Phase I Study of Niraparib with Radiotherapy for Treatment of Metastatic Invasive Carcinoma of the Cervix (NIVIX)

Purpose: This Phase I/II study aimed to evaluate the safety, tolerability, and efficacy of two dose levels (100 mg and 200 mg) of concurrent and adjuvant niraparib, an oral poly(ADPribose) polymerase (PARP) 1 and 2 inhibitor, as a radiosensitizer in women with treatment responsive metastatic cervical cancer.

Methodology: Women over 18 years with good performance status, adequate organ function, and FIGO stage IIIC2 or stage IV cervical cancer were eligible for inclusion. Subjects must have had 3-6 cycles of platinum-based chemotherapy with partial response (PR) by RECIST criteria 4-12 weeks prior to initiation of definitive regional radiation. Niraparib was administered daily starting on initiation of radiation therapy and continued through 28 days after completion of radiation, with dosing held on days of brachytherapy administration and resumed the following day. Initial treatment dose was 100 mg, with dose escalation planned to 200 mg for every 3 patients accrued if dose-limiting toxicity (DLT) remained low. Radiotherapy was delivered using external beam radiation 45 Gy to the whole pelvis or extended field including para-aortic nodes using intensity modulated radiation therapy (IMRT) with integrated nodal boosts to 55-57.5 Gy, followed by brachytherapy. Patient quality of life metrics were collected using the FACT-Cx questionnaire given at baseline, weekly during radiation therapy, and at each oncology follow up appointment.

Results: The study was planned for enrollment of up to 24 subjects, but closed due to slow accrual and an expected change in standard of care. The study enrolled 4 patients on dose level 1. One patient was dosed incorrectly and was taken off-study, 2 patients experienced DLT’s (thrombocytopenia, platelet count < 75,000) and discontinued niraparib therapy, and 1 patient tolerated niraparib at the prescribed 100 mg dose without significant toxicity. All patients were able to complete the planned course of radiation therapy, with the exception of one patient who missed a single fraction of treatment. With a median of 18 (range 13 - 30) months of follow-up, no patients showed clinical or radiographic evidence of pelvic recurrence after therapy. One patient with de novo liver metastases prior to chemotherapy with initial treatment response progressed in the liver.

Conclusions: In this limited set of patients who received induction style platinum-based chemotherapy, the primary dose limiting toxicity of niraparib in combination with radiation therapy was thrombocytopenia. Patients on this trial achieved a median 18 months of pelvic progression free survival, however larger phase II/III studies are needed to corroborate these findings. (Funded by GlaxoSmithKline Pharmaceuticals)

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