Phase I study of niraparib with radiotherapy for treatment of metastatic and locally advanced invasive carcinoma of the cervix (NIVIX).

Introduction: This Phase I study evaluated the safety and tolerability of concurrent niraparib, an oral poly(ADP-ribose) polymerase (PARP) 1/2 inhibitor, with definitive radiotherapy in women with locally advanced or platinum-sensitive metastatic cervical cancer. Dose escalation followed a Bayesian Optimal Interval (BOIN) design with a target dose-limiting toxicity (DLT) rate of 30%. Methods: Women ≥18 years with FIGO stage IIIC2 (bulky nodes >1 cm) or stage IV cervical cancer demonstrating response to platinum-based induction chemotherapy were eligible. Niraparib 100 mg was administered daily concurrent with pelvic radiotherapy (45-57.5 Gy via IMRT with nodal boosts) and brachytherapy, continuing 28 days post-radiation. Per the BOIN design, dose escalation occurred if the observed DLT rate fell below the pre-specified boundary of 0.2365; de-escalation occurred if it exceeded 0.3585. DLTs were defined per protocol as grade ≥4 non-hematologic toxicity, grade 4 thrombocytopenia ≥14 days, grade 3-4 thrombocytopenia with bleeding, or toxicity causing >28-day niraparib delay or >2-day radiation delay. Results: Four patients were enrolled at the 100 mg dose level before study closure due to slow accrual and anticipated changes in standard of care. Two patients (NVX-1, NVX-4) completed concurrent niraparib without protocol-defined DLT. Two patients (NVX-2, NVX-3) discontinued niraparib due to treatment-limiting grade 2 thrombocytopenia (CTCAE v4.0; nadirs 71,000/μL and 53,000/μL); these events did not meet protocol DLT criteria, and no bleeding occurred. The observed DLT rate of 0/4 (0%) fell below the escalation boundary; however, the study closed before dose escalation. Both patients who discontinued had baseline platelet counts <150,000/μL and significant comorbidities (HIV/cirrhosis; suspected chemotherapy-related marrow injury), whereas the two who completed therapy had counts >250,000/μL. All patients completed radiotherapy and achieved local disease control at minimum 12-month follow-up. Conclusion: Concurrent niraparib 100 mg with pelvic radiotherapy was feasible without protocol-defined DLTs. Treatment-limiting grade 2 thrombocytopenia occurred in patients with identifiable risk factors including low baseline platelet counts, hepatic dysfunction, and low body weight. These hypothesis-generating findings support further investigation with attention to patient selection criteria in future trials combining PARP inhibitors with radiotherapy.