| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| WOMEN WITH ER-POSITIVE/HER2-NEGATIVE, EARLY STAGE BREAST CANCER |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 19.0 |
| 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 | 100000004864 |
|
| 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 |
The primary objective of this study is to evaluate the efficacy of letrozole plus GDC-0032 versus letrozole plus placebo in women with ER+/HER2- early stage breast cancer, as measured by the following co-primary endpoints:
•Tumor overall objective response rate (ORR) by centrally assessed breast magnetic resonance imaging (MRI) via modified Response Evaluation Criteria in Solid Tumors (RECIST) in all enrolled patients and PIK3CA MT patients
•pCR rate in breast and axilla (ypT0/Tis ypN0) by local evaluation in all enrolled patients and PIK3CA MT patients |
|
| E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives of this study are the following:
•Tumor ORR, assessed by centrally assessed breast MRI via modified Response Evaluation Criteria in Solid Tumors (RECIST) in PIK3CA WT patients
•pCR rate in breast and axilla (total pCR ypT0/Tis ypN0) by local evaluation in PIK3CA WT patients |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Histologically confirmed invasive breast carcinoma, with all of the following characteristics:
– Primary tumor ≥ 2 cm in largest diameter (cT1-3) by MRI. In the case of a multifocal tumor (defined as the presence of two or more foci of cancer within the same breast quadrant), the largest lesion must be ≥ 2 cm and designated as the “target” lesion for all subsequent tumor evaluations.
– Stage I to operable Stage III breast cancer
– Documentation confirming the absence of distant metastasis (M0) as
determined by institutional practice (in patients where there may be a
reasonable suspicion of advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and symptoms).
• ER-positive and HER2-negative breast cancer, as per local laboratory or regional definition
• Breast cancer eligible for primary surgery
• Tumor tissue from FFPE core biopsy of breast primary tumor that is confirmed as evaluable for PIK3CA mutation status by central histopathology laboratory
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Fasting glucose ≤125 mg/dL
• Adequate hematological, renal, and hepatic function, as follows:
– Absolute neutrophil count ≥ 1500/μL
– Platelets count ≥100,000/μL |
|
| E.4 | Principal exclusion criteria |
•Any prior treatment for primary invasive breast cancer
•Patients with cT4 or cN3 stage breast tumors
•Metastatic (Stage IV) breast cancer
•Bilateral invasive breast cancer
•Multicentric breast cancer (the presence of more than one tumor in different quadrants of the breast)
•Patients who have undergone excisional biopsy of primary tumor and/or axillary lymph nodes
•Patients who have undergone sentinel lymph node biopsy prior to study treatment
• Patients for whom upfront chemotherapy is clinically judged appropriate as optimal neoadjuvant treatment
• Patients for whom immediate surgery is indicated
•Type 1 or 2 diabetes requiring antihyperglycemic medication
•Inability or unwillingness to swallow pills
•Malabsorption syndrome or other condition that would interfere with enteric absorption |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-primary endpoints:
1) Tumor ORR, assessed by modified RECIST criteria by breast MRI (centrally assessed) in all enrolled patients and PIK3CA MT patients
2) Rate of pCR in breast and axilla (total pCR) after completion of study drug in all enrolled patients and PIK3CA MT patients |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Tumor ORR evaluated prior to initiating study treatment (baseline) and after completion of study treatment (16 weeks)
2) pCR evaluated after completion of study treatment (16 weeks) |
|
| E.5.2 | Secondary end point(s) |
1) Tumor ORR after completion of study treatment, assessed by modified RECIST criteria by breast MRI (centrally assessed) in PIK3CA WT patients
2) Rate of pCR in breast and axilla (total pCR) after completion of study drug in PIK3CA WT patients
The following will be performed in all enrolled patients and separated by PIK3CA mutation status:
3) ORR by clinical breast examination, mammography and breast ultrasound
4) Ki67 values at baseline, Week 3, and surgery
5) Change in Ki67 from baseline to Week 3; baseline to surgery, and Week 3 to surgery
6) PEPI score
7) Change in enhancing tumor volume from baseline to surgery as measured by breast MRI
8) Evaluation of different definitions of pCR including the following: a) ypT0, ypN0, and b) ypT0/is, ypNX (breast pCR).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| For secondary endpoints involving ORR and change in enhancing tumor volume, timepoints are prior to initiating study treatment and after completion of study treatment (16 weeks). For pCR and PEPI score, timepoint is completion of study treatment (16 weeks). For Ki67 analyses, timepoints are as listed with surgery occurring within 1 week of completion of the study treatment (16 weeks). |
|
| 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 | Yes |
| 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 | Yes |
| 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 | 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 | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 |
| Austria |
| Belgium |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Switzerland |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| The end of the study is defined as the date when the last patient has her postsurgery visit. The total duration of the study is expected to be approximately 24 months for enrollment, plus 5.5 months after last patient in. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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