Locally advanced unresectable or metastatic triple-negative (estrogen receptor, progesterone receptor, and HER2 negative) breast cancer or locally advanced unresectable or metastatic hormone receptor–positive, HER2-negative breast cancer with PIK3CA/AKT1/PTEN-altered tumor and no prior chemotherapy in the advanced setting MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer S
Conditions
Interventions
Product Name: ipatasertib 100mg
Product Code: RO5532961
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ipatasertib
Current
Sponsors
F. Hoffmann-La Roche Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: General Inclusion Criteria - Woman or man age =>18 years at the time of signing the Informed Consent Form - Adequate hematologic and organ function - Life expectancy of at least 6 months - For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per year during the treatment period and for at least 28 days after the last dose of ipatasertib/placebo, 5 months after the last dose of Atezo and 6 months after the last dose of Pac, whichever occurs later, and agreement to refrain from donating eggs during this same period - For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm during the treatment period and for 28 days after the last dose of Ipat or 6 months after the last dose of Pac, whichever occurs later - For any patients enrolled in the extended enrollment phase (i.e., China extension phase): patient is a current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry Disease-Specific Inclusion Criteria - Locally assessed, histologically documented TNBC or HR+/HER2-adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to resection with curative intent - Measurable disease according to RECIST v1.1 - Eligible for taxane monotherapy - HR+/HER2– breast cancer that is not considered appropriate for endocrine-based therapy and that meets one of the following inclusion criteria: - Patient has recurrent disease (locoregional or metastatic) during adjuvant endocrine therapy (i.e. =5 years of being on therapy) - If patient has de novo metastatic disease, patient has progressive disease within 6 months of being on first-line endocrine treatment of metastatic disease. - Submission of a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or a minimum of 20 freshly cut unstained, serial tumor slides from the most recently collected tumor tissue for central molecular analysis. Cytologic or FNA samples are not acceptable. Tumor tissue from bone metastases that is subject to decalcification is not acceptable. - If the patient already has PIK3CA/AKT1/PTEN alteration results available from the FMI commercial tissue-based NGS assay known as FoundationONE CDx TM, then reduced tissue requirements may be required (upon approval by the Medical Monitor) - This tumor tissue sample is required to be submitted as described above for all patients, i.e., if local assessment of PIK3CA/AKT1/PTEN alteration status or central ctDNA is used to confirm biomarker eligibility tumor tissue is still required to assess alteration status centrally - Confirmation of biomarker eligibility, i.e., valid results from either central testing or local testing (at a CLIA or equivalently accredited laboratory) of tumor tissue or blood demonstrating PIK3CA/AKT1/PTEN-altered status Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 360 F.1.3 Elderly (
Exclusion criteria
Exclusion criteria: General Exclusion Criteria: - History of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills - Active infection requiring systemic anti-microbial treatment (including antibiotics anti-fungals, anti-viral agents) - Known HIV infection and clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis, current drug or alcohol abuse, or cirrhosis - Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of Cycle 1 or anticipation of need for a major surgical procedure during the course of the study - New York Heart Association Class II, III, or IV heart failure; LVEF 480 milliseconds - History or presence of an abnormal ECG that is clinically significant in the investigator's opinion - Need for chronic corticosteroid therapy of >=10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease - Treatment with approved or investigational cancer therapy within 14 days prior to Day 1 of Cycle 1 - Any other disease, metabolic dysfunction, physical exam finding, or clinical laboratory finding that, in the investigator's opinion, may contraindicate the use of an investigational drug Disease-Specific Exclusion Criteria: - History of or known presence of brain or spinal cord metastases, as determined by CT or MRI evaluation during screening or prior radiographic assessments - Any previous chemotherapy for inoperable locally advanced or metastatic TNBC or HR+/HER2– adenocarcinoma of the breast - Unresolved, clinically significant toxicity from prior therapy - Patients with HR+/HER2– breast cancer, for whom endocrine therapy (alone or with approved targeted therapy such as CDK4/6 inhibitors or everolimus) is considered an appropriate option per local clinical guidelines, i.e., all patients enrolled must not be appropriate candidates for endocrine-based therapy at time of screening - Patients who have received palliative radiation treatment to peripheral sites for pain control and whose last treatment was completed 14 days prior to Day 1 of Cycle 1 may be enrolled in the study if they have recovered from all acute, reversible effects (e.g., to Grade 1 or resolved by enrollment) - Uncontrolled pleural effusion, pericardial effusion, or ascites tumorrelated pain, and hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy - Malignancies other than breast cancer within 5 years prior to Day 1 of Cycle 1 except for appropriately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, or Stage I uterine cancer Ipatasertib-Specific Exclusion Criteria: - History of Type I or Type II diabetes
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Up to approximately 53 months, until disease progression, or lost to follow-up or consent withdrawal;Primary end point(s): 1. Investigator-assessed Progression free survival through the use of RECIST v1.1, or death from any cause, whichever occurs first;Main Objective: • To evaluate the efficacy of ipatasertib (Ipat)_+ paclitaxel (Pac) [Cohort A and B] compared with placebo + Pac and Ipat + Pac + atezolizumab [Atezo] (Cohort C) based on progression-free survival (PFS) defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using RECIST v1.1, or death from any cause, whichever occurs first.; Secondary Objective: • To evaluate the efficacy of Ipat+ Pac (Cohort A and B) compared with placebo + Pac and Ipat + Pac + Atezo (Cohort C) based on Objective response rate, Duration of response, Clinical benefit rate, Overall survival (OS), 1 year PFS and OS (Cohort C only) • To evaluate patient-reported outcomes (PRO) of global health status (GHS)/ health-related quality of life (HRQoL) associated with Ipat + Pac compared with placebo + Pac (Cohort A and B), and with Ipat + Pac + Atezo (Cohort C). • To evaluate PROs of disease-related pain of Ipat+ Pac compared with placebo + Pac (Cohort B only) and of Ipat + Pac + Atezo (Cohort C) • To evaluate the safety of Ipat + Pac compared with placebo + Pac (Cohort A and B) Ipat + Pac + Atezo (Cohort C) • To evaluate the immune response to Atezo • To characterize the pharmacokinetics of Ipat and its metabolite (G-037720) (all Cohorts) and Atezo (Cohort C) when administered in combination with Pac | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): For Cohorts A; B; C 1. Objective response rate 2. Duration of response 3. Clinical benefit rate 4. Overall survival 5. Mean and mean changes from baseline global health status (GHS)/ healt-related quality of life (HRQoL) score as measured by the GHS/HRQoL scale 6. Time to deterioration in pain, measured from the baseline pain scale score 7. Incidence of adverse events as assessed by the investigator, with severity determined through the use of NCI CTCAE v4.0 8. Incidence of prespecified adverse events 9. Change from baseline in targeted vital signs 10. Change from baseline in targeted clinical laboratory test results 11. Plasma concentration of ipatasertib and G-037720 at specified timepoints for analysis using population PK methodology For Cohort C only 12. 1 year PFS 13. 1 year OS 14. Serum concentration of Atezo at specified timepoints 15. Incidence of anti-drug antibodies (ADAs) to Atezo during the study relative to the prevalence of ADAs at baseline ; Timepoint(s) of evaluation of this end point: 1-3. Up to approximately 53 months, until disease progression or death 4-6. Up to approximately 53 months, until death or lost to follow-up or consent withdrawal 7. Up to 28 days after the last dose of study treatment or initiation of new anticancer therapy, except for Serious Adverse Events considered related to study treatment 8-10. Up to 28 days after the last dose of study treatment or initiation of new anticancer therapy 11. Day 1 and Day 15 of Cycle 1, and on Day 15 of Cycle 3 12-13. 1 year 14. Day 1, 15 of Cycle 1 and 3, Day 1 of Cycle 2, 4, 8, 12, 16 and treatment | — |
Countries
Australia, Belgium, Brazil, Canada, Costa Rica, Czech Republic, France, Germany, Greece, Hungary, Italy, Japan, Korea, Republic of, Macedonia, the former Yugoslav Republic of, Mexico, Peru, Poland, Russian Federation, Singapore, Slovenia, Spain, Taiwan, Ukraine, United Kingdom, United States
Contacts
Public ContactTrial Information Support Line-TISL
F. Hoffmann-La Roche Ltd
Outcome results
None listed