Efficacy and Safety of High Dose Aprepitant Treatment in Patients With Advanced Non-Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT04840004
• Recruitment Status: Recruiting
• First Posted: April 9, 2021
• Last Update Posted: May 4, 2021
• Sponsor: PlusVitech S.L.
• Collaborator: ECONiX Araştırma Analiz ve Danışmanlık A.Ş.
• Information provided by (Responsible Party): PlusVitech S.L.

Study Description

Brief Summary:

Lung cancer is one of the most common causes of cancer death in worldwide. It is projected that the vast majority, approximately 80% -85% of all lung cancer diagnosis is Non-Small Cell Lung Cancer (NSCLC). Although there are significant improvements in the treatment of Lung Cancer in recent years, there is still an unmet medical need for a specific population which have advanced NSCLC and mostly is refractory to existing treatments. NK-1 antagonists are generally safe and well-tolerated drugs and approved for the treatment of chemotherapy induced vomiting and nausea. However, the recent findings in preclinical studies and preliminary results of some case reports have suggested that their potential in cancer treatment may not be limited to only antiemetic effects.

In addition to the role of NK-1 pathway in emesis, the neuropeptide substance P (SP) binds to Neurokinin-1(NK-1) receptor and this binding regulates the carcinogenic cell proliferation, exerts an antiapoptotic effect, stimulates cell migration that leads to invasion and metastasis of tumor cells and lastly stimulates neoangiogenesis via endothelial cell proliferation. In this regard, the antitumoral effects of NK-1 antagonists against different types of cancer are a leading area of research interest and need for further investigation.

Currently, there are three NK-1 receptor antagonists approved by health authorities: Aprepitant (Emend), its pro-drug, fosaprepitant (Ivemend) and rolapitant (Varubi). All of these drugs are non-peptid NK antagonists and have lipophilic properties. Therefore, they are not degraded by peptidase and can cross the blood-brain barrier (4). In addition to the potential effects of NK-1 antagonists in tumor area, their penetration to central nervous system may also prevent from or reduce the brain metastasis.

The long term use of aprepitant as off-label is relatively common. In several case reports, long term use of aprepitant, up to 18 months, was successfully demonstrated in the treatment of refractory nausea and vomiting due to gastroparesis or other unexplained reasons. Additionally, in a very recent publication, it was reported that for the nausea and vomiting associated gastroparesis, long-term off label use of aprepitant was successfully received and well tolerated by three children (5 to 19 month-old) in the course of allogenic hematopoietic stem cell transplantation.

In the light of findings in preclinical studies, the antitumor effects of NK-1 antagonists are dose-dependent and the higher doses than approved antiemetic effective dose are need to achieve the antitumor activity. For aprepitant which will be used in present study, it has been recommended >20 mg/kg/day and prolonged use for antitumor activity. In a case report, prolonged use of standard aprepitant dose in a patient with metastatic breast cancer, had resulted with a reduction in CA153 tumor marker levels. In another recently published case report, a patient with lung cancer was treated with combination of aprepitant (1140 mg/day) and radiotherapy for 45 days, it has been reported that the tumor massed had disappeared without any side effect related to aprepitant treatment. It is fact that the evidence is not clear yet and further investigation in clinical trial settings is still needed for the evaluation of the efficacy and safety of high doses and long-term use of aprepitant, especially when administered alone to determine its own effect.

Condition or disease	Intervention/treatment	Phase
Non Small Cell Lung Cancer; Advanced Cancer; Refractory Cancer	Drug: Aprepitant	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Long Term and High Dose Aprepitant Treatment in Patients With Advanced and Refractory Non-Small Cell Lung Cancer
• Actual Study Start Date: March 10, 2021
• Estimated Primary Completion Date: December 15, 2021
• Estimated Study Completion Date: December 15, 2021

Arms and Interventions

Arm	Intervention/treatment
Aprepitant; One arm study.	Drug: Aprepitant; Since there is no specific dose range is available for testing the anti-tumor effects of aprepitant in clinical trials settings, in the present study the dose of aprepitant will be up-titrated 250/160/160 mg to maximum 1000/640/640 mg as described in study methodology section.

Outcome Measures

Primary Outcome Measures :

1. Effect [ Time Frame: 12 months ]
   The primary objective of this trial is to demonstrate the effect of high dose and long-term use of aprepitant on tumor response.

Secondary Outcome Measures :

1. Progression Free Survival and Overall Survival [ Time Frame: 12 months ]
   Progression free survival (PFS) and overall survival (OS). PFS will be defined as the time from the date of patients' registration to the date of the evidence of progressive disease, death due to any cause, or the last date the patient will be known to be progression-free or alive. OS will be calculated from the date of patients' registration to the date of death from any cause or the last date the patient will be known to be alive.
2. High Dose [ Time Frame: 12 months ]
   The evaluation of plasma concentration of high doses of aprepitant treatment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Female or male with age > 18 years' old Personally signed and dated informed consent that indicating that the participant ( or a legal representative) has been informed of all aspects of the study Histologically or cytologically confirmed non-small cell lung cancer(NSCLC) NSCLC patients who are not suitable for surgery or radical radiotherapy or chemotherapy, or who have failed to or are intolerable for standard treatment in local advanced or metastatic NSCLC Diagnosis of a metastatic or locally advanced NSCLC with molecular profile EGFR (-), ALK (-) and ROS-1 (-), refractory to existing treatments Evidence of disease radiological measurable. Defined as at least one target lesion that can be accurately measured by imaging, at least one dimension as ≥20 mm with conventional computed tomography (CT), ≥10 mm with spiral CT scan (≥15mm for lymph node) Absence of untreated or symptomatic brain metastases or that requires the use of steroids.

Life expectancy of at least three months in the opinion of investigators ECOG performance status of 0-1 Time since last treatment received: 3 weeks from last QT cycle or 6 weeks if nitrosiureas, at least 2 weeks from the last RT session before the first administration of study drug (The administration of palliative radiotherapy for bone pain is allowed by any time)

Laboratory results required at the screening visit:

Neutrophils> 1500 / mm3 Haemoglobin> 9.0g / dl Platelets> 100,000 / mm3 Total bilirubin <1.5 times above the normal ranges Transaminases: AST, ALT <2 times above the normal ranges, If there are liver metastases <5 times above normal values.

Serum creatinine <1.5 times above the normal ranges Female participants childbearing potential, must have a negative pregnancy test

Exclusion Criteria:

Pregnant female patients, Breastfeeding female patients Patients unable to meet the requirements (inclusion criteria) of the study Know hypersensitivity, history of allergic or anaphylactic reaction to any NK-1 antagonist ECOG performance status ≥2 Any acute, chronic or psychiatric medical condition or laboratory abnormality that may increase the risk associated with the participation or aprepitant administration in the study or may interfere with interpretation of the results, and in judgment of the investigator, would make the participant inappropriate for entry into this study.

Current history of alcoholism or drug addiction to DSM-IV criteria within 12 months prior to screening.

Patients with major organ dysfunctions and heart disease Patients with active tuberculosis Participation in any other clinical studies (phases I - IV) within 1 month or 5 half-lives, or participation in any clinical study of NK-1 antagonists within 1 year of screening visit.

Subjects who are directly involved in the conduct of the study, and their family members, site staff members supervised by study investigators.

Contacts and Locations

Contacts

Contact: Sahin Lacin, MD, PhD; +902124447000; sahin.lacin@yeditepe.edu.tr

Contact: Guvenc Kockaya, MD, PhD; +902124447000; guvenc.kockaya@yeditepe.edu.tr

Locations

Turkey

Yeditepe University Hospital; Recruiting

Istanbul, Turkey

Contact: Sahin Lacin, MD, PhD sahin.lacin@yeditepe.edu.tr

Contact: Guvenc Kockaya, MD, PhD guvenc.kockaya@yeditepe.edu.tr

Sponsors and Collaborators

PlusVitech S.L.

ECONiX Araştırma Analiz ve Danışmanlık A.Ş.

Investigators

• Principal Investigator: Sahin Lacin; Yeditepe University

More Information

• Responsible Party: PlusVitech S.L.
• ClinicalTrials.gov Identifier: NCT04840004
• Other Study ID Numbers: PLUSV_00
• First Posted: April 9, 2021
• Last Update Posted: May 4, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Aprepitant; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Neurokinin-1 Receptor Antagonists; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action