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FIERCE-21: Phase 1b/2 study of docetaxel + b-701, a selective inhibitor of FGFR3, in relapsed or refractory (R/R) metastatic urothelial carcinoma (mUCC).
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2018
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Tumor BiologyUrologyMetastatic Urothelial CarcinomaGenitourinary CancerMedicineMetronomic TherapySelective InhibitorCancer Cell BiologyPathologyPhase 1B/2Molecular OncologyPoor PrognosisCancer TreatmentFgfr3 M/fOncologyRadiation OncologyFgfr3 Gene MutationsCancer Research
4534 Background: Patients with locally advanced or metastatic urothelial carcinoma (mUCC) have a poor prognosis. FGFR3 is frequently overexpressed in UCC and 15-20% of patients with mUCC have FGFR3 gene mutations or fusions (M/F). B-701 is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. FIERCE-21 is a Phase 1b/2 study designed to evaluate B-701 alone or in combination with docetaxel (D). Methods: The study consists of a Phase 1b lead-in (P1b) followed by Phase 2 (P2) expansion and a randomized phase. Eligible patients P1b: the study enrolled mUCC R/R excluding prior taxane treatment, and ECOG > 1. Treatment: B-701 at 25 mg/kg and D at 75 mg/m2 q3w. Efficacy was assessed by investigators (RECIST 1.1). Primary objective: Determine P2 dose and evaluate safety and efficacy. Results: 19 patients were enrolled in P1b: median age 66 yrs, ECOG 1 = 58%, Hgb < 10 gm/dL 5%, liver metastases 26%, ≥ 2 prior regimens 63%, best response to prior therapy PD 52%. Six patients were positive for FGFR3 M/F. Grade ≥3 AEs occurring in ≥ 2 patients were typical of D at this dose and schedule [decreased neutrophil count (26.3%), neutropenia (10.5%), decreased WBC (10.5%)]. Two patients had D dose reductions and no subjects had dose reductions of B-701 or discontinued treatment due to AE. Two patients died, 1 with PD and bleeding, and 1 with MAHA associated with infection and recurrent thrombosis. Four subjects are alive (3 M/F). Median OS has not been reached in M/F vs 5.3 months in WT. Conclusions: B-701 combined with standard dose D in an every 3 week schedule in patients with mUCC was well-tolerated with expected myelosuppression. Enhanced activity was seen in the FGFR3 M/F compared to WT patients. Phase 2 expansion is currently enrolling FGFR3 M/F patients (B-701 monotherapy vs. combination B-701+D). Clinical trial information: NCT02401542.