Phase III Safety Study of Intravenous NEPA

A Novel Fixed Antiemetic Combination of Fosnetupitant and Palonosetron in Patients Receiving Highly Emetogenic Chemotherapy

L. Schwartzberg; E. Roeland; Z. Andric; D. Kowalski; J. Radic; D. Voisin; G. Rizzi; R. Navari; R. J. Gralla; M. Karthaus

Disclosures

Ann Oncol. 2018;29(7):1535-1540. 

In This Article

Abstract and Introduction

Abstract

Background: NEPA, an oral fixed combination of the NK1RA netupitant (300 mg) and clinically/pharmacologically distinct 5-HT3RA palonosetron (PALO, 0.50 mg), is the first fixed antiemetic combination to have been approved. A single oral NEPA capsule plus dexamethasone (DEX) given before anthracycline–cyclophosphamide (AC) and non-AC highly emetogenic chemotherapy (HEC) showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) over PALO plus DEX for 5 days postchemotherapy. The safety of NEPA was well-established in the phase II/III clinical program in 1169 NEPA-treated patients. An intravenous (i.v.) formulation of the NEPA combination (fosnetupitant 235 mg plus PALO 0.25 mg) has been developed.

Patients and methods: This randomized, multinational, double-blind, stratified (by sex and country) phase III study (NCT02517021) in chemotherapy-naïve patients with solid tumors assessed the safety of a single dose of i.v. NEPA infused over 30 min before initial and repeated cycles of HEC. Patients received either i.v. NEPA or oral NEPA, both with oral DEX on days 1–4. Safety was assessed primarily by treatment-emergent adverse events (AEs) and electrocardiograms.

Results: A total of 404 patients completed 1312 cycles. The incidence and type of treatment-emergent AEs were similar for both treatment groups with the majority of AEs as mild/moderate in intensity. There was no increased incidence of AEs in subsequent cycles in either group. The incidence of treatment-related AEs was similar and relatively low in both groups (12.8% i.v. NEPA and 11.4% oral NEPA during the entire study), with constipation being the most common (6.4% i.v. NEPA, 6.0% oral NEPA). No serious treatment-related AEs occurred in either group. No infusion site or anaphylactic reactions related to i.v. NEPA occurred. No clinically relevant changes in QTc and no cardiac safety concerns were observed.

Conclusions: Intravenous NEPA was well-tolerated with a similar safety profile to oral NEPA in patients with various solid tumors receiving HEC.

Introduction

The development of new antiemetics has substantially changed the landscape for prevention of chemotherapy-induced nausea and vomiting (CINV). The current antiemetic armamentarium now allows for prevention of emesis in most cancer patients receiving emetogenic chemotherapy, while improvements in prevention of nausea are less pronounced, particularly during the delayed phase following chemotherapy.

With an improved understanding of CINV neuropharmacology and the development of new agents targeting different receptors involved in the CINV process, multi-agent antiemetic prophylactic combinations are recommended for the highly emetogenic chemotherapy (HEC) setting. Unfortunately, adherence to antiemetic guideline recommendations is suboptimal,[1,2] potentially in part due to the perceived complexity of these antiemetic combinations. A recently published survey of United States (US)-based oncology nurses not only revealed inconsistencies between antiemetic practice patterns and antiemetic guideline recommendations, but also revealed a discrepancy between nurses' reports of high proportions of patients with inadequate CINV control despite their belief in adequate guidelines adherence.[3]

Multiple classes of antiemetics are available in different formulations [e.g. oral, intravenous (i.v.), transdermal], offering options for healthcare providers and patients in various settings. Providing alternate drug formulations can help address unmet needs of patients and prescribers by promoting greater patient adherence to prescribed treatment regimens.

NEPA is the first and only fixed antiemetic combination agent and is comprised of netupitant, a highly selective NK1 receptor antagonist (RA) and palonosetron (PALO), an established pharmacologically distinct 5-HT3RA.[4,5] Approval of oral NEPA (netupitant 300 mg/PALO 0.50 mg) in the US and Europe was based on studies demonstrating that a single oral NEPA capsule plus dexamethasone (DEX) given before cisplatin– and anthracycline–cyclophosphamide (AC)-based chemotherapy demonstrated superior efficacy in preventing CINV over PALO plus DEX for 5 days postchemotherapy.[6–8] The safety of oral NEPA was also well-established in the phase II/III clinical program in 1169 NEPA-treated patients in single or repeated cycles.[9]

To offer additional convenience for patients and healthcare providers, a fixed i.v. combination formulation of NEPA was developed using a water-soluble phosphorylated pro-drug of netupitant called fosnetupitant. Intravenous fosnetupitant chloride at dosages from 20 to 390 mg has been administered to ~180 healthy volunteers in prior studies, with a good safety profile.[10] The selected bioequivalent dose of fosnetupitant for the i.v. formulation is 235 mg (corresponding to 260 mg of fosnetupitant chloride).[10] The selected i.v. dose for PALO is 0.25 mg, the same registered dose of i.v. Aloxi®. Fosnetupitant does not require any surfactant, emulsifier or solubility enhancer to get a clear injectable solution. The formulation of i.v. NEPA has been simplified reducing the number of excipients and associated toxicities.[11]

Given the demonstrated bioequivalence of 235 mg i.v. fosnetupitant and the netupitant component of oral NEPA (300 mg netupitant + 0.25 mg PALO) in terms of netupitant area under the curve, a phase III study was designed with the primary objective to assess the overall safety and tolerability of a single dose of i.v. NEPA administered with DEX over initial and repeated cycles of HEC.

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