Dexamethasone-sparing Approach Including NEPA Against Emesis Caused by Cisplatin (LUNG-NEPA)

A Standard Regimen of Dexamethasone in Comparison to Two Dex-sparing Regimens in Addition to NEPA in Preventing CINV in naïve NSCLC Patients to be Treated With Cisplatin Based Chemotherapy: a Three-arm, Open-label, Randomized Study

This study evaluates the possibility to reduce the total dose of dexamethasone, when administered with NEPA, to prevent chemotherapy-induced nausea and vomiting (CINV) in Non-Small Cell Lung Cancer (NSCLC) patients receiving a cisplatin-based chemotherapy

Study Overview

• Status: Unknown
• Conditions: Chemotherapy-induced Nausea and Vomiting
• Intervention / Treatment: Drug: Netupitant/Palonosetron; Drug: Dexamethasone

Detailed Description

On day 1 (day of chemotherapy), all eligible patients will receive oral NEPA (300 mg netupitant/0.5 mg palonosetron), 60 minutes before chemotherapy, and intravenous dexamethasone 12 mg, 30 minutes before chemotherapy initiation.

For the prevention of delayed CINV, patients will be assigned randomly to one of the following treatment arms:

• Test arm A: no further anti-emetic prophylaxis on days 2 thorough 4;
• Test arm B: oral dexamethasone 4 mg once per day in the morning of days 2 and 3;
• Reference arm C: oral dexamethasone 4 mg twice per day on days 2 thorough 4.

• Study Type: Interventional
• Enrollment (Actual): 261
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Bari, Italy
    • A.O.U. Consorziale Policlinico di Bari
  • Bari, Italy
    • IRCCS Istituto Tumori "Giovanni Paolo II"
  • Brescia, Italy
    • ASST Spedali Civili di Brescia
  • Cosenza, Italy
    • Azienda Ospedaliera Cosenza
  • Lecco, Italy
    • ASST Lecco - P.O. "A. Manzoni"
  • Modena, Italy
    • A.O.U. Policlinico di Modena
  • Monza, Italy
    • Ospedale San Gerardo - Asst Monza
  • Napoli, Italy
    • A.O.R.N. dei Colli - Ospedale Monaldi
  • Palermo, Italy
    • Casa di Cura di Alta Specialità Dip. Oncologico di III livello "La Maddalena"
  • Perugia, Italy
    • Ospedale S. Maria Della Misericordia
  • Piacenza, Italy
    • Ospedale di Piacenza
  • Reggio Emilia, Italy
    • IRCCS Arcispedale S. Maria Nuova
  • Roma, Italy
    • A.O. San Camillo Forlanini
  • Roma, Italy
    • Policlinico Tor Vergata
  • Roma, Italy
    • A.O. San Giovanni - Addolorata
  • Roma, Italy
    • Fondazione Policlinico "A. Gemelli" - Università Cattolica Sacro Cuore
  • Roma, Italy
    • Istituto Nazionale Tumori "Regina Elena"
  • Sassari, Italy
    • Ospedale Civile SS. Annunziata
  • Siracusa, Italy
    • Ospedale Umberto I - RAO SR
  • Taranto, Italy
    • P.O. "San Giuseppe Moscati"
  • Treviso, Italy
    • Azienda ULSS 2 Marca Trevigiana - Ospedale di Treviso
  • Verona, Italy
    • A.O.U.I. Verona - Policlinico "G.B. Rossi"
  • BG
    • Treviglio, BG, Italy
      • ASST Bergamo Ovest - Ospedale di Teviglio
  • BL
    • Feltre, BL, Italy
      • Azienda ULSS 1 Dolomiti - Ospedale Santa Maria del Prato
  • MI
    • Legnano, MI, Italy
      • Asst Ovest Milanese - Ospedale Di Legnano
  • TO
    • Orbassano, TO, Italy
      • AOU San Luigi Gonzaga

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients ≥ 18 years old.
• Histologically or cytologically confirmed diagnosis of NSCLC
• Patients naїve to cisplatin-containing chemotherapy as well as any prior chemotherapy containing either highly or moderately emetogenic agents given for NSCLC or other malignancy.
• Patients scheduled to receive their first cycle of cisplatin-based chemotherapy at a dose ≥70 mg/m2 either alone or in combination with other agents of low or minimal potential of emetogenicity (i.e., pemetrexed, gemcitabine±bevacizumab, vinorelbine) as neo-adjuvant, adjuvant or palliative therapy. Patients with progressive disease on therapy with an EGFR-TKI (Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors) and scheduled to receive cisplatin-based chemotherapy will be eligible for the study.
• ECOG (Eastern Cooperative Oncology Group) Performance Status of 0-1.
• Body Mass Index ≥18.5.
• Written informed consent before study entry.
• If women of childbearing potential age: effective contraceptive measures must be used during all the planned course of chemotherapy and up to 30 days after last NEPA administration.
• Normal hepatic function (≤2 times the upper limit of normal for liver transaminases) and renal function (creatinine ≤ 1.5 times the upper limit of normal).
• Ability and willingness of the patient to complete the diary and study questionnaires.

Exclusion Criteria:

• Symptomatic brain metastases.
• Patients scheduled to receive radiation therapy to the abdomen or pelvis within 1 week before day 1 or between day 1 and 5 following the first cycle of chemotherapy.
• Patients scheduled to receive concurrent chemo/radiotherapy for NSCLC.
• Treatment with investigational medications within 30 days before the study medication.
• Myocardial infarction within the last 6 months.
• Documented or known hypersensitivity to 5HT3RA (5-Hydroxytryptamine Receptor 3 Antagonists) or NK-1RA (Neurokinin-1 Receptor Antagonist) and excipients (see section 6.1 of Akynzeo SPC).
• Uncontrolled diabetes mellitus or active infection.
• Nausea and vomiting in the 24 hours before study treatment.
• Chronic use of systemic corticosteroids (except for topical and inhaled corticosteroids) or any other agent with anti-emetic potential. Patients receiving dexamethasone on the day before chemotherapy for prevention of the pemetrexed-induced skin rash will be eligible for the study.
• Patient's inability to take oral medication.
• Gastrointestinal obstruction or active peptic ulcer.
• Pregnancy or breast feeding.
• Prior malignancies at other sites except surgically treated non-melanoma skin cancer, superficial cervical cancer, or other cancer from which the patient had been disease-free for at least 5 years (see also inclusion criteria if prior chemotherapy treatment).
• Psychiatric or CNS (Central Nervous System) disorders interfering with ability to comply with study protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm A; Oral Netupitant/Palonosetron (NEPA) and intravenous Dexamethasone (DEX) on Day 1 of chemotherapy. No further anti-emetic prophylaxis on days 2 thorough 4.	Drug: Netupitant/Palonosetron; NEPA is adiministered 60 minutes before chemotherapy, on day 1; Other Names: Netupitant/Palonosetron 300-0.5 milligrams Oral Capsule [AKYNZEO]; Drug: Dexamethasone; Intravenous dexamethasone 12 mg is administered 30 minutes before chemotherapy initiation, on day 1. The administration of DEX in the subsequent days (2-4) depends on the randomly assignement to treatment arm
EXPERIMENTAL: Arm B; Oral Netupitant/Palonosetron (NEPA) and intravenous Dexamethasone (DEX) on Day 1 of chemotherapy. Oral dexamethasone 4 mg once per day in the morning of days 2 and 3.	Drug: Netupitant/Palonosetron; NEPA is adiministered 60 minutes before chemotherapy, on day 1; Other Names: Netupitant/Palonosetron 300-0.5 milligrams Oral Capsule [AKYNZEO]; Drug: Dexamethasone; Intravenous dexamethasone 12 mg is administered 30 minutes before chemotherapy initiation, on day 1. The administration of DEX in the subsequent days (2-4) depends on the randomly assignement to treatment arm
ACTIVE_COMPARATOR: Arm C; Oral Netupitant/Palonosetron (NEPA) and intravenous Dexamethasone (DEX) on Day 1 of chemotherapy. Oral dexamethasone 4 mg twice per day on days 2 thorough 4.	Drug: Netupitant/Palonosetron; NEPA is adiministered 60 minutes before chemotherapy, on day 1; Other Names: Netupitant/Palonosetron 300-0.5 milligrams Oral Capsule [AKYNZEO]; Drug: Dexamethasone; Intravenous dexamethasone 12 mg is administered 30 minutes before chemotherapy initiation, on day 1. The administration of DEX in the subsequent days (2-4) depends on the randomly assignement to treatment arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR)	The proportion of patients achieving a complete response, defined as no emetic episode and no use of rescue medication, during the overall study period (day 1 thorough 5) of the first cycle of chemotherapy.	During the overall phase (day 1 thorough 5) of the first cycle of cisplatin-based chemotherapy (each cycle is 7 or 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR (acute and delayed).	No emetic episode and no use of rescue medication, during the acute and delayed phases	During the acute (within 24 hours post-chemotherapy) and delayed (days 2 thorough 5) phases of the first cycle of cisplatin-based chemotherapy (each cycle is 7 or 21 days)
Complete control	No emetic episode, no rescue medication, and no more than mild nausea. Severity of nausea will be self-reported by the patient using a verbal scale (none, mild, moderate, and severe).	During the acute (within 24 hours post-chemotherapy), delayed (days 2 thorough 5) and overall (days 1 thorough 5) phases of the first cycle of cisplatin-based chemotherapy (each cycle is 7 or 21 days)
Proportion of patients with no emetic episode	No emetic episode	During the acute (within 24 hours post-chemotherapy), delayed (days 2 thorough 5) and overall (days 1 thorough 5) phases of the first cycle of cisplatin-based chemotherapy (each cycle is 7 or 21 days)
Proportion of patients with no nausea	No nausea. Severity of nausea will be self-reported by the patient using a verbal scale (none, mild, moderate, and severe).	During the acute (within 24 hours post-chemotherapy), delayed (days 2 thorough 5) and overall (days 1 thorough 5) phases of the first cycle of cisplatin-based chemotherapy (each cycle is 7 or 21 days)
Impact of nausea and vomiting on patient's quality of life	Impact of nausea and vomiting on patient's quality of life as recorded by the Italian version of the FLIE (Functional Living Index-Emesis) questionnaire, according to subjective assessment by each patient on day 6. The questionnaire consists of 18 questions: the first set of 9 questions refers to nausea and the second set of 9 questions refers to vomiting. Each question uses a visual analogue scale. Scale ranges are 1-7 (in some questions 1 indicates no effect on patient's quality of life, in other questions 1 indicates a great deal of an effect on patient's quality of life).	On day 6 of the first cycle of cisplatin-based chemotherapy (each cycle is 7 or 21 days)
Patient global satisfaction with anti-emetic therapy,	Patient global satisfaction with antiemetic therapy, as measured by a Visual Analogue Scale (VAS) on day 6. Scale ranges are 0-10 (0 represents maximum dissatisfaction, 10 represents maximum satisfaction)	On day 6 of the first cycle of cisplatin-based chemotherapy (each cycle is 7 or 21 days)
Safety profile	Safety profile according to NCI-CTCAE version 5.0	During all the safety study period (up to three weeks after the start of cisplatin-based chemotherapy)
Cross-sectional baseline evaluation of weight loss (WL)	Weight loss will be assessed through the BMI (Body Mass Index) adjusted weight loss grading system (WLGS). WL as classified according to WLGS, a grading system using the combination of %WL and BMI categories. The analysis will be laid out in a 5x5 matrix representing five different %WL categories within each of the five different BMI categories (25 possible combinations of WL and BMI). Percentage of WL will be defined as follows: [(current weight in Kg - previous weight in Kg)/previous weight in Kg] x 100. Previous patient weight (i.e., the usual weight) within the last 6 months (or "usual weight") will be also collected at baseline. BMI will be calculated as current weight/square of the body height (Kg/m2);	During the Screening phase (up to 7 days before the first cycle of chemotherapy administration - each cycle is 7 or 21 days)
Nutritional intake	Nutritional intake will be assessed with an ad hoc question adapted from the Patient Generated-Subjective Global Assessment (PG-SGA) questionnaire.	During the Screening phase (up to 7 days before the first cycle of chemotherapy administration - each cycle is 7 or 21 days)
Cancer-related symptom self-assessment	Cancer-related symptom self-assessment, as recorded by the Italian version of the ESAS (Edmonton Symptom Assessment Scale) questionnaire, according to subjective assessment by each patient on day 1 (before cisplatin-based chemotherapy initiation), will be performed. The ESAS is a validated symptom inventory tool assessing the current intensity of 10 common symptoms in cancer patients, each with an 11-point numerical rating scale from 0 (no symptom) to 10 (worst intensity).	On day 1 of the first cycle of cisplatin-based chemotherapy (each cycle is 7 or 21 days)
Cancer-related symptom self-assessment association with WLGS and nutritional intake	The association between Cancer-related symptom self-assessment and WLGS and nutritional intake will be examined using linear regression models.	On day 1 of the first cycle of cisplatin-based chemotherapy (each cycle is 7 or 21 days)

Collaborators and Investigators

• Sponsor: Consorzio Oncotech
• Investigators: Study Chair: Emilio Bria, MD, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, UCSC - Rome (Italy); Study Director: Luigi Celio, MD, Fondazione IRCCS "Istituto Nazionale Tumori" - Milan (Italy)

Publications and helpful links

General Publications

• Celio L, Cortinovis D, Cogoni AA, Cavanna L, Martelli O, Carnio S, Collova E, Bertolini F, Petrelli F, Cassano A, Chiari R, Zanelli F, Pisconti S, Vittimberga I, Letizia A, Misino A, Gernone A, Bonizzoni E, Pilotto S, De Placido S, Bria E. Evaluating the impact of chemotherapy-induced nausea and vomiting on daily functioning in patients receiving dexamethasone-sparing antiemetic regimens with NEPA (netupitant/palonosetron) in the cisplatin setting: results from a randomized phase 3 study. BMC Cancer. 2022 Aug 24;22(1):915. doi: 10.1186/s12885-022-10018-3.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 25, 2016
• Primary Completion (ANTICIPATED): April 1, 2020
• Study Completion (ANTICIPATED): April 1, 2020

Study Registration Dates

• First Submitted: December 11, 2019
• First Submitted That Met QC Criteria: December 16, 2019
• First Posted (ACTUAL): December 17, 2019

Study Record Updates

• Last Update Posted (ACTUAL): April 3, 2020
• Last Update Submitted That Met QC Criteria: April 2, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: lung cancer; nausea; vomiting; DEX-Sparing
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Nausea; Vomiting; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Serotonin Agents; Serotonin Antagonists; Serotonin 5-HT3 Receptor Antagonists; Dexamethasone; Palonosetron
• Other Study ID Numbers: LUNG-NEPA