E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
First line of treatment for Estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
Breast cancers have different receptors which can affect the response to treatment - in this study patients with tumors which are ER-positive, and HER2-negative will be treated. |
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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) |
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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) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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) |
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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 combined with palbociclib compared with letrozole combined with palbociclib on the basis of progression-free survival |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the efficacy of GDC-9545 combined with palbociclib compared with letrozole combined with palbociclib on the basis of overall survival, objective response rate, duration of response, clinical benefit rate, time to deterioration, time to deterioration in pain presence and interference, time to deterioration in physical functioning, time to deterioration in role functioning, time to deterioration in global health status -To evaluate the safety of GDC-9545 combined with palbociclib compared with letrozole combined with palbociclib -To characterize the GDC-9545 pharmacokinetics profile when given in combination with palbociclib -To characterize the palbociclib pharmacokinetics profile when given in combination with GDC-9545 or in combination with letrozole
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
– Age >= 18 years at time of signing Informed Consent Form – For women who are premenopausal or perimenopausal or men: treatment with approved LHRH agonist therapy for the duration of study treatment – Locally advanced (recurrent or progressed) or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent – Documented ER-positive tumor and HER2-negative tumor, assessed locally – Confirmed availability of the most recently collected and representative tumor tissue specimen suitable for biomarker testing – Patients who have bilateral breast cancers which are both ER positive and HER2 negative can be included in the study because the metastases are suitably targeted by the study treatments. If patients have bilateral tumors which are of different biomarker status, then proof of the ER and HER2 status of the metastases is required for study entry – No history of systemic anti-cancer therapy for locally advanced (recurrent or progressed) or metastatic disease – Disease recurrence from early-stage breast cancer after standard adjuvant endocrine therapy meeting one of the following criteria: • Received at least 24 months of AI treatment (i.e., anastrozole, letrozole, or exemestane) as part of their neoadjuvant/adjuvant therapy without disease progression during treatment and disease-free interval since the completion of AI treatment must be greater than 12 months • Received at least 24 months of tamoxifen treatment as part of their neoadjuvant/adjuvant therapy without disease progression during treatment and disease-free interval since the completion of tamoxifen treatment must be greater than 12 months • For patients who received both AI and tamoxifen as part of their neoadjuvant/adjuvant therapy, they must have received at least 24 consecutive months of either AI or tamoxifen without disease progression during treatment and disease-free interval since the completion of the last treatment must be greater than 12 months – Once the 20% tamoxifen-only cap has been reached, patients must have received 24 months of prior AI as the last adjuvant treatment and the disease-free interval since the completion of AI treatment must be greater than 12 months – Measurable disease as defined per RECIST v.1.1 or bone only disease which must have at least one predominantly lytic bone lesion confirmed by CT or MRI which can be followed – Eastern Cooperative Oncology Group Performance Status 0-1 – Adequate organ function – Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE v5.0 Grade ≤ 1 (except alopecia, Grade ≤ 2 peripheral neuropathy or other toxicities not considered a safety risk for the patient per investigator's judgment) – For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, as defined in the protocol – For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm, as defined in the protocol (and this includes the use of a condom to prevent the potential transfer of study medication or its metabolites to the partner in body fluids) – Ability to comply with the study protocol, in the investigator's judgment – Willing and able to use an electronic device for PRO data collection – For patients enrolled in an extended China enrollment phase at NMPA-recognized sites: current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry – Prior treatment with letrozole in the locally advanced or metastatic setting is allowed for a maximum of 28 days prior to randomization. |
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E.4 | Principal exclusion criteria |
– Disease recurrence during or within 12 months of completing prior neoadjuvant or adjuvant treatment with any CDK4/6 inhibitor – Prior treatment with a SERD – Treatment with any investigational therapy within 28 days prior to study treatment – Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days prior to randomization – Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination half-lives (whichever is longer) prior to randomization – History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I endometrial cancer – Advanced, symptomatic, visceral spread that is at risk of life-threatening complications – Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease – Active cardiac disease or history of cardiac dysfunction – Active viral infection is clinically defined as requiring treatment with antiviral therapy or the presence of positive test results for hepatitis B (hepatitis B surface antigen [HBsAg] and/or total hepatitis B core antibody [anti-HBc]) or HCV antibody. Patients are not required to have HBV, or HCV assessments at screening if these assessments have not been previously performed – Serious infection requiring oral or IV antibiotics, or other clinically significant infection within 14 days prior to randomization. Patients who fully recovered from serious or clinically significant infections at least 14 days prior to screening are eligible – For patients who have been successfully treated for viral hepatitis, the possibility of re activation of the virus or reinfection with viral hepatitis should be considered by the Investigator and the overall potential benefits associated with study treatment for the patient should be deemed to exceed the overall risks. – Known HIV infection – 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 – Pregnant or breastfeeding - Participants with first‑degree heart block may be considered for inclusion following consultation with a cardiologist and determination that no additional cardiac risks are present. - Participants with pacemakers to treat more severe heart blocks and other arrhythmias are permitted. - Patients with history of well-controlled atrial fibrillation are eligible.
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Progression-free survival as determined by the investigator |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Approximately 82 months |
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E.5.2 | Secondary end point(s) |
Efficacy, Safety, Pharmacokinetic: 1. Overall survival 2. Objective response rate as determined by the investigator 3. Duration of response as determined by the investigator 4. Clinical benefit rate as determined by the investigator 5. Time to deterioration in pain level 6. Time to deterioration in pain presence and interference, in physical functioning, in role functioning, and in global health status 7. Incidence and severity of adverse events, with severity determined according to NCI CTCAE v5.0 8. Change from baseline in targeted vital signs 9. Plasma concentration of GDC-9545 at specified timepoints 10. Plasma concentration of palbociclib at specified timepoints
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-7. Approximately 82 months 8. From baseline (Day-28 to -1) to 82 months 9. Day 1 and 15 of Cycle 1, Day 1 of Cycle 2, 4, 8, and 16 and at treatment discontinuation 10. Day 1 and 15 of Cycle 1
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 118 |
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 |
Argentina |
New Zealand |
Peru |
Switzerland |
Ukraine |
Hong Kong |
Australia |
Belgium |
Brazil |
Canada |
China |
Denmark |
France |
Germany |
Greece |
Hungary |
Italy |
Korea, Republic of |
Mexico |
Poland |
Portugal |
South Africa |
Spain |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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The end of this study (global phase and China extension phase) is defined as the date when the last patient, last visit occurs or the date at which the last data point required for statistical analysis or overall survival follow-up is received from the last patient, whichever occurs later. The end of the study is expected to occur at least 60 months after the last patient is enrolled. In addition, the Sponsor may decide to terminate the study at any time. |
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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 | 82 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 82 |