| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable locally advanced or metastatic melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025669 |
| E.1.2 | Term | Malignant melanoma stage II |
| 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 |
| To evaluate the efficacy of atezozolizumab + cobimetinib + vemurafenib compared to placebo + cobimetinib + vemurafenib |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the efficacy of atezolizumab + cobimetinib + vemurafenib compared to placebo + cobimetinib + vemurafenib using objective response rate, duration of response, overall survival, change in quality of life, health reported outcomes and global health status. To evaluate the safety of atezolizumab + cobimetinib + vemurafenib compared to placebo + cobimetinib + vemurafenib. To evaluate the pharmacokinetics of atezolizumab, cobimetinib and vemurafenib and cobimetinib and vemurafenib when administered together. |
|
| 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 Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma, as defined by the American Joint Committee on Cancer, 7th revised edition
- 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 initiation of study treatment, with the exception of amylase, lipase, and LDH where up to 28 days is acceptable (using central laboratory result)
– Amylase and lipase >= 1.5 x ULN
–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)
- AST and ALT ≤ 2.0×ULN
- ALP ≤ 2.5×ULN or, for patients with documented liver or bone metastases, ALP ≤ 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 patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5×ULN within 28 days prior to initiation of study treatment
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen and stable INR during the 28 days immediately preceding initiation of study treatment
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of <1% per year during the treatment period and for 6 months after the final dose of study treatment. Women must 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 |
|
| E.4 | Principal exclusion criteria |
• Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study
• Traumatic injury within 2 weeks prior to initiation of study treatment
• Palliative radiotherapy within 14 days prior to initiation of study treatment
• Active malignancy (other than BRAFV600 mutation−positive melanoma) or malignancy within 3 years prior to screening are excluded, with the exception of resected melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or any other curatively treated malignancies from which the patient has been disease-free for at least 3 years
• History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
• History of clinically significant cardiac dysfunction, including the following:
-Poorly controlled hypertension, defined as sustained, uncontrolled, nonepisodic baseline hypertension consistently above 159/99 mmHg despite optimal medical management
• Untreated or actively progressing CNS lesions (carcinomatous meningitis)
• History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm)
• History of leptomeningeal metastatic disease
• History of intracranial hemorrhage
• Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease) other than cancer
• Anticipated use of any concomitant medication during or within 7 days prior to initiation of study treatment that is known to cause QT prolongation (which may lead to torsades de pointes)
• Any psychological, familial, sociological, or geographical condition that may hamper compliance with the protocol and follow-up after treatment discontinuation
• History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment
• Pregnant or breastfeeding, or intending to become pregnant during the study
• Prior allogeneic stem cell or solid organ transplantation
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• History of autoimmune disease
• Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, and other inherited liver disease as well as active viral disease
• Active tuberculosis
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
• Signs or symptoms of infection within 2 weeks prior to initiation of study treatment
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
• Treatment with systemic immunosuppressive medication (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor (TNF)-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study
• Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells
• Known hypersensitivity to any component of the atezolizumab, cobimetinib, or vemurafenib formulations
• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Treatment with any other investigational agent or participation in another clinical study with therapeutic intent
• Inability or unwillingness to swallow pills
• Requirement for concomitant therapy or food that is prohibited during the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| When 300 PFS events have occurred |
|
| E.5.2 | Secondary end point(s) |
•PFS, defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first
•Objective response, defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1
•DOR, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first
•OS, defined as the time from randomization to death from any cause
•2-year landmark survival, defined as survival at 2 years
•Time to deterioration in global health status, defined as the time from randomization to first observed ≥ 10 point decrease in EORTC QLQ-C30 linearly transformed global health status scale score that is sustained for two consecutive assessments or followed by death while the patient is on treatment
Time to deterioration in physical functioning, defined as the time from randomization to first observed ≥10 point decrease in EORTC QLQ-C30 linearly transformed physical functioning scale score that is sustained for two consecutive assessments or followed by death while the patient is on treatment
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS – analysis will be performed when approximately 385 deaths have occurred |
|
| 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) | 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Canada |
| Israel |
| New Zealand |
| Switzerland |
| Russian Federation |
| Austria |
| Belgium |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Korea, Republic of |
| United Kingdom |
|
| 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 study will end when all patients enrolled have been followed until death, withdrawal of consent, lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first. see protocol section 3.2 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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