),
complete left bundle branch block, high-grade AV block (e.g. bifascicular block,
Mobitz type II and third-degree AV block).

- Any episode of atrial fibrillation in the prior 12 months.

- Long QT syndrome or family history of idiopathic sudden death or congenital long
QT syndrome.

- Concomitant use of medication(s) with a known risk to prolong the QT interval
and/or known to cause Torsades de Pointe that cannot be discontinued (within 5
half-lives or 7 days prior to starting study drug) or replaced by safe
alternative medication.

- Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening.

- Currently receiving any known strong inducers or inhibitors of CYP3A4/5 which cannot
be discontinued 7 days prior to starting study drug

- Subject is currently receiving or has received systemic corticosteroids <14 days prior
to starting study drugs. The following uses of corticosteroids are permitted: single
doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive
airways diseases), eye drops or local injections (e.g., intra-articular).

- Subject is currently receiving warfarin or other coumarin-derived anticoagulant for
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
heparin (LMWH), or fondaparinux is allowed.

- Subject with a Child-Pugh score B or C.

- Subjects taking herbal supplements (St. John's Wort, gingko biloba, etc.) should
discontinue these supplements 14 days prior to study registration.

- Consumption of grapefruit, grapefruit hybrids, pummelos, star-fruit, Seville oranges
or products containing the juice of each within 7 days prior to study registration.