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.