Data from first 12 subjects-primary endpoint not met. Data analysis underway.

This multicenter phase II trial will evaluate palbociclib (PD-0332991) in patients with metastatic urothelial carcinoma (UC) with cyclin-dependent kinase inhibitor 2A (CDKN2A) (also referred to as p16) loss and positive Retinoblastoma (Rb) expression after failure of first-line chemotherapy.

This multicenter phase II trial will evaluate palbociclib (PD-0332991) in patients with metastatic urothelial carcinoma (UC) with cyclin-dependent kinase inhibitor 2A (CDKN2A) (also referred to as p16) loss and positive Retinoblastoma (Rb) expression after failure of first-line chemotherapy. The study will enroll up to 40 patients to identify 36 evaluable patients, using a Simon's two-stage design, with a primary endpoint of progression free survival (PFS) at 4 months (PFS4). Secondary objectives include estimating median PFS, overall survival (OS), response rate (RR) and exploratory objectives include an evaluation of molecular predictors of response and resistance.

Inclusion Criteria:

• Age ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) Performance status of ≤ 2 (see section 11.1, Appendix A)

• Histologically confirmed UC of the bladder, urethra, ureter or renal pelvis with Rb+/CDKN2A- based on immunohistochemistry (IHC) of tissue blocks or unstained slides performed within a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory at University of North Carolina (UNC); if stage I of original cohort indicates futility, molecular requirement for eligibility will change to Rb+/CCND1 overexpression (also based on IHC); see statistical section, section 8.0)

• Metastatic disease that is not amenable to curative surgery or radiation

• Prior treatment with ≤ two prior cytotoxic regimens; prior therapy must have consisted of at least one of the following: cisplatin, carboplatin, paclitaxel, docetaxel or gemcitabine. If the only prior cytotoxic therapy was administered in the perioperative i.e. neoadjuvant or adjuvant settings, patient is eligible provided the interval from end of therapy to the diagnosis of metastatic disease is less than one year.

• Progressive disease during or after treatment with at least one of the agents listed above

• At least one measurable disease site (as defined by Response Evaluation Criteria In Solid Tumors (RECIST)1.1) that has not been previously irradiated

• No prior therapy with a CDK 4/6 inhibitor; prior anti PD-1 and anti PD-L1 therapy is permitted

• Washout period should be at least 2 weeks for prior chemotherapy or radiation therapy 3.1.10 Resolution of all acute toxic effects of prior chemotherapy, radiotherapy, surgery to ≤ grade 1 per NCI Common Terminology Criteria for Adverse Events (CTCAE)v4 except neuropathy which may be ≤ grade 2

• No active brain metastases

• Adequate bone marrow, liver and renal functions as assessed by the following:

  • Hemoglobin ≥ 8 g/dL;
  • Absolute neutrophil count ≥ 1,500/uL;
  • Platelets ≥ 75,000 g/uL;
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN);
  • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN;
  • serum creatinine ≤ 2.5 times ULN;

• Negative serum pregnancy test in women of child-bearing potential within 7 days of D1 of treatment

• If fertile, agree to use effective contraception (condom or other barrier methods, oral contraceptives, implantable contraceptives, intrauterine devices) during trial

• Life expectancy greater than 3 months

• Subject must be able to give written Institutional Review Board (IRB) approved informed consent and be able to follow protocol requirements

Exclusion Criteria:

• Any prior treatment with any investigational drug within the preceding 4 weeks
• Any concurrent active malignancy requiring treatment (other than basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, superficial bladder tumors, other malignancies curatively treated > 3 years prior to study entry) or patients with adenocarcinoma of the prostate that has been surgically treated and with a post-treatment prostate-specific antigen (PSA) that is non-detectable.
• Unstable systemic disease or active uncontrolled infection
• Major surgery, open biopsy or significant traumatic injury within 4 weeks prior to study entry
• Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville oranges, pomelos, and exotic citrus fruits from 7 days prior to the dose of study medication and during the entire study due to potential CYP3A4 interaction with the study medication. Orange juice is allowed.
• Intake of any herbal preparations or medications (including, but not limited to, Saint John's Wort and ginkgo biloba) and dietary supplements within 7 days prior to first dose of study drug
• Unable or unwilling to discontinue use of any drug known to be a strong or moderate inhibitor or inducer of CYP3A4 (prohibited inducers and inhibitors must be discontinued within 2 weeks prior to first dose of study drug; see section 11.2 Appendix B); unable or unwilling to discontinue use of any proton pump inhibitor; see section 11.2, Appendix B
• Any malabsorption problem that, in the investigator's opinion, would prevent adequate absorption of the study drug
• Inability to swallow oral medications
• Pregnant or breast-feeding
• Substance abuse, or medical, psychological or social conditions that may interfere with the patient's participation in the study or the evaluation of the study results
• Other serious, ongoing, non-malignant disease or infection that would compromise protocol objectives