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Giada Rizzi - One of the best experts on this subject based on the ideXlab platform.
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phase iiib safety and efficacy of intravenous Nepa for prevention of chemotherapy induced nausea and vomiting cinv in patients with breast cancer receiving initial and repeat cycles of anthracycline and cyclophosphamide ac chemotherapy
Oncologist, 2020Co-Authors: Lee S Schwartzberg, Giada Rizzi, Daniel Voisin, Rudolph M Navari, Rebecca Clarksnow, Ekaterine Arkania, Irena Radyukova, Kamal Patel, Rita Wickham, Richard J GrallaAbstract:BACKGROUND: Nepa, a combination antiemetic of a neurokinin-1 (NK1 ) receptor antagonist (RA) (netupitant [oral]/fosnetupitant [intravenous; IV]) and 5-HT3 RA, palonosetron] offers 5-day CINV prevention with a single dose. Fosnetupitant solution contains no allergenic excipients, surfactant, emulsifier, or solubility enhancer. A phase III study of patients receiving cisplatin found no infusion-site or anaphylactic reactions related to IV Nepa. However, hypersensitivity reactions and anaphylaxis have been reported with other IV NK1 RAs, particularly fosaprepitant in patients receiving anthracycline-cyclophosphamide (AC)-based chemotherapy. This study evaluated the safety and efficacy of IV Nepa in the AC setting. MATERIALS AND METHODS: This phase IIIb, multinational, randomized, double-blind study enrolled females with breast cancer naive to highly or moderately emetogenic chemotherapy. Patients were randomized to receive a single 30-minute infusion of IV Nepa or single oral Nepa capsule on day 1 prior to AC, in repeated (up to 4) cycles. Oral dexamethasone was given to all patients on day 1 only. RESULTS: A total of 402 patients were included. The adverse event (AE) profiles were similar for IV and oral Nepa and consistent with those expected. Most AEs were mild or moderate with a similarly low incidence of treatment-related AEs in both groups. There were no treatment-related injection-site AEs and no reports of hypersensitivity or anaphylaxis. The efficacy of IV and oral Nepa were similar, with high complete response (no emesis/no rescue) rates observed in cycle 1 (overall [0-120 hours] 73.0% IV Nepa, 77.3% oral Nepa) and maintained over subsequent cycles. CONCLUSION: IV Nepa was highly effective and safe with no associated hypersensitivity and injection-site reactions in patients receiving AC. IMPLICATIONS FOR PRACTICE: As a combination of a neurokinin-1 (NK1 ) receptor antagonist (RA) and 5-HT3 RA, Nepa offers 5-day chemotherapy-induced nausea and vomiting prevention with a single dose and an opportunity to improve adherence to antiemetic guidelines. In this randomized multinational phase IIIb study, intravenous (IV) Nepa (fosnetupitant/palonosetron) was safe and highly effective in patients receiving multiple cycles of anthracycline-cyclophosphamide (AC)-based chemotherapy. Unlike other IV NK1 RAs, the IV Nepa combination solution does not require any surfactant, emulsifier, or solubility enhancer and contains no allergenic excipients. Hypersensitivity reactions and anaphylaxis have been reported with other IV NK1 RAs, most commonly with fosaprepitant in the AC setting. Importantly, there were no injection-site or hypersensitivity reactions associated with IV Nepa.
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pharmacokinetic profile and safety of intravenous Nepa a fixed combination of fosnetupitant and palonosetron in cancer patients prevention of chemotherapy induced nausea and vomiting associated with highly emetogenic chemotherapy
European Journal of Pharmaceutical Sciences, 2019Co-Authors: Galina Kurteva, Giada Rizzi, Nataliya P Chilingirova, Tatiana Caccia, Valentino J Stella, Alberto BernareggiAbstract:Abstract Nepa is the fixed combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant and the 5-hydroxytryptamine-3 receptor antagonist palonosetron. The intravenous (i.v.) formulation of Nepa (fosnetupitant 235 mg/palonosetron 0.25 mg) was developed to enhance the convenience of Nepa administration. In a phase 3 study, i.v. Nepa showed acceptable safety with low risk for injection-site reactions. This study evaluated the pharmacokinetics and safety of i.v. Nepa in cancer patients. This was a single-center, single-dose phase 1 study in patients receiving highly emetogenic chemotherapy. Patients received a 30-min infusion of i.v. Nepa plus oral dexamethasone (12 mg) prior to chemotherapy, and oral dexamethasone (8 mg/daily) on days 2–4. Twenty-four patients received the complete i.v. Nepa infusion volume. Fosnetupitant maximum plasma concentration (Cmax) was reached at the end of infusion and decreased to Fosnetupitant conversion to netupitant occurred rapidly in cancer patients. Netupitant and palonosetron pharmacokinetic profiles in i.v. Nepa were similar to those reported for oral Nepa. i.v. Nepa was well tolerated with a similar safety profile to oral Nepa. i.v. Nepa provides additional administration convenience. Clinical trial registration number: EudraCT 2015-004750-18.
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phase iii safety study of intravenous Nepa a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy
Annals of Oncology, 2018Co-Authors: Lee S Schwartzberg, Giada Rizzi, Eric Roeland, Z Andric, Dariusz M Kowalski, J Radic, Daniel Voisin, Rudolph M Navari, Richard J Gralla, Meinolf KarthausAbstract: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-naive 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.
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efficacy and safety of oral Nepa netupitant palonosetron the first fixed combination antiemetic in patients with gynecological cancers receiving platinum based chemotherapy
International Journal of Gynecological Cancer, 2018Co-Authors: Snežana M Bosnjak, Giada Rizzi, Ljiljana Stamatovic, Maria Elisa Borroni, Karin JordanAbstract:Objective Patients with gynecological cancers are at high risk for chemotherapy-induced nausea and vomiting (CINV) after platinum-based chemotherapy (CT). Nepa (300-mg netupitant, 0.50-mg palonosetron) is the first oral fixed-combination antiemetic. Pivotal trials demonstrated the superiority of oral Nepa over intravenous palonosetron in preventing CINV after highly emetogenic (anthracycline-cyclophosphamide–based [AC] and cisplatin-based [non-AC]) CT. This post hoc subset analysis considered patients with gynecological cancer receiving cisplatin- or carboplatin-based CT from 1 pivotal trial and from 1 multicycle safety trial to evaluate the efficacy of oral Nepa in preventing CINV. Methods Single-dose Nepa was given before CT in combination with dexamethasone. The efficacy end points for the acute (0–24 hours), delayed (25–120 hours), and overall (0–120 hours) CINV phases after CT included complete response (CR; no emesis, no rescue medication) and no significant nausea ( Results For cisplatin-induced CINV, Nepa achieved high CR rates (acute phase: >90%; delayed, overall phases: ≥85%). For carboplatin-induced CINV, Nepa was also highly effective, with high acute, delayed, and overall CR rates (cycle 1: >75%; cycles 2–4: >95%). No significant nausea rates were more than 90% and more than 80% in the acute and delayed phases, respectively, for patients receiving cisplatin or carboplatin. Nepa was well tolerated. Conclusions Results suggest that oral Nepa is effective and safe in preventing CINV in patients with gynecological cancers treated with cisplatin- or carboplatin-based CT. Single fixed-combination Nepa is a convenient option for CINV prevention in high-risk CINV patients.
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phase iii safety evaluation of intravenous Nepa a novel fixed antiemetic combination of fosnetupitant and palonosetron over multiple cycles
Journal of Clinical Oncology, 2017Co-Authors: Lee S Schwartzberg, Giada Rizzi, Z Andric, Dariusz M Kowalski, Daniel Voisin, Meinolf KarthausAbstract:122Background: Nepa is an oral fixed combination of the selective NK1 receptor antagonist (RA), netupitant (300 mg), and pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), combining two guideline-recommended antiemetic classes in a convenient single capsule. Oral Nepa has shown superior prevention of chemotherapy-induced nausea and vomiting (CINV) over oral PALO, sustained efficacy over multiple cycles, and well-established safety in >1500 patients (pts). To offer additional convenience for health care practitioners and pts, an intravenous (IV) formulation of the Nepa fixed combination (fosnetupitant 235 mg/PALO 0.25 mg) was developed. Methods: This randomized, multinational, double-blind, stratified (by gender/country) phase 3 study in chemotherapy-naive pts with solid tumors was designed to assess the safety of a single 30-minute infusion of IV Nepa prior to initial/up to 4 repeated cycles of highly emetogenic chemotherapy (HEC). Patients received either IV Nepa or oral Nepa, both with ora...
Lee S Schwartzberg - One of the best experts on this subject based on the ideXlab platform.
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phase iiib safety and efficacy of intravenous Nepa for prevention of chemotherapy induced nausea and vomiting cinv in patients with breast cancer receiving initial and repeat cycles of anthracycline and cyclophosphamide ac chemotherapy
Oncologist, 2020Co-Authors: Lee S Schwartzberg, Giada Rizzi, Daniel Voisin, Rudolph M Navari, Rebecca Clarksnow, Ekaterine Arkania, Irena Radyukova, Kamal Patel, Rita Wickham, Richard J GrallaAbstract:BACKGROUND: Nepa, a combination antiemetic of a neurokinin-1 (NK1 ) receptor antagonist (RA) (netupitant [oral]/fosnetupitant [intravenous; IV]) and 5-HT3 RA, palonosetron] offers 5-day CINV prevention with a single dose. Fosnetupitant solution contains no allergenic excipients, surfactant, emulsifier, or solubility enhancer. A phase III study of patients receiving cisplatin found no infusion-site or anaphylactic reactions related to IV Nepa. However, hypersensitivity reactions and anaphylaxis have been reported with other IV NK1 RAs, particularly fosaprepitant in patients receiving anthracycline-cyclophosphamide (AC)-based chemotherapy. This study evaluated the safety and efficacy of IV Nepa in the AC setting. MATERIALS AND METHODS: This phase IIIb, multinational, randomized, double-blind study enrolled females with breast cancer naive to highly or moderately emetogenic chemotherapy. Patients were randomized to receive a single 30-minute infusion of IV Nepa or single oral Nepa capsule on day 1 prior to AC, in repeated (up to 4) cycles. Oral dexamethasone was given to all patients on day 1 only. RESULTS: A total of 402 patients were included. The adverse event (AE) profiles were similar for IV and oral Nepa and consistent with those expected. Most AEs were mild or moderate with a similarly low incidence of treatment-related AEs in both groups. There were no treatment-related injection-site AEs and no reports of hypersensitivity or anaphylaxis. The efficacy of IV and oral Nepa were similar, with high complete response (no emesis/no rescue) rates observed in cycle 1 (overall [0-120 hours] 73.0% IV Nepa, 77.3% oral Nepa) and maintained over subsequent cycles. CONCLUSION: IV Nepa was highly effective and safe with no associated hypersensitivity and injection-site reactions in patients receiving AC. IMPLICATIONS FOR PRACTICE: As a combination of a neurokinin-1 (NK1 ) receptor antagonist (RA) and 5-HT3 RA, Nepa offers 5-day chemotherapy-induced nausea and vomiting prevention with a single dose and an opportunity to improve adherence to antiemetic guidelines. In this randomized multinational phase IIIb study, intravenous (IV) Nepa (fosnetupitant/palonosetron) was safe and highly effective in patients receiving multiple cycles of anthracycline-cyclophosphamide (AC)-based chemotherapy. Unlike other IV NK1 RAs, the IV Nepa combination solution does not require any surfactant, emulsifier, or solubility enhancer and contains no allergenic excipients. Hypersensitivity reactions and anaphylaxis have been reported with other IV NK1 RAs, most commonly with fosaprepitant in the AC setting. Importantly, there were no injection-site or hypersensitivity reactions associated with IV Nepa.
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abstract p5 14 07 avoidable acute care involving chemotherapy induced nausea and vomiting cinv among patients with breast cancer receiving anthracycline cyclophosphamide ac with Nepa prophylaxis relative to other antiemetics an external control arm a
Cancer Research, 2020Co-Authors: Lee S Schwartzberg, Rudolph M Navari, Rebecca Clarksnow, Rita Wickham, Kathryn J Ruddy, Thomas W Leblanc, Gary Binder, William L Bailey, Ravi Potluri, Luke M SchmeroldAbstract:Background: Anthracycline and cyclophosphamide (AC) is a highly emetogenic chemotherapy (HEC) regimen. Combination netupitant/palonosetron (Nepa) + dexamethasone (DEX) is guideline-recommended for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in HEC and moderately emetogenic chemotherapy. CMS’ OP-35 measure deems 30-day post-chemotherapy acute care as avoidable if involving nausea and emesis (NV) or any of 8 other toxicities. Results will be publicly reported and impact Medicare reimbursement. CMS (2017) found that 10% of >58,000 patients with avoidable acute care after chemotherapy involved NV. Because Nepa is new, insufficient real world data exist to assess its CINV resource use. CINV-related acute-care after Nepa prophylaxis in AC has been reported in a prospective clinical trial. Our aim was to compare these rates to those seen after prophylaxis with other antiemetics for AC outside of a clinical trial. Methods: Pre-specified endpoints in a prospective trial of oral or IV Nepa + DEX in AC included acute-care use (emergency [ED] visits or inpatient admissions [IP]) involving CINV, defined as emesis or rescue drug use ≤5 days after AC, and concomitant ED/IP in the same period. We also evaluated CINV-related acute care after non-Nepa prophylaxis for AC in breast cancer from 10/2012-8/2018 in IBM Explorys electronic health records. We age-matched patients 3:1 to the Nepa trial. We further adjusted the event rate to address under-reporting of a) CINV rates (vs. 49.2% for aprepitant in AC in a clinical trial [Warr 2005]) and b) acute-care use, projected at 17-50% at sites external to the dataset. To compare the resulting adjusted event rate to the Nepa study, we conducted 10,000 Monte Carlo simulations, using random probabilities from 5.2-8.7% for Explorys patients, and from 0-2% for Nepa patients to address potential reporting variability, despite the trial including daily patient diaries. Analysis of data was limited to the first two cycles, the median duration in the Nepa trial. Results: In the Nepa trial, 402 patients received ≥1 cycle; 391 completed two cycles. Nine patients had IP admissions; none involved CINV. Five patients had 6 total ED visits; one met criteria for involving CINV; the resulting rate of acute care rate involving CINV was 0.25 per 100 patients. For other antiemetics, 2598 patients received AC (excluding Nepa prophylaxis). Among 1206 age-matched to the Nepa trial, 15 patients had acute-care events in the first 2 cycles, (1.24 per 100 patients), an odds ratio of 1:5.1 (CI 0.7-38.5) in favor of Nepa. After adjusting via the simulation, the odds ratio was 1:8.3 (CI: 2.43-24.21) in favor of Nepa. Conclusions: Comparing CINV-related acute care seen in a large prospective trial relative to real-world evidence in patients with breast cancer treated with AC, Citation Format: Lee Schwartzberg, Kathryn J Ruddy, Rudolph M Navari, Thomas W LeBlanc, Rebecca Clark-Snow, Rita Wickham, Gary Binder, William L. Bailey, Ravi Potluri, Luke M Schmerold, Eros Papademetriou, Eric J Roeland. Avoidable acute care involving chemotherapy-induced nausea and vomiting (CINV) among patients with breast cancer receiving anthracycline + cyclophosphamide (AC) with Nepa prophylaxis relative to other antiemetics: An external control arm analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-07.
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efficacy of intravenous iv Nepa a fixed nk1 5 ht3 receptor antagonist combination for prevention of emesis following highly emetogenic chemotherapy hec
Journal of Clinical Oncology, 2018Co-Authors: Eric Roeland, Richard J Gralla, Li Zhang, Paul J Hesketh, Lee S SchwartzbergAbstract:194Background: An IV formulation of Nepa (fixed combination of fosnetupitant 235 mg and palonosetron 0.25 mg) was recently approved offering clinicians an additional antiemetic treatment option. Approval of IV Nepa was based on showing pharmacokinetic bioequivalence and comparable safety to oral Nepa. This post-hoc analysis presents the efficacy of IV Nepa relative to that of oral Nepa and other NK1 RAs in the HEC setting. Methods: Data is compiled from 3 pivotal Nepa registration studies in a total of 951 adult chemotherapy-naive patients with solid tumors undergoing predominantly cisplatin-based HEC. All studies had similar inclusion/exclusion criteria. IV Nepa was administered as a single 30-min infusion and a single capsule of oral Nepa was given prior to HEC. All patients received dexamethasone (DEX) on Days 1-4. Data is also compiled from registration HEC trials on other NK1 RA (aprepitant, fosaprepitant, rolapitant) regimens. No emesis rates are summarized for the overall phase (0-120h) of the init...
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phase iii safety study of intravenous Nepa a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy
Annals of Oncology, 2018Co-Authors: Lee S Schwartzberg, Giada Rizzi, Eric Roeland, Z Andric, Dariusz M Kowalski, J Radic, Daniel Voisin, Rudolph M Navari, Richard J Gralla, Meinolf KarthausAbstract: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-naive 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.
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phase iii safety evaluation of intravenous Nepa a novel fixed antiemetic combination of fosnetupitant and palonosetron over multiple cycles
Journal of Clinical Oncology, 2017Co-Authors: Lee S Schwartzberg, Giada Rizzi, Z Andric, Dariusz M Kowalski, Daniel Voisin, Meinolf KarthausAbstract:122Background: Nepa is an oral fixed combination of the selective NK1 receptor antagonist (RA), netupitant (300 mg), and pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), combining two guideline-recommended antiemetic classes in a convenient single capsule. Oral Nepa has shown superior prevention of chemotherapy-induced nausea and vomiting (CINV) over oral PALO, sustained efficacy over multiple cycles, and well-established safety in >1500 patients (pts). To offer additional convenience for health care practitioners and pts, an intravenous (IV) formulation of the Nepa fixed combination (fosnetupitant 235 mg/PALO 0.25 mg) was developed. Methods: This randomized, multinational, double-blind, stratified (by gender/country) phase 3 study in chemotherapy-naive pts with solid tumors was designed to assess the safety of a single 30-minute infusion of IV Nepa prior to initial/up to 4 repeated cycles of highly emetogenic chemotherapy (HEC). Patients received either IV Nepa or oral Nepa, both with ora...
Matti Aapro - One of the best experts on this subject based on the ideXlab platform.
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a randomized phase iii study evaluating the efficacy of single dose Nepa a fixed antiemetic combination of netupitant and palonosetron versus an aprepitant regimen for prevention of chemotherapy induced nausea and vomiting cinv in patients receiving
Annals of Oncology, 2018Co-Authors: L Zhang, S Lu, J Feng, Arunee Dechaphunkul, Jinjia Chang, Dong Wang, Salvatore Chessari, C Lanzarotti, Karin Jordan, Matti AaproAbstract:ABSTRACT Background Co-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize chemotherapy-induced nausea and vomiting (CINV) control in patients receiving highly emetogenic chemotherapy (HEC). Nepa, a fixed combination of a highly selective NK1 receptor antagonist, netupitant (300 mg), and the pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), has shown superior CINV prevention compared with PALO in cisplatin and anthracycline/cyclophosphamide-based settings. This study is the first head-to-head comparison of Nepa versus an aprepitant (APR)/granisetron (GRAN) regimen. Patients and methods This randomized, double-blind phase III study conducted in Asia was designed with the primary objective to demonstrate non-inferiority of a single oral dose of Nepa compared with a 3-day oral APR/GRAN regimen in chemotherapy-naive patients receiving cisplatin-based HEC. All patients also received oral dexamethasone (DEX) on days 1–4. The primary efficacy endpoint was complete response (CR: no emesis/no rescue medication) during the overall (0–120 h) phase. Non-inferiority was defined as a lower 95% CI greater than the non-inferiority margin set at −10%. Secondary efficacy endpoints included no emesis, no rescue medication, and no significant nausea (NSN). Results Treatment groups were comparable for the 828 patients analyzed: predominantly male (71%); mean age 54.5 years; ECOG 0–1 (98%); lung cancer (58%). Nepa demonstrated non-inferiority to APR/GRAN for overall CR [Nepa 73.8% versus APR/GRAN 72.4%, 95% CI (−4.5%, 7.5%)]. No emesis [Nepa 75.0% versus APR/GRAN 74.0%, 95% CI (−4.8%, 6.9%)] and NSN rates [Nepa 75.7% versus APR/GRAN 70.4%, 95% CI (−0.6%, 11.4%)] were similar between groups, but significantly more Nepa patients did not take rescue medication [Nepa 96.6% versus APR/GRAN 93.5%, 95% CI (0.2%, 6.1%)]. Nepa was well tolerated with a similar safety profile to APR/GRAN. Conclusions In this first study comparing NK1RA regimens and DEX, Nepa administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC.
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efficacy of Nepa netupitant palonosetron across multiple cycles of chemotherapy in breast cancer patients a subanalysis from two phase iii trials
The Breast, 2017Co-Authors: Hope S. Rugo, Giada Rizzi, Giorgia Rossi, Matti AaproAbstract:Abstract Objectives Breast cancer (BC) patients represent a high-risk population for experiencing chemotherapy-induced nausea and vomiting (CINV), since they frequently receive highly emetogenic anthracycline-cyclophosphamide–based (AC) chemotherapy, and are often female and young, two predisposing risk factors for CINV. Guidelines recommend the combination of a neurokinin-1 receptor antagonist (NK1RA), 5-hydroxytryptamine-3 RA (5-HT3RA), and dexamethasone (DEX) for CINV prophylaxis in AC-treated patients. This post-hoc analysis evaluated the efficacy of Nepa, a fixed combination of netupitant (NETU [NK1RA]) and palonosetron (PALO [5-HT3RA]) in BC patients from two phase III studies. Methods Overall, 1460 BC patients received AC (Study 1) or non-AC (Study 2) therapy over 6060 cycles. Randomized patients received DEX with either Nepa or oral PALO (Study 1), or Nepa or aprepitant+oral PALO (Study 2) before chemotherapy. Results In AC-receiving patients, overall complete response (CR) rates with Nepa+DEX were statistically significantly higher than oral PALO+DEX rates (cycles 1–4: 73.9% vs 65.9%, 80.0% vs 66.0%, 83.6% vs 69.9%, 83.6% vs 74.4%, respectively). Overall, no significant nausea (NSN) rates were also superior with Nepa+DEX vs oral PALO+DEX (respectively, 74.2%–79.9% vs 68.5%–74.9%). A greater proportion of Nepa+DEX patients experienced “no-impact-on-daily-life” due to CINV (78.4% vs 71.4%) in cycle 1. In non-AC–receiving patients, prophylaxis with Nepa+DEX resulted in high CR and NSN rates across 1–4 chemotherapy cycles; no formal comparison with the control arm was performed. Conclusion Nepa+DEX administered as a single dose is an effective option for preventing CINV in BC patients receiving AC and non-AC, across multiple chemotherapy cycles. Clinical trials registration numbers Study 1: NCT01339260 , Study 2: NCT01376297 .
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Abstract P1-10-06: Nausea control and quality-of-life benefit with Nepa, the first combination antiemetic agent, in patients with breast cancer receiving anthracycline/cyclophosphamide (AC) chemotherapy
Cancer Research, 2016Co-Authors: Hope S. Rugo, Matti Aapro, Giada RizziAbstract:Background : Patients (pts) with breast cancer (BC) are at high risk for developing chemotherapy-induced nausea and vomiting (CINV) due to the emetogenicity of chemotherapy (often AC-based) and predisposing risk factors including young age and female gender. For pts receiving AC, antiemetic guidelines recommend prophylactic administration of an NK 1 receptor antagonist (RA), a 5-HT 3 RA, and dexamethasone (DEX). Nepa is the first fixed combination agent approved in oncology; comprised of a highly selective NK 1 receptor antagonist (RA), netupitant (300 mg), and the pharmacologically/clinically distinct 5-HT 3 RA, palonosetron (PALO 0.50 mg). Nepa has shown superior complete response (no emesis/no rescue use) rates compared with oral PALO in a Phase 3 trial in pts receiving AC ( Aapro, Ann Oncol 2014 ) and in that study9s BC subset. Despite progress in prevention of vomiting, nausea control remains suboptimal, particularly in the delayed phase (days 2-5), and debate exists whether NK 1 RAs improve nausea control. The objective of this post-hoc analysis was to evaluate whether Nepa showed nausea and associated quality-of-life (QOL) benefits in the subset of patients with BC in this trial. Methods : The subset of chemotherapy-naive BC pts from this multinational, randomized, double-blind Phase 3 study were included in this analysis. Patients received either a single dose of Nepa or oral PALO prior to AC along with oral DEX 12 mg (Nepa) or 20 mg (PALO). No significant nausea (NSN: max Results : 1412 patients with BC were included for a total of 5839 AC cycles. NSN rates were similar for both groups in the acute phase, superior for Nepa during cycles 1, 2 and 4 in the delayed phase, and superior for Nepa during cycles 1-4 in the overall phase. This corresponded with a significantly greater proportion of Nepa patients reporting NIDL compared with PALO due to nausea (71% vs 65%; p=0.007) in cycle 1. Conclusions : While other NK 1 RAs have not consistently shown benefit in improving nausea control over 5-HT 3 RA + DEX, in this study Nepa significantly improved prevention of nausea over oral PALO in BC patients receiving AC. In addition, Nepa was superior to PALO in reducing the negative impact of nausea on patients9 daily functioning. As the first fixed antiemetic drug combination, Nepa is highly effective and offers the convenience of a single dose administered with DEX on Day 1 only. Citation Format: Rugo HS, Aapro M, Rizzi G. Nausea control and quality-of-life benefit with Nepa, the first combination antiemetic agent, in patients with breast cancer receiving anthracycline/cyclophosphamide (AC) chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-06.
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cardiac safety of Nepa a fixed dose antiemetic combination administered prior to anthracycline based chemotherapy
Blood, 2014Co-Authors: Meinolf Karthaus, Giada Rizzi, Matti Aapro, Marco PalmasAbstract:Background: Cardiotoxicity is a well-known risk associated with anthracyclines, a widely prescribed class of chemotherapeutic agents. While the cumulative dose represents the greatest risk factor, concomitant use of other chemotherapy, such as cyclophosphamide can also contribute to this risk. As supportive care agents may be necessary to manage side effects associated with anthracycline treatment, it is critical that these agents do not contribute to the potential for cardiac adverse effects. Nepa is a unique fixed-dose antiemetic combination of netupitant (NETU), a new highly-selective NK 1 receptor antagonist (RA) and palonosetron (PALO), an established pharmacologically distinct 5-HT 3 RA with a clean cardiac safety profile (Morganroth, ESMO 2007). Superiority of Nepa over oral PALO in preventing chemotherapy-induced nausea and vomiting associated with anthracycline-cyclophosphamide (AC) chemotherapy was recently demonstrated in a large multicycle study in solid tumors (Aapro, ASCO 2014). Because AC is also part of treatment utilized for hematologic malignancies, such as the CHOP combination, an evaluation of the cardiac safety of Nepa in this study is relevant to the hematology setting. Methods: This multinational, randomized, double-blind, parallel group study compared a single oral dose of Nepa (NETU 300 mg + PALO 0.50 mg) versus a single oral 0.50 mg dose of PALO in chemotherapy-naive patients receiving AC chemotherapy for solid tumors during cycle 1 and during a multicycle extension. All patients also received oral dexamethasone on Day 1 (12 mg in the Nepa arm and 20 mg in the PALO arm). Cardiac safety was evaluated by cardiac adverse events, ECG changes, cardiac troponin levels (a biomarker used for early detection of cardiotoxicity) and left ventricular ejection fraction (LVEF, by ECHO). Results: 1450 and 1286 patients were included in the safety population for cycle 1 (n = 725 each group) and the multicycle extension (n = 635 Nepa, 651 PALO), respectively; 76% of all patients completed at least 4 cycles. Treatment groups were comparable with the majority of patients being female (98%) and white (80%), with a mean age of 54 years. The percentage of patients with at least one treatment-emergent adverse event (AE) classified as a cardiac disorder was similar for both groups in cycle 1 (2.6% Nepa vs. 2.1% PALO) and during the multicycle extension (5.0% vs. 4.6%). Overall, four AEs (n = 1 Nepa, n = 3 PALO) were classified as serious while none were considered related to study treatment. The percent of patients with treatment-emergent ECG abnormalities was comparable between groups. In cycle 1, the most frequently reported abnormalities were flat T waves (12.6% and 12.1% for Nepa and PALO, respectively). ST depression was the same in both groups (6.5%). The mean changes in QTcF were small and similar between groups and returned to baseline at 120 hours. The percentage of patients with increases from baseline of > 60 ms in QTcF were 0.7% and 1.1% for Nepa and PALO, respectively. This pattern for ECG abnormalities and QTcF changes was similar in the multicycle extension with no differences seen between groups. Similar proportions of patients had high troponin levels (ie, >0.12 ng/mL) in cycle 1 (0.1% Nepa vs. 0.3% PALO) and in the multicycle extension (3.4% Nepa vs. 2.9% PALO). Of these, 0.4% Nepa and 0.7% PALO had troponin values greater than 0.50 ng/mL. In the majority of cases, the high values developed in cycles 5 and 6. Mean LVEF changes from screening to end of study were negligible and comparable between groups. Conclusions: In this large study of 1450 patients, there was no indication of increased cardiac safety concerns with the Nepa combination relative to PALO after single or repeated cycles of anthracycline-based chemotherapy. Consequently, clinicians can utilize this highly effective convenient, fixed-dose antiemetic drug combination with the knowledge that Nepa is not expected to contribute to the potential for cardiotoxicity seen with anthracyclines or other chemotherapies. Disclosures Karthaus: Helsinn Healthcare: Honoraria. Off Label Use: Nepa is a combination antiemetic currently under FDA review. Aapro: Helsinn Healthcare: Consultancy, Honoraria. Rizzi: Helsinn Healthcare: Employment. Palmas: Helsinn Healthcare: Employment.
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a randomized phase iii study evaluating the efficacy and safety of Nepa a fixed dose combination of netupitant and palonosetron for prevention of chemotherapy induced nausea and vomiting following moderately emetogenic chemotherapy
Annals of Oncology, 2014Co-Authors: Matti Aapro, Giada Rizzi, Hope S. Rugo, Maria Elisa Borroni, G Rossi, Igor Bondarenko, T Sarosiek, Cristina Oprean, Servando Cardonahuerta, V LorussoAbstract:ABSTRACT Background Antiemetic guidelines recommend co-administration of agents that target multiple molecular pathways involved in emesis to maximize prevention and control of chemotherapy-induced nausea and vomiting (CINV). Nepa is a new oral fixed-dose combination of 300 mg netupitant, a highly selective NK1 receptor antagonist (RA) and 0.50 mg palonosetron (PALO), a pharmacologically and clinically distinct 5-HT3 RA, which targets dual antiemetic pathways. Patients and methods This multinational, randomized, double-blind, parallel group phase III study (NCT01339260) in 1455 chemotherapy-naive patients receiving moderately emetogenic (anthracycline–cyclophosphamide) chemotherapy evaluated the efficacy and safety of a single oral dose of Nepa versus a single oral dose (0.50 mg) of PALO. All patients also received oral dexamethasone (DEX) on day 1 only (12 mg in the Nepa arm and 20 mg in the PALO arm). The primary efficacy end point was complete response (CR: no emesis, no rescue medication) during the delayed (25–120 h) phase in cycle 1. Results The percentage of patients with CR during the delayed phase was significantly higher in the Nepa group compared with the PALO group (76.9% versus 69.5%; P = 0.001), as were the percentages in the overall (0–120 h) (74.3% versus 66.6%; P = 0.001) and acute (0–24 h) (88.4% versus 85.0%; P = 0.047) phases. Nepa was also superior to PALO during the delayed and overall phases for all secondary efficacy end points of no emesis, no significant nausea and complete protection (CR plus no significant nausea). Nepa was well tolerated with a similar safety profile as PALO. Conclusions Nepa plus a single dose of DEX was superior to PALO plus DEX in preventing CINV following moderately emetogenic chemotherapy in acute, delayed and overall phases of observation. As a fixed-dose antiemetic drug combination, Nepa along with a single dose of DEX on day 1 offers guideline-based prophylaxis with a convenient, single-day treatment.
Meinolf Karthaus - One of the best experts on this subject based on the ideXlab platform.
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abstract p1 11 10 efficacy of Nepa as antiemetic prophylaxis in breast cancer patients receiving highly or moderately emetogenic chemotherapy interim results of a german prospective non interventional study
Cancer Research, 2019Co-Authors: Jorg Schilling, C Hielscher, C Hanusch, Christian M Kurbacher, Steffi Busch, Meinolf KarthausAbstract:Background The oral fixed dose combination of netupitant and palonosetron Nepa has been approved for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in cancer patients receiving cisplatin-based highly emetogenic (HEC) or moderately emetogenic chemotherapy (MEC). The primary objective of the prospective, non-interventional study (NIS) AkyPRO is the evaluation of quality of life in adults receiving MEC or HEC and Nepa for CINV prevention. Secondary endpoints are efficacy and safety of Nepa. Here we present an interim analysis of Nepa efficacy in the subgroup of breast cancer patients, who represent the largest subgroup (66%) of enrolled patients. Since September 2015, 2427 patients have been enrolled, of whom 986 are breast cancer patients. Methods The NIS has been designed to evaluate Nepa in 2,500 cancer patients receiving single day or two day MEC or HEC. QoL is recorded by FLIE questionnaires. Efficacy (complete response (CR, no vomiting, no rescue medication)), additional medication, and adverse events are recorded in patient diaries over three consecutive chemotherapy cycles. Additionally, physicians report their efficacy assessments of Nepa online, using an eCRF. Results At the cut-off date November 11, 2017, 2427 patients had been enrolled in the study. For the interim analysis 986 breast cancer patients were evaluated who had been fully documented in the eCRF at the cut-off date. 95% had an ECOG performance status of 0 or 1. 51% received adjuvant, 44% neoadjuvant, and 5% palliative chemotherapy. 80% of patients received HEC, mostly (79%) anthracycline/cyclophosphamide (AC) combinations. Of the women receiving MEC, the majority were treated with carboplatin-based regimens (9%). 7% of patients received other MEC regimens. 81.4-82.8 % of patients reported CR in cycles 1-3 and more than 93% of patients reported no emesis during the 3 treatment cycles covered in the patient diaries. No significant nausea was reported by 62.7-64.2% of patients. Physicians rated the efficacy of the antiemetic prophylaxis with Nepa using the 4 categories very good, good, satisfactory, and poor. In cycles 1 and 2, more than 89% of physicians rated the efficacy of Nepa very good or good. In cycle 3, 90.6% rated it very good or good. In addition to reporting CR, nausea and emesis episodes in their patient diaries, patients used the same 4 categories to assess the efficacy of Nepa at the end of each treatment cycle. Efficacy assessments of physicians and patients were very similar, with 87% of patients choosing very good or good in cycle 1 compared to 89% of physicians. Nepa was well tolerated. Low-grade constipation (14.9%) and insomnia (8.3%) were the most frequent treatment-related adverse event. Conclusion In this real life study, Nepa was effective in the prevention of CINV in the subgroup of breast cancer patients receiving HEC or MEC. The efficacy assessments by patients and physicians were comparable, with approximately 90% good or very good efficacy for 3 consecutive cycles. More than 93% of patients reported no emesis and more than 81% reported CR during the 5 days post-chemotherapy during all 3 cycles. The study is ongoing. Citation Format: Schilling J, Hielscher C, Hanusch C, Kurbacher C, Busch S, Karthaus M. Efficacy of Nepa as antiemetic prophylaxis in breast cancer patients receiving highly or moderately emetogenic chemotherapy – Interim results of a German prospective, non-interventional study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-10.
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phase iii safety study of intravenous Nepa a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy
Annals of Oncology, 2018Co-Authors: Lee S Schwartzberg, Giada Rizzi, Eric Roeland, Z Andric, Dariusz M Kowalski, J Radic, Daniel Voisin, Rudolph M Navari, Richard J Gralla, Meinolf KarthausAbstract: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-naive 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.
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phase iii safety evaluation of intravenous Nepa a novel fixed antiemetic combination of fosnetupitant and palonosetron over multiple cycles
Journal of Clinical Oncology, 2017Co-Authors: Lee S Schwartzberg, Giada Rizzi, Z Andric, Dariusz M Kowalski, Daniel Voisin, Meinolf KarthausAbstract:122Background: Nepa is an oral fixed combination of the selective NK1 receptor antagonist (RA), netupitant (300 mg), and pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), combining two guideline-recommended antiemetic classes in a convenient single capsule. Oral Nepa has shown superior prevention of chemotherapy-induced nausea and vomiting (CINV) over oral PALO, sustained efficacy over multiple cycles, and well-established safety in >1500 patients (pts). To offer additional convenience for health care practitioners and pts, an intravenous (IV) formulation of the Nepa fixed combination (fosnetupitant 235 mg/PALO 0.25 mg) was developed. Methods: This randomized, multinational, double-blind, stratified (by gender/country) phase 3 study in chemotherapy-naive pts with solid tumors was designed to assess the safety of a single 30-minute infusion of IV Nepa prior to initial/up to 4 repeated cycles of highly emetogenic chemotherapy (HEC). Patients received either IV Nepa or oral Nepa, both with ora...
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cardiac safety of Nepa a fixed dose antiemetic combination administered prior to anthracycline based chemotherapy
Blood, 2014Co-Authors: Meinolf Karthaus, Giada Rizzi, Matti Aapro, Marco PalmasAbstract:Background: Cardiotoxicity is a well-known risk associated with anthracyclines, a widely prescribed class of chemotherapeutic agents. While the cumulative dose represents the greatest risk factor, concomitant use of other chemotherapy, such as cyclophosphamide can also contribute to this risk. As supportive care agents may be necessary to manage side effects associated with anthracycline treatment, it is critical that these agents do not contribute to the potential for cardiac adverse effects. Nepa is a unique fixed-dose antiemetic combination of netupitant (NETU), a new highly-selective NK 1 receptor antagonist (RA) and palonosetron (PALO), an established pharmacologically distinct 5-HT 3 RA with a clean cardiac safety profile (Morganroth, ESMO 2007). Superiority of Nepa over oral PALO in preventing chemotherapy-induced nausea and vomiting associated with anthracycline-cyclophosphamide (AC) chemotherapy was recently demonstrated in a large multicycle study in solid tumors (Aapro, ASCO 2014). Because AC is also part of treatment utilized for hematologic malignancies, such as the CHOP combination, an evaluation of the cardiac safety of Nepa in this study is relevant to the hematology setting. Methods: This multinational, randomized, double-blind, parallel group study compared a single oral dose of Nepa (NETU 300 mg + PALO 0.50 mg) versus a single oral 0.50 mg dose of PALO in chemotherapy-naive patients receiving AC chemotherapy for solid tumors during cycle 1 and during a multicycle extension. All patients also received oral dexamethasone on Day 1 (12 mg in the Nepa arm and 20 mg in the PALO arm). Cardiac safety was evaluated by cardiac adverse events, ECG changes, cardiac troponin levels (a biomarker used for early detection of cardiotoxicity) and left ventricular ejection fraction (LVEF, by ECHO). Results: 1450 and 1286 patients were included in the safety population for cycle 1 (n = 725 each group) and the multicycle extension (n = 635 Nepa, 651 PALO), respectively; 76% of all patients completed at least 4 cycles. Treatment groups were comparable with the majority of patients being female (98%) and white (80%), with a mean age of 54 years. The percentage of patients with at least one treatment-emergent adverse event (AE) classified as a cardiac disorder was similar for both groups in cycle 1 (2.6% Nepa vs. 2.1% PALO) and during the multicycle extension (5.0% vs. 4.6%). Overall, four AEs (n = 1 Nepa, n = 3 PALO) were classified as serious while none were considered related to study treatment. The percent of patients with treatment-emergent ECG abnormalities was comparable between groups. In cycle 1, the most frequently reported abnormalities were flat T waves (12.6% and 12.1% for Nepa and PALO, respectively). ST depression was the same in both groups (6.5%). The mean changes in QTcF were small and similar between groups and returned to baseline at 120 hours. The percentage of patients with increases from baseline of > 60 ms in QTcF were 0.7% and 1.1% for Nepa and PALO, respectively. This pattern for ECG abnormalities and QTcF changes was similar in the multicycle extension with no differences seen between groups. Similar proportions of patients had high troponin levels (ie, >0.12 ng/mL) in cycle 1 (0.1% Nepa vs. 0.3% PALO) and in the multicycle extension (3.4% Nepa vs. 2.9% PALO). Of these, 0.4% Nepa and 0.7% PALO had troponin values greater than 0.50 ng/mL. In the majority of cases, the high values developed in cycles 5 and 6. Mean LVEF changes from screening to end of study were negligible and comparable between groups. Conclusions: In this large study of 1450 patients, there was no indication of increased cardiac safety concerns with the Nepa combination relative to PALO after single or repeated cycles of anthracycline-based chemotherapy. Consequently, clinicians can utilize this highly effective convenient, fixed-dose antiemetic drug combination with the knowledge that Nepa is not expected to contribute to the potential for cardiotoxicity seen with anthracyclines or other chemotherapies. Disclosures Karthaus: Helsinn Healthcare: Honoraria. Off Label Use: Nepa is a combination antiemetic currently under FDA review. Aapro: Helsinn Healthcare: Consultancy, Honoraria. Rizzi: Helsinn Healthcare: Employment. Palmas: Helsinn Healthcare: Employment.
Richard J Gralla - One of the best experts on this subject based on the ideXlab platform.
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phase iiib safety and efficacy of intravenous Nepa for prevention of chemotherapy induced nausea and vomiting cinv in patients with breast cancer receiving initial and repeat cycles of anthracycline and cyclophosphamide ac chemotherapy
Oncologist, 2020Co-Authors: Lee S Schwartzberg, Giada Rizzi, Daniel Voisin, Rudolph M Navari, Rebecca Clarksnow, Ekaterine Arkania, Irena Radyukova, Kamal Patel, Rita Wickham, Richard J GrallaAbstract:BACKGROUND: Nepa, a combination antiemetic of a neurokinin-1 (NK1 ) receptor antagonist (RA) (netupitant [oral]/fosnetupitant [intravenous; IV]) and 5-HT3 RA, palonosetron] offers 5-day CINV prevention with a single dose. Fosnetupitant solution contains no allergenic excipients, surfactant, emulsifier, or solubility enhancer. A phase III study of patients receiving cisplatin found no infusion-site or anaphylactic reactions related to IV Nepa. However, hypersensitivity reactions and anaphylaxis have been reported with other IV NK1 RAs, particularly fosaprepitant in patients receiving anthracycline-cyclophosphamide (AC)-based chemotherapy. This study evaluated the safety and efficacy of IV Nepa in the AC setting. MATERIALS AND METHODS: This phase IIIb, multinational, randomized, double-blind study enrolled females with breast cancer naive to highly or moderately emetogenic chemotherapy. Patients were randomized to receive a single 30-minute infusion of IV Nepa or single oral Nepa capsule on day 1 prior to AC, in repeated (up to 4) cycles. Oral dexamethasone was given to all patients on day 1 only. RESULTS: A total of 402 patients were included. The adverse event (AE) profiles were similar for IV and oral Nepa and consistent with those expected. Most AEs were mild or moderate with a similarly low incidence of treatment-related AEs in both groups. There were no treatment-related injection-site AEs and no reports of hypersensitivity or anaphylaxis. The efficacy of IV and oral Nepa were similar, with high complete response (no emesis/no rescue) rates observed in cycle 1 (overall [0-120 hours] 73.0% IV Nepa, 77.3% oral Nepa) and maintained over subsequent cycles. CONCLUSION: IV Nepa was highly effective and safe with no associated hypersensitivity and injection-site reactions in patients receiving AC. IMPLICATIONS FOR PRACTICE: As a combination of a neurokinin-1 (NK1 ) receptor antagonist (RA) and 5-HT3 RA, Nepa offers 5-day chemotherapy-induced nausea and vomiting prevention with a single dose and an opportunity to improve adherence to antiemetic guidelines. In this randomized multinational phase IIIb study, intravenous (IV) Nepa (fosnetupitant/palonosetron) was safe and highly effective in patients receiving multiple cycles of anthracycline-cyclophosphamide (AC)-based chemotherapy. Unlike other IV NK1 RAs, the IV Nepa combination solution does not require any surfactant, emulsifier, or solubility enhancer and contains no allergenic excipients. Hypersensitivity reactions and anaphylaxis have been reported with other IV NK1 RAs, most commonly with fosaprepitant in the AC setting. Importantly, there were no injection-site or hypersensitivity reactions associated with IV Nepa.
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efficacy of intravenous iv Nepa a fixed nk1 5 ht3 receptor antagonist combination for prevention of emesis following highly emetogenic chemotherapy hec
Journal of Clinical Oncology, 2018Co-Authors: Eric Roeland, Richard J Gralla, Li Zhang, Paul J Hesketh, Lee S SchwartzbergAbstract:194Background: An IV formulation of Nepa (fixed combination of fosnetupitant 235 mg and palonosetron 0.25 mg) was recently approved offering clinicians an additional antiemetic treatment option. Approval of IV Nepa was based on showing pharmacokinetic bioequivalence and comparable safety to oral Nepa. This post-hoc analysis presents the efficacy of IV Nepa relative to that of oral Nepa and other NK1 RAs in the HEC setting. Methods: Data is compiled from 3 pivotal Nepa registration studies in a total of 951 adult chemotherapy-naive patients with solid tumors undergoing predominantly cisplatin-based HEC. All studies had similar inclusion/exclusion criteria. IV Nepa was administered as a single 30-min infusion and a single capsule of oral Nepa was given prior to HEC. All patients received dexamethasone (DEX) on Days 1-4. Data is also compiled from registration HEC trials on other NK1 RA (aprepitant, fosaprepitant, rolapitant) regimens. No emesis rates are summarized for the overall phase (0-120h) of the init...
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phase iii safety study of intravenous Nepa a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy
Annals of Oncology, 2018Co-Authors: Lee S Schwartzberg, Giada Rizzi, Eric Roeland, Z Andric, Dariusz M Kowalski, J Radic, Daniel Voisin, Rudolph M Navari, Richard J Gralla, Meinolf KarthausAbstract: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-naive 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.
