Carcinoma, Transitional Cell
Conditions
Keywords
Urothelial carcinoma
Brief summary
This is a randomized, open-label, multicenter Phase 2/3 study to evaluate the efficacy and safety of rogaratinib (BAY 1163877) compared to chemotherapy in patients with FGFR-positive locally advanced or metastatic urothelial carcinoma who have received prior platinum-containing chemotherapy. The primary objective is to demonstrate the superiority of rogaratinib over chemotherapy in terms of objective response rate (before: overall survivial) of urothelial carcinoma patients with FGFR positive tumors. At randomization, patients will have locally advanced or metastatic urothelial carcinoma and have received at least one prior platinum-containing chemotherapy regimen. Only patients with FGFR1 or 3 positive tumors can be randomized into the study. Archival tumor tissue is adequate for testing of FGFR1 and 3 mRNA expressions, which will be determined centrally using an RNA in situ hybridization (RNA-ISH) test. Approximately 42 % of UC patients with locally advanced or metastatic UC are identified as FGFR-positive by the RNA-ISH cut-off applied.
Interventions
Rogaratinib administered as oral (p.o.) tablets twice daily (b.i.d.) continuously
DRUGChemotherapy
Chemotherapy as taxane (docetaxel or paclitaxel) or vinflunine administered through intravenous (i.v.) infusion every 3 weeks (on day 1 of a 21-day cycle) The choice of the chemotherapy is at the discretion of the investigator, taking into consideration the status of the authorization or treatment guidelines in the given country.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Existence of archival or fresh biopsy for FGFR testing. Mandatory FGFR testing of patients will be performed prior to start of screening. The timing of the FGFR test is at the discretion of the investigator. Investigators should ensure all patients will be eligible in terms of disease status and lines of treatment. * Documented urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra meeting all of the following criteria * Histologically confirmed (Patients with mixed histologies are required to have a dominant transitional cell pattern.) * Locally advanced (T4, any N; or any T, N 2-3) or metastatic disease (any T, any N and M1). Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3). * ECOG (Eastern Cooperative Oncology Group) Performance Status of 0 or 1 * Disease progression during or following treatment with at least one platinum-containing regimen (patients should have been treated for at least 2 cycles). In patients who received prior adjuvant/ neoadjuvant platinum-containing chemotherapy, progression had to occur within 12 months of treatment. * High FGFR1 or 3 mRNA expression levels in archival or fresh tumor biopsy specimen quantified as outlined in the lab manual * At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) in contrast enhanced (unless contraindicated) CT or MRI
Exclusion criteria
* Previous or concurrent cancer except * cervical carcinoma in situ * treated basal-cell or squamous cell skin carcinoma * any cancer curatively treated \> 3 years before randomization * curatively treated incidental prostate cancer (T1/T2a) * Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies) or with taxanes or vinflunine * More than two prior lines of systemic anti-cancer therapy for urothelial carcinoma given for advanced unresectable/ metastatic disease * Ongoing or previous anti-cancer treatment within 4 weeks before randomization. * Unresolved toxicity higher than National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE v.4.03) Grade 1 attributed to any prior therapy/ procedure excluding alopecia, anemia and/ or hypothyroidism * History or current condition of an uncontrolled cardiovascular disease including any of the following conditions: * Congestive heart failure (CHF) NYHA (New York Heart Association) \> Class 2 * Unstable angina (symptoms of angina at rest) or new-onset angina (within last 3 months before randomization) * Myocardial infarction (MI) within past 6 months before randomization * Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with arrhythmia under control with anti-arrhythmic therapy such as beta-blockers or digoxin are eligible. * Arterial or venous thrombotic events or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before randomization * Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia) * Current diagnosis of any retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion * Any hemorrhage / bleeding event ≥ CTCAE v.4.03 Grade 3 within 4 weeks before randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) - Central Assessment | From start of treatment up to end of active follow-up, approximately 29 months | ORR is defined as the percentage of participants with complete response (CR) or partial response (PR). participants for whom overall best response is not CR or PR, as well as participants without any post-baseline tumor assessment will be considered non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-control Rate (DCR) - Central Assessment | From start of treatment till end of active follow-up, approximately 29 months | DCR was defined as the percentage of participants whose overall best response was not a progressive disease (i.e., CR, PR, stable disease \[SD\] or Non CR/Non PD). |
| Progression-free Survival (PFS) - Central Assessment | From start of treatment till end of active follow-up, approximately 29 months | Progression free survival (PFS) was defined as the time (days) from randomization to date of first observed disease progression (radiological or clinical assessment or both) or death due to any cause (if death occurred before progression was documented). |
| Duration of Response (DOR) - Central Assessment | From start of treatment till end of active follow-up, approximately 29 months | DOR (for patients with PR and CR only) was defined as the time from the first documented objective response of PR or CR, whichever was noted earlier, to disease progression (including symptomatic deterioration) or death, whichever was earlier |
| Number of Participants With Treatment Emergent Adverse Events | From start of treatment up to 30 days after the last administration of study treatment, approximately 29 months | A treatment-emergent event was defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of study treatment |
Countries
Australia, Austria, Belgium, Canada, China, Czechia, Denmark, Finland, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Netherlands, Poland, Portugal, Russia, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study enrolled participants at 111centers in 28 countries from 31 MAY 2018 (first participant first visit) to 27 OCT 2020 (last participant last visit).
Pre-assignment details
A total of 718 participants signed the informed consent for prescreening, of which 256 participants completed the prescreening, while 462 participants discontinued the prescreening. The discontinuations were due to screening failure (322), other reasons (98), withdrawal by the participant (22), and death (20).
Participants by arm
| Arm | Count |
|---|---|
| Rogaratinib (BAY1163877)_Overall Population Participants who were randomized to this group following a 1:1 ratio received rogaratinib 600 mg orally twice a day (b.i.d.) continuously, during a 21-day treatment cycle. | 87 |
| Chemotherapy_Overall Population Participants who were randomized to this group following a 1:1 ratio received chemotherapy (docetaxel, paclitaxel or vinflunine) at the discretion of the investigator, as intravenous (i.v.) infusion once every three weeks (on day 1 of a 21-day cycle). | 88 |
| Total | 175 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Discontinued (disc) treatment (trt): Death | 6 | 4 |
| Overall Study | Disc trt: Adverse Event (AE) | 13 | 9 |
| Overall Study | Disc trt:AE not asso. w/ clinical disease progress | 1 | 4 |
| Overall Study | Disc trt: clinical progression | 1 | 5 |
| Overall Study | Disc trt: Lost to follow up | 0 | 1 |
| Overall Study | Disc trt: Other | 1 | 0 |
| Overall Study | Disc trt: Physician decision | 0 | 5 |
| Overall Study | Disc trt: radiological progression | 58 | 50 |
| Overall Study | Disc trt: Withdrawal by participant | 6 | 4 |
| Overall Study | Study drug never administered | 1 | 6 |
Baseline characteristics
| Characteristic | Chemotherapy_Overall Population | Total | Rogaratinib (BAY1163877)_Overall Population |
|---|---|---|---|
| Age, Continuous | 66.4 years STANDARD_DEVIATION 10.3 | 67.0 years STANDARD_DEVIATION 9.3 | 67.7 years STANDARD_DEVIATION 8.3 |
| Cancer Category Location of primary cancer: bladder | 45 Participants | 101 Participants | 56 Participants |
| Cancer Category Location of primary cancer: Proximal urethra | 1 Participants | 3 Participants | 2 Participants |
| Cancer Category Location of primary cancer: Renal pelvis | 28 Participants | 40 Participants | 12 Participants |
| Cancer Category Location of primary cancer: Ureter | 14 Participants | 31 Participants | 17 Participants |
| Cancer stage at study entry Stage III B | 3 Participants | 4 Participants | 1 Participants |
| Cancer stage at study entry Stage IV | 12 Participants | 17 Participants | 5 Participants |
| Cancer stage at study entry Stage IV A | 24 Participants | 37 Participants | 13 Participants |
| Cancer stage at study entry Stage IV B | 48 Participants | 115 Participants | 67 Participants |
| Cancer stage at study entry Unknown | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 154 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 20 Participants | 10 Participants |
| FGFR expression from Targos Negative | 14 Participants | 27 Participants | 13 Participants |
| FGFR expression from Targos Not assessed | 5 Participants | 10 Participants | 5 Participants |
| FGFR expression from Targos Positive | 69 Participants | 138 Participants | 69 Participants |
| PIK3CA and/or RAS activating mutations Absent | 69 Participants | 134 Participants | 65 Participants |
| PIK3CA and/or RAS activating mutations Present | 10 Participants | 20 Participants | 10 Participants |
| PIK3CA and/or RAS activating mutations Unknown | 9 Participants | 21 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 48 Participants | 23 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 16 Participants | 8 Participants |
| Race (NIH/OMB) White | 55 Participants | 110 Participants | 55 Participants |
| Sex: Female, Male Female | 70 Participants | 145 Participants | 75 Participants |
| Sex: Female, Male Male | 18 Participants | 30 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 47 / 86 | 45 / 82 |
| other Total, other adverse events | 85 / 86 | 77 / 82 |
| serious Total, serious adverse events | 39 / 86 | 33 / 82 |
Outcome results
Primary
Objective Response Rate (ORR) - Central Assessment
ORR is defined as the percentage of participants with complete response (CR) or partial response (PR). participants for whom overall best response is not CR or PR, as well as participants without any post-baseline tumor assessment will be considered non-responders.
Time frame: From start of treatment up to end of active follow-up, approximately 29 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rogaratinib (BAY1163877)_Overall Population | Objective Response Rate (ORR) - Central Assessment | 19.5 percentage of participants |
| Chemotherapy_Overall Population | Objective Response Rate (ORR) - Central Assessment | 21.6 percentage of participants |
| Rogaratinib_WT Population | Objective Response Rate (ORR) - Central Assessment | 19.4 percentage of participants |
| Chemotherapy_WT Population | Objective Response Rate (ORR) - Central Assessment | 23.8 percentage of participants |
p-value: =0.699195% CI: [-14, 9.9]Fisher Exact
p-value: =0.794495% CI: [-18.9, 9.9]Fisher Exact
Secondary
Disease-control Rate (DCR) - Central Assessment
DCR was defined as the percentage of participants whose overall best response was not a progressive disease (i.e., CR, PR, stable disease \[SD\] or Non CR/Non PD).
Time frame: From start of treatment till end of active follow-up, approximately 29 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rogaratinib (BAY1163877)_Overall Population | Disease-control Rate (DCR) - Central Assessment | 50.6 percentage of participants |
| Chemotherapy_Overall Population | Disease-control Rate (DCR) - Central Assessment | 55.7 percentage of participants |
| Rogaratinib_WT Population | Disease-control Rate (DCR) - Central Assessment | 53.2 percentage of participants |
| Chemotherapy_WT Population | Disease-control Rate (DCR) - Central Assessment | 63.5 percentage of participants |
p-value: =0.796295% CI: [-19.9, 9.7]Fisher Exact
p-value: =0.910995% CI: [-27.5, 6.9]Fisher Exact
Secondary
Duration of Response (DOR) - Central Assessment
DOR (for patients with PR and CR only) was defined as the time from the first documented objective response of PR or CR, whichever was noted earlier, to disease progression (including symptomatic deterioration) or death, whichever was earlier
Time frame: From start of treatment till end of active follow-up, approximately 29 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rogaratinib (BAY1163877)_Overall Population | Duration of Response (DOR) - Central Assessment | 4.9 months |
| Chemotherapy_Overall Population | Duration of Response (DOR) - Central Assessment | 5.8 months |
| Rogaratinib_WT Population | Duration of Response (DOR) - Central Assessment | 5.1 months |
| Chemotherapy_WT Population | Duration of Response (DOR) - Central Assessment | 7.0 months |
Secondary
Number of Participants With Treatment Emergent Adverse Events
A treatment-emergent event was defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of study treatment
Time frame: From start of treatment up to 30 days after the last administration of study treatment, approximately 29 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rogaratinib (BAY1163877)_Overall Population | Number of Participants With Treatment Emergent Adverse Events | Any TEAE | 86 Participants |
| Rogaratinib (BAY1163877)_Overall Population | Number of Participants With Treatment Emergent Adverse Events | Any drug related TEAE | 81 Participants |
| Chemotherapy_Overall Population | Number of Participants With Treatment Emergent Adverse Events | Any TEAE | 82 Participants |
| Chemotherapy_Overall Population | Number of Participants With Treatment Emergent Adverse Events | Any drug related TEAE | 76 Participants |
Secondary
Progression-free Survival (PFS) - Central Assessment
Progression free survival (PFS) was defined as the time (days) from randomization to date of first observed disease progression (radiological or clinical assessment or both) or death due to any cause (if death occurred before progression was documented).
Time frame: From start of treatment till end of active follow-up, approximately 29 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rogaratinib (BAY1163877)_Overall Population | Progression-free Survival (PFS) - Central Assessment | 2.7 months |
| Chemotherapy_Overall Population | Progression-free Survival (PFS) - Central Assessment | 3.2 months |
| Rogaratinib_WT Population | Progression-free Survival (PFS) - Central Assessment | 2.8 months |
| Chemotherapy_WT Population | Progression-free Survival (PFS) - Central Assessment | 4.0 months |
p-value: 0.917195% CI: [0.88, 2.043]Log Rank
p-value: =0.867295% CI: [0.853, 1.762]Log Rank