E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with metastatic or locally advanced, triple-negative adenocarcinoma of the breast that have not received prior systemic therapy for metastatic breast cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with metastatic (cancer that has spread) or locally advanced (cancer that has regrown at or near the original site) triple-negative breast cancer (TNBC) that have not received treatment |
|
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 | PT |
E.1.2 | Classification code | 10075566 |
E.1.2 | Term | Triple negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 |
Cohort I: •To estimate the clinical benefit of cobimetinib (CTB) plus paclitaxel (PAC) relative to placebo plus PAC, as measured by investigator-assessed progression free survival (PFS) in patients with locally advanced or metastatic TNBC Cohort II: •To estimate the clinical benefit of CTB plus atezolizumab (ATZ) plus PAC, as measured by overall response rate (ORR) Cohort III: •To estimate the clinical benefit of CTB plus ATZ plus nab-paclitaxel nab-PAC, as measured by ORR
|
|
E.2.2 | Secondary objectives of the trial |
Cohort I: •To determine the ORR Cohort I, II, and III: •To evaluate the safety and tolerability of CTB administered in combination with PAC; CTB and ATZ administered with PAC; and CTB and ATZ administered with nab-PAC in patients with locally advanced or metastatic TNBC •To determine ORR unconfirmed(ORR_uc), and duration of response (DOR) of CTB plus PAC and placebo plus PAC; CTB plus ATZ plus PAC; and CTB plus ATZ plus nab-PAC •To evaluate overall survival (OS) benefit of CTB plus PAC and placebo plus PAC •To evaluate the OS and PFS of CTB plus ATZ plus PAC; and CTB plus ATZ plus nab-PAC •To characterize the pharmacokinetics (PK) of CTB and PAC; CTB, ATZ, and PAC; and CTB, ATZ, and nab-PAC when administered in combination (safety run-in) •To characterize the PK of CTB and to investigate the relationship between CTB exposure and efficacy and safety outcomes using population approaches (expansion stage)
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Signed informed consent form - Women and men, age >= 18 years - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or1 - Histologically confirmed estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the breast, with measurable metastatic or locally advanced disease - Locally advanced disease must not be amenable to resection with curative intent - Measurable disease, according to response evaluation criteria in solid tumours (RECIST), v1.1 - Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first dose of study drug treatment: –Absolute neutrophil count (ANC) >= 1.5 × 10 exp9/L –Platelet count >= 100 × 10 exp9/L –Hemoglobin >= 9 gram (g)/decilitre (dL) –Albumin >= 2.5 g/dL –Bilirubin <= 1.5 × the upper limit of normal (ULN) –Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase <= 3 × ULN, with the following exceptions: -Patients with documented liver metastases: AST and/or ALT <= 5 × ULN -Patients with documented liver or bone metastases: alkaline phosphatase <= 5 × ULN –Serum creatinine <= 1.5 × ULN or creatinine clearance (CrCl) >= 40 mL/min on the basis of measured CrCl from a 24-hour urine collection or Cockroft-Gault glomerular filtration rate estimation: (140-age) x (weight in kg) x (0.85 if female) 72 x (serum creatinine in milligram/dL) - Ability and capacity to comply with the study and follow-up procedure - For female patients (and female partners of male patients) who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of paclitaxel/nab-paclitaxel,at least 5 months after the last dose of atezolizumab, and 3 months after the last dose of cobimetinib. - The determination of TNBC status should, whenever possible, utilize tissue from a metastatic or recurrent lesion and where more than one biopsy source is available; priority should be given to the most recent sample. - Patients who have not had HER2, ER, or PR testing, and thus, the HER2, ER, and PR status of the breast adenocarcinoma is unknown, are not eligible - Men must agree not to donate sperm or have intercourse with a female partner without using appropriate barrier contraception during the treatment period and for 6 months after the last dose of paclitaxel/nab-paclitaxel and 3 months after the last dose of Cobimetinib. Male patients should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) or lower fertility with paclitaxel. |
|
E.4 | Principal exclusion criteria |
- Known HER2 positive, ER positive, or PR positive breast cancer by local laboratory assessment (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the Medical Monitor to establish eligibility of patient) - HER2 positivity is defined as one of the following: immunohistochemistry (IHC) 3 positive or in situ hybridization (ISH) positive - ER and PR positivity is defined positive for ER or PR if a finding of >=1% of tumor cell nuclei are immunoreactive - Patients who have not had HER2, ER, or PR testing, and thus, the HER2, ER, and PR status of the breast adenocarcinoma is unknown, are not eligible - Any prior chemotherapy, hormonal, or targeted therapy, for inoperable locally advanced or mTNBC - Prior chemotherapy (including taxanes) and/or radiation in the neoadjuvant or adjuvant setting is allowable if treatment occurred >= 6 months prior to initiation of study treatment (Cycle [C] 1 Day [D]1) - Any systemic anti-cancer therapy within 3 weeks[W] prior to C1, D1 - Any radiation treatment to metastatic site within 28 days of C1, D1 - Major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to C1, D1, or anticipation of need for major surgical procedure during the course of the study - Prior therapy with bevacizumab, sorafenib, sunitinib, or other putative vascular endothelial growth factor pathway−targeted therapy within 2 years of start of study treatment - Prior exposure to experimental treatment targeting rapidly accelerated fibrosarcoma (Raf), MEK (MAPK [Mitogen-activated protein kinases]/Erk kinase), or the MAPK pathway - Previous therapy with Akt, phosphoinositide 3-kinase (PI3K), and/or mechanistic target of rapamycin (mTOR) inhibitors - Prior therapy with trastuzumab - Grade >= 2 peripheral neuropathy - Brain metastases (symptomatic or non-symptomatic) that have not been treated previously, are progressive, or require any type of therapy (e.g. radiation, surgery or steroids) to control symptoms from brain metastases within 30 days prior to first study treatment dose - History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration - Patients will be excluded if they currently have the following risk factors for RVO: -Uncontrolled glaucoma with intra-ocular pressures >= 21 mmHg -Serum cholesterol >= Grade 2 -Hypertriglyceridemia >= Grade 2 -Hyperglycemia (fasting) >= Grade 2 -Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower - Use of strong cytochromes P450 (CYP)3A4/5 inhibitors such as but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, and voriconazole - Strong CYP3A4/5 inducers such as but not limited to rifampin, carbamazepine, rifapentine, phenytoin, and phenobarbital - The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment: -St. John's wort or hyperforin (potent CYP3A4 enzyme inducer) -Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor) - Pregnancy (positive serum pregnancy test) or lactation - Uncontrolled serious medical or psychiatric illness - Active infection requiring intravenous (IV) antibiotics on Cycle 1 Day 1 - Prior allogeneic stem cell or solid organ transplantation - History of autoimmune diseases or autoimmune-related hypothyroidism - History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis - Positive test for human immunodeficiency virus - Active hepatitis [hep] B or hep C (except for positive antibody test) - Active tuberculosis - Prior treatment with CD 137 agonists or immune checkpoint blockade therapies - Treatment with systemic immunostimulatory agents within 4W or five half-lives of the drug (whichever is shorter) prior to randomization - Treatment with systemic corticosteroids or immunosuppressive medications within 2W prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial - Patients who have a history of hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil) nab-PAC and any of the excipients, chimeric or humanized antibodies, fusion proteins, chinese hamster ovary cells or any component of the ATZ formulation Atezolizumab-Specific Exclusion Criteria (Cohorts II and III Only) History of clinically significant cardiac dysfunction (section 4.1.2) |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Cohort I: 1. The primary efficacy endpoint is PFS, defined as the time from randomization to the first occurrence of disease progression or relapse, as determined by investigator as per RECIST v1.1, or death on study from any cause, whichever occurs first Cohort II & Cohort III: 2. ORR, defined as the proportion of a partial response or complete response occurring after randomization and confirmed >= 28 days later as determined by the investigator using RECIST v1.1
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. The PFS analysis will be performed after approximately 60 investigator assessed PFS events (estimated to be approximately 21 months after the first patient is enrolled) 2. Every 8 weeks +/- 1 week (after every 2 treatment cycles) from the date of first study drug administration (Cycle 1 Day 1) until disease progression or the patient dies
|
|
E.5.2 | Secondary end point(s) |
Cohort I, Cohort II, and Cohort III: 1. Overall survival, defined as the time from randomization to death from any cause, regardless of whether the death occurs during the study or following treatment discontinuation. For patients who have not died, OS will be censored at the date of last contact. OS will be analyzed similarly to the primary endpoint. 2. Nature, frequency, and severity of adverse events as graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 3. Changes in vital signs and clinical laboratory results 4. ORR_uc, defined as the rate of a partial response or complete response occurring after randomization as determined by the investigator using RECIST v1.1, confirmation not required 5. DOR, defined as the time from the first occurrence of a documented objective response to the time of relapse, as determined by the investigator using RECIST v1.1 or death from any cause during the study, whichever occurs first 6. Maximum plasma concentrations (Cmax) 7. Minimum plasma concentration (Cmin) 8. Total exposure (AUC [area under curve] 0-τ [tau]) Cohort I: 9. ORR, defined as the rate of a partial response or complete response occurring after randomization and confirmed >= 28 days later as determined by the investigator using RECIST v1.1 Cohort II and Cohort III: 10. PFS, defined as the time from randomization to the first occurrence of disease progression or relapse as determined by the investigator using RECIST v1.1 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1&10. Every 12 wks until death, withdrawal of consent, or loss to follow-up 2. From randomization & study drug administration at every assessment & for 28 days (+/- 7 days) after LD of drug until resolution. 3. Screening visit, Day 1, 8 and 15 of every treatment cycle & at treatment discontinuation visit 4-5, 9. Every 8 wks (+/- 1 wk) (after every 2 treatment cycles) from date of first study drug administration (Cycle 1 Day 1) until disease progression or patient dies 6-8. Cycle 1 Day 8, Cycle 1 Day 15, and Cycle 2 Day 15 for Cohort I; & Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 2, 4, 8 & every 8 cycles thereafter, treatment discontinuation visit & 120 (+/-30) days after LD of ATZ for Cohort II & III. |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
study start with an open label safety run in stage prior to a random. placebo controlled expansion. |
|
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 | 32 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Czech Republic |
France |
Italy |
Korea, Republic of |
Spain |
Taiwan |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
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
|
|
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 | 0 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |