| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic triple-negative breast cancer (TNBC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| TNBC refers to any breast cancer that does not express estrogen receptor or progesterone receptor, and does not over-express human epidermal growth factor receptor 2 |
|
| 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 | 21.1 |
| 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 the experimental arm treatment compared with control arm treatment in each cohort based on investigator-assessed progression-free survival (PFS) and overall survival (OS) |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
• Efficacy of the experimental arm treatment compared with control arm treatment in each cohort, based on objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR); in patients with PIK3CA/AKT1/PTEN-altered tumors in each cohort based on PFS, OS, ORR, DOR, CBR
• Patient-reported outcomes (PROs) of function, global health status (GHS)/ quality of life (QoL) associated with ipat+pac (doublet) and triplet compared to control arm; using functional, GHS/QoL scales of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire- Core 30 (EORTC QLQ-C30)
• Safety of the experimental arm treatment in each cohort
• Pharmacokinetics of atezo, ipat, ipat metabolite (G-0377720) in each cohort
• Immune response to atezo in each cohort
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Women or men, age >= 18 years
- Willingness and ability to complete all study-related assessments, including PRO assessments, in the investigator’s judgment
- Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of Cycle 1
- Life expectancy of at least 6 months
- For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 28 days after the final dose of ipat/placebo, 5 months after the final dose of atezo /placebo, and 6 months after the final dose of pac, whichever occurs later
- For men: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating sperm, with female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 28 days after the final dose of ipat /placebo, or 6 months after the final dose of pac, whichever occurs later
- For any patients enrolled in the extended enrollment phase: patient is a current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry
Disease-Specific Inclusion Criteria
- Appropriate candidate for paclitaxel monotherapy if tumor PD-L1 status is unknown or non-positive; appropriate candidate for paclitaxel and atezolizumab if tumor PD-L1 status is positive
- Histologically documented triple-negative adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to resection with curative intent
- Submittal of a formalin-fixed, paraffin-embedded tumor tissue block or a minimum of 15 freshly cut unstained, serial tumor slides from the most recently collected tumor tissue. Cytologic or fine-needle aspiration samples are not acceptable. Tumor tissue from bone metastases that is subject to decalcification is not acceptable |
|
| E.4 | Principal 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, unwillingness to swallow pills
-Active infection requiring systemic anti-microbial treatment
-Known HIV infection and clinically significant history of liver disease consistent with Child-Pugh Class B or C
-Current treatment with anti-viral therapy for hepatitis B virus
-Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day1 Cycle1 or anticipation of need for a major surgical procedure during the study
-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 Day1 Cycle1
-Congenital long QT syndrome or screening QT interval corrected through use Fridericia's formula >480 ms
-Current treatment with medications used at doses known to cause clinically relevant prolongation of QT/QTc interval
-History or presence of an abnormal Electrocardiogram that is clinically significant in the investigator's opinion
-Requirement for chronic corticosteroid therapy of >10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or imunosuppressant agents 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, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications
Disease-Specific Exclusion Criteria
-History of or known presence of brain or spinal cord metastases, as determined by computed tomography or magnetic resonance imaging evaluation during screening or prior radiographic assessments
-Known CNS disease
-Known germline BRCA1/2 deleterious mutation unless the patient is not an appropriate candidate for a PARP-inhibitor
-Any previous systemic therapy for inoperable locally advanced or metastatic triple-negative adenocarcinoma of the breast
-Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy
-Patients who have received palliative radiotherapy to peripheral sites for pain control and whose last treatment was completed 14 days prior to Day1 Cycle1 may be enrolled in the study if they have recovered from all acute reversible effects
-Uncontrolled pleural effusion, pericardial effusion or ascites, tumor-related pain hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
-Malignancies other than breast cancer within 5 years prior to Day1 Cycle1 except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma or Stage I uterine cancer
Pac-Specific Exclusion Criteria
-Known hypersensitivity or contraindication to any component of the study treatments
-Grade >=2 peripheral neuropathy
Ipat-Specific Exclusion Criteria
-History of Type I or Type II diabetes mellitus requiring insulin or active inflammatory bowel disease or active bowel inflammation
-Grade >=2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia
-Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, aspergillosis, active tuberculosis or history of opportunistic infections
-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
Atezo -Specific Exclusion Criteria
-Active or history of autoimmune disease or immune deficiency
-History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis or evidence of active pneumonitis on screening chest CT scan
-Prior allogeneic stem cell or solid organ transplantation
-Treatment with a live attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such vaccine during treatment with atezo or within 5 months after the final dose of atezo
-History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
-Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies
-Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug prior to initiation of study treatment
-Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medication during the trial |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Investigator-assessed PFS according to RECIST v1.1 in experimental arm treatment compared with control arm treatment in each cohort (i.e., Arm A vs. Arm C and Arm B vs. Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2)
2. OS in experimental arm treatment compared with control arm treatment in each cohort (i.e., Arm A vs. Arm C and Arm B vs. Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. ORR, DOR, CBR as determined by the investigator according to RECIST v1.1 in experimental arm treatment compared with control arm treatment in each cohort (i.e., Arm A vs. Arm C and Arm B vs. Arm C in Cohort 1 and Arm A vs. Arm B in Cohort 2)
2. Mean and mean changes from baseline score in function (role, physical) and GHS/QoL by assessment timepoint and between treatment arms, as measured using the Functional and the GHS/QoL scales of the EORTC QLQ-C30
3. PFS, OS, ORR for patients with PD-L1-non-positive tumor patients who are administered with atezo in combination with ipat and pac (Arm A vs. Arm B in Cohort 1)
4. PFS, OS, CBR, DOR for patients in experimental arm treatment compared with control arm treatment in patients with PIK3CA/AKT1/PTEN-altered tumors in each cohort,
5. Incidence and severity of adverse events, with severity determined by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0
6. Change from baseline in targeted vital signs
7. Change from baseline in targeted clinical laboratory test results
8. Plasma concentration of ipat and its metabolite (G037720) at specified timepoints
9. Serum concentration of atezo at specified timepoints
10. Prevalence of anti-drug antibodies (ADAs) to atezo at baseline and incidence of ADAs to atezo during the study |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 76 months
2. From baseline (Day 1 of Cycle 1) and Day 15 of Cycle 1 and 2; Day 1 of Cycle 3-5 and beyond, study drug discontinuation visit (SDDV) [>= 28 days after final dose], post -treatment follow-up visit
3-4. Up to 76 months
5. From baseline to SDDV
6. From baseline to 28 days after final dose
7. Day 1 and 15 of Cycle 1 Day 15 of Cycle 3
8-10. Baseline, Day 15 of Cycle 1; Day 1 of Cycle 2-4, 8, 12 and 16 and at SDDV |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 5 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Colombia |
| Costa Rica |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Greece |
| Hong Kong |
| Hungary |
| India |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Peru |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Singapore |
| South Africa |
| Spain |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| 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 this study is defined as the date when the last patient, last visit occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. In addition, the Sponsor may decide to terminate the study at any time |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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