Locally Advanced or Metastatic Urothelial Cell Carcinoma, Urinary Bladder Disease, Urological Diseases
Conditions
Keywords
Urothelial Cell Carcinoma, UCC, bladder cancer, vofatamab, FGFR3, invasive bladder cancer, targeted therapy, Transitional Cell Carcinoma, TCC, Phase 2, second line therapy, monoclonal antibody, docetaxel, combination therapy, Phase 1, monotherapy, B-701
Brief summary
This is a Phase 1/2(b), sequential, dose escalation, open-label, randomized expansion, multicenter, efficacy and safety study of vofatamab alone or in combination with docetaxel, or versus docetaxel in FGFR3 mutant/fusion subjects with Stage IV, locally advanced or metastatic UCC who have relapsed after, or are refractory to at least one prior line of chemotherapy. This study is divided into 3 phases: Phase 1b (Cohort 1), Phase 2 (Cohorts 2 and 3), and Phase 2b (Monotherapy Expansion Phase and Randomized Phase).
Detailed description
This is a Phase 1/2(b), sequential, dose escalation, open-label, randomized expansion, multicenter, efficacy and safety study of vofatamab alone or in combination with docetaxel, or versus docetaxel in FGFR3 mutant/fusion subjects with Stage IV, locally advanced or metastatic UCC who have relapsed after, or are refractory to at least one prior line of chemotherapy. Vofatamab is a novel monoclonal antibody specific for fibroblast growth factor receptor 3 (FGFR3) that is being developed to target FGFR3-positive tumors. This study is divided into 3 phases: Phase 1b (Cohort 1), Phase 2 (Cohorts 2 and 3), and Phase 2b (Monotherapy Expansion Phase and Randomized Phase).
Interventions
Sponsors
Rainier Therapeutics
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
Key Disease Specific Inclusion Criteria: 1. Stage IV, locally advanced or metastatic (T4b, any N; or any T, N2-3) urothelial bladder cancer or TCC arising in another location of the urinary tract, including urethra, ureter, and renal pelvis 2. Histological or cytological diagnosis of UCC. 3. Relapsed after or are refractory to at least one prior line of chemotherapy which has not included a taxane (with the exception of Cohort 3 of Phase 2 and Phase 2b Monotherapy Expansion of Phase 2b which will allow the enrollment of patients with prior treatment with a taxane) 4. Subjects must have received at least one prior chemotherapeutic regimen (at least one cycle each) for advanced or metastatic/recurrent disease, of which at least one regimen included a platinum agent (unless contraindicated). 5. Prior neoadjuvant or adjuvant chemotherapy (without a taxane, except Cohort 3 of Phase 2 and Phase 2b Monotherapy Expansion, which will allow the enrollment of subjects with prior treatment with a taxane) is permitted and will not be counted as first-line chemotherapy, as long as the subject has not progressed within 12 months of the last dose. 6. Measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Phase 2 and Phase 2b Specific Inclusion Criteria: 1. Patient must be confirmed to have a FGFR3 genomic alteration at the time of documentation of advanced disease. 2. Relapsed after or are refractory to an immune checkpoint inhibitor. This inclusion criterion does not apply if the checkpoint inhibitor is contraindicated. Main
Exclusion criteria
* Prior anti-cancer therapy within 2 weeks prior to Cycle 1, Day 1 * Prior treatment with an inhibitor that is targeted primarily to FGFRs * Clinically significant comorbid medical conditions or lab abnormalities * History of major bleeding (requiring a blood transfusion ≥ 2 units) not related to a tumor within the past 12 months * History of clinically significant coagulation or platelet disorder in the past 12 months * Currently receiving anticoagulation treatment * Incomplete healing from wounds from prior surgery * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at screening * Presence of positive test results for Hepatitis B or Hepatitis C * Known history of human immunodeficiency virus (HIV) seropositive status
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Efficacy Outcome: Progression Free Survival (PFS) | 3-4 years | Efficacy of vofatamab plus docetaxel, compared with docetaxel plus placebo, and vofatamab alone as measured by PFS; measured from randomization to first occurrence of disease progression (per RECIST v1.1) or death, whichever occurs first. A patient has had to receive at least one vofatamab dose. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), 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. |
Countries
Czechia, Italy, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vofatamab Plus Docetaxel IV infusion of docetaxel, 75 mg/m2, followed by IV infusion of vofatamab, 25 mg/kg, on day one of each 21-day cycle. One additional IV infusion of vofatamab (25 mg/kg) given on Day 8 of Cycle 1.
Dosing with vofatamab and docetaxel will continue in each patient until disease progression, unacceptable toxicity, death, or study exit, including withdrawal of patient consent or study termination. Docetaxel treatment beyond 12 cycles of therapy may be considered at the discretion of the treating investigator and Medical Monitor.
Vofatamab
Docetaxel | 40 |
| Vofatamab IV infusion vofatamab, 25 mg/kg on day one each 21-day cycle. One additional IV infusion of vofatamab (25 mg/kg) given on Day 8 of Cycle 1.
Dosing of vofatamab will continue in each patient until disease progression, unacceptable toxicity, death, or study exit, including withdrawal of patient consent or study termination.
Vofatamab | 30 |
| Placebo Plus Docetaxel IV infusion of docetaxel, 75 mg/m2, followed by IV infusion of placebo on day one of each 21-day cycle.
One additional IV infusion of placebo given on Day 8 of Cycle 1. Dosing of docetaxel and placebo will continue in each patient until disease progression, unacceptable toxicity, death, or study exit, including withdrawal of patient consent or study termination. Docetaxel treatment beyond 12 cycles of therapy may be considered at the discretion of the treating investigator and Medical Monitor
Docetaxel
Placebo | 0 |
| Total | 70 |
Baseline characteristics
| Characteristic | Vofatamab Plus Docetaxel | Vofatamab | Placebo Plus Docetaxel | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 20 Participants | 18 Participants | 0 Participants | 38 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 12 Participants | 0 Participants | 32 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 12 Participants | 0 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 36 Participants | 18 Participants | 0 Participants | 54 Participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 0 Participants | 13 Participants |
| Sex: Female, Male Male | 33 Participants | 24 Participants | 0 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 40 | 1 / 30 | 0 / 0 |
| other Total, other adverse events | 40 / 40 | 30 / 30 | 0 / 0 |
| serious Total, serious adverse events | 21 / 40 | 6 / 30 | 0 / 0 |
Outcome results
Primary
Primary Efficacy Outcome: Progression Free Survival (PFS)
Efficacy of vofatamab plus docetaxel, compared with docetaxel plus placebo, and vofatamab alone as measured by PFS; measured from randomization to first occurrence of disease progression (per RECIST v1.1) or death, whichever occurs first. A patient has had to receive at least one vofatamab dose. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), 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: 3-4 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mut/Fus Phase 1 | Primary Efficacy Outcome: Progression Free Survival (PFS) | 6.82 Months | Standard Deviation 5.35 |
| Wild Type Phase 1 | Primary Efficacy Outcome: Progression Free Survival (PFS) | 2.83 Months | Standard Deviation 2.73 |
| Mut/Fus Phase 2 | Primary Efficacy Outcome: Progression Free Survival (PFS) | 4.40 Months | Standard Deviation 4.15 |
| Mut/Fus Phase 2 Monotherapy | Primary Efficacy Outcome: Progression Free Survival (PFS) | 4.45 Months | Standard Deviation 3.27 |
| Mut/Fus Phase 2b Monotherapy | Primary Efficacy Outcome: Progression Free Survival (PFS) | 2.23 Months | Standard Deviation 1.45 |