Two Phase III Trials Find Rolapitant Effective, Well-Tolerated for Preventing CINV

Bernardo Rapoport, MD

A single oral dose of the novel NK-1 receptor antagonist rolapitant was found to be effective, safe, and long-lasting for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients whose cancer was being treated with either highly or moderately emetogenic chemotherapy, according to results from two phase III randomized trials reported at the 2014 MASCC/ISOO Symposium on Supportive Care in Cancer.

Rolapitant is a potent, selective, NK-1 receptor antagonist, with a half-life of approximately 180 hours and an ability, with a single dose, to prevent CINV over a 5-day period, explained Bernardo Rapoport, MD, from the Department of Oncology at The Medical Oncology Center of Rosebank, Johannesburg, South Africa, who presented the phase III trial results for patients being treated with highly emetogenic chemotherapy (HEC).¹

A 200-mg dose of rolapitant could provide over 90% NK-1 brain receptor occupancy, Rapoport noted. “This is very important, because it is different from the other NK-1 inhibitors,” he said, adding that there is a reduced risk of drug—drug interactions, “because this drug, as opposed to other NK-1 inhibitors, is not an inducer or inhibitor of CYP 3A4.”

Rolapitant previously demonstrated safety and efficacy as a single 200-mg oral dose in a large randomized phase II study, Rapoport explained. The two current, phase III, double-blind, double-dummy, global studies he presented at MASCC have identical designs and endpoints (HEC1 [n = 526 patients] and HEC 2 [n = 544]).

Patients in the HEC studies were chemotherapy naïve and scheduled to receive cisplatin-based chemotherapy at a dose of 60 mg/m² or higher. In both trials, patients were randomized 1:1 to rolapitant 200 mg or placebo prior to initiation of HEC, with both the treatment and control arms also receiving a 5HT₃ antagonist (granisetron) and a corticosteroid (dexamethasone). Treatment arms were well balanced in both studies, and the primary endpoint was complete response ([CR] defined as no emesis or use of rescue medication).

The primary endpoint was achieved in both trials. Results are for three phases: acute (0-24 hours), delayed (>24 hours to 120 hours), and overall (0-120 hours). In the HEC1 study, rolapitant was significantly superior to the control arm in the delayed setting (72.7% CR vs 58.4, respectively; P <.001) and acute (83.7% vs 73.7%; P = .005) phase, as well as the overall phase (70.1% vs 56.5%; P = .001).

In the HEC 2 study, rolapitant was significantly superior to the control arm in the delayed setting (70.1% vs 61.9%, respectively; P = .043) but not in the acute (83.4% vs 79.5%; P = .233) or the overall phase (67.5% vs 60.4%; P = .084).

Overall, treatment-emergent adverse events (TEAEs) were similar between rolapitant and the control, with constipation and asthenia the most frequently reported TEAE in both cohorts; most TEAEs were considered by the investigator to be related to chemotherapy or the underlying cancer.

A related presentation focused on a phase III trial evaluating rolapitant in 1332 patients receiving moderately emetogenic chemotherapy (MEC).² The design of MEC trial was similar overall to the HEC studies, explained trial investigator Lee S. Schwartzberg, MD, FACP, Division Chief, Hematology and Oncology at the University of Tennessee Health Sciences Center in Memphis.

Subjects were naïve to HEC or MEC, and MEC included use of cyclophosphamide IV (<1500 mg/m²), doxorubicin, epirubicin, carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin, or cytarabine IV (>1g/m²) and a length of each chemotherapy cycle of 2 weeks or more. Patients were randomized equally to receive either rolapitant 200 mg or placebo prior to receiving MEC, with both groups also receiving granisetron and dexamethasone.

The results of this trial again showed that the primary endpoint of CR was achieved, with rolapitant demonstrating statistically superior CR over the placebo group for the delayed phase (71.3% vs 61.6%, respectively; P <.001) and the overall phase (68.6% vs 57.8%; P <.001), but not the acute phase (83.5% vs 80.3%; P = 0.143).

Schwartzberg noted that Kaplan-Meier analysis revealed that rolapitant protection initiates in the acute phase (with separation of curves beginning about 10 hours after MEC) and is maintained in the delayed phase.

“There is a clear suggestion of a plateau effect occurring at 48 hours and beyond as opposed to the control arm,” Schwartzberg said. The Kaplan-Meier curves were statistically significant for between-group comparisons (P <.001). Rolapitant also was well tolerated in the MEC setting, and AEs were generally similar across the treatment groups.

References

1. Rapoport B, Poma A, Hedley ML, et al. Phase 3 trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving highly emetogenic chemotherapy (HEC). Presented at: MASCC/ISOO International Symposium on Supportive Care in Cancer; June 26-28, 2014; Miami, Florida. Abstract 0387.
2. Schnadig I, Modiano M , Poma A, et al. Phase 3 trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (MEC). Presented at: MASCC/ISOO International Symposium on Supportive Care in Cancer; June 26-28, 2014; Miami, Florida. Abstract 0384.

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