None listed
Conditions
Brief summary
GRWD5769 is a first-in-class, orally bioavailable small molecule inhibitor of ERAP1, developed for immune-oncology applications, particularly for solid malignancies. Thid study aims to compare the bioavailability of a new tablet formulation versus the existing capsule formulation and to assess the effect of food on drug absorption in healthy adults. The rationale for developing a tablet is to reduce pill burden and improve participant convenience. This is a Phase 1, open-label, randomized, cross-over study in healthy adults (18–65 years) consisting of 2 and up to 3 parts: Part A1: Compares 800 mg tablet (2 x 400 mg) vs. 800 mg capsule (4 x 200 mg) in fasted state. Optional Part A2: If needed, compares 400 mg tablet vs. 400 mg capsule. Part B: Assesses food effect on the selected formulation/dose (fed vs. fasted).
Interventions
There will be up to 3 parts conducted in the study, Part A1, A2, and Part B.
Part A1 will look at bioavailability of 800mg GRWD5769 in the fasted state.
Part A2 will look at bioavailability of 400mg GRWD5769 in the fed and fasted state, but is optional, and will only be conducted if recommended to the sponsor by the study scientific review committee after review of Part A1.
Part B will look at food-effect.
The intervention for each Part consists of a 14-day screening period, followed by Treatm
There will be up to 3 parts conducted in the study, Part A1, A2, and Part B. Part A1 will look at bioavailability of 800mg GRWD5769 in the fasted state. Part A2 will look at bioavailability of 400mg GRWD5769 in the fed and fasted state, but is optional, and will only be conducted if recommended to the sponsor by the study scientific review committee after review of Part A1. Part B will look at food-effect. The intervention for each Part consists of a 14-day screening period, followed by Treatment Period 1, Washout period, Treatment Period 2, and then an End of Treatment visit. Participants will be admitted and remain at the research unit for the entirety of each Treatment Period (5-6 days). Dosing occurs after eligibility confirmation and randomization. Healthy participants will be administered GRWD5769 as a single 800 mg dose to evaluate the bioavailability of a GRWD5769 tablet formulation relative to a GRWD5769 capsule formulation; if these 2 formulations are determined not to be comparable at an 800mg dose (Part A1), the bioavailability of a GRWD5769 tablet formulation relative to a GRWD5769 capsule formulation will be re-evaluated at a 400mg dose (Part A2). A Safety Review Committee will review available safety/PK data for Part A1 and make recommendations regarding the GRWD5769 formulation and dose for a food-effect evaluation (Part B). Part A: Please note that this Part is fasted. GRWD5769 is to be administered once orally, with a full cup (250 mL) of non-carbonated, room temperature water. Participants must fast for 2 hours prior to, and for 1 hour following each dose of GRWD5769 (water is permitted). Part A1 a) an 800mg dose of GRWD5769 will be provided b) This Part consists of two different arms: (1) the Film Coated Tablet Formulation and (2) the Capsule Formulation. Approximately 18 participants will be randomised in a ratio of 1:1 to receive both treatment formulations in one of 2 treatment sequences: Sequence 1: Treatment Period 1: 4 x 200 mg GRWD5769 capsules in the fasted state followed by Treatment Period 2: 2 x 400mg GRWD5769 tablets in the fasted state Sequence 2: Treatment Period 1: 2 x 400mg GRWD5769 tablets in the fasted state followed by Treatment Period 2: 4 x 200 mg GRWD5769 capsules in the fasted state c) There is a minimum 48 hour 'wash out' period between Treatment Period 1 and Treatment Period 2 d) Participants will be observed when dosing to ensure adherence to dosage requirements. Part A2 (Optional) This Part would commence if the 2 formulations above are determined not to be comparable at an 800 mg dose, the bioavailability of a GRWD5769 Film Coated Tablet Formulation relative to a GRWD5769 Capsule Formulation will be re-evaluated at a 400 mg dose. A Safety Review Committee (SRC) will make recommendations to the Sponsor regarding GRWD5769 formulation and dose for food-effect evaluation: a) a 400mg dose of GRWD5769 will be provided: Sequence 1: Treatment Period 1: 2 x 200 mg GRWD5769 capsules in the fed or fasted state followed by Treatment Period 2: 1 x 400mg GRWD5769 tablets in the fed or fasted state. Sequence 2: Treatment Period 1: 1 x 400mg GRWD5769 tablets in the fed or fasted state followed by Treatment Period 2: 2 x 200 mg GRWD5769 capsules in the fed or fasted state. b) Participants will be observed when dosing to ensure adherence to dosage requirements. Part B: Participants in the fed state will receive a high calorie/high fat breakfast according to the US FDA guidance, consisting of 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes, and 236 mL of whole milk. Fasted participants must fast for at least 10 hours prior to, and for at least 4 hours following, each dose of GRWD5769 Part B a) an 800mg dose of GRWD5769 will be provided: Sequence 1: Treatment Period 1: 2 x 200 mg GRWD5769 capsules in the fed state followed by Treatment Period 2: 1 x 400mg GRWD5769 tablets in the fed state Sequence 2: Treatment Period 1: 1 x 400mg GRWD5769 tablets in the fed state followed by Treatment Period 2: 2 x 200 mg GRWD5769 capsules in the fed state. b) there is a minimum 48 hours 'wash out' period between the fed/fasted assessments, c) Participants will be observed when dosing to ensure adherence to dosage requirements.
Sponsors
Greywolf Therapeutics
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
To be eligible for this study, a participant must meet all the following inclusion criteria: 1. Aged 18 to 65 years (inclusive) at the time of informed consent. 2. Able and willing to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures. 3. Able and willing to attend the necessary visits to the Clinical Research Unit (CRU) and comply with the requirements of the Protocol. 4. Willing to consume meals provided by the CRU. 5. At the discretion of the PI (or designee), in good general health, with no significant medical history, and have no clinically significant abnormalities on physical examination at Screening and/or before administration of GRWD5769 on Day 1 of Treatment Period 1. 6. Body mass index of at least 18.0 and no more than 32.0 kg/m2 and weight of at least 50 kg. 7. Nonsmoker and must not have used any nicotine-containing products (eg, cigars, cigarettes, vapes) within 2 months prior to Screening. 8. Clinical laboratory values within normal range at Screening and/or Day -1 of Treatment Period 1 as specified by the testing laboratory, unless deemed not clinically significant by the PI (or designee). 9. Not pregnant or breastfeeding, or willing to cease breastfeeding. 10. Female participants must be of non-childbearing potential ie, surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit) or post-menopausal (where post-menopausal is defined as no menses for 12 months without an alternative medical cause and if post-menopausal within the 6 months prior to the Screening visit a follicle-stimulating hormone [FSH] level consistent with post-menopausal status, per local laboratory guidelines), or, if of childbearing potential: - Must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test within 24 hours prior to administration of GRWD5769 on Day 1 of Treatment Period 1. - Must agree not to attempt to become pregnant. - Must not donate ova from signing consent until at least 33 days (ie, 30 days + minimum of 5 × half-lives of GRWD5769) after the last dose of GRWD5769. - If not exclusively in a same sex relationship, must agree to use adequate contraception (which is defined as use of a condom by the male partner combined with use of a highly effective method of contraception) from signing the consent form until at least 6 months after the last dose of GRWD5769. Note: FSH testing is required at Screening for female participants who report as post-menopausal (where post-menopausal is defined as no menses for 12 months without an alternative medical cause) if the female was determined to be post-menopausal within the 6 months prior to the Screening visit. Otherwise, and for females who are post-menopausal with no menses for at least 18 months, FSH testing is not required. If serum FSH levels are below the cut-off limit as defined by the local testing laboratory, participants will be considered to be of childbearing potential and will be required to use appropriate contraception for the duration of the study. Note: A highly effective method of contraception is one that has a failure rate of < 1% when used consistently and correctly and for this study includes the following: For Female Participants (of Childbearing Potential): - Established use of oral, injected or implanted hormonal methods of contraception associated with inhibition of ovulation. - Placement of an intrauterine device (IUD) or intrauterine system (IUS). - Vasectomised partner (ie, a female participant’s male partner has undergone effective surgical sterilisation [ie, documented azoospermia at least 90 days after the procedure] before the female participant entered the study and he is the sole sexual partner of the female participant during the study). - Abstinence from heterosexual intercourse (acceptable only if it is the participant’s usual form of birth control/lifestyle choice). Examples of non-acceptable methods of contraception include: - Condoms alone or double barrier. - Periodic abstinence (eg, calendar, ovulation, symptothermal, post ovulation). - Withdrawal. Male participants must: - Agree not to donate sperm from the time of signing consent until at least 93 days (90 days + minimum of 5 × half-lives of GRWD5769) after the last dose of GRWD5769. - If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use a condom plus a highly effective method of contraception from the time of signing consent until at least 93 days after the last dose of GRWD5769. Note: A highly effective method of contraception is one that has a failure rate of less than 1% when used consistently and correctly and for this study includes the following: For Female Partners (Who Are of Childbearing Potential) of Male Participants: - Established use of oral, injected or implanted hormonal methods of contraception associated with inhibition of ovulation. - Placement of an IUD or IUS. - Vasectomised partner (ie, the male participant has undergone effective surgical sterilisation before entering the study).
Exclusion criteria
A participant who meets any of the following exclusion criteria must be excluded from the study: 1. Underlying physical or psychological medical condition that, in the opinion of the PI (or designee), would make the participant unlikely to comply with the protocol or complete the study per protocol. 2. Blood or plasma donation or had significant blood loss (more than 500 mL) within 30 days prior to administration of GRWD5769 on Day 1 of Treatment Period 1. 3. Fever (body temperature at or greater than 38°C) or symptomatic viral or bacterial infection within 2 weeks prior to Screening. 4. Infections requiring parenteral antibiotics within 6 months prior to Screening. 5. Known medical history of infection or risk factors for human immunodeficiency virus (HIV) and/or hepatitis B or C infection. 6. History of life-threatening infection (eg, meningitis). 7. Vaccination with a live vaccine within 4 weeks prior to administration of GRWD5769 on Day 1 of Treatment Period 1 or vaccination with a non-live vaccine within 14 days prior to administration of GRWD5769 on Day 1 of Treatment Period 1. 8. Poor pill swallowing ability. 9. History of severe allergic or anaphylactic reactions, or sensitivity to GRWD5769 or its constituents. 10. History of malignancy, except for non-melanoma skin cancer, excised more than 2 years ago and cervical intraepithelial neoplasia that has been successfully cured more than 5 years prior to Screening. 11. Abnormal ECG findings at Screening, Day -1 and/or Day 1 (pre-dose) that are considered by the PI (or designee) to be clinically significant including: - Mean QT interval corrected by Fridericia’s formula (QTcF) > 450 ms for males at both Screening and prior to administration of GRWD5769 on Day 1 of Treatment Period 1. - Mean QTcF > 470 ms for females at both Screening and prior to administration of GRWD5769 on Day 1 of Treatment Period 1. - Any clinically important abnormalities in rhythm, conduction, or morphology on resting ECG (eg, complete left bundle branch block, third degree heart block). - Any factor that in the opinion of the PI (or designee) increases the risk of QTc prolongation or arrythmic events. Note: The mean of triplicate readings (taken within 10 minutes with each reading separated by 1 to 5 minutes) will be used to determine eligibility. 13. History or presence of a condition associated with significant immunosuppression. 14. Exposure to any drugs that cause significant immunosuppression (including experimental therapies as part of a clinical study) within 4 months or 5 half-lives (whichever is longer) prior to Screening. 15. ALP, AST, and ALT > 1.5 × ULN at Screening. 16. Positive toxicology screening panel (urine test including qualitative identification of barbiturates, tetrahydrocannabinol [THC], amphetamines, benzodiazepines, opiates, and cocaine) or alcohol breath test. 17. History of substance abuse or dependency or history of recreational intravenous (IV) drug use over the last 5 years (by self-declaration). 18. Regular alcohol consumption defined as > 10 standard drinks per week (where 1 standard drink = 360 mL of beer, 45 mL of 40% spirit or a 150 mL glass of wine) or > 4 standard drinks on any single day. 19. Unwilling to abstain from alcohol from 48 hours prior to admission to the CRU through to the EOS Visit. 20. Use of any investigational medical device or investigational drug within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to administration of GRWD5769 on Day 1 of Treatment Period 1. Note: Participants who plan to complete Day 1 of Treatment Period 1 at least 48 hours after the last dose administration of GRWD5769 (to maintain a minimum 48-hour washout) are permitted to enrol in Part A2 (Bioavailability – 400 mg GRWD5769) (if applicable) and/or Part B (Food-effect). 21. Use of any prescription drugs (other than hormonal contraception; oral contraceptive pills, long-acting implantable hormones, injectable hormones, a vaginal ring, or an IUD), over-the-counter medication, herbal remedies, supplements or vitamins within 30 days prior to administration of GRWD5769 on Day 1 of Treatment Period 1 or anticipated use during the course of the study without prior approval of the PI (or designee) and Novotech MM. Note: Simple analgesia (paracetamol, nonsteroidal anti-inflammatory drug [NSAID]) may be permitted at the discretion of the PI (or designee). 22. Use of any strong inhibitors or inducers of CYP3A4 including medications, herbal supplements (eg, St John’s wort) within 30 days prior to administration of GRWD5769 on Day 1 of Treatment Period 1 or anticipated use during the course of the study. 23. Use of any prescription or non-prescription medication (including herbal remedies, vitamins, and nutritional supplements) that are potential CYP3A4 substrates or may be affected by Breast Cancer Resistance Protein (BCRP) / Organic Anion Transporting Polypeptide (OATP) 1B1 / B3 hepatic uptake sensitivity within 30 days prior to administration of GRWD5769 on Day 1 of Treatment Period 1 or anticipated use during the course of the study. 24. Use of any food or drinks that are strong inhibitors or inducers of CYP3A4 (eg, grapefruit juice, pomegranate, starfruit or pomelo) within 14 days prior to administration of GRWD5769 on Day 1 of Treatment Period 1 or anticipated use during the course of the study without prior approval of the PI (or designee) and Novotech MM. 25. Unwilling to refrain from strenuous exercise (including weightlifting) from 48 hours prior to admission to the CRU and through to the EOS Visit. 26 Anything that the PI (or designee) considers would jeopardise the safety of the participant, prevent complete participation in the study, or compromise interpretation of study data.
Outcome results
None listed