A Study of Ipatasertib (GDC-0068) in Combination With Paclitaxel as Neoadjuvant Treatment for Participants With Early Stage Triple Negative Breast Cancer

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, multicenter, pre-operative Phase II study designed to estimate the efficacy of ipatasertib combined with paclitaxel chemotherapy versus placebo combined with paclitaxel chemotherapy in women with Stage Ia - IIIa triple-negative breast adenocarcinoma. The anticipated time on study treatment is 12 weeks.

Official Title
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A Phase II Randomized, Double-Blind, Study of Ipatasertib (GDC-0068), an Inhibitor to AKT, in Combination With Paclitaxel as Neoadjuvant Treatment for Patients With Early Stage Triple Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Ipatasertib
* Drug: Paclitaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal or postmenopausal women Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Histologically documented, Stage Ia to operable Stage IIIa, triple-negative carcinoma of the breast with primary tumor greter than or equal to (>/=) 1.5 centimeters (cm) in largest diameter (cT1-3) by MRI Adequate hematologic and organ function within 14 days before the first study treatment Availability of tumor tissue from formalin-fixed, paraffin-embedded (FFPE) core biopsy of breast primary tumor For female participants of childbearing potential, agreement to use highly effective form(s) of contraception for the duration of the study and for at least 6 months after last dose of study treatment Exclusion Criteria: Known human epidermal growth factor 2 (HER2)-positive, estrogen receptor (ER)-positive, or progesterone receptor (PgR)-positive breast cancer Any prior treatment for the current primary invasive breast cancer Participants with cT4 or cN3 stage breast tumors Metastatic (Stage IV) breast cancer Bilateral invasive breast cancer Multicentric breast cancer Any disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk from treatment complications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ipatasertib + Paclitaxel<br>Participants will receive ipatasertib orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel intravenous (IV) infusion every week (QW) for 3 cycles (12 total doses). | Drug: Ipatasertib<br>* Ipatasertib will be administered at a dose of 400 milligrams (mg) orally daily on Days 1-21 of each 28-day cycle for 3 cycles.<br>* Other names: GDC-0068;Drug: Paclitaxel<br>* Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m^2) as IV infusion QW for 3 cycles.<br>|
| Placebo Comparator: Placebo + Paclitaxel<br>Participants will receive placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel IV infusion QW for 3 cycles (12 total doses). | Drug: Paclitaxel<br>* Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m^2) as IV infusion QW for 3 cycles.<br>Drug: Placebo<br>* Participants will receive placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pathological Complete Response (pCR) in Breast and Axilla as Defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer Staging System (in All Participants) | pCR was defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer (AJCC) Staging System with the following determination for breast and axilla by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue and N0: no cancer found in the lymph nodes. | Surgery visit (at approximately Weeks 14 to 19) | 
| Percentage of Participants With pCR in Breast and Axilla as Defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer Staging System (in Participants Who Have Phosphatase and Tensin Homolog [PTEN]-Low Tumors) | pCR was defined by ypT0/Tis ypN0 in the AJCC Staging System with the following determination for breast and axilla by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue and N0: no cancer found in the lymph nodes. | Surgery visit (at approximately Weeks 14 to 19) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in All Participants) | pCR was defined by ypT0/Tis in the AJCC Staging System with the following determination for breast by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue. | Surgery visit (at approximately Weeks 14 to 19) | 
| Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in Participants Who Have PTEN-low Tumors) | pCR was defined by ypT0/Tis in the AJCC Staging System with the following determination for breast by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue. | Surgery visit (at approximately Weeks 14 to 19) | 
| Percentage of Participants With Objective Tumor Response by Magnetic Resonance Imaging (MRI), As Assessed by Investigator Per the Modified Response Evaluation Criteria in Solid Tumors (RECIST) (in All Participants) | Objective tumor response (OR) was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. OR was the sum of complete response (CR) and partial response (PR). CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | Screening up to disease progression or death (assessed at screening, pre-surgical visit [approximately Weeks 10-12], early termination visit [up to Week 16]) | 
| Percentage of Participants With Objective Tumor Response by MRI, As Assessed by Investigator Per Modified RECIST (in Participants Who Have PTEN-low Tumors) | ORR was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. ORR was the sum of complete response (CR) and partial response (PR). CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. | Screening up to disease progression or death (assessed at screening, pre-surgical visit [approximately Weeks 10-12], early termination visit [up to Week 16]) | 
| Percentage of Participants With pCR in Breast and Axilla as Defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer Staging System (in Participants Who Are Akt Diagnostic Positive [Dx+]) | pCR was defined by ypT0/Tis ypN0 in the AJCC Staging System with the following determination for breast and axilla by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue and N0: no cancer found in the lymph nodes. | Surgery visit (at approximately Weeks 14 to 19) | 
| Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in Participants Who Are Akt Dx+) | pCR was defined by ypT0/Tis in the AJCC Staging System with the following determination for breast by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue. | Surgery visit (at approximately Weeks 14 to 19) | 
| Percentage of Participants With pCR According to American Joint Committee on Cancer Staging System, by Breast Cancer Subtype | pCR was defined by ypT0/Tis in the AJCC Staging System with the following determination for breast subtypes by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue. The intrinsic molecular subtypes of breast cancer included here are luminal A (LumA), Her-2, basal-like, normal and unknown. | Surgery visit (at approximately Weeks 14 to 19) | 
| Percentage of Participants With Response to Undergoing Breast Conserving Surgery (BCS) Among Participants With T2 or T3 Tumors | After neoadjuvant treatment, the number of patients who is appropriate for breast conserving surgery is reported as a measure of efficacy of the treatment to shrink the tumor enough for patients to benefit from less aggressive surgical management. Breast-conserving surgery was defined as removal of part of the breast tissue during surgery. T2 or T3 in the AJCC Staging System were defined as follows: T2: tumor was more than 2 centimeter (cm) but no more than 5 cm across; T3: tumor was larger than 5 cm across. | Surgery visit (at approximately Weeks 14 to 19) | 
| Percentage of Participants With Response to Conversion to BCS Among Participants With T2 or T3 Tumors | After neoadjuvant treatment, the number of patients who is appropriate for breast conserving surgery is reported as a measure of efficacy of the treatment to shrink the tumor enough for patients to benefit from less aggressive surgical management. Breast-conserving surgery was defined as removal of part of the breast tissue during surgery. T2 or T3 in the AJCC Staging System were defined as follows: T2: tumor was more than 2 centimeter (cm) but no more than 5 cm across; T3: tumor was larger than 5 cm across. | From screening to surgery visit (at approximately Weeks 14 to 19) | 
| Percentage of Participants With Adverse Events | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Screening up to Week 24 | 
| Plasma Concentrations of Ipatasertib on Day 1 and Day 8 | Plasma samples for pharmacokinetic characterization was collected at various timepoints in all participants. | 0.5 and 4 hours post dose on Day 1 of Cycle 1, 166 and 170 hours post dose from Day 1 of Cycle 1 (Cycle length = 28 days) | 
| Minimum Observed Plasma Concentration (Cmin) of Ipatasertib | Plasma samples for pharmacokinetic characterization was collected on Day 1 and Day 8 in all participants. | 0.5 and 4 hours post dose on Day 1 of Cycle 1, 166 and 170 hours post dose from Day 1 of Cycle 1 (Cycle length = 28 days) |