A study to evaluate the effects of multiple doses of itraconazole and carbamazepine on processing of giredestrant by the body in healthy female participants
| ISRCTN | ISRCTN16366416 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN16366416 |
| Secondary identifying numbers | GP44001 |
- Submission date
- 05/03/2024
- Registration date
- 14/03/2024
- Last edited
- 13/03/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Other
Plain English summary of protocol
Background and study aims
Cancer is a health condition where the body's cells start growing and multiplying in an uncontrolled and abnormal way. Instead of following the usual pattern of cell growth, these cells form a lump or mass called a tumor. Breast cancer is a health condition where cancer cells form in the breast. Despite how well the available treatments are working, the cancer ultimately returns in many patients after it improved for a while, or the cancer stops responding to the treatment. This study tests a medicine called giredestrant. It is being developed to treat breast cancer with estrogen receptors, which are little proteins found in the cancer cells. Giredestrant is an experimental medicine. This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved giredestrant for the treatment of breast cancer. This study aims to test how much giredestrant reaches the bloodstream and how long the body takes to get rid of it when it is given along with itraconazole or carbamazepine to healthy female participants who are unable to become pregnant.
Who can participate?
Healthy females of 18-65 years of age with breast cancer, who could not become pregnant took part in the study. Patients treated with any drug that specifically works on the estrogen receptors, which are little proteins found in the cancer cells, are unable to take part in this study.
People who are pregnant, or breastfeeding are unable to take part in the study.
What does the study involve?
Participants will be screened to check if they can participate in the study. The screening period will take place approximately 5 weeks before the start of treatment.
Everyone who joins this study will be split into two groups, Group A and Group B. Both groups receive two treatment periods, Periods 1 and 2. Participants are able to take part in only one group of the study.
In Group A, participants are given giredestrant, as a pill by mouth on Day 1 of Period 1 and then on Day 4 of Period 2 along with itraconazole given as an oral liquid. Participants are given itraconazole on Days 1 to 14 of Period 2.
In Group B participants are given giredestrant, as a pill by mouth on Day 1 of Period 1 and then on Day 15 of Period 2 along with carbamazepine, also given as a pill by mouth. Participants are given carbamazepine on Days 1 to 21 of Period 2.
This is an open-label study. This means everyone involved, including the participant and the study doctor, will know the study treatment the participant has been given.
During this study, the participants are confined at the study site for at least 26 days (Group A) or at least 31 days (Group B). Participants received a follow-up telephone call from the study doctor to check on their well-being after approximately 8 to 10 days of completing the study treatment. Total time of participation in the study was about 6 weeks for group A and 7 weeks for group B, excluding the 5 weeks of screening. Participants had the right to stop study treatment and leave the study at any time if they wished to do so.
What are the possible benefits and risks of participating?
Taking part in the study may or may not make participants feel better. However, the information collected in the study can help other people with similar health conditions in the future.
It may not have been fully known at the time of the study how safe and well the study treatment worked. The study involves some risks to the participants. However, these risks are generally not greater than those related to routine medical care or the natural progression of the health condition. People interested in taking part are informed about the risks and benefits, as well as any additional procedures or tests they may need to undergo. All details of the study are described in an informed consent document. This includes information about possible effects and other options for treatment.
Risks associated with the study drugs
Participants may have unwanted effects of the drugs used in this study. These unwanted effects can be mild to severe, even life-threatening, and vary from person to person. During this study, participants will have regular check-ups to see if there are any unwanted effects.
Giredestrant:
Participants are told about the known unwanted effects of giredestrant and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines. Known unwanted effects include pain or stiffness in the joints (arthralgia), frequent watery stools (diarrhea), the feeling of spinning, being unsteady and losing balance (dizziness), tiredness, muscle or bone pain, queasy feeling in the stomach that gives the sensation of wanting to vomit (nausea).
Itraconazole:
Participants are told about the known unwanted effects of itraconazole. Known unwanted effects include shortness of breath, headache, the feeling of spinning, being unsteady and losing balance, heartburn, runny nose, a persistent feeling of sadness, and loss of interest that can affect daily functioning (depression), hair loss, and fever.
Carbamazepine:
Participants are told about the known unwanted effects of carbamazepine. Known unwanted effects include increased thoughts of suicide, liver damage feeling of spinning, being unsteady, and losing balance, frequent watery stools, heart failure, blurred vision, and fainting.
Where is the study run from?
Genentech
When is the study starting and how long is it expected to run for?
January 2022 to May 2022
Who is funding the study?
Genentech
Who is the main contact?
rocheisrctn-mail@xogene.com
Contact information
Public, Scientific, Principal Investigator
Building 1, Grenzacherstrasse 124
Basel
CH-4070
Switzerland
| Phone | +1 888-662-6728 |
|---|---|
| global-roche-genentech-trials@gene.com |
Study information
| Study design | Phase I open-label single-dose fixed-sequence two-part drug-drug interaction (DDI) study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Pharmaceutical testing facility, Telephone |
| Study type | Other |
| Participant information sheet | No participant information sheet available |
| Scientific title | A phase I, open-label, single-dose, fixed-sequence, two-part study to evaluate the effect of itraconazole and carbamazepine on giredestrant pharmacokinetics in healthy female subjects of non-childbearing potential |
| Study objectives | The main purpose of this study is to assess the effect of multiple oral doses of itraconazole (ITZ) and carbamazepine (CBZ) on the single-dose pharmacokinetics (PK) of giredestrant in healthy female participants of non-childbearing potential. |
| Ethics approval(s) |
Approved 24/02/2022, Salus IRB (2111 W. Braker Lane Suite 100, Austin, Texas, 78758, United States of America; +1 512-380-1244; salus@salusirb.com), ref: None provided |
| Health condition(s) or problem(s) studied | Healthy female participants |
| Intervention | Participants will be assigned to either Part A or Part B of the study. Each part consisted of 2 periods. Part A - Period 1: Participants received giredestrant, 10 mg, orally, on Day 1 of Period 1. Part A - Period 2: Participants received itraconazole, 200 milligrams (mg), orally, twice daily (BID), on Day 1, and once daily (QD) on Days 2 to 14 of Period 2. Participants also received giredestrant, 200 mg, orally, along with itraconazole on Day 4 of Period 2. There was a washout period of at least 10 days between the first giredestrant dose and the first ITZ dose. Part B - Period 1: Participants received giredestrant, 30 mg, orally, on Day 1 of Period 1. Part B - Period 2: Participants received carbamazepine, 100 mg, orally, BID, on Days 1 to 3, 200 mg on Days 4 to 6, 300 mg on Days 7 to 19, 200 mg on Day 20, and 100 mg on Day 21 of Period 2. Participants also received giredestrant, 30 mg, orally along with carbamazepine on Day 15 of Period 2. There was a washout period of at least 10 days between the 2 giredestrant doses. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacokinetic, DDI study |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | Giredestrant, Itraconazole, Carbamazepine |
| Primary outcome measure | 1. Part A: Maximum observed concentration (Cmax) of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 4 up to Day 15 in Period 2 of Part A 2. Part A: Time to maximum observed concentration (tmax) of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 4 up to Day 15 in Period 2 of Part A 3. Part A: Area under the concentration-time curve from hour 0 to last measurable concentration (AUC0-t) of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 4 up to Day 15 in Period 2 of Part A 4. Part A: Area under the concentration-time curve extrapolated to infinity (AUC 0-∞) of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 4 up to Day 15 in Period 2 of Part A 5. Part A: Apparent terminal elimination rate constant (λz) of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 4 up to Day 15 in Period 2 of Part A 6. Part A: Apparent terminal elimination half-life (t1/2) of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 4 up to Day 15 in Period 2 of Part A 7. Part A: Apparent total clearance (CL/F) of giredestrant determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 4 up to Day 15 in Period 2 of Part A 8. Part A: Apparent volume of distribution (Vz/F) of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 4 up to Day 15 in Period 2 of Part A 9. Part A: Percentage of AUC0-∞ extrapolated (%AUCextrap) of giredestrant in plasma measured determined using the non-compartmental analysis approach at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 4 up to Day 15 in Period 2 of Part A 10. Part B: Cmax of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 15 up to Day 22 in Period 2 of Part B 11. Part B: Tmax of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 15 up to Day 22 in Period 2 of Part B 12. Part B: AUC0-t of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 15 up to Day 22 in Period 2 of Part B 13. Part B: AUC 0-∞ of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 15 up to Day 22 in Period 2 of Part B 14. Part B: λz of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 15 up to Day 22 in Period 2 of Part B 15. Part B: T1/2 of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 15 up to Day 22 in Period 2 of Part B 16. Part B: CL/F of giredestrant determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 15 up to Day 22 in Period 2 of Part B 17. Part B: Vz/F of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 15 up to Day 22 in Period 2 of Part B 18. Part B: %AUCextrap of giredestrant in plasma determined using the non-compartmental analysis approach from samples collected at predose and multiple time points post-dose from Day 1 up to Day 8 in Period 1 and Day 15 up to Day 22 in Period 2 of Part B |
| Secondary outcome measures | 1. Part A: Number of participants with adverse events (AEs) and severity of AEs determined according to National Cancer Institute Common Terminology Criteria For Adverse Events (NCI CTCAE) from Day 1 up to follow-up (up to approximately 35 days) 2. Part B: Number of participants with AEs and severity of AEs determined according to NCI CTCAE from Day 1 up to follow-up (up to approximately 40 days) 3. Part B: Number of participants with suicidal ideation or behavior, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) score from screening up to follow-up (up to approximately 75 days) |
| Overall study start date | 21/01/2022 |
| Completion date | 25/05/2022 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 65 Years |
| Sex | Female |
| Target number of participants | 33 |
| Total final enrolment | 33 |
| Key inclusion criteria | 1. Females of non-childbearing potential and either postmenopausal and with a negative pregnancy test result at screening (serum test) and check-in (Day -1; urine test) of Period 1. 2. Females with body mass index (BMI) range 18.5 to 32.0 kilograms per meter square (kg/m2), inclusive, at screening. 3. Females in good health, determined by no clinically significant findings from medical history, 12-lead electrocardiogram (ECG), or vital signs. 4. Negative hepatitis panel (hepatitis B surface antigen and hepatitis C virus antibody) and negative human immunodeficiency virus (HIV) antibody screens. |
| Key exclusion criteria | 1. Female participant with a significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal (GI), neurological, or psychiatric disorder (as determined by the investigator). 2. History of stomach or intestinal surgery (including cholecystectomy) or resection that would potentially alter absorption and/or excretion of orally administered drugs except that appendectomy and hernia repair were allowed (unless performed within 12 months prior to screening). 3. Malabsorption syndrome or other condition that would interfere with enteral absorption. 4. Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance < 70 milliliters/minute (mL/min) using the Cockcroft-Gault equation. 5. History of active or latent tuberculosis (TB), regardless of treatment history, or positive QuantiFERON TB Gold test. 6. History of previous use of tamoxifen, aromatase inhibitors, giredestrant, or any other endocrine agent for the treatment of breast cancer. 7. The use of hormone replacement therapy or selective estrogen receptor (ER) modulators (selective estrogen receptor modulators (SERMs); e.g., raloxifene) within 1 year prior to Check-in (Day -1) or 8. The use of oral antibiotics within 4 weeks or intravenous (IV) antibiotics within 8 weeks prior to check-in (Day -1). 9. Use of any moderate or strong cytochrome P450 (CYP3A) inhibitor or inducer within 30 days or 5 half-lives, whichever is longer, prior to Check-in (Day-1). 10. The use or intent to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John’s wort, within 30 days prior to Check-in (Day -1). 11. Female subject having a history of any malignancy, within 5 years prior to screening. 12. Positive for the human leukocyte antigen-B (HLA-B*1502) allele (Part B only). |
| Date of first enrolment | 05/04/2022 |
| Date of final enrolment | 14/04/2022 |
Locations
Countries of recruitment
- United States of America
Study participating centre
33014-3616
United States of America
Sponsor information
Industry
Building 1, Grenzacherstrasse 124
Basel
CH-4070
Switzerland
| Phone | +1 888-662-6728 |
|---|---|
| global-roche-genentech-trials@gene.com | |
| Website | https://www.roche.com/about |
"ROR" |
https://ror.org/04gndp242 |
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Genentech, Inc., Genentech USA, Inc., Genentech USA
- Location
- United States of America
Results and Publications
| Intention to publish date | 25/04/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are not expected to be made available due to participant-level data not being a regulatory requirement. |
Editorial Notes
06/03/2024: Study's existence confirmed by the Salus institutional Review Board (IRB).
