Healthy
Conditions
Brief summary
The purpose of this study is to evaluate the safety and tolerability of ascending doses of the MEK-inhibitor zapnometinib (ATR-002) given as single doses (SAD Part) and as multiple doses for 7 days (MAD Part) in healthy subjects.
Detailed description
This is a Phase 1, single-center, randomized, double-blind, controlled clinical trial (zapnometinib vs. placebo in the SAD/MAD Parts; 'fed' vs. 'fasted' in the FDI Part, 'probe substance' (repaglinide or celecoxib) in combination with zapnometinib vs. probe substance alone in the DDI part). The study will assess the safety, tolerability, PK (applicable to SAD/MAD Part) and PD (applicable to SAD Part only) effects of zapnometinib versus a matching placebo (applicable to SAD/MAD Part) in healthy subjects. The FDI cohorts will investigate the possible impact of a standard breakfast high in fat content in comparison to administration in fasted state. The DDI cohorts with celecoxib and repaglinide will investigate a possible drug-drug interaction.
Interventions
DRUGATR-002
300 mg tablets for oral intake
DRUGPlacebo
matching tablets for oral intake
DRUGRepaglinide
0,5 mg tablets for oral intake
DRUGCelecoxib
100 mg capsules for oral intake
Sponsors
Atriva Therapeutics GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Masking description
matching placebo tablets
Intervention model description
Randomized, double-blind, placebo-controlled, mono-centre; SAD, MAD, FDI, DDI part
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements, prohibitions and restrictions listed in the informed consent form (ICF) and in this protocol. 2. Subject has been informed both verbally and in writing about the objectives of the clinical trial, the methods, the anticipated benefits and potential risks and the discomfort to which he/she may be exposed, and has given written consent to participation in the trial prior to trial start and any trial-related procedure. 3. Study participant must be at least 18 years of age and not older than 55 years of age at the time of signing the ICF. 4. Non-smokers or ex-smokers who had stopped smoking for at least 5 years prior to start of the clinical study. 5. In good physical and mental health as determined on the basis of medical history and general physical examination performed at screening. 6. Hematology and chemistry parameters, pulse rate and/or blood pressure, and ECG within the reference range for the population studies, or showing no clinically relevant deviations, as judged by the Investigator (Note that some defined clinical laboratory parameters must not exceed the upper limit of reference range - see Exclusion Criterion #3). 7. Negative urine test for selected drugs of abuse at screening and upon check-in at the clinical site. Note: Subjects should not consume poppy-seeds within 72 h before screening and before each urine drug screening because this can falsify the results of the opiate urine drug test. 8. Negative alcohol breath test at screening and upon check-in at the clinical site. 9. Negative hepatitis panel (including hepatitis B surface antigen \[HBsAg\] and anti-hepatitis C virus \[HCV\] antibodies) and negative human immunodeficiency virus (HIV) antibody screens and negative SARS-CoV-2 PCR test. 10. Body weight at least 70 kg for males and 60 kg for females and have a body mass index (BMI) ≥ 18.0 kg/m2 and \< 29.9 kg/m2. 11. Male or female. Pregnancy and Contraception 12. Female subjects must be of non-childbearing potential, as follows. A female study participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: 1. At least 1 year post-menopausal (amenorrhea \>12 months in the absence of an alternative medical cause and follicle-stimulating hormone \>30 mIU/mL in women not using hormonal contraception or hormonal replacement therapy) prior to screening; 2. Surgically sterile (bilateral oophorectomy, hysterectomy, bilateral salpingectomy, or bilateral tubal ligation). To protect partners from possible exposure to study medication in semen, male subjects must use a condom during the study, even if they have had a vasectomy or their partner is not of childbearing potential, and they must not plan to father a child, or donate sperm, during the study, and for 4 months after their final dose of study medication. Note: medically acceptable methods of contraception that may be used by the partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, and etonogestrel implant.
Exclusion criteria
1. Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-study screening assessment that could interfere with the objectives of the study or the safety of the subject. Note: Blood pressure and heart rate at the screening examination outside the ranges 90- 139 mmHg systolic, 50-89 mmHg diastolic; heart rate 50-90 bpm are considered as
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of participants with TEAEs and SAEs, with abnormal ECG readings, abnormal vital signs, and abnormal laboratory parameters | From 1st administration of study drug (SAD/MAD Day 1; DDI Day -1) up to 21 days after last dosing |
Secondary
| Measure | Time frame |
|---|---|
| FDI cohort (two-period fixed-sequence design 'fasted' vs. 'fed'): AUC0-∞ | Day 1 to Day 7 |
| DDI part: Cmax | Day -1 and Day 1 |
| DDI part: tmax | Day -1 and Day 1 |
| DDI part: t1/2 | Day -1 and Day 1 |
| DDI part: AUC0-t | Day -1 and Day 1 |
| DDI part: AUC0-∞ | Day -1 and Day 1 |
| SAD part: Cmax | Day 1 to Day 7 |
| SAD part: tmax | Day 1 to Day 7 |
| SAD part: t1/2 | Day 1 to Day 7 |
| SAD part: AUC0-t | Day 1 to Day 7 |
| FDI cohort (two-period fixed-sequence design 'fasted' vs. 'fed'): AUC0-t | Day 1 to Day 7 |
| MAD part: Cmax | postdose on Day 1 |
| MAD part: tmax | postdose on Day 1 |
| MAD part: Ctrough | Day 2 to Day 7 |
| MAD part: t1/2 | postdose on Day 7 |
| MAD part: AUC0-t | postdose on Day 7 |
| SAD part: percent MEK inhibition by measuring the reduction of ERK phosphorylation after study drug administration as compared to baseline in stimulated PBMCs isolated from blood samples from study participants | up to day 5 |
| FDI cohort (two-period fixed-sequence design 'fasted' vs. 'fed'): Cmax | Day 1 to Day 7 |
| FDI cohort (two-period fixed-sequence design 'fasted' vs. 'fed'): tmax | Day 1 to Day 7 |
| FDI cohort (two-period fixed-sequence design 'fasted' vs. 'fed'): t1/2 | Day 1 to Day 7 |
| SAD part: AUC0-∞ | Day 1 to Day 7 |
Countries
Germany
Outcome results
None listed