Urothelial Carcinoma
Conditions
Keywords
Muscle-invasive cisplatin-ineligible, urothelial carcinoma of the bladder, radical cystectomy., epacadostat, retifanlimab, TIM-3, LAG-3
Brief summary
This is a multicenter, open-label, randomized, Phase 2 umbrella study of various neoadjuvant treatment combinations in participants who have muscle-invasive urothelial carcinoma of the bladder and are cisplatin-ineligible or refusing cisplatin therapy and awaiting radical cystectomy.
Detailed description
Participants will be stratified based on Programmed cell Death-Ligand 1 (PD-L1) Combined Positive Score ( CPS) \< 10 and PD-L1 CPS ≥ 10.
Interventions
DRUGretifanlimab
retifanlimab will be administered via IV over 30 minutes (+ 15 min) on Day 1 of each 28-day cycle, up to 3 cycles,
DRUGepacadostat
epacadostat will be administered daily twice daily orally up to and including day of surgery.
DRUGINCAGN02385
INCAGN02385 will be administered via IV over 30 minutes (-5/+10 min) every 2 weeks.
DRUGINCAGN02390
INCAGN02390 will be administered via IV over 30 minutes (-5/+10 min) every 2 weeks.
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open Label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed transitional cell urothelial carcinoma. Participants with mixed histologies are required to have a dominant (ie, 50% at least) transitional cell pattern. * Clinical stage T2-T3b, N0, M0 muscle invasive urothelial carcinoma by CT (or MRI) (Stage II-IIIA per AJCC 2018) * Refuse cisplatin therapy (does not apply in France) or are ineligible for cisplatin therapy per modified Galsky criteria with exclusion of Eastern Cooperative Oncology Group( ECOG) PS 2 participants * Eligible for radical cystectomy * Eastern Cooperative Oncology Group (ECOG) Performance Status( PS) 0 or 1. * Pretreatment tumor biopsy must be a tumor block or 20 unstained slides from biopsy of primary tumor containing at least 20% tumor. * Willingness to avoid pregnancy or fathering children from screening through 100 days in the US and 190 days in Europe after the last dose of study drug
Exclusion criteria
* Participation in any other study in which receipt of an investigational study drug or device occurred within 28 days or 5 half-lives (whichever is longer) before first dose. * Previously received systemic therapy for bladder cancer or received prior treatment with checkpoint inhibitor agents (such as anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4). * Evidence of measurable nodal or metastatic disease. * Concurrent anticancer therapy. * Has had major surgery within 4 weeks before enrollment (C1D1). * Has had known additional malignancy other than muscle-invasive Urothelial Bladder Cancer ( miUBC) that is progressing or requires active treatment, along with some protocol exceptions, or history of other malignancy within 2 years of study entry, with some predefined-protocol exceptions. * Has active autoimmune disease requiring systemic immunosuppression with corticosteroids (\> 10 mg daily doses of prednisone or equivalent) or immunosuppressive drugs within 2 years of Day 1 of study treatment. * Participants with laboratory values outside of protocol defined ranges. * Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (\> 10 mg/day of prednisone or equivalent). * Has a known active hepatitis B (defined as HBsAg and total anti-HBc positive results) or hepatitis C (HCV Ab positive result and HCV RNA \>LLoD) or HIV,HBV, HCV or hepatitis virus coinfection. * Participants with HIV+ disease along with protocol defined exceptions that don't have undetectable viral load along with other protocol exceptions. * Has known carcinomatous meningitis. * Active infection requiring systemic antibiotics ≤ 14 days from first dose of study drug. * Participants with known or suspected active COVID-19 infection. * Use of probiotics within 28 days from first dose of study drug. * Current use of prohibited medication as per protocol. * Has not recovered to ≤ Grade 1 from toxic effects of previous therapy and/or complications from previous surgical intervention. * History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. A screening QTcF interval \> 450 milliseconds is excluded. * History of a gastrointestinal condition (eg, inflammatory bowel disease, Crohn's disease, ulcerative colitis) that may affect oral drug absorption. * Has received a live vaccine within 30days of planned start of study therapy * Participants with impaired cardiac function or clinically significant cardiac disease * Prior allogenic tissue/solid organ transplant * Evidence of interstitial lung disease or active, noninfectious pneumonitis. * Has known hypersensitivity to any of the study drugs, excipients, including mannitol or another monoclonal antibody which cannot be controlled with standard measures (eg, antihistamines and corticosteroids). * Any ≥ Grade 2 immune-related toxicity while receiving prior immunotherapy. * History of serotonin syndrome after receiving 1 or more serotonergic drugs. * Concomitant use of medications that are known to be substrates of CYP1A2, CYP2C8, or CYP2C19 with narrow therapeutic window are prohibited (see Section 6.6.3). * Patients who are receiving or required to receive medications that are known to be UGT1A9 inhibitors (see Section 6.6.3).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CD8+ Lymphocytes Within the Resected Tumor | up to 69 days | Fold Change from Baseline in CD8+ lymphocytes = CD8+ Lymphocytes at cystectomy divided by CD8+ lymphocytes at Screening. Translational data in all but the retifanlimab 500 mg Q4W treatment group were limited and insufficient to assess this outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | up to 159 days | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study drug. |
| Number of Participants With Any ≥Grade 3 TEAE | up to 159 days | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study drug. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal. |
| Pathological Complete Response Rate | up to 69 days | Pathological complete response rate was defined as the percentage of participants with ypT0N0. |
| Major Pathological Response | up to 69 days | Major pathological response was defined as the percentage of participants with residual ypT0/1/a/isN0M0. |
Countries
France, Italy, United States
Participant flow
Pre-assignment details
Participants were enrolled at 2 study centers in the United States, 2 study centers in Italy, and 1 study center in France.
Participants by arm
| Arm | Count |
|---|---|
| Epacadostat 600 mg BID + Retifanlimab 500 mg Q4W Participants received oral epacadostat 600 milligrams (mg) twice daily (BID) + intravenous retifanlimab 500 mg every 4 weeks (Q4W; on Day 1 of each 28-day cycle). Treatment continued for 4 to 10 weeks, as long as participants did not meet any criteria for study withdrawal. | 3 |
| Retifanlimab 500 mg Q4W Participants received intravenous retifanlimab 500 mg Q4W (on Day 1 of each 28-day cycle). Treatment continued for 4 to 10 weeks, as long as participants did not meet any criteria for study withdrawal. | 20 |
| Epacadostat 600 mg BID Participants received oral epacadostat 600 mg BID. Treatment continued for 4 to 10 weeks, as long as participants did not meet any criteria for study withdrawal. | 2 |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W Participants received intravenous retifanlimab 500 mg Q4W (on Day 1 of each 28-day cycle) + intravenous INCAGN02385 350 mg every 2 weeks (Q2W). Treatment continued for 4 to 10 weeks, as long as participants did not meet any criteria for study withdrawal. | 4 |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W Participants received intravenous retifanlimab 500 mg Q4W (on Day 1 of each 28-day cycle) + intravenous INCAGN02385 350 mg Q2W + intravenous INCAGN02390 400 mg Q2W. Treatment continued for 4 to 10 weeks, as long as participants did not meet any criteria for study withdrawal. | 1 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Surgery Delayed 140 Days Post-Last Dose Due to AE; Follow-up Data Not Collected | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W | Epacadostat 600 mg BID + Retifanlimab 500 mg Q4W | Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W | Total | Epacadostat 600 mg BID | Retifanlimab 500 mg Q4W |
|---|---|---|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 3.86 | 75.7 years STANDARD_DEVIATION 6.66 | NA years | NA years | 65.0 years STANDARD_DEVIATION 1.41 | 71.1 years STANDARD_DEVIATION 6.08 |
| Race/Ethnicity, Customized Cannot Be Reported Due to Participant Privacy | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 4 Participants | 2 Participants | 0 Participants | 22 Participants | 1 Participants | 15 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 1 Participants | 0 Participants | 7 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized White/Caucasian | 4 Participants | 2 Participants | 0 Participants | 24 Participants | 2 Participants | 16 Participants |
| Sex/Gender, Customized Cannot Be Reported Due to Participant Privacy | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Sex/Gender, Customized Female | 1 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 2 Participants |
| Sex/Gender, Customized Male | 3 Participants | 3 Participants | 0 Participants | 25 Participants | 1 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 20 | 0 / 2 | 0 / 4 | 0 / 1 |
| other Total, other adverse events | 3 / 3 | 18 / 20 | 2 / 2 | 4 / 4 | 1 / 1 |
| serious Total, serious adverse events | 0 / 3 | 4 / 20 | 0 / 2 | 1 / 4 | 1 / 1 |
Outcome results
Primary
Change From Baseline in CD8+ Lymphocytes Within the Resected Tumor
Fold Change from Baseline in CD8+ lymphocytes = CD8+ Lymphocytes at cystectomy divided by CD8+ lymphocytes at Screening. Translational data in all but the retifanlimab 500 mg Q4W treatment group were limited and insufficient to assess this outcome measure.
Time frame: up to 69 days
Population: Translation Evaluable Population: all participants who enrolled in the study who received at least 4 weeks of neoadjuvant study treatment (needed to receive the last dose of epacadostat within 2 days prior to the day of surgery or needed to receive the last dose of retifanlimab and/or INCAGN02385 and/or INCAGN02390 within the 7 weeks prior to day of surgery) and provided evaluable paired biopsies (pretreatment core biopsy and surgical resection biopsy)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Retifanlimab 500 mg Q4W | Change From Baseline in CD8+ Lymphocytes Within the Resected Tumor | 0.791 log 2 of fold change | Standard Deviation 0.9332 |
p-value: 0.0925paired t-test
Secondary
Major Pathological Response
Major pathological response was defined as the percentage of participants with residual ypT0/1/a/isN0M0.
Time frame: up to 69 days
Population: Efficacy Population. The 80% confidence interval was estimated using the Clopper-Pearson method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epacadostat 600 mg BID + Retifanlimab 500 mg Q4W | Major Pathological Response | 100 percentage of participants |
| Retifanlimab 500 mg Q4W | Major Pathological Response | 50 percentage of participants |
| Epacadostat 600 mg BID | Major Pathological Response | 50 percentage of participants |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W | Major Pathological Response | 50 percentage of participants |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W | Major Pathological Response | 100 percentage of participants |
Secondary
Number of Participants With Any ≥Grade 3 TEAE
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study drug. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5 Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal.
Time frame: up to 159 days
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Epacadostat 600 mg BID + Retifanlimab 500 mg Q4W | Number of Participants With Any ≥Grade 3 TEAE | 2 Participants |
| Retifanlimab 500 mg Q4W | Number of Participants With Any ≥Grade 3 TEAE | 9 Participants |
| Epacadostat 600 mg BID | Number of Participants With Any ≥Grade 3 TEAE | 0 Participants |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W | Number of Participants With Any ≥Grade 3 TEAE | 2 Participants |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W | Number of Participants With Any ≥Grade 3 TEAE | 1 Participants |
Secondary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore have been any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE was defined as an AE that was reported for the first time or the worsening of a pre-existing event after the first dose of study drug.
Time frame: up to 159 days
Population: Safety Population: all participants who received at least 1 dose of study treatment. Treatment groups were determined according to the actual treatment the participant received regardless of the assigned study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Epacadostat 600 mg BID + Retifanlimab 500 mg Q4W | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 3 Participants |
| Retifanlimab 500 mg Q4W | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 18 Participants |
| Epacadostat 600 mg BID | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 2 Participants |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 4 Participants |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 1 Participants |
Secondary
Pathological Complete Response Rate
Pathological complete response rate was defined as the percentage of participants with ypT0N0.
Time frame: up to 69 days
Population: Efficacy Population: all participants with secondary efficacy endpoint data available for both Baseline and post-Baseline measurements. The 80% confidence interval was estimated using the Clopper-Pearson method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Epacadostat 600 mg BID + Retifanlimab 500 mg Q4W | Pathological Complete Response Rate | 100 percentage of participants |
| Retifanlimab 500 mg Q4W | Pathological Complete Response Rate | 40 percentage of participants |
| Epacadostat 600 mg BID | Pathological Complete Response Rate | 0 percentage of participants |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W | Pathological Complete Response Rate | 0 percentage of participants |
| Retifanlimab 500 mg Q4W + INCAGN02385 350 mg Q2W + INCAGN02390 400 mg Q2W | Pathological Complete Response Rate | 100 percentage of participants |