Phase 1/2 study of oral rucaparib: Final phase 1 results.

Drugs targeting several pathways are increasingly used to treat 'platinum-resistant' EOC. Currently, drugs targeting the angiogenesis pathway have been shown to significantly improve patient outcome. Studies are also being undertaken with inhibitors of poly(ADP-ribose) polymerase (PARP), targeting the DNA repair pathway as it is possible that the benefits seen with these agents in 'platinum-sensitive' disease will apply to those with 'platinum-resistant' disease. The discovery of predictive biomarkers that identify patients which benefit from these targeted therapies is paramount to the success of these treatments in the future.

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“…A similar degree of antitumor activity has been seen with rucaparib [77] and niraparib [78], both oral inhibitors of PARP-1 and PARP-2.…”

Section: Targeting Dna Repairsupporting

confidence: 59%

An overview of early investigational therapies for chemoresistant ovarian cancer

Marchetti¹,

Ledermann

Panici

2015

Expert Opinion on Investigational Drugs

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“…From a tolerability perspective, treatment with PARP inhibitors is commonly associated with dose interruptions, and a smaller proportion of patients require dose reduction and treatment discontinuation. The most common AEs leading to treatment discontinuation include nausea, vomiting, anemia, and thrombocytopenia [5,6,[12][13][14][15][16].…”

Section: Discussionmentioning

confidence: 99%

Safety and pharmacokinetics of veliparib extended‐release in patients with advanced solid tumors: a phase I study

et al. 2018

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The poly(ADP‐ribose) polymerase‐1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended‐release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib‐ER up to 800 mg once daily or 600 mg twice daily. Dose‐limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28‐day cycles). Seventy‐one patients (n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility (BRCA) gene mutations. Single‐dose veliparib‐ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration‐time curve compared with veliparib immediate‐release (IR). Three patients experienced DLTs (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP2D and MTD for veliparib‐ER were 400 mg BID. The most frequent adverse events (AEs) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment‐related AEs were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib‐ER, versus veliparib‐IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA‐mutated breast cancers.

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“…Clinical data show gBRCA mut tumors respond to rucaparib therapy [81,82], as do tumors with other HR defects [75]. To address the issue of identifying PARPi therapy beyond gBRCA mut , a collaboration with Foundation Medicine to develop a biomarker assay for BRCA-like tumors based on genomic scarring is underway [56].…”

Section: • • Companion Diagnostic Developmentmentioning

confidence: 99%

“…No G4 events were treatment-associated, and dose-dependent G2/3 myelosuppression occurred in 50%, which was manageable with dose reduction. Treatment-related AEs with ≥10% patient involvement included: G1/2 fatigue (30%), nausea (30%), vomiting (23%), diarrhea (13%), anorexia (11%); and G2/3 anemia (29%/29%), thrombocytopenia (0/14%) and neutropenia (29%/0) [81]. With acceptable tolerance and encouraging clinical benefit, the RP2D was determined (600 mg b.i.d.)…”

Section: Clinical Efficacymentioning

confidence: 99%

Evaluation of Rucaparib and Companion Diagnostics in the PARP Inhibitor Landscape for Recurrent Ovarian Cancer Therapy

2016

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Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy. Comparable to rucaparib development, other PARP inhibitors, such as olaparib, niraparib, veliparib and talazoparib, are developing CDx tests for targeted therapy. PARP inhibitor clinical trials and CDx assays are discussed in this review, as are potential PARP inhibitor combination therapies and likely resistance mechanisms.

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Phase 1/2 study of oral rucaparib: Final phase 1 results.

Cited by 27 publications

References 0 publications

An overview of early investigational therapies for chemoresistant ovarian cancer

An overview of early investigational therapies for chemoresistant ovarian cancer

Safety and pharmacokinetics of veliparib extended‐release in patients with advanced solid tumors: a phase I study

Evaluation of Rucaparib and Companion Diagnostics in the PARP Inhibitor Landscape for Recurrent Ovarian Cancer Therapy

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