| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic BRAFV600 wild-type melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Melanoma is a type of skin cancer that develops from the pigment-containing cells known as melanocytes |
|
| 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 | 10040808 |
| E.1.2 | Term | Skin 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 |
| •To evaluate the efficacy of cobimetinib plus atezolizumab compared with pembrolizumab, as measured by the primary endpoint of progression-free survival (PFS) by independent review committee |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of cobimetinib plus atezolizumab compared with pembrolizumab, as measured by
•Investigator-assessed PFS
•Objective response rate
•Disease control rate
•Duration of response
•Overall survival (OS) and 2-year landmark OS
•Change from baseline in HRQoL
•To evaluate the safety of cobimetinib plus atezolizumab compared with pembrolizumab
•To characterize the cobimetinib and atezolizumab pharmacokinetics when administered in combination in this patient population
•To evaluate the immune response to atezolizumab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease-Specific Inclusion Criteria
- Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma
- Naive to prior systemic anti-cancer therapy for melanoma
- Documentation of BRAFV600 wild-type status in melanoma tumor tissue through use of a clinical mutation test approved by the local health authority
- A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or 20 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study entry. If 20 slides are not available or the tissue block is not of sufficient size, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor.
- Measureable disease according to RECIST v1.1
General Inclusion Criteria
- Age >=18 years at time of signing Informed Consent Form
- Ability to comply with the study protocol, in the investigator’s judgment
- Histologically or cytologically confirmed BRAFV600 wild-type melanoma
- ECOG Performance Status of 0 or 1
- Life expectancy >=3 months
- Adequate hematologic and end-organ function
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use at least two forms of effective contraceptive with a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of cobimetinib and at least 5 months after the last dose of atezolizumab or pembrolizumab after the last dose of cobimetinib and atezolizumab, respectively
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures (e.g. condom), and agreement to refrain from donating sperm, for at least 3 months after the last dose of cobimetinib
- Willingness and ability of patients to use an electronic device to report selected study outcomes
|
|
| E.4 | Principal exclusion criteria |
General Exclusion Criteria
- Inability to swallow medications
- Malabsorption condition that would alter the absorption of orally administered medications
- Pregnancy, breastfeeding, or intention of becoming pregnant during the study
- History of severe hypersensitivity reactions to components of the cobimetinib, atezolizumab, pembrolizumab, or ipilimumab formulations
- Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation of need for such a vaccine during the study
- Any anti-cancer therapy, including chemotherapy or hormonal therapy, within 2 weeks prior to initiation of study treatment
- Treatment with systemic immunostimulatory agents within 28 days or 5 half-lives of the drug, whichever is shorter, prior to Day 1 of Cycle 1
- Treatment with systemic immunosuppressive medications within 2 weeks prior to Day 1 of Cycle 1
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study
Cancer-Related Exclusion Criteria
- Ocular melanoma
- Major surgery or radiotherapy within 21 days prior to Day 1 of Cycle 1 or anticipation of needing such procedure while receiving study treatment
- Uncontrolled tumor-related pain
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days
- Active or untreated CNS metastases
Exclusions Related to Cardiovascular Disease
- Unstable angina, new-onset angina within last 3 months, myocardial infarction within the last 6 months prior to Day 1 of Cycle 1, or current congestive heart failure classified as New York Heart Association Class II or higher
- LVEF below institutional lower limit of normal or <50%, whichever is lower
- Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline hypertension consistently above 159/99 mmHg despite optimal medical management
- History or presence of an abnormal ECG that is clinically significant in the investigator’s opinion, including complete left bundle branch block, second- or third degree heart block, or evidence of prior myocardial infarction
Exclusions Related to Infections
- HIV infection
- Active tuberculosis infection
- Severe infections within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- Signs or symptoms of clinically relevant infection within 2 weeks prior to Day 1 of Cycle 1
- Treatment with oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1
- Active or chronic viral hepatitis B or C infection
Exclusions Related to Ocular Disease
- Known risk factors for ocular toxicity
Exclusions Related to Autoimmune Conditions and Immunomodulatory Drugs
- Active or history of autoimmune disease or immune deficiency
- Prior allogeneic stem cell or solid organ transplantation
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
- Treatment with systemic immunosuppressive medications within 2 weeks prior to Day 1, Cycle 1
Exclusions Related to Other Medical Conditions or Medications
- Active malignancy (other than melanoma) or a prior malignancy within the past 3 years
- Any Grade >=3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1
- History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to Day 1
- Proteinuria >3.5 g/24 hr
- Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during study treatment
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. PFS, as determined by the IRC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. PFS, as determined by the investigator
2. Objective response rate
3. Disease control rate
4. Duration of objective response
5. Overall survival
6. Two-year landmark overall survival
7. Change from baseline in HRQoL scores, as assessed through use of the two-item global health status (GHS)/ quality of life (QoL) subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30)
8. Occurrence and severity of adverse events, with severity determined through use of NCI CTCAE v4.0
9. Change from baseline in selected vital signs
10. Change from baseline in selected clinical laboratory test results
11. Plasma concentration of cobimetinib at specified timepoints
12. Serum concentration of atezolizumab at specified timepoints
13. Incidence of anti-drug antibodies (ADAs) during the study relative to the prevalence of ADAs at baseline
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Approximately 17 months
2-5. Up to 7 years
6. at 2 years
7-10. Up to 7 years
11. Day 1 and 15 of Cycle 1
12-13. Day 1 of Cycle 1, 2, 3, etc; at treatment discontinuation visit
|
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 16 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Norway |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| Switzerland |
| 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 study will end when all patients enrolled have been followed until death, withdrawal of consent, loss to follow-up, or the Sponsor decides to end the trial, whichever occurs first. Patients may continue on study treatment until the development of progressive disease, unacceptable toxicity, and/or withdrawal of consent, see protocol section 2.4 |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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