A Phase 2/3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate Plus Prednisone with or without Abemaciclib in Patients with Metastatic Castration-Resistant Prostate Cancer

[1] Male patients, 18 years of age or greater; willing and able to provide
written informed consent., [2] Histologically confirmed adenocarcinoma of the
prostate. Well-differentiated neuroendocrine carcinoma, small cell or large
cell neuroendocrine carcinoma, sarcomatoid, and carcinoid tumors are
excluded., [3] Metastatic prostate cancer documented by positive bone scan
and/or measurable soft tissue metastatic lesions by computed tomography (CT) or
magnetic resonance imaging (MRI). If lymph node metastasis is the only evidence
of metastasis, it must be >=1.5cm in the short axis. Visceral metastasis,
including to liver, is allowed., [4] Serum testosterone level <= 1.73 nmol/L (50
ng/dL) at the Screening visit. Patients who have not undergone orchiectomy are
required to continue androgen-deprivation therapy (LHRH agonists/antagonists)
throughout the study., [5] Progressive disease at study entry demonstrated
during continuous androgen deprivation therapy (ADT)/post orchiectomy defined
as one or more of the following criteria:, •Sequence of at least 2 rising PSA
values at a minimum of 1-week intervals with the last result being at least 1.0
ng/ml if confirmed rise is the only indication of progression. Patients who
received an anti-androgen must have PSA progression after withdrawal (>= 4 weeks
since last flutamide or >= 6 weeks since last bicalutamide or nilutamide).,
•Radiographic progression per RECIST1.1 for soft tissue and/or per PCWG3 for
bone, (i.e., appearance of >=2 new bone lesions), with or without PSA
progression., [6] Patient must have discontinued all previous treatments for
cancer (except androgen-deprivation therapy and bone loss prevention
treatment), must have recovered from of all acute toxic effects of prior
therapy or surgical procedure to Grade <= 1 or baseline (as per Common
Terminology Criteria for Adverse Events 5.0) prior to randomization, with the
exception of alopecia or peripheral neuropathy AND have a washout period from
last dose of prior systemic or radiation therapy as follows:
- Patients must discontinue flutamide at least 4 weeks, bicalutamide and
nilutamide at least 6 weeks, prior to randomization.
- At least 4 weeks must have elapsed from the use of 5-α reductase inhibitors
(eg,
dutasteride, finasteride), estrogens, and cyproterone to randomization.
- At least 4 weeks must have elapsed from the use of chemotherapy (ie,
docetaxel,
for mHSPC) to randomization.
- At least 4 weeks must have elapsed from major surgery or radiation therapy
prior
to randomization., [7] Able and willing to undergo tumor biopsy of at least
one metastatic site (mandatory for part 1 and 2, optional for part 3), which
should be collected following determination of eligibility and before
initiating study treatment. [8] Have adequate organ function. [9] Eastern
Cooperative Oncology Group (ECOG) performance status (PS) 0-1. [10] Willing to
comply with study procedures, able to swallow large capsules. Patients with
reproductive potential must agree to use effective contraception and to not
donate sperm during the study and for at least 3 months following the last dose
of study treatment.

[11] Prior therapy with CYP17 inhibitors (including abiraterone acetate,
TAK-700, TOK-001 and ketoconazole), [12] Prior treatment with abemaciclib or
any CDK4 & 6 inhibitors, [13] Known or suspected contraindications or
hypersensitivity to abiraterone acetate, prednisone or abemaciclib or to any of
the excipients. , [14] Prior cytotoxic chemotherapy for metastatic castration
resistant prostate cancer (patients treated with docetaxel in the mHSPC are
eligible), Prior radiopharmaceuticals for prostate cancer, or prior
enzalutamide, apalutamide, sipuleucel-T. Patients who had prior radiation or
surgery to all target lesions., [15] Are currently enrolled in a clinical study
involving an investigational product or any other type of medical research
judged not to be scientifically or medically compatible with this study. Have
participated in clinical trial for which treatment assignment is still blinded.
If patient has participated in a clinical study involving an investigational
product, 3 months or 5 half-lives (whichever is shorter) should have passed.
If a patient is currently enrolled in a clinical trial involving non-approved
use of a device, then agreement with the investigator and Lilly Clinical
Research Physician/ Clinical Research Scientist (CRP/CRS) is required to
establish eligibility., [16] Gastrointestinal disorder affecting absorption or
inability to swallow large pills, [17] Have prior malignancies or active
concurrent malignancy (with the exception of non-melanomatous skin cancer).
Patients with carcinoma in situ of any origin and patients with prior
malignancies who are in remission and whose likelihood of recurrence is very
low per Investigator's judgement are eligible for this study. The Lilly
CRP/CRS will approve enrollment of patients with prior malignancies in
remission before these patients are enrolled., [18] The patient has serious
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, 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)., [19] The patient has an history of any
of the following conditions: syncope of cardiovascular etiology, ventricular
arrhythmia of pathological origin (including, but not limited to, ventricular
tachycardia and ventricular fibrillation), or sudden cardiac arrest. Atrial
Fibrillation, or other cardiac arrhythmia requiring medical therapy., [20]
Clinically significant heart disease as evidenced by myocardial infarction,
arterial thrombotic events in the past 6 months, severe or unstable angina, or
New York Heart Association (NYHA) Class II-IV heart failure or cardiac ejection
fraction measurement of < 50% at baseline., [21] Patients with clinically
active or chronic liver disease, moderate/severe hepatic impairment (Child-Pugh
Class B and C), ascites or bleeding disorders secondary to hepatic
dysfunction., [22] History of adrenal dysfunction, [23] The patient has active
systemic infections (for example, bacterial infection
requiring intravenous [IV] antibiotics at time of initiating study treatment,
fungal infection, or detectable viral infection requiring systemic therapy) or
viral load (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., [24] Known or suspected CNS
metastatic disease (Baseline screening for CNS metastases is not required
unless presence of signs and/or symptoms of involvement)., [25] Uncontrolled
hypertension (systolic BP >= 160 mmHg or diastolic BP >= 95 mmHg). Patients with
a history of hypertension are allowed provided blood pressure is controlled by
anti-hypertensive treatment, [26] Life expectancy < 6 months, [27] Patient
treated with drugs known to be strong inhibitors or strong or moderate inducers
of cytochrome P450 3A4 (CYP3A4), and the treatment cannot be discontinued or
switched to a different medication at least five half-lives prior to starting
study drug. , [28] Have received recent (within 4 weeks prior to randomization)
live vaccination. Seasonal flu vaccines that do not contain a live virus are
permitted., [29] Untreated spinal cord compression or evidence of spinal
metastases with risk of spinal compression. Structurally unstable bone lesions
suggesting impending fracture.