A Clinical Trial to Assess Safety and Pharmacokinetics of Fosnetupitant 235 Mg and Metabolites in Healthy Volunteers

This clinical trial will include two parts, i.e., Part A and Part B.

The goal of the Part A is to define the shortest safe and tolerable duration of an intravenous injection of Fosnetupitant 235 mg solution among 4 durations tested in male and female adult healthy volunteers. In study part A, researchers will compare Fosnetupitant 235 mg solution to Akynzeo® solution.

The duration determined in Part A will be investigated in study Part B.

The Part B of the study was not performed.

The registered product Akynzeo® (235 mg fosnetupitant/0.25 mg palonosetron) solution for intravenous injection, used before chemotherapy, is to be diluted up to a final volume of 50 mL and administered during 30 min infusion. With the aim to facilitate and improve the use of this kind of products, the Sponsor Helsinn focused on the development of a ready to use solution, not requiring additional dilutions, and to be administered as a bolus injection. The product developed by Helsinn is a liquid formulation for infusion, containing exclusively fosnetupitant 235 mg free base.

Aim of the present open label, single dose, two parts (part A and part B) phase I study is to evaluate the safety and the pharmacokinetic profile of this new product, i.e., Fosnetupitant 235 mg ready to use solution for intravenous injection. In addition, the pharmacokinetic profile of fosnetupitant, netupitant (fosnetupitant is rapidly converted in netupitant after intravenous administration) and netupitant metabolites (M1, M2 and M3) will be investigated after a 30-min infusion of the registered Akynzeo® liquid formulation.

Part A of the study:

In cohort 1, 10 healthy volunteers will receive a dose of Fosnetupitant 235 mg solution as a one single 30-min intravenous infusion and additional 10 subjects will receive a single intravenous dose of Akynzeo® solution as a one single 30-min intravenous infusion, according to a parallel group design.

In each of 3 consecutive cohorts (cohorts 2, 3 and 4), 10 healthy volunteers will receive a single intravenous dose of Fosnetupitant 235 mg solution at a predefined infusion duration and will be sequentially treated as 3 subgroups of 3, 3, and 4 subjects, respectively.

A staggered approach with decreasing infusion time duration will be applied, from cohort 1 to cohort 4, to the administration of Fosnetupitant free base 235 mg solution, as follows:

Cohort 1: 30 min Cohort 2: 15 min Cohort 3: 5 min Cohort 4: 2 min

At the end of cohort 1 and of each subgroup of cohorts 2, 3 and 4, safety and tolerability results will be evaluated by the Investigator and the study Sponsor Medical Expert. Predefined stopping rules will be considered for deciding about continuing with the next cohort treatment and a shorter injection duration of Fosnetupitant 235 mg solution. Specifically, after cohort 1, if the injection duration of 30 min proves to be safe and well tolerated, 15 min injection duration will be tested in cohort 2. If the injection duration of 15 min proves to be safe and well-tolerated, 5 min injection duration will be tested in cohort 3. If the injection duration of 5 min proves to be safe and well tolerated, a 2 min injection will be tested in cohort 4.

The selected shortest (safe and tolerable) injection duration determined in Part A will be investigated in study Part B.

The study was prematurely terminated after the end of Part A and study Part B was not performed.

Eligibility Criteria:
Inclusion criteria

1. Informed consent: signed written informed consent before inclusion in the study
2. Sex and Age: healthy men/women volunteers, 18-55 years old (inclusive)
3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive
4. Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, pulse rate 50-99 bpm, measured after 5 min at rest in the sitting position
5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study
6. Contraception and fertility (women only): women of childbearing potential defined as a non-menopausal woman who has not had a bilateral oophorectomy or medically documented ovarian failure and/or at risk for pregnancy must agree, signing the informed consent form, to use a highly effective method of contraception throughout the study and to continue for 14 days after the last dose of the study treatment. Highly effective contraceptive measures include:

   1. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit.
   2. A non-hormonal intrauterine device \[IUD\] for at least 2 months before the screening visit
   3. A sterile or vasectomized sexual partner
   4. True (long-term) heterosexual abstinence, defined as refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject, while periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), lactational amenorrhea and withdrawal are not acceptable.

   Women of non-child-bearing potential or in post-menopausal status defined as such when there is either:
   1. 12 months of spontaneous amenorrhea or
   2. 6 months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL or
   3. 6 weeks documented postsurgical bilateral oophorectomy with or without hysterectomy will be admitted. For all women, pregnancy test result must be negative at screening and admission (Day -1).
7. Contraception (men only): men will either be sterile or agree to use one of the following approved methods of contraception from the first study drug administration until at least 14 days after the last administration, also in case their partner is currently pregnant:

   1. A male condom with spermicide
   2. A sterile sexual partner or a partner in post-menopausal status for at least one year
   3. Use by the female sexual partner of an IUD, a female condom with spermicide, a contraceptive sponge with spermicide, a diaphragm with spermicide, a cervical cap with spermicide, or hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit Men must accept to inform their partners of the participation in the clinical study. Furthermore, they will not donate sperm from the date of the informed consent form's signature, throughout the study, and for at least 14 days after the last dose of the study treatment. These requirements are based upon the availability and results of reproductive toxicity data.

Exclusion criteria

1. 12-leads Electrocardiogram (ECG) (supine position): clinically significant abnormalities at screening. With regards to QTc, the following will be considered as exclusion criterion: mean corrected QT (QTcF) \> 450 ms. HR \< 50 or \> 99 bpm. PR \< 100 or \>220 ms. QRS \> 120 ms. Relevantly abnormal T-wave patterns
2. Physical examination findings: clinically significant abnormal physical findings which could interfere with the objectives of the study
3. Laboratory analyses: clinically significant abnormal laboratory values at screening, indicative of physical illness or suggesting the subject's exclusion, in his/her best interest
4. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study
5. Diseases: significant history, in the opinion of the Investigator, of renal, hepatic, gastrointestinal, cardiovascular (in particular, heart failure, hypokalemia, family history of Long QT Syndrome, history of superficial thrombophlebitis or deep vein thrombosis), respiratory, skin, hematological, endocrine or neurological diseases that may interfere with the aim of the study
6. Medications: medications, including over the counter (OTC) medications and herbal remedies in the 2 weeks before the first visit of the study. Hormonal contraceptives for women are allowed
7. CYP3A4 inducers and inhibitors: use of any inducer or inhibitor of CYP3A4 enzymes (drugs, food, herbal remedies) in the 28 days or in the 7 days, respectively, before the planned first study drug administration and during the whole study
8. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study
9. Blood donation or significant blood loss: blood donations or significant blood loss in the 3 months before the first visit of this study
10. Drug, alcohol, caffeine, tobacco: history of drug, alcohol \[\>1 drink/day for women and \>2 drinks/day for men, defined according to the USDA Dietary Guidelines 2020-2025 (11)\], caffeine (\>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes/day)
11. Drug test: positive result at the urine drug screening test at screening or Day -1
12. Alcohol test: positive salivary alcohol test at Day -1
13. Diet: abnormal diets (\<1600 or \>3500 kcal/day) or substantial changes in eating habits in the 4 weeks before screening; vegetarians
14. Pregnancy (women only): positive or missing pregnancy test at screening or Day -1, pregnant or lactating women
15. Netupitant studies: enrolment in a previous study of netupitant or fosnetupitant (alone or in combination with palonosetron)