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Pharmacokinetics (PK) and Safety of Intravenous Fixed Combination Fosnetupitant/Palonosetron (IV NEPA) for Prevention of Chemotherapy-Induced Nausea and Vomiting in Highly Emetogenic Chemotherapy (HEC)

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Pharmacokinetics (PK) and Safety of Intravenous Fixed Combination Fosnetupitant/Palonosetron (IV NEPA) for Prevention of Chemotherapy-Induced Nausea and Vomiting in Highly Emetogenic Chemotherapy (HEC)

Galina Kurteva, MD, PhD1, Nataliya Chilingirova, MD, PhD1, Giada Rizzi, MSc2, Tatiana Caccia, MSc2, Alberto Bernareggi, PhD2,*

1University Specialized Hospital for Active Treatment in Oncology, Medical Oncology Clinic, Sofia, Bulgaria; 2Helsinn Healthcare SA, Pazzallo (Lugano), Switzerland

*Presenting author.

BACKGROUND

  • NEPA is a fixed combination antiemetic, composed of the highly selective neurokinin-1 receptor antagonist (RA) (NK1RA) netupitant and the clinically and pharmacologically distinct second-generation 5-hydroxytryptamine-3 (5-HT3) RA palonosetron.1-4

  • International antiemetic guidelines from the Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommend oral NEPA as an option for the prevention of acute and delayed nausea and vomiting associated with moderately and HEC.5-7

  • In pivotal trials, a single oral NEPA dose plus dexamethasone (DEX) has shown superiority over oral palonosetron plus DEX in preventing chemotherapy-induced nausea and vomiting during the 1- to 5-day period(s) following treatment with cisplatin- and anthracycline-cyclophosphamide (AC)-based chemotherapy regimens, leading to its approval in the US and Europe.8,9

  • To offer an additional administration option for healthcare providers and patients, an IV fixed combination NEPA formulation has been developed and is currently under US Food and Drug Administration (FDA) evaluation.

    • IV NEPA (fosnetupitant/palonosetron) is administered as a 30-minute infusion

       

  • Fosnetupitant, a water-soluble phosphorylated prodrug of netupitant, is used in the IV formulation. In a previous phase 1 dose-finding, PK study in 147 healthy volunteers (data on file):

    • Fosnetupitant was rapidly converted to netupitant

    • The 235-mg IV dose of free-base fosnetupitant (corresponding to a 260-mg dose of fosnetupitant chloride hydrochloride) was bioequivalent to the netupitant 300-mg dose in the approved oral NEPA formulation

       

  • The palonosetron dose in the IV NEPA formulation is 0.25 mg, which corresponds with the approved palonosetron IV dose (Aloxi®)10

    • Single-dose palonosetron 0.25 mg IV, administered as a 30-minute infusion, was noninferior to the approved 30-second bolus in patients receiving HEC, with comparable safety profiles11,12

       

  • Fosnetupitant requires no surfactant, emulsifier, or solubility enhancer to obtain a clear injectable solution; this is complemented by a reported, very low-risk profile for unexpected allergic reactions.13

  • Recently, a phase 3 pre-approval safety trial has shown favorable safety and tolerability of IV NEPA, with a safety profile similar to that of oral NEPA in patients with solid tumors receiving HEC.13

  • In addition, a similar phase 3b study evaluating the safety of IV NEPA in patients receiving AC-based chemotherapy is underway.

     

OBJECTIVES

  • Primary objective: Assess the PK profile of fosnetupitant, netupitant, its main active metabolites M1, M2, and M3, and palonosetron after a single 30-minute infusion of IV NEPA administered with oral DEX in cancer patients scheduled to receive a cycle of HEC.

  • Secondary objectives: Evaluate the safety and tolerability of a single administration of IV NEPA with oral DEX in this patient population.

     

METHODS

Study design and treatment

  • Open-label, single-center, single-dose phase 1 study in chemotherapy-naive or –non-naive cancer patients (Eudra CT number: 2015-004750-18).

  • All patients received a single 30-minute IV infusion of NEPA in 5% glucose (total volume 50 mL) on day 1, before the start of a reference HEC.

  • Oral DEX was administered on day 1 (12 mg) immediately before the initiation of IV NEPA infusion, and on days 2 to 4 (8 mg).

     

Main eligibility criteria

  • Male or female patients ≥18 years of age, Eastern Cooperative Oncology Group performance status ≤2, and confirmed solid tumor malignancy.

  • Scheduled to receive a cycle of the following reference HEC, alone or in combination with other chemotherapeutic agents on day 1:

    • Single IV cisplatin dose (≥70 mg/m2); cyclophosphamide ≥1500 mg/m2; carmustine >250 mg/m2; dacarbazine; mechlorethamine

Assessments

  • Blood samples for PK analysis were collected within 30 minutes pre-dose and at 30 minutes (end of infusion), 45 minutes, and 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, 96, 144, and 192 hours after the start of IV NEPA infusion.

  • Plasma concentrations of fosnetupitant, netupitant, netupitant metabolites M1, M2, and M3, and palonosetron were analyzed by validated liquid chromatography-tandem mass spectrometry methods.

  • PK parameters were calculated using noncompartmental analysis from plasma concentrations.

  • Safety was evaluated on the basis of the frequency and severity of treatment-emergent adverse events (TEAEs)/serious TEAEs. TEAE severity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.14

  • Additional safety variables included: vital signs, 12-lead electrocardiogram, physical examination, and clinical laboratory tests.

     

Statistical methods

  • The PK population consisted of patients who received the entire volume of the IV NEPA infusion solution (50 mL) and for whom at least the area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUClast) could be estimated for fosnetupitant, netupitant, and palonosetron. The PK population was used for demography and PK analyses.

  • The safety population included all patients who received IV NEPA, including patients who received partial infusion volumes. The safety population was used for demography, other baseline characteristics, and for safety analyses.

  • Patient demographics, PK, and safety assessments were summarized using descriptive statistics.

RESULTS

Study patients

  • A total of 36 patients were enrolled. Patient demographic and disease characteristics are summarized in Table 1.

    • All 36 patients received IV NEPA and constitute the safety population. Overall, 53% were female, 100% were white, and mean age was 60 years

    • Twenty-four patients received the entire IV NEPA infusion volume and are included in the PK population. Overall, 54% were female, 100% were white, and mean age was 62 years

      • Twelve patients were excluded from the PK population for receiving an incomplete infusion volume due to technical issues with the infusion pump

         

  • All patients completed the study. Cisplatin was the reference HEC for all 36 patients.

 

 PK analysis

  • In total, 24 patients received the antiemetic treatment as planned, ie, 50 mL of IV NEPA infused over 30 minutes plus oral DEX. Main PK parameters are summarized in Table 2. There were no apparent gender-based differences in PK parameters of all analytes.

 

Fosnetupitant PK profile

  • Mean maximum plasma concentration (Cmax) of 3478 ng/mL was reached at the end of the 30-minute infusion period (median time to Cmax [tmax]: 0.53 h). Mean exposure (AUC∞) was 1401 h∙ng/mL (Table 2, Figure 1).

  • Thirty minutes after the end of infusion, the mean plasma concentration of unchanged fosnetupitant was 26 ng/mL, ie, <1% of Cmax.

  • Mean systemic plasma clearance (CL) and volume of distribution (Vd) were high (CL: 249 L/h; Vd: 296 L) (Table 2).

 

 PK profile of netupitant and its main metabolites M1, M2, M3

  • Mean netupitant Cmax of 590 ng/mL was reached shortly after the end of infusion (median tmax: 0.56 h). Mean netupitant AUC was 15588 h∙ng/mL (Table 2, Figure 1).

  • Mean netupitant plasma concentrations declined gradually after the peak, with a mean apparent terminal half-life of 143.7 h (Table 2). Low levels of netupitant were still detectable 192 h (8 days) after administration.

  • Metabolites reached Cmax at a median tmax of 2 h (M2) or 12 h (M1 and M3). Their exposure ratio (RAUC[Mi/Netu]) relative to netupitant was on average 0.32 (M1), 0.21 (M2), and 0.28 (M3) (Table 2).

 

Palonosetron PK profile

  • Mean Cmax of 0.823 ng/mL was reached at the end of the 30-minute infusion (median tmax: 0.58 h). Mean AUC was 36.07 h∙ng/mL (Table 2, Figure 1). Concentrations declined after the peak, with a mean apparent terminal half-life of 58.4 h (Table 2).

  • Mean CL was low (7.61 L/h), whereas Vd was high (594 L) (Table 2).

 

Safety of IV NEPA

    • A total of 62 TEAEs, all of mild or moderate severity, were experienced by 22 of 36 (61%) patients. An overview of TEAEs occurring in >5% of patients (N = 36) is shown in Table 3.

    • Most common TEAEs were constipation (22%), nausea (14%), and peripheral swelling (11%)

    • A total of 14 study drug-related TEAEs were reported in 8 (22%) patients

    • No injection site reactions related to IV NEPA were observed

      • Chemotherapy treatment-related side effects included peripheral swelling, peripheral edema, and erythema in 4 (11%), 2 (6%), and 1 (3%) patients, respectively

    • Five DEX-related TEAEs were reported in 4 (11%) patients, including dyspepsia, erythema, flushing, and hypertension

      • There were no signals of QTc prolongation.

      • No serious TEAEs or deaths occurred during the study. None of the patients withdrew from the study due to TEAEs.

       CONCLUSIONS

        • After IV NEPA 30-minute infusion:

        • The PK parameters of netupitant, its metabolites, and palonosetron were similar to those previously shown after oral NEPA in cancer patients15

        • Fosnetupitant was rapidly converted to netupitant, as indicated by netupitant Cmax reached in almost all patients at the end of the 30-minute infusion

          • Single-dose IV NEPA 30-minute infusion was well tolerated. The safety profile of IV NEPA is comparable to the well-characterized safety profile of oral NEPA16 and is consistent with that observed in the recent phase 3 IV NEPA safety study in cancer patients.13

          • No injection site reactions related to IV NEPA were reported

            • IV NEPA fixed combination could offer additional convenience and options for cancer patients and healthcare practitioners, and is currently under FDA evaluation.

               

               

               REFERENCES: 1. Rojas C, et al. Molecular mechanisms of 5-HT3 and NK1 receptor antagonists in prevention of emesis. Eur J Pharmacol (2014) 722:26–37. 2. Navari RM, et al. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med (2016) 374:1356–67. 3. Akynzeo (netupitant and palonosetron) [prescribing information]. Dublin, Ireland: Helsinn Birex Pharmaceuticals Ltd.; 2015. 4. Akynzeo (netupitant and palonosetron) [prescribing information]. Dublin, Ireland: Helsinn Birex Pharmaceuticals Ltd.; 2016. 5. Roila F, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol (2016) 27(suppl 5):v119–33. 6. Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol (2017) 35(28):3240–61. 7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Antiemesis. Version 2.2017. 2017. 8. Hesketh PJ, et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol (2014) 25(7):1340–6. 9. Aapro M, et al. 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. Ann Oncol (2014) 25(7):1328–33.10. Aloxi® (palonosetron HCl) [prescribing information]. Lugano, Switzerland: Helsinn Healthcare SA; 2015. 11. Karthaus M, et al. Phase III study of palonosetron (PALO) given as 30-min IV infusion (IV inf) versus 30-sec IV bolus (IV bol) for prevention of chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy (HEC). J Clin Oncol (2017) 35(31 suppl): abstract 227. 12. Karthaus M, et al. Phase 3 efficacy and safety study of palonosetron IV infusion versus IV bolus for chemotherapy-induced nausea and vomiting (CINV) prophylaxis following highly emetogenic chemotherapy (HEC). Support Care Cancer (2017) 25(suppl 2): abstract eP010. 13. Schwartzberg L, et al. Phase 3 safety evaluation of an intravenous formulation of NEPA, a novel fixed antiemetic combination of fosnetupitant and palonosetron. Ann Oncol (2017) 28(suppl 5): poster 1547PD. 14. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 2010. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_.... Accessed February 5, 2018. 15. European Medicines Agency. Assessment report: Akynzeo. 2015. EMA/236963/2015. 16. Gralla RJ, et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol (2014) 25(7):1333–9.

              ACKNOWLEDGEMENTS: The authors would like to acknowledge and thank the patients, investigators, and the study team at the participating center. The trial was sponsored by Helsinn Healthcare SA, Lugano, Switzerland. Editorial and medical writing assistance was provided by Iratxe Abarrategui, PhD, CMPP, from TRM Oncology, The Hague, The Netherlands, and funded by Helsinn Healthcare SA, Lugano, Switzerland. The authors are fully responsible for all content and editorial decisions for this poster.

              CONFLICTS OF INTEREST: Galina Kurteva: no conflict of interest; PI in the clinical trial. Nataliya Chilingirova: no conflict of interest; SI in the clinical trial. Giada Rizzi: employee of Helsinn. Tatiana Caccia: employee of Helsinn. Alberto Bernareggi: employee of Helsinn.

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