| General information |
| Database: | DB00527 |
| Objective: | They investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. |
| Authors: | Sandhu SK, et al |
| Title: | The poly(ADPribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 doseescalation trial. |
| Journal: | Lancet Oncol. |
| Year: | 2013 |
| PMID: | 23810788 |
| Trial Design |
| Clinical Trial Id: | NCT00749502 |
| Agent: | niraparib
|
| Target: | The poly(ADPribose) polymerase
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a twopart, phase I doseescalation trial |
| Key Patients Feature: | Eligible patients had advanced solid malignancies;were not suitable to receive any established treatments;were aged at least 18 years; had a life expectancy of atleast 12 weeks; had an Eastern Cooperative OncologyGroup performance status of 2 or less; had assessabledisease; had adequate haematological, renal, and liverfunction; and had discontinued any previous anticancertreatment or radiotherapy at least 4 weeks previously.Patients were excluded if they had previously received a PARP inhibitor, had residual toxic effects ofgrade 2 or more (assessed with National Cancer InstituteCommon Terminology Criteria for Adverse Events[CTCAE]) from previous treatment, were pregnant orbreastfeeding, or had uncontrolled medical disorders. |
| Biomarker: | Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. |
| Biomark Analysis: | 8(40% [95% CI 1964]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [793]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic highgrade serous ovarian cancer, non small cell lung cancer, and prostate cancer. They recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. |
| Control Group Info: | single arm |
| Treatment Info: | In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, they further investigated the maximum tolerated dose in patients with sporadic platinumresistant highgrade serous ovarian cancer and sporadic prostate cancer. They obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. |
| Primary End Point: | the safety, tolerability, doselimiting toxic effects (DLTs), maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic profiles |
| Secondary End Point: | NA |
| Patients Number: | 100 |
| Trial Results |
| DLT_MTD: | A recommendedphase 2 dose of niraparib:300 mg/day;Doselimiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). |
| Objective Response Rate: | NA |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Common treatmentrelated toxic eff ects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. |
| Conclusions: | A recommendedphase 2 dose of 300 mgday niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARPmediated transcription in cancer. |