A phase I dose-escalation and PK study of continuous oral rucaparib in patients with advanced solid tumors.

Abstract

2585 Background: Rucaparib, a potent, oral small molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and -2, is being developed for treatment of homologous recombination repair deficient (HRD) ovarian cancer. This study evaluated oral rucaparib as monotherapy. Primary objectives were to define maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and PK of continuous oral rucaparib. Methods: A standard 3+3 dose escalation design was used. Intra-patient dose escalation was allowed. Patients (pts) aged ≥18 with advanced solid tumor that progressed on standard treatments were recruited. Rucaparib was taken orally qd or bid until disease progression. Plasma PK assessments included full profile, trough levels, and food effect. Results: 29 pts (median age 52 yrs [range 21-71]; 26 female; 15 ECOG PS=0; 17 breast cancer (BC), 7 ovarian/peritoneal cancer (OC), 5 other tumor) were enrolled in 6 dose cohorts to date (40, 80, 160, 300 and 500 mg qd, 240 mg bid). Evaluation of 360 mg bid rucaparib is nearly complete. No DLTs have occurred and no pts have discontinued treatment due to toxicity. Treatment-related adverse events (primarily CTCAE grade 1-2) reported in ≥2 of 29 pts include fatigue (n=5), anorexia (n=3), nausea (n=3), vomiting (n=3), and diarrhea (n=2). To date, two pts (1 OC, 1 BC; both BRCA1mut) treated with 300 mg qd rucaparib achieved PR at wk 6; both are ongoing in wk 17. An additional 10 pts (5 OC, 4 BC, 1 CRC; 7 BRCAmut, 2 BRCAunk, 1 BRCAwt) achieved best response of stable disease (SD) >12 wks thus far; 4 pts (3 OC, 1 BC) are ongoing at 17 (n=2) and 30 (n=2) wks. Overall disease control rate (CR+PR+SD>12 wks) in OC pts across all dose levels was 86% (6/7). Dose proportional PK was observed up to 500 mg qd with mean t1/2 of 15 h (range 4.3 - 29 h). Following qd dosing, steady state was achieved by Day 8. As expected, bid dosing increased trough levels above 2 µM target with low interpatient variability. Conclusions: Continuous oral rucaparib is very well tolerated, with encouraging clinical activity, including objective responses and durable SD, observed during dose-escalation. Once confirmed, the RP2D will be evaluated in platinum-sensitive OC pts with a gBRCA mutation. Clinical trial information: NCT01482715.

Drug Monographs: Olaratumab and Rucaparib

“…21 Central Nervous System: Agitation (grade 3) <1% 21 ; dizziness (grade 1) 10%, 17 (grade 1 or 2) 21%, 21 (grade 2) 1%, 17 (grade 3) <1% 21 ; headache (grade 1) 15%, 17 (grade 1 or 2) 17%, 21 (grade 2) 6% 17 ; insomnia (grade 1 or 2) 12% 21 ; “low mood” (grade 1) 4%, 17 (grade 3) 1% 17 ; mental status changed (grade 3) <1% 21 ; presyncope (grade 1 or 2) 1%, 21 (grade 3) <1% 21 ; syncope (grade 3) 1%. 21 Constitutional: Abdominal distension (grade 1 or 2) 21% 21 ; asthenia 35% 24 ; arthralgia (grade 1) 4%, 17 (grade 2) 3% 17 ; fatigue 17% to 41%, 22–24 (grade 1) 26%, 17 (grade 1 or 2) 69%, 21 (grade 2) 19%, 17 (grade 3) 6% to 9%, 17,21 (grade 3 or 4) 11% 25 ; malaise (grade 1 or 2) 1%, 21 (grade 3) <1% 21 ; myalgia (grade 1) 3%, 17 (grade 1 or 2) 7%, 21 (grade 2) 1%, 17 (grade 3) <1% 21 ; pruritus (grade 1) 5%, 17 (grade 2) 1% 17 ; pyrexia (grade 1 or 2) 12%, 21 (grade 3) <1% 21 ; decreased weight (grade 1 or 2) 8%, 21 (grade 3) <1%. 21 Dermatologic: Alopecia (grade 1) 8%, 17 (grade 1 or 2) 10% 21 ; photosensitivity (grade 1 or 2) 13%.…”

“…21 Endocrine/Metabolic: Hyperglycemia (grade 1 or 2) 2%, 21 (grade 3) 1% 21 ; hypomagnesemia (grade 3) <1% 21 ; hypokalemia (grade 1 or 2) 3%, 21 (grade 3) 2% 21 ; hyponatremia (grade 1 or 2) <1%, 21 (grade 3) 2% 21 ; hypophosphatemia (grade 1 or 2) <1%, 21 (grade 3) 2%. 21 Gastrointestinal: Anorexia 10% to 11%, 22,23 (grade 1) 9%, 17 (grade 1 or 2) 39%, 21 (grade 2) 1%, 17 (grade 3) 2% 21 ; constipation (grade 1) 8%, 17 (grade 1 or 2) 45%, 21 (grade 2) 1%, 17 (grade 3) 1% 21 ; diarrhea 7% to 13%, 22,23 (grade 1) 14%, 17 (grade 1 or 2) 30%, 21 (grade 2) 1%, 17 (grade 3) 3% 21 ; dysgeusia (grade 1) 5% to 43%, 17,21 (grade 2) 1% 17 ; dyspepsia (grade 1 or 2) 9%, 21 (grade 3) <1% 21 ; hemorrhage (rectal) (grade 1 or 2) 2%, 21 (grade 3) <1% 21 ; mucosal inflammation (grade 1 or 2) 3%, (grade 3) <1% 21 ; nausea 10% to 55%, 22–25 (grade 1) 28%, 17 (grade 1 or 2) 75%, 21 (grade 2) 5%, 17 (grade 3) 2% to 4% 17,21,23 ; stomatitis (grade 1 or 2) 10%, 21 (grade 3) <1% 21 ; vomiting 10% to 23%, 22,23 (grade 1) 9%, 17 (grade 1 or 2) 45%, 21 (grade 2) 4%, 17 (grade 3) 2% 21 ; xerostomia (grade 1) 4%. 17 Hematologic: Anemia 37% to 41%, 24,25 (grade 1 or 2) 14%, 21 (grade 2) 5% to 29%, 17,23 (grade 3) 21% to 29%, 21,23 (grade 3 or 4) 26%, 25 (grade 4) 1% 21 ; febrile neutropenia (grade 4) <1% 21 ; granulocytopenia (grade 3) <1% 21 ; intestinal obstruction (large) (grade 4) <1%, 21 (small) (grade 1 or 2) <1%, 21 (grad...…”

“…Constitutional: Abdominal distension (grade 1 or 2) 21% 21 ; asthenia 35% 24 ; arthralgia (grade 1) 4%, 17 (grade 2) 3% 17 ; fatigue 17% to 41%, 22–24 (grade 1) 26%, 17 (grade 1 or 2) 69%, 21 (grade 2) 19%, 17 (grade 3) 6% to 9%, 17,21 (grade 3 or 4) 11% 25 ; malaise (grade 1 or 2) 1%, 21 (grade 3) <1% 21 ; myalgia (grade 1) 3%, 17 (grade 1 or 2) 7%, 21 (grade 2) 1%, 17 (grade 3) <1% 21 ; pruritus (grade 1) 5%, 17 (grade 2) 1% 17 ; pyrexia (grade 1 or 2) 12%, 21 (grade 3) <1% 21 ; decreased weight (grade 1 or 2) 8%, 21 (grade 3) <1%. 21…”

“…Gastrointestinal: Anorexia 10% to 11%, 22,23 (grade 1) 9%, 17 (grade 1 or 2) 39%, 21 (grade 2) 1%, 17 (grade 3) 2% 21 ; constipation (grade 1) 8%, 17 (grade 1 or 2) 45%, 21 (grade 2) 1%, 17 (grade 3) 1% 21 ; diarrhea 7% to 13%, 22,23 (grade 1) 14%, 17 (grade 1 or 2) 30%, 21 (grade 2) 1%, 17 (grade 3) 3% 21 ; dysgeusia (grade 1) 5% to 43%, 17,21 (grade 2) 1% 17 ; dyspepsia (grade 1 or 2) 9%, 21 (grade 3) <1% 21 ; hemorrhage (rectal) (grade 1 or 2) 2%, 21 (grade 3) <1% 21 ; mucosal inflammation (grade 1 or 2) 3%, (grade 3) <1% 21 ; nausea 10% to 55%, 22–25 (grade 1) 28%, 17 (grade 1 or 2) 75%, 21 (grade 2) 5%, 17 (grade 3) 2% to 4% 17,21,23 ; stomatitis (grade 1 or 2) 10%, 21 (grade 3) <1% 21 ; vomiting 10% to 23%, 22,23 (grade 1) 9%, 17 (grade 1 or 2) 45%, 21 (grade 2) 4%, 17 (grade 3) 2% 21 ; xerostomia (grade 1) 4%. 17…”

PARP Inhibitors for Recurrent Ovarian Carcinoma: Current Treatment Options and Future Perspectives

“…The efficacy and tolerability of oral rucaparib monotherapy have been tested in clinical studies. In addition to good tolerability [27], antitumour effect has been shown among patients with ovarian and peritoneal carcinoma both in platinum-sensitive and platinum-resistant disease (total tumour follow-up rate 86%) with doses between 40 to 500 mg rucaparib daily and 240 mg rucaparib twice daily respectively [28]. There is also published data on rucaparib in combination with cytostatic drugs.…”