(CLONEVO): Cell cycLe inhbitiON to Target the EVolution of UrOthelial Cancer

A Window-of-Opportunity Trial of Abemaciclib followed by radical cystectomy in patients with
Platinum-Ineligible Urothelial Carcinoma to Evaluate CDK4/6-Dependent Phosphorylation of
Pocket Proteins and Clonal Evolution Dynamics. Subjects will be treated with Abemaciclib at
200 mg every 12 hours for at least 4 weeks (and likely slightly longer depending upon
surgical date). Individual dose reductions will be made on the basis of the AEs observed. In
the absence of treatment delays due to adverse event(s), treatment will be continued until
the surgical date unless any of the following criteria applies: 1-Disease progression;
2-Intercurrent illness that prevents further administration of treatment; 3-Unacceptable
adverse event(s) as a result of Abemaciclib; 4- Patient decides to withdraw from the study;
5-General or specific changes in the patient's condition render the patient unacceptable for
further treatment in the judgment of the investigator. Patients will be followed with
history, physical, and blood tests at each visit to monitor for toxicity. Patients will be
followed for survival endpoints following completion of this study for 3 years after surgery
or until death. Patients removed from study for unacceptable adverse events will be followed
until resolution or stabilization of the adverse event.

Inclusion Criteria:

- Age ≥ 18 years old at time of informed consent

- Histologically confirmed MIBC (T2-T4) pure or mixed histology urothelial carcinoma
[urothelial carcinoma should be the dominant (>50%) histology].

- Refusing cisplatin-based chemotherapy or ineligible for cisplatin-based chemotherapy
due to at least one of the following:

1. Creatinine clearance < 60 mL/min (by Cockgroft-Gault calculation and/or measured
creatinine clearance)

2. Hearing loss ≥ grade 2 by CTCAE criteria and/or;

3. Neuropathy ≥ grade 2 by CTCAE criteria and/or

4. Heart failure NYHA ≥ III

- Medically fit for TURBT and radical cystectomy

- Adequate organ and marrow function as defined below:

1. Absolute neutrophil count ≥ 1.5 K/mm3

2. White blood cell count (WBC) > 3.0 K/mm3

3. Platelets ≥ 100 K/mm3

4. Hemoglobin ≥ 9 g/dL

5. Serum total bilirubin ≤ 1.5 x ULN

6. ALT and AST ≤ 2.5 x ULN

7. Serum creatinine clearance (CrCl) ≥ 30 ml/min using the Cockcroft-Gault or
measurement with 24 hour urine collection

Exclusion Criteria:

- Patients with locally advanced unresectable or metastatic urothelial carcinoma as
assessed on baseline radiographic imaging obtained within 28 days prior to study
enrollment. Low volume (<1.5 cm) suspicious lymph node metastases in the pelvis are
allowed if they are in the LN dissection template field. The required radiographic
imaging includes:

1. Abdomen/pelvis - CT/MRI

2. Chest - chest x-ray or CT scan

3. Bone scan or FDG-PET/CT in the presence of bone pain or unexplained elevated
alkaline phosphatase

- Patients with another active second malignancy other than non-melanoma skin cancers
and localized prostate cancer. Patients that have completed all necessary therapy and
are considered to be <30% risk of relapse are not considered to have an active second
malignancy and are eligible for enrollment.

- Patients who have received anti-cancer therapy including chemotherapy, radiotherapy,
immunotherapy, and monoclonal antibodies ≤ 4 weeks prior to starting study drug, or
who have not recovered from the side effects of such therapy

- Patients with any concurrent severe and/or uncontrolled medical conditions which could
compromise participation in the study

- Have an active systemic fungal and/or known viral infection (for example, human
immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C
antibodies).

- Subjects who received a strong CYP3A inhibitor within 7 days prior to the first dose
of study drug, or patients who require continuous treatment with a strong CYP3A
inhibitor

- Pregnant or breast-feeding women

- Women who do not agree to use a medically approved contraceptive method during the
treatment period and for 3 months following the last dose of Abemaciclib

- Men who do not agree to use a reliable method of birth control and to not donate sperm
during the study and for at least 3 months following the last dose of Abemaciclib

- Subjects unwilling or unable to comply with the protocol