| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer is a cancer that develops in the tissues of the breast and has the potential to spread outside of the breast |
|
| 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 | 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 | 100000004864 |
|
| 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 | 10072740 |
| E.1.2 | Term | Locally advanced 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 |
| • To evaluate the efficacy of ipatasertib + paclitaxel compared with placebo + paclitaxel 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 |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of ipatasertib + paclitaxel compared with placebo + paclitaxel based on Objective response rate (ORR), Duration of response (DOR), Clinical benefit rate, Overall survival (OS)
• To evaluate patient-reported outcomes (PRO) of global health status (GHS)/ health-related quality of life (HRQoL) associated with ipatasertib + paclitaxel compared with placebo + paclitaxel
• To evaluate PROs of disease-related pain of ipatasertib + paclitaxel compared with placebo + paclitaxel (Cohort B only)
• To evaluate the safety of ipatasertib + paclitaxel compared with placebo + paclitaxel
• To characterize the pharmacokinetics of ipatasertib and its metabolite (G-037720) when administered in combination with paclitaxel
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General Inclusion Criteria
- Woman or man age =>18 years at the time of signing the Informed Consent Form
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- 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 and 6 months after the last dose of paclitaxel, 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 ipatasertib or 6 months after the last dose of paclitaxel, 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 (receptor status should be assessed in most recent biopsy, i.e. recurrent or metastatic tissue where applicable and if safely accessible per ASCO/CAP guidance)
- Measurable disease according to Response Evaluation Criteria in Solid Tumors (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:
o Patient has recurrent disease (locoregional or metastatic) during adjuvant endocrine therapy (i.e. ≤5 years of being on therapy)
o 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)
o 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
|
|
| E.4 | Principal exclusion criteria |
General Exclusion Criteria:
- Inability to comply with study and follow-up procedures
- 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, and anti-viral agents)
- Known HIV infection
- Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), 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
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 28 days after the last dose of ipatasertib/placebo and within 6 months after the last dose of paclitaxel, whichever occurs later
- New York Heart Association Class II, III, or IV heart failure; left ventricular ejection fraction <50%; or active ventricular arrhythmia requiring medication
- Current unstable angina or history of myocardial infarction within 6 months prior to Day 1 of Cycle 1
- Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula (QTcF) >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 examination 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 computed tomography (CT) or magnetic resonance imaging (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 (e.g., bone metastases) 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
- Uncontrolled tumor-related pain
- Uncontrolled 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 mellitus requiring insulin
- Grade >=2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia
- History of or active inflammatory bowel disease or active bowel inflammation
- Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia)
- Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug
- Prior treatment with an Akt inhibitor. Note that prior PI3K or mTOR inhibitors are allowed.
Paclitaxel-Specific Exclusion Criteria:
- Known hypersensitivity or contraindication to any component of the study treatments, including the paclitaxel excipient macrogolglycerol ricinoleate
- Grade >=2 peripheral neuropathy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Investigator-assessed Progression free survival through the use of RECIST v1.1, or death from any cause, whichever occurs first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 53 months, until disease progression, or lost to follow-up or consent withdrawal |
|
| E.5.2 | Secondary end point(s) |
1. Objective response rate
2. Duration of response
3. Clinical benefit rate
4. Overall survival
5. Mean and mean changes from baseline GHS/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 |
|
| E.5.2.1 | 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 |
|
| 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 | 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) | 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 | Yes |
| 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) | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| 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 |
| 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 |
|
| 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
|
Date when the last patient, last visit occurs or date at which the last data point required for statistical analysis or safety follow-up is
received from the last patient, whichever occurs later |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
Print
