E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Estrogen Receptor (ER)-Positive and HER2-Negative Untreated Early Breast Cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Uncontrolled breast tissue growth that expresses estrogen receptor (cells have receptors that use the hormone estrogen to grow) and negative HER2 receptor (cancer has low levels of the protein HER2) |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10070575 |
E.1.2 | Term | Estrogen receptor positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10070577 |
E.1.2 | Term | Oestrogen receptor positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10083232 |
E.1.2 | Term | HER2 negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
-To evaluate the efficacy of GDC-9545 compared with anastrozole on the basis of the central assessment of changes in Ki67 scores |
|
E.2.2 | Secondary objectives of the trial |
-To evaluate the clinical efficacy of GDC-9545 plus palbociclib compared with anastrozole plus palbociclib on the basis of objective response rate and complete cell cycle arrest rate
-To evaluate the safety of GDC-9545 plus palbociclib compared with anastrozole plus palbociclib
-To characterize the pharmacokinetic profile of GDC-9545 alone and when administered in combination with palbociclib
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Postmenopausal women age >= 18 years
-Histologically confirmed operable or inoperable invasive breast carcinoma
ocT1c (>= 1.5 cm)-cT4a-c breast cancer at presentation
Primary tumor must be >= 1.5 cm in longest diameter by ultrasound.
-Measurable disease by ultrasound as defined per mRECIST
-Patients with multifocal tumors (more than one mass confined to the same quadrant as the primary tumor) if all lesions are sampled and confirmed as ER-positive/HER2-negative invasive breast cancer and at least one lesion is >= 1.5 cm in longest diameter by ultrasound
-Patients with multicentric tumors (multiple tumors involving more than one quadrant) if all discrete lesions are sampled and confirmed as ER-positive/HER2-negative invasive breast cancer and at least one lesion is >= 1.5 cm in longest diameter by ultrasound
-Candidate for neoadjuvant treatment and considered appropriate for endocrine therapy
-Willingness to undergo breast surgery after neoadjuvant treatment and to provide three mandatory tumor samples
-Documented ER-positive tumor in accordance to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (Allison et al.2020), assessed locally and defined as >= 1% of tumor cells stained positive on the basis of the most recent tumor biopsy
-Documented progesterone receptor status (positive or negative) as per local assessment
-Documented HER2-negative tumor in accordance to 2018 ASCO/CAP guidelines (Wolff et al. 2018), assessed locally on the most recent tumor biopsy
-Ki67 score >= 5% analyzed centrally or locally
-Eastern Cooperative Oncology Group Performance Status 0-1
-Adequate organ function
|
|
E.4 | Principal exclusion criteria |
-Stage IV (metastatic) breast cancer
-Inflammatory breast cancer (cT4d)
-Bilateral invasive breast cancer
-History of invasive breast cancer, ductal carcinoma in situ or lobular carcinoma in situ and other malignancy within 5 years prior to screening
-Previous systemic or local treatment for the primary breast cancer currently under investigation
-History of any prior treatment with AIs, tamoxifen, selective estrogen receptor down regulator, or cyclin-dependent kinase 4 and 6 inhibitors
-Major surgery within 4 weeks prior to randomization
-Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including hepatitis
-Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
-History of allergy to anastrozole, or palbociclib or any of its excipients
-Known issues with swallowing oral medication
-History of documented hemorrhagic diathesis, coagulopathy, or thromboembolism
-Active cardiac disease or history of cardiac dysfunction
-Current treatment with medications that are well known to prolong the QT interval
-Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery including gastric resection
-Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination half-lives prior to randomization
-Serious infection requiring oral or IV antibiotics, or other clinically significant infection within 14 days prior to screening
-Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Central assessment of changes in Ki67 scores from baseline to Week 2 (Day 15 [+ 1 day]) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From baseline (Day-28 to-1) to Week 2 (Day 15 [+ 1 day]) |
|
E.5.2 | Secondary end point(s) |
1. Objective response rate by ultrasound
2. Complete cell cycle arrest rate
3. Incidence and severity of adverse events, with severity determined in accordance to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
4. Change from baseline in targeted vital signs
5. Change from baseline in targeted clinical laboratory test results
6. Plasma concentration of GDC-9545 at specified timepoints
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At Week 18
2. Between Week 18 and Week 20
3-5. Up to end of study visit Week 22 or 28 days after last study dose
6. Visits: C0D1, D15; C1D1, C1D15, C2D1, C2D15, C3D1, C4D1
|
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
China |
Germany |
Hungary |
Korea, Republic of |
Poland |
Russian Federation |
Spain |
Taiwan |
Ukraine |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of this study is defined as the date when the last patient, last visit, occurs or the date of Sponsor decision to end the study, whichever is earlier. The end of the study is expected to occur approximately 6 months after the last patient is enrolled. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 13 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 19 |