Phase II Trial of Palbociclib in Patients With Metastatic Urothelial Cancer After Failure of First-Line Chemotherapy
Condition: Metastatic Urothelial Carcinoma (UC)
MeSH terms: Carcinoma, Transitional Cell
Intervention: Palbociclib
Intervention description: 125 mg capsule will be taken once per day orally and continuously for 3 weeks followed by 1 week off.
Intervention MeSH terms: Palbociclib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: metastatic urothelial carcinoma (UC); LCCC 1406; Lineberger; palbociclib

Summary:

      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.
    

Eligibility criteria:

        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