Urothelial Carcinoma
Conditions
Keywords
Locally advanced or metastatic urothelial carcinoma, Bladder cancer, Checkpoint inhibition, FGFR inhibition
Brief summary
FORT-2 is designed to evaluate safety, efficacy, RP2D and PK of rogaratinib in combination with atezolizumab in patients with untreated FGFR-positive urothelial carcinoma. The study originally comprised two separate parts: Phase 1b (Part A) and Phase 2 (Part B). The study parts differ in design, objectives, and treatment. The primary objectives of this Phase 1b study (Part A) are to determine the safety, tolerability, RP2D and pharmacokinetics of rogaratinib in combination with atezolizumab in these patients. The primary objective of the Part B is to compare progression-free survival (PFS) according to RECIST v1.1 of rogaratinib in combination with atezolizumab over placebo in combination with atezolizumab in untreated patients with FGFR-positive locally advanced or metastatic urothelial carcinoma. Of note, patients who participate in Part A are not allowed to participate in Part B. Part B will be initiated once the data from Part A supports continuation of the study, even if this occurs prior to primary completion of Part A. The sponsor may decide not to continue the study as a whole after completion of Part A if the data do not support further development. Part B of the study will no longer be conducted.
Interventions
Part A:Rogaratinib will be administered orally until disease progression, unacceptable toxicity or consent withdrawal. The starting dose of 800 mg b.i.d. will be confirmed using a dose selection design.
DRUGAtezolizumab
Part A: A fixed dose of 1200 mg atezolizumab will be administered through intravenous (i.v.) infusion on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity or consent withdrawal.
Sponsors
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Part A is open-label.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Existence of archival or fresh tumor biopsy specimen for FGFR1/3 mRNA expression testing * High FGFR1 or 3 mRNA expression levels (RNAscope score of 3+ or 4+) in archival or fresh tumor biopsy specimen * Documented locally advanced (T4, any N; or any T, N2-3) or metastatic urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria: * No prior systemic treatment for locally advanced or metastatic urothelial carcinoma. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval \> 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment-naïve in the metastatic setting. Prior local intra-vesical chemotherapy or prior local immunotherapy is allowed if completed at least 4 weeks before the first study drug administration. Regionally available standard of care options must be considered for all patients. * Ineligibility for cisplatin-based chemotherapy as defined by any one of the following criteria: * Impaired renal function (GFR \> 30 but \< 60 mL/min/1.73 m2) according to the modification of diet in renal disease (MDRD) abbreviated formula * A Hearing loss (measured by audiometry) of \> 25 dB at two contiguous test frequencies in at least one ear. * Grade ≥ 2 peripheral neuropathy (i.e. sensory alteration or paresthesia including tingling) * Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1.
Exclusion criteria
* Active symptomatic or untreated brain metastases as determined by CT or MRI evaluation during screening and prior radiographic assessment. * History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, granulomatosis with polyangiitis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. * History or current condition of an uncontrolled cardiovascular disease including any of the following conditions: * Congestive heart failure (CHF) NYHA Class 2 or greater, unstable angina (symptoms of angina at rest) or * New-onset angina (within last 3 months before the first study drug administration) * Myocardial infarction (MI) within past 6 months before the first study drug administration * Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. * Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or known left ventricular ejection fraction \< 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate. * Current diagnosis of any retinal disorders including retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion. * Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia). * Concomitant therapies that are known to increase serum calcium or phosphate levels (i.e. antacids, phosphate-containing laxatives oral/rectal, potassium phosphate) and that cannot be discontinued or switched to a different medication before the first study drug administration * Treatment with systemic corticosteroids or other systemic immunosuppressant medications within 2 weeks before the first study drug administration, or anticipated requirement for systemic immunosuppressive medications during the trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Dose-limiting Toxicities(DLTs) | Up to 21 days |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | up to 90 days after the last study medication intake, an average of 60 days |
| Number of Participants With Drug-related TEAEs | up to 90 days after the last study medication intake, an average of 60 days |
| Number of Participants With Treatment-emergent Serious Adverse Events(TESAEs) | up to 90 days after the last study medication intake, an average of 60 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Plasma Concentration (Cmax) of Rogaratinib | At cycle 1 Day 1 | — |
| Area Under the Rogaratinib Concentration Versus Time Curve (AUC) | At cycle 1 Day 1, 0-t(last) | — |
| Objective Response Rate(ORR) | Up to 5 months | Objective response rate (ORR) was defined as the percentage of patients with complete response (CR) or partial response (PR). Patients for whom best overall tumor response was not CR or PR, as well as patients without any post-baseline tumor assessment were considered non-responders. For all patients, the best overall tumor response was determined locally by investigators using the RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Countries
Austria, France, Germany, Italy, Japan, South Korea, Spain, United States
Participant flow
Recruitment details
The study was conducted at 30 study centers in 8 countries (4 in Austria, 3 in France, 3 in Germany, 5 in Italy, 4 in Japan, 3 in South Korea, 4 in Spain, and 4 in the US) between 15 May 2018 (first informed consent) and 10 July 2024 (last participant last visit). Only Part A of the study was completed. Part B was not started in line with the protocol. The decision not to conduct Part B was not related to safety concerns but was based on an overall strategic business decision
Pre-assignment details
A total of 54 FGFR mRNA-positive subjects (35.3%) successfully completed the prescreening. Of these, 37 subjects (68.5%) completed the screening and were assigned to treatment and 31.5% prematurely discontinued the screening: 29.6% due to screening failure and 1.9% (1 subject) due to withdrawal by subject.
Participants by arm
| Arm | Count |
|---|---|
| Rogaratinib 800 mg BID + Atezolizumab Participants receiving 800 mg Rogaratinib twice daily plus Atezolizumab | 11 |
| Rogaratinib 600 mg BID + Atezolizumab Participants receiving 600 mg Rogaratinib twice daily plus Atezolizumab | 26 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 7 |
| Overall Study | End of study treatment | 0 | 2 |
| Overall Study | Lack of Efficacy | 3 | 10 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | Total | Rogaratinib 600 mg BID + Atezolizumab | Rogaratinib 800 mg BID + Atezolizumab |
|---|---|---|---|
| Age, Customized 85 years and over | 1 Participants | 1 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 4 Participants | 2 Participants | 2 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65-84 years | 32 Participants | 23 Participants | 9 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 23 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 32 Participants | 23 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 11 | 11 / 26 |
| other Total, other adverse events | 11 / 11 | 26 / 26 |
| serious Total, serious adverse events | 8 / 11 | 14 / 26 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities(DLTs)
Time frame: Up to 21 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rogaratinib 800 mg BID + Atezolizumab | Number of Participants With Dose-limiting Toxicities(DLTs) | 1 Participants |
| Rogaratinib 600 mg BID + Atezolizumab | Number of Participants With Dose-limiting Toxicities(DLTs) | 4 Participants |
Primary
Number of Participants With Drug-related TEAEs
Time frame: up to 90 days after the last study medication intake, an average of 60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rogaratinib 800 mg BID + Atezolizumab | Number of Participants With Drug-related TEAEs | 11 Participants |
| Rogaratinib 600 mg BID + Atezolizumab | Number of Participants With Drug-related TEAEs | 26 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time frame: up to 90 days after the last study medication intake, an average of 60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rogaratinib 800 mg BID + Atezolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 11 Participants |
| Rogaratinib 600 mg BID + Atezolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 26 Participants |
Primary
Number of Participants With Treatment-emergent Serious Adverse Events(TESAEs)
Time frame: up to 90 days after the last study medication intake, an average of 60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rogaratinib 800 mg BID + Atezolizumab | Number of Participants With Treatment-emergent Serious Adverse Events(TESAEs) | 8 Participants |
| Rogaratinib 600 mg BID + Atezolizumab | Number of Participants With Treatment-emergent Serious Adverse Events(TESAEs) | 14 Participants |
Secondary
Area Under the Rogaratinib Concentration Versus Time Curve (AUC)
Time frame: At cycle 1 Day 1, 0-t(last)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Rogaratinib 800 mg BID + Atezolizumab | Area Under the Rogaratinib Concentration Versus Time Curve (AUC) | 59187.389 µg*h/l | Standard Deviation 1.513 |
| Rogaratinib 600 mg BID + Atezolizumab | Area Under the Rogaratinib Concentration Versus Time Curve (AUC) | 45768.289 µg*h/l | Standard Deviation 1.449 |
Secondary
Maximal Plasma Concentration (Cmax) of Rogaratinib
Time frame: At cycle 1 Day 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Rogaratinib 800 mg BID + Atezolizumab | Maximal Plasma Concentration (Cmax) of Rogaratinib | 13207.846 µg/l | Standard Deviation 1.379 |
| Rogaratinib 600 mg BID + Atezolizumab | Maximal Plasma Concentration (Cmax) of Rogaratinib | 10372.864 µg/l | Standard Deviation 1.404 |
Secondary
Objective Response Rate(ORR)
Objective response rate (ORR) was defined as the percentage of patients with complete response (CR) or partial response (PR). Patients for whom best overall tumor response was not CR or PR, as well as patients without any post-baseline tumor assessment were considered non-responders. For all patients, the best overall tumor response was determined locally by investigators using the RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 5 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rogaratinib 800 mg BID + Atezolizumab | Objective Response Rate(ORR) | complete response | 1 Participants |
| Rogaratinib 800 mg BID + Atezolizumab | Objective Response Rate(ORR) | partial response | 1 Participants |
| Rogaratinib 800 mg BID + Atezolizumab | Objective Response Rate(ORR) | no response | 9 Participants |
| Rogaratinib 600 mg BID + Atezolizumab | Objective Response Rate(ORR) | complete response | 4 Participants |
| Rogaratinib 600 mg BID + Atezolizumab | Objective Response Rate(ORR) | partial response | 10 Participants |
| Rogaratinib 600 mg BID + Atezolizumab | Objective Response Rate(ORR) | no response | 12 Participants |