| General information |
| Database: | DB00242 |
| Objective: | Poly(ADPribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP1 and PARP2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. 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: | PARP1 and PARP2
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a phase I doseescalation study |
| Key Patients Feature: | patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. |
| Biomarker: | BRCA1 and BRCA2 mutation carriers;PTEN expression and ETS rearrangements |
| Biomark Analysis: | 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. Toxic effects were assessed by common toxicity criteria and RECIST. 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. |
| Primary End Point: | safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity |
| Secondary End Point: | NA |
| Patients Number: | 100 |
| Trial Results |
| DLT_MTD: | 300 mg/day was established as the maximum tolerated dose. 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: | Eight (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.No correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer was reported. |
| 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 effects 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. |