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

• ClinicalTrials.gov Identifier: NCT02301988
• Recruitment Status: Completed
• First Posted: November 26, 2014
• Results First Posted: September 20, 2018
• Last Update Posted: October 17, 2018
• Sponsor: Genentech, Inc.
• Collaborator: SOLTI Breast Cancer Research Group
• Information provided by (Responsible Party): Genentech, Inc.

Tracking Information

• First Submitted Date: November 24, 2014
• First Posted Date: November 26, 2014
• Results First Submitted Date: July 26, 2018
• Results First Posted Date: September 20, 2018
• Last Update Posted Date: October 17, 2018
• Actual Study Start Date: February 17, 2015
• Actual Primary Completion Date: August 2, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 22, 2018)

• 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) [ Time Frame: Surgery visit (at approximately Weeks 14 to 19) ]
  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.
• 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) [ Time Frame: Surgery visit (at approximately Weeks 14 to 19) ]
  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.

• Original Primary Outcome Measures (submitted: November 24, 2014): Pathological complete response (pCR) rate in breast and axilla [ Time Frame: Following completion of neoadjuvant therapy and surgery, approximately 17 weeks ]

Current Secondary Outcome Measures (submitted: August 22, 2018)

• Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in All Participants) [ Time Frame: Surgery visit (at approximately Weeks 14 to 19) ]
  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.
• 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) [ Time Frame: Surgery visit (at approximately Weeks 14 to 19) ]
  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.
• 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) [ Time Frame: Screening up to disease progression or death (assessed at screening, pre-surgical visit [approximately Weeks 10-12], early termination visit [up to Week 16]) ]
  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.
• Percentage of Participants With Objective Tumor Response by MRI, As Assessed by Investigator Per Modified RECIST (in Participants Who Have PTEN-low Tumors) [ Time Frame: Screening up to disease progression or death (assessed at screening, pre-surgical visit [approximately Weeks 10-12], early termination visit [up to Week 16]) ]
  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.
• 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+]) [ Time Frame: Surgery visit (at approximately Weeks 14 to 19) ]
  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.
• 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+) [ Time Frame: Surgery visit (at approximately Weeks 14 to 19) ]
  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.
• Percentage of Participants With pCR According to American Joint Committee on Cancer Staging System, by Breast Cancer Subtype [ Time Frame: Surgery visit (at approximately Weeks 14 to 19) ]
  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.
• Percentage of Participants With Response to Undergoing Breast Conserving Surgery (BCS) Among Participants With T2 or T3 Tumors [ Time Frame: Surgery visit (at approximately Weeks 14 to 19) ]
  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.
• Percentage of Participants With Response to Conversion to BCS Among Participants With T2 or T3 Tumors [ Time Frame: From screening to surgery visit (at approximately Weeks 14 to 19) ]
  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.
• Percentage of Participants With Adverse Events [ Time Frame: Screening up to Week 24 ]
  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.
• Plasma Concentrations of Ipatasertib on Day 1 and Day 8 [ Time Frame: 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) ]
  Plasma samples for pharmacokinetic characterization was collected at various timepoints in all participants.
• Minimum Observed Plasma Concentration (Cmin) of Ipatasertib [ Time Frame: 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) ]
  Plasma samples for pharmacokinetic characterization was collected on Day 1 and Day 8 in all participants.

Original Secondary Outcome Measures (submitted: November 24, 2014)

• Objective tumor response by MRI, as assessed by the investigator per modified Response Evaluation Criteria in Solid Tumors [ Time Frame: Response by MRI will be assessed after 3 cycles (12 weeks) and at any time progression is suspected ]
• pCR rate in breast, as defined by ypT0/Tis in the American Joint Committee on Cancer staging system by local pathology evaluation [ Time Frame: Approximately week 17 ]
• Efficacy (composite outcome measure): rates of BCS and conversion to BCS in patients with T2 or T3 tumors [ Time Frame: Approximately week 17 ]
• Safety (composite outcome measure): Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v4.0 [ Time Frame: From baseline to 30 days after the last dose of study drug ]
• Pharmacokinetics (composite outcome measure): PK parameters of ipatasertib plasma concentration over time (exposure following first dose [AUC0-24] and steady state (AUCss), trough concentration [Cmin], apparent clearance [CL/F]) [ Time Frame: Day 1 and 8 sampling in Cycle 1 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Ipatasertib (GDC-0068) in Combination With Paclitaxel as Neoadjuvant Treatment for Participants With Early Stage Triple Negative Breast Cancer
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Ipatasertib
  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.
  Other Name: GDC-0068
• Drug: Paclitaxel
  Paclitaxel will be administered at a dose of 80 milligrams per square meter (mg/m^2) as IV infusion QW for 3 cycles.
• Drug: Placebo
  Participants will receive placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles.

Study Arms

• Experimental: Ipatasertib + Paclitaxel
  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).
  Interventions:

  • Drug: Ipatasertib
  • Drug: Paclitaxel
• Placebo Comparator: Placebo + Paclitaxel
  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).
  Interventions:

  • Drug: Paclitaxel
  • Drug: Placebo

• Publications *: Oliveira M, Saura C, Nuciforo P, Calvo I, Andersen J, Passos-Coelho JL, Gil Gil M, Bermejo B, Patt DA, Ciruelos E, de la Pena L, Xu N, Wongchenko M, Shi Z, Singel SM, Isakoff SJ. FAIRLANE, a double-blind placebo-controlled randomized phase II trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer. Ann Oncol. 2019 Aug 1;30(8):1289-1297. doi: 10.1093/annonc/mdz177.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 11, 2017): 151
• Original Estimated Enrollment (submitted: November 24, 2014): 150
• Actual Study Completion Date: August 2, 2017
• Actual Primary Completion Date: August 2, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Portugal, Spain, United States

Administrative Information

• NCT Number: NCT02301988
• Other Study ID Numbers: GO29505; 2014-003029-16 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Genentech, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Genentech, Inc.
• Original Study Sponsor: Same as current
• Collaborators: SOLTI Breast Cancer Research Group

Investigators

• Study Director: Clinical Trials; Genentech, Inc.

• PRS Account: Genentech, Inc.
• Verification Date: September 2018