077: TABLET: Relative Bioavailability & Bioequivalence Study of Niraparib Tablets & Capsules in Patients With Advanced Solid Tumors

Statement of Purpose, Innovation or Hypothesis: Niraparib is a poly (ADP-ribose) polymerase inhibitor, approved as a maintenance treatment for patients with advanced ovarian cancer and under investigation in solid tumors, available in 100 mg capsules (starting dose: 200 or 300 mg/day). Compared with capsules, tablets have improved stability in hot and humid conditions. This study assessed the relative bioavailability (BA; Stage 1 [S1]) and bioequivalence (BE; Stage 2 [S2]) between niraparib tablets and capsules.
Description of Methods and Materials: This was a US, open-label, multicenter, single-cohort, randomized-sequence study with an optional extension phase. Eligible patients were ≥18 years, had histologically/cytologically confirmed advanced solid tumors (metastatic or local), disease progression despite standard therapy (if available) and ECOG performance scores of 0–2. Patients were dosed 1x300 mg tablet or 3x100 mg capsules then crossed over to the other treatment after full washout. Pharmacokinetic (PK) parameters were assessed up to 168 hours post-niraparib dose; safety was assessed throughout and for 30 days after last dose (90 days for serious adverse events). A comparison of the log-transformed PK parameters (maximum observed plasma concentration [Cmax], area under the plasma concentration–time curve from time 0 to time of the last quantifiable concentration [AUC0–t] and from time 0 extrapolated to infinity [AUC0–∞]) was carried out to evaluate the formulations using a linear mixed‑effects model with fixed effects for sequence, period and treatment and random effect for patient nested within sequence.
Data and

Results: Patients in both stages completed study drug and washout/PK periods and had sufficient PK samples to estimate PK parameters in both periods. In S1 (n=29), a comparable BA performance of both formulations was demonstrated; the 90% confidence intervals (CI) of the geometric least square means (LSM) for Cmax, AUC0–t, and AUC0–∞ for tablet/capsule were within prespecified 0.80–1.25 limits (intra-patient variability: 12.4–21.9%). An initial 7-day washout period between PK assessments was extended to 14 days in S2 due to significant carryover reported in 6 patients in S1. In S2 (n=108), niraparib PK characteristics were similar following dosing with tablet or capsule (Table 1); LSM ratios of the key parameters were close to unity and 90% CI for the ratio of Cmax, AUC0–t, and AUC0–∞ were within prespecified 0.80–1.25 limits required to demonstrate BE. No new safety signals were reported.
Interpretation, Conclusion or Significance: Both niraparib formulations were bioequivalent and can be used interchangeably.
Additional Authors: Afshin Dowlati, MD[11], Debra L. Richardson, MD[12], Christina Faltermeier, PhD[13], Reginald Ewesuedo, MD[10*], Michelle Kneissl, PhD[10*] *At time of study Affiliations: [11]Univ Hosp Seidman Cancer Ctr and Case Western Reserve Univ Cleveland, OH, USA; [12]Stephenson Cancer Ctr/Univ of Oklahoma Health Sciences Ctr and Sarah Cannon Research Inst, Oklahoma City, OK, USA; [13]IQVIA, Kansas City, MO, USA.
Disclosures: GF reports honoraria for Rocky Mountain Oncology Society; consulting or advisory roles individually for EMB Serono and to the institute for Fujifilm, Silicon Therapeutics, Navire, Turning Point Therapeutics, Silicon Therapeutics, Predicine, Inspirna, Regeneron, Jubilant Pharmaceuticals, BostonGene, AbbVie, Teon Therapeutics, Merck (to the institute); research funding to the institute for Millennium, EMD Serono, Celgene, MedImmune, Genmab, Vegenics, Novartis, AstraZeneca, Incyte, ARMO BioSciences, Kolltan Pharmaceuticals, 3-V Biosciences, Abbvie, Aileron Therapeutics, DelMar Pharmaceuticals, eFFECTOR Therapeutics, Strategia Therapeutics, Fujifilm, Hutchison MediPharma, Regeneron, Biothera, Curegenix, Curis, Lilly, Jounce Therapeutics, OncoMed, Precision Oncology, Syndax, Taiho Pharmaceutical, Tesaro, Takeda, BeiGene, Ignyta, Merck, Rgenix, Tarveda Therapeutics, Tocagen, Loxo, Jacobio, Ciclomed, miRNA Therapeutics, Celldex, ADC Therapeutics, Amgen, Exelixis, Bioatla, Turning Point Therapeutics, Ribon Therapeutics, Cyteir, Xencor, Daiichi Sankyo, Epizyme, Abbisko, Prelude Therapeutics, Poseida Therapeutics, Oncorus, Synthorx, BioInvent, Sapience Therapeutics, Bicycle Therapeutics, Silicon Therapeutics, PureTech, Immunogen/MacroGenics, IgM Biosciences, Navire, TeneoBio, Erasca, Inc, Erasca, Inc, RasCal, Boehringer Ingelheim, Pyramid Biosciences, Samumed, ABL Bio, Freenome, Artios, NiKang Therapeutics, Molecular Templates, Sirnaomics, Accutar Biotech, Relay Therapeutics, Simcha Therapeutics, Black Diamond Therapeutics, Seattle Genetics, Jubilant Pharmaceuticals, Metabomed, Agenus, Tallac Therapeutics, Zhuhai Yufan, Mirati Therapeutics, Immunitas, Jazz Pharmaceuticals, Bayer; patents, royalties, other intellectual property for ‘Handbook of Targeted Cancer Therapy’; and travel, accommodation, expenses for Millennium, Sarah Cannon Research Institute, EMD Serono, Bristol-Myers Squibb, Fujifilm, Amgen, Synthorx / Sanofi. 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