Metastatic Urothelial Carcinoma (UC)
Conditions
Keywords
metastatic urothelial carcinoma (UC), LCCC 1406, Lineberger, palbociclib
Brief 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.
Detailed description
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.
Interventions
DRUGPalbociclib
125 mg capsule will be taken once per day orally and continuously for 3 weeks followed by 1 week off.
Sponsors
Pfizer
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 4 Months | Estimate progression free survival (PFS) at 4 months in patients with metastatic urothelial cancer (UC) who have progressed after first-line chemotherapy. PFS is defined as the percent of patients who are alive and free from progression at 4 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 4 Months | PFS is defined as the time from D1 of treatment until progression or death as a result of any cause. Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Overall Survival (OS) | Patients will be followed for up to 5 years after removal from study therapy or death, whichever occurs first. | Overall survival is defined as the time from day 1 of treatment until death as a result of any cause. |
| Response Rate (RR) - Total Number of Patients With Complete Response (CR) and/or Partial Response (PR) | 4 Months | Estimate response rate (RR) in patients with metastatic UC who have progressed after first-line chemotherapy. Response rate will be the number of patients with complete response and/or partial response. Response will be based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Number of Participants With Adverse Events | 30 Days | Characterize the safety profile of palbociclib in patients with metastatic UC after first-line chemotherapy. The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. |
Countries
United States
Participant flow
Recruitment details
12 patients were enrolled between April 2015 and January 2017.
Pre-assignment details
34 patients were screened, 25 were eligible based on tumor immunohistochemistry (IHC) demonstrating p16 loss and intact retinoblastoma. Of those, 12 patients were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Single Arm (Single Arm Trial) Palbociclib
Palbociclib: 125 mg capsule will be taken once per day orally and continuously for 3 weeks followed by 1 week off. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Single Arm (Single Arm Trial) |
|---|---|
| Age, Continuous | 68 years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 5 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 6 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Hemoglobin <10 g/dL | 2 Participants |
| Hemoglobin >= 10 g/dL | 10 Participants |
| Liver Metastases No | 12 Participants |
| Liver Metastases Yes | 0 Participants |
| Number of prior systemic therapy regiments (including immunotherapy) 1 | 7 Participants |
| Number of prior systemic therapy regiments (including immunotherapy) 2 | 3 Participants |
| Number of prior systemic therapy regiments (including immunotherapy) 3 | 2 Participants |
| Primary Tumor Site Bladder | 7 Participants |
| Primary Tumor Site Upper Tract | 4 Participants |
| Primary Tumor Site Urethra | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 12 Participants |
| Setting of prior platinum-based chemotherapy Both | 2 Participants |
| Setting of prior platinum-based chemotherapy Metastatic only | 2 Participants |
| Setting of prior platinum-based chemotherapy Perioperative only | 8 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 8 Participants |
| Time from prior therapy >=12 months | 2 Participants |
| Time from prior therapy 3-6 months | 5 Participants |
| Time from prior therapy < 3 months | 4 Participants |
| Time from prior therapy 6-9 months | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 3 / 12 |
Outcome results
Primary
Progression Free Survival
Estimate progression free survival (PFS) at 4 months in patients with metastatic urothelial cancer (UC) who have progressed after first-line chemotherapy. PFS is defined as the percent of patients who are alive and free from progression at 4 months.
Time frame: 4 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm (Single Arm Trial) | Progression Free Survival | 2 Participants |
Secondary
Number of Participants With Adverse Events
Characterize the safety profile of palbociclib in patients with metastatic UC after first-line chemotherapy. The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.
Time frame: 30 Days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm (Single Arm Trial) | Number of Participants With Adverse Events | Any Adverse Event | 12 Participants |
| Single Arm (Single Arm Trial) | Number of Participants With Adverse Events | Any Treatment Related Adverse Event | 11 Participants |
| Grade >=3 Adverse Event | Number of Participants With Adverse Events | Any Adverse Event | 11 Participants |
| Grade >=3 Adverse Event | Number of Participants With Adverse Events | Any Treatment Related Adverse Event | 9 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from day 1 of treatment until death as a result of any cause.
Time frame: Patients will be followed for up to 5 years after removal from study therapy or death, whichever occurs first.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm (Single Arm Trial) | Overall Survival (OS) | 6.3 Months |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from D1 of treatment until progression or death as a result of any cause. Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: 4 Months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm (Single Arm Trial) | Progression Free Survival (PFS) | 1.9 Months |
Secondary
Response Rate (RR) - Total Number of Patients With Complete Response (CR) and/or Partial Response (PR)
Estimate response rate (RR) in patients with metastatic UC who have progressed after first-line chemotherapy. Response rate will be the number of patients with complete response and/or partial response. Response will be based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 4 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm (Single Arm Trial) | Response Rate (RR) - Total Number of Patients With Complete Response (CR) and/or Partial Response (PR) | 0 Participants |