High Risk Neuroblastoma;Therapeutic area: Diseases [C] - Cancer [C04]

Trade Name: Dinutuximab beta EUSA
Product Name: Dinutuximab beta EUSA
Pharmaceutical Form: Concentrate and solvent for solution for infusion
INN or Proposed INN: dinutuximab beta
Other descriptive name: ch14.18/CHO
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 4.5-

Trade Name: Proleukin 18x10^6 IU
Pharmaceutical Form: Powder for injection
INN or Proposed INN: Aldesleukin
CAS Number: 110942-02-4
Current Sponsor code: Proleukin
Other descriptive name: ALDESLEUKIN
Concentration unit: million IU million international units
Concentration type: equal
Concentration number: 3-

Criteria for participation in trial

Inclusion criteria:
- Established diagnosis of neuroblastoma according to the International Neuroblastoma Staging System (INSS)
- Age below 21 years.
- High-risk neuroblastoma, defined as either:
a) INSS stages 2, 3, 4 and 4s with MYCN amplification, or
b) INSS stage 4 without MYCN amplification aged = 12 months
- Patients who have received no previous chemotherapy except for 1 cycle of etoposide and carboplatin (Vp/Carbo). In this situation patients will receive Rapid COJEC induction and the first COJEC cycle may be replaced by the first cycle of Vp/Carbo.
- Written informed consent, including agreement of parents or legal guardian for minors, to enter a randomised study if the criteria for randomisation are met.
- Tumour cell material available for determination of biological prognostic factors.
- Registration of all eligibility criteria with the data centre within 6 weeks from diagnosis.
- Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
- Provisional follow up of 5 years.
- National and local ethical committee approval.

Are the trial subjects under 18? yes
Number of subjects for this age range: 3300
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 12
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria

Exclusion criteria:
Any negative answer concerning the inclusion criteria of the study and R4 will render the patient ineligible for the corresponding therapy phase.

MILD ALZHEIMER’S DISEASE
MedDRA version: 20.0Level: HLTClassification code 10001897Term: Alzheimer's disease (incl subtypes)System Organ Class: 100000004852;Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Product Name: Gantenerumab
Product Code: Ro 490-9832/F12
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: GANTENERUMAB
CAS Number: n/a
Current Sponsor code: RO4909832
Other descriptive name: human anti-Aß antibody
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 105-
Pharmaceutical form of the placebo: Solution for injection in pre-filled syringe
Route of administration of the placebo: Subcutaneous use

Product Name: Gantenerumab
Product Code: Ro 490-9832/F14
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: GANTENERUMAB
CAS Number: n/a
Current Sponsor code: RO4909832
Other descriptive name: human anti-Aß antibody
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 225-
Pharmaceutical form of the placebo: Solution for injection in pre-filled syringe
Route of administration of the placebo: Subcutaneous use

Product Name: Gantenerumab
Product Code: Ro 490-9832/F10
Pharmaceutical Form: Solution for injection
INN or Proposed INN: GANTENERUMAB
CAS Number: n/a
Current Sponsor code: RO4909832
Other descriptive name: human anti-Aß antibody
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-

Criteria for participation in trial

Inclusion criteria:
Part 1
- Adult patients, 50 to 90 years of age, inclusive
- Clinical diagnosis of probable mild Alzheimer disease based on NINCDS/ADRDA criteria or major NCD due to AD of mild severity, whether or not receiving AD approved medication
- Availability of a person ('caregiver') who in the investigator's judgment has frequent and sufficient contact with the patient, and is able to provide accurate information regarding the patient's cognitive and functional abilities
- Fluency in the language of the tests used at the study site
- Willingness and ability to complete all aspects of the study
- Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
- If currently receiving approved medications for AD, doses must have been stable for 3 months prior to screening
- Agreement not to participate in other research studies for the duration of this trial and its associated substudies

Part 2
- All patients who have been randomized and are actively participating in the study at the time of the amendment approval in their respective country will be eligible to participate in the OLE. Patients in the open label extension will be given the option of extending open-label treatment beyond the initial 2 years
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 900

Exclusion criteria

Exclusion criteria:
Part 1
- Dementia or NCD due to a condition other than AD, including, but not limited to, frontotemporal dementia, Parkinson disease, dementia with Lewy bodies, Huntington disease, or vascular dementia
- History or presence of clinically evident vascular disease potentially affecting the brain that in the opinion of the investigator has the potential to affect cognitive function
- History or presence of stroke within the past 2 years or documented history of transient ischemic attack within the last 12 months
- History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease with associated cognitive deficits
- History of schizophrenia, schizoaffective disorder, or bipolar disorder
- Alcohol and/or substance use disorder (according to the DSM-5) within the past 2 years (nicotine use is allowed)
- History or presence of atrial fibrillation
- Within the last 2 years, unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, cardiac failure New York Heart Association Class II or higher)
- Uncontrolled hypertension
- Chronic kidney disease
- Impaired hepatic function

Left ventricular dysfunction following an acute myocardial infarction.
MedDRA version: 20.0Level: PTClassification code 10000891Term: Acute myocardial infarctionSystem Organ Class: 10007541 - Cardiac disorders;Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Trade Name: Entresto
Product Name: LCZ696 50 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
Other descriptive name: SACUBITRIL VALSARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Entresto
Product Name: LCZ696 100 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
Other descriptive name: SACUBITRIL VALSARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Entresto
Product Name: LCZ696 200 mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: sacubitril/valsartan
Other descriptive name: SACUBITRIL VALSARTAN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Diovan
Product Name: Diovan 40 mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VALSARTAN
CAS Number: 137862-53-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Diovan
Product Name: Diovan 80 mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VALSARTAN
CAS Number: 137862-53-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Tritace
Product Name: Ramipril 1.25 mg
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Ramipril
CAS Number: 87333-19-5
Other descriptive

Criteria for participation in trial

Inclusion criteria:
1. Male or female patients = 18 years of age.
2. Diagnosis of spontaneous AMI based on the universal MI definition with randomization to occur between 12 hours and 7 days after index event presentation.
3. Evidence of LV systolic dysfunction and/or pulmonary congestion requiring intravenous treatment associated with the index MI event defined as:
• LVEF =40% after index MI presentation and prior to randomization and/or
• Pulmonary congestion requiring intravenous treatment during the index hospitalization
4. At least one of the following 8 risk factors:
• Age = 70 years
• eGFR <60 mL/min/1.73 m2 based on MDRD formula at screening visit
• Type I or II diabetes mellitus
• Documented history of prior MI
• Atrial fibrillation as noted by ECG, associated with index MI
• LVEF <30% associated with index MI
• Worst Killip class III or IV associated with index MI requiring intravenous treatment
• STEMI without reperfusion therapy within the first 24 hours after presentation
5. Hemodynamically stable defined as:
• SBP = 100 mmHg at randomization for patients who received ACEi/ARB during the last 24 hours prior to randomization
• SBP = 110 mmHg at randomization for patients who did not receive ACEi/ARB during the last 24 hours prior to randomization
• No IV treatment with diuretics, vasodilators, vasopressors and/or inotropes during the 24 hours prior to randomization
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 2208
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2442

Exclusion criteria

Exclusion criteria:
1. Known history of chronic HF prior to randomization
2. Cardiogenic shock within the last 24 hours prior to randomization
3. Persistent clinical HF at the time of randomization
4. Coronary artery bypass graft (CABG) performed or planned for index MI
5. Clinically significant right ventricular MI as index MI
6. Symptomatic hypotension at screening or randomization
7. Patients with a known history of angioedema
8. Stroke or transient ischemic attack within one month prior to randomization
9. Known or suspected bilateral renal artery stenosis
10. Clinically significant obstructive cardiomyopathy
11. Open-heart surgery performed within one month prior to rand or planned cardiac surgery w/in the 3 months prior to rand
12. eGFR < 30 ml/min/1.73 m2 as measured by MDRD at screening
13. Serum potassium > 5.2 mmol /L at (or equivalent plasma potassium value) randomization
14. Known hepatic impairment (as evidenced by total bilirubin > 3.0 mg/dL or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as esophageal varices
15. Previous use of LCZ696 or Entresto
16. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin) within the past 3 years with a life expectancy of less than 1year.
17. History of hypersensitivity to the study drugs or drugs of similar chemical classes or known intolerance or contraindications to study drugs or drugs of similar chemical classes including ACE inhibitors, ARB or NEP inhibitors
18. Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception

Moderately to Severely Active Crohn’s Disease (CD)
MedDRA version: 20.0Level: LLTClassification code 10013099Term: Disease CrohnsSystem Organ Class: 100000004856;Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Product Name: Filgotinib
Product Code: GS-6034
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: FILGOTINIB
Other descriptive name: Filgotinib
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Filgotinib
Product Code: GS-6034
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: FILGOTINIB
Other descriptive name: Filgotinib
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Criteria for participation in trial

Inclusion criteria:
Subjects must meet all of the following inclusion criteria to be eligible for participation in either the Cohort A or B Induction Study.
• Must have the ability to understand and sign a written ICF, which must be obtained prior to initiation of study procedures
• Males or non-pregnant, non-lactating females, ages 18 to 75 years, inclusive based on the date of the screening visit
• Females of childbearing potential must have a negative pregnancy test at screening and baseline
• Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
• Documented diagnosis of CD with a minimum disease duration of 6 months with involvement of the ileum and/or colon at a minimum
• Moderately or severely active CD
• Meet one of the protocol specified tuberculosis (TB) screening criteria
• May be receiving the following drugs (subjects on these therapies must be willing to remain on stable doses for the times noted in the protocol)
- Oral 5-aminosalicylate (5-ASA) compounds
- Azathioprine or 6-mercaptopurine (6-MP) or methotrexate (MTX)
- Oral corticosteroid therapy
- Antibiotics for the treatment of CD
• Willingness to refrain from live or attenuated vaccines during the study and for 12 weeks after last dose
• Must be up to date on colorectal cancer screening and surveillance as standard of care according to local guidelines

Subjects must meet all of the additional inclusion criteria to be eligible for participation in Cohort A Induction Study.
• Previously demonstrated an inadequate clinical response, loss of response to, or intolerance to at least one of the following agents (depending on current country treatment recommendations/guidelines):
- Corticosteroids
- Immunomodulators

Subjects must meet all of the additional inclusion criteria to be eligible for participation in Cohort B induction study.
• Previously demonstrated an inadequate clinical response, loss of response to, or intolerance to at least one of the following agents (depending on current country treatment recommendations/guidelines):
- TNFa Antagonists
- Vedolizumab
- Ustekinumab
• Must not have used any TNFa antagonist or vedolizumab = 8 weeks prior to screening, ustekinumab IV or SC = 12 weeks prior to screening, or any other biologic agent = 8 weeks prior to screening or within 5 times the half-life of the biologic agent prior to screening, whichever is longer

Subjects must meet all of the following inclusion criteria to be eligible for participation in the Maintenance Study.
• Completion of Cohort A or B induction study with either clinical remission by PRO2 or endoscopic response at Week 10
• Willingness to refrain from live or attenuated vaccines during the study and for 12 weeks after last dose
• May be on oral corticosteroid therapy (prednisone prescribed at a stable dose = 30 mg/day or budesonide at a dose of = 9 mg/day); dose must remain stable to Week 14
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1214
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 106

Exclusion criteria

Exclusion criteria:
Subjects who meet any of the following exclusion criteria are not to be enrolled in either the Cohort A or B induction study
• Pregnant or lactating females
• Males and females of reproductive potential who are unwilling to abide by protocol-specified contraceptive methods
• Females who may wish to become pregnant and/or plan to undergo egg donation or egg harvesting for the purpose of current or future fertilization during the course of the study and up to 35 days after the last dose of the study drug
• Male subjects unwilling to refrain from sperm donation during the study and for at least 90 days after the last dose of study drug
• Known hypersensitivity to filgotinib, its metabolites, or formulation excipients
• Currently have complications of CD
• Have any current or prior abscesses, unless they have been drained and treated at least 6 weeks prior to Day 1 and are not anticipated to require surgery
• History of major surgery or trauma within 30 days prior to screening
• Presence of ulcerative colitis (UC), indeterminate colitis, ischemic colitis, fulminant colitis, or toxic mega-colon
• History of total colectomy, subtotal-colectomy, presence of ileostomy or colostomy, or likely requirement for surgery during the study
• Dependence on parenteral nutrition
• History or evidence of incompletely resected colonic mucosal dysplasia
• Stool sample positive for Clostridium difficile (C. diff) toxin, pathogenic Escherichia coli (E. coli), Salmonella species (spp), Shigella spp, Campylobacter spp, or Yersinia spp
• Stool sample positive for ova and parasites test (O&P) unless approved by the medical monitor
• Active clinically significant infection or any infection requiring hospitalization or treatment with intravenous anti-infectives within 30 days of screening (or 8 weeks of Day 1); or any infection requiring oral anti-infective therapy within 2 weeks of screening (or 6 weeks of Day 1)
• Infection with HIV, hepatitis B, or hepatitis C
• Presence of Child-Pugh Class C hepatic impairment
• Active TB or history of latent TB that has not been treated
• History of malignancy within the last 5 years except for subjects who have been treated or resected for non-melanoma skin cancer or cervical carcinoma in situ
• History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma
• History of treatment with lymphocyte-depleting therapies, including but not limited to alemtuzumab, cyclophosphamide, total lymphoid radiation, and rituximab
• History of cytapheresis = 2 months prior to screening
• Use of any prohibited concomitant medications as described in the protocol
• Any chronic medical condition (including, but not limited to, cardiac or pulmonary disease) or psychiatric problem (including, but not limited to alcohol or drug abuse) that, in the opinion of the Investigator or Sponsor, would make the subject unsuitable for the study or would prevent compliance with the study protocol
• Administration of a live or attenuated vaccine within 30 days of randomization
• History of opportunistic infection or immunodeficiency syndrome
• Currently on any chronic systemic (oral or intravenous) anti-infective therapy for chronic infection (such as pneumocystis (PCP), cytomegalovirus (CMV), herpes zoster, atypical mycobacteria)
• History of disseminated Staphylococcus aureus
• History of symptomatic herpes zoster or herpes simplex within 12 weeks of screening, or any history of diss

Advanced or metastatic Non-small cell lung cancer (NSCLC)
MedDRA version: 20.0Level: PTClassification code 10029521Term: Non-small cell lung cancer stage IIIBSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10059515Term: Non-small cell lung cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04]

Product Name: Alectinib
Product Code: RO5424802/F03
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ALECTINIB
Current Sponsor code: Ro542-4802/F03, Ro542-4802/F16
Other descriptive name: ALK INHIBITOR
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Product Name: Atezolizumab (MPDL3280A)
Product Code: RO5541267
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ATEZOLIZUMAB
Current Sponsor code: RO5541267
Other descriptive name: MPDL3280A
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 60-

Trade Name: ALIMTA 500 mg powder for concentrate for solution for infusion
Product Name: Pemetrexed
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: PEMETREXED
CAS Number: 137281-23-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Trade Name: Gemcitabine Actavis 38 mg/ml powder for solution for infusion
Product Name: Gemcitabine
Pharmaceutical Form: Lyophilisate for solution for infusion
INN or Proposed INN: GEMCITABINE
CAS Number: 95058-81-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-

Trade Name: Cisplatin NeoCorp 1 mg/ml
Product Name: Cisplatin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Cisplatin
Other descriptive name: CISPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Trade Name: Carboplatin-Teva 10 mg/ml Concentrate for Solution for Infusion
Product Name: Carboplatin
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Carboplatin
Other descriptive name: CARBOPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Trade Name: Gitrabin 38 mg/mL powder for solution for infusion
Product Name: Gemcitabine
Pharmaceutical Form: Lyophilisate for sol

Criteria for participation in trial

Inclusion criteria:
- Histologically or cytologically confirmed diagnosis of unresectable Stage IIIb not amenable to treatment with combined modality chemoradiation (advanced) or Stage IV (metastatic) NSCLC
- Age >=18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
- Measurable disease (as defined by RECIST, v1.1)
- Adequate recovery from most recent systemic or local treatment for cancer
- Adequate organ function
- Life expectancy >=12 weeks
- For female patients of childbearing potential and male patients, willingness to use acceptable methods of contraception
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 284
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 284

Exclusion criteria

Exclusion criteria:
- Inability to swallow oral medication
- Women who are pregnant or lactating
- Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments
- History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, limited stage bladder cancer, Stage I uterine cancer, or other cancers from which the patient has been disease-free for at least 2 years
-Significant cardiovascular disease
-Known HIV positivity or AIDS-related illness
-Either a concurrent condition or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or confounds the ability to interpret data from the study
-Inability to comply with other requirements of the protocol

Relapsing-Remitting Multiple Sclerosis
MedDRA version: 20.0Level: PTClassification code 10063399Term: Relapsing-remitting multiple sclerosisSystem Organ Class: 10029205 - Nervous system disorders;Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Product Name: BG00012
Product Code: BG00012
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Dimethyl Fumarate
CAS Number: 624497
Current Sponsor code: BG00012
Other descriptive name: DIMETHYL FUMARATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 120-

Criteria for participation in trial

Inclusion criteria:
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.

2. Subjects who participated in and completed as per protocol previous BG00012 clinical studies 109MS301 or 109MS302, including those subjects who received an open-label, approved MS therapy and completed the modified visit schedule.

3. All male subjects and female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 30 days after their last dose of BG00012.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1738
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria

Exclusion criteria:
1. Any significant change in medical history in subjects from 109MS301 or 109MS302, including laboratory tests, or current clinically significant condition that in the opinion of the Investigator would have excluded the subjects' participation from their previous study. The Investigator must re-review the subject's medical fitness for participation and consider any diseases that would preclude treatment.

2. Subjects from 109MS301 or 109MS302 who discontinued BG00012 due to an AE or due to reasons other than protocol-defined relapse/disability progression.

3. Subjects from 109MS301 or 109MS302 who discontinued BG00012 due to disability progression or relapses and did not follow the modified visit schedule up to Week 96.

4. History of malignancy.

5. History of severe allergic or anaphylactic reactions.

6. Alanine transaminase (ALT), aspartate transaminase (AST), or gamma-glutamyltransferase (GGT) >3 times the upper limit of normal (ULN).

7. Female subjects considering becoming pregnant while in the study, currently pregnant, or breast feeding.

8. Previous participation in this study (109MS303).

9. Unwillingness or inability to comply with the requirements of the protocol including the presence of any condition (physical, mental, or social) that is likely to affect the subject's ability to comply with the protocol.

10. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the subject unsuitable for enrollment.

non-small cell lung cancer (NSCLC)
MedDRA version: 20.0Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04]

Trade Name: Zykadia
Product Code: LDK378
Pharmaceutical Form: Capsule, hard
Other descriptive name: LDK378
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Trade Name: ALIMTA 500 mg poeder voor concentraat voor oplossing voor intraveneuze infusie
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: PEMETREXED
CAS Number: 137281-23-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-

Trade Name: Docetaxel Sandoz 10 mg/ml concentraat voor oplossing voor infusie
Product Name: Docetaxel
Pharmaceutical Form: Concentrate for solution for infusion
Other descriptive name: DOCETAXEL
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Criteria for participation in trial

Inclusion criteria:
English 1. Patient has a histologically or cytologically confirmed diagnosis of
non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase
(ALK) positive as assessed by FDA approved Vysis ALK Break Apart FISH
Probe Kit (Abbott Molecular Inc) test and scoring algorithm (including
positivity criteria). If documentation of ALK rearrangement is not
available, the test to confirm ALK rearrangement must be performed
according to the above
criterion, using a new tumor biopsy obtained prior to the first dose of
study treatment (LDK378 or chemotherapy) or archival tumor obtained
at or since the time of diagnosis prior to study entry. The test will be
performed at a Novartis designated central laboratory.
2. Patient has stage IIIB or IV diagnosis and must have received
previous treatment with crizotinib and one regimen of platinum doublet,
cytotoxic chemotherapy for the treatment of locally advanced or
metastatic NSCLC.
3. Patient has at least one measurable lesion as defined by RECIST 1.1. A
previously irradiated site lesion may only be counted as a target lesion if
there is clear sign of progression since the irradiation
Other protocol-defined inclusion criteria may apply
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 126
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 110

Exclusion criteria

Exclusion criteria:
1. Patient with known hypersensitivity to any of the excipients of LDK378 (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
2. Patient with a history of severe hypersensitivity reaction to pemetrexed or docetaxel or any knownexcipients of these drugs.
3. Patient with symptomatic central nervous system (CNS) metastases who is neurologically unstable or has required increasing doses of steroids within the 2 weeks prior to screening
to manage CNS symptoms.

Other protocol-defined exclusion criteria may apply

Heart failure with preserved ejection fraction
MedDRA version: 20.1Level: LLTClassification code 10069211Term: Diastolic heart failureSystem Organ Class: 100000004849
MedDRA version: 20.0Level: LLTClassification code 10019279Term: Heart failureSystem Organ Class: 100000004849;Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Product Name: LCZ696 50mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: not available
Other descriptive name: LCZ696
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: LCZ696 100mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: not available
Other descriptive name: LCZ696
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: LCZ696 200mg
Product Code: LCZ696
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: not available
Other descriptive name: LCZ696
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Diovan
Product Name: Diovan 40mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VALSARTAN
CAS Number: 137862-53-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Diovan
Product Name: Diovan 80mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VALSARTAN
CAS Number: 137862-53-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Diovan
Product Name: Diovan 160mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: VALSARTAN
CAS Number: 137862-53-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 160-
Pharmaceutical form of the placebo: Film-coated tablet
Route

Criteria for participation in trial

Inclusion criteria:
- Left ventricular ejection fraction (LVEF) =45% prior to study entry.
- Symptom(s) of heart failure (HF) and requiring treatment with diuretic(s) for HF =30 days prior to study entry.
- Current symptom(s) of HF.
- Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by
echocardiogram.
- At least one of the following: a HF hospitalization within 9 months prior to study entry and/or an elevated NT-proBNP.
- Other protocol-defined inclusion criteria may apply.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 990
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 3310

Exclusion criteria

Exclusion criteria:
- Any prior echocardiographic measurement of LVEF < 40%.
- Acute coronary syndrome (including myocardial infarction (MI)), cardiac surgery, other major cardiovascular surgery
within 3 months, or urgent percutaneous coronary intervention (PCI) within 30 days of entry.
- Any clinical event within 6 months that could have reduced the LVEF (e.g., MI, coronary artery bypass graft [CABG]), unless an echo measurement was performed after the event confirming the LVEF to be = 45%.
- Current acute decompensated HF requiring therapy.
- Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB) or a renin inhibitor.
- Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dl, or body mass index (BMI) > 40 kg/m2.
- Systolic blood pressure (SBP) = 180 mmHg at entry, or SBP >150 mmHg and <180 mmHg at entry unless the patient is receiving 3 or more antihypertensive drugs.
- Other protocol-defined exclusion criteria may apply.

NON-SMALL CELL LUNG CANCER AFTER PLATINUM FAILURE
MedDRA version: 20.0Level: LLTClassification code 10029514Term: Non-small cell lung cancer NOSSystem Organ Class: 100000004864;Therapeutic area: Diseases [C] - Cancer [C04]

Product Code: MPDL3280A-RO5541267
Pharmaceutical Form: Solution for infusion
Current Sponsor code: MPDL3280A
Other descriptive name: RO5541267
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 60-

Trade Name: Docetaxel
Pharmaceutical Form: Concentrate and solvent for concentrate for solution for infusion
Current Sponsor code: RO-0647746
Other descriptive name: DOCETAXEL
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Criteria for participation in trial

Inclusion criteria:
•Histologically or cytologically documented locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC
•Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to be evaluable for tumor PD-L1 expression prior to study enrollment
•Disease progression during or following treatment with a prior platinum-containing regimen for locally advanced, unresectable/inoperable or metastatic NSCLC or disease recurrence within 6 months of treatment with a platinum-based adjuvant/neoadjuvant regimen
•Measurable disease, as defined by RECIST v1.1
•ECOG performance status of 0 or 1
•Life expectancy > 12 weeks
• For female patients of childbearing potential, agreement (by patient) to remain abstinent (refrain from heterosexual intercourse) or to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) during the treatment period and to continue its use for 5 months after the last dose of atezolizumab
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 900
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 200

Exclusion criteria

Exclusion criteria:
•Received therapeutic oral or IV antibiotics within 2 weeks prior to randomization
•Major surgical procedure within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis
•Administration of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation that such a live attenuated vaccine will be required during the study
•Positive test for HIV
•Untreated or symptomatic central nervous system metastases
•History of autoimmune disease

Patients with ALK-positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)
MedDRA version: 20.0Level: PTClassification code 10059515Term: Non-small cell lung cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04]

Product Name: Brigatinib
Product Code: AP26113
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Brigatinib
CAS Number: 1197953-54-0
Current Sponsor code: AP26113
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-

Product Name: Brigatinib
Product Code: AP26113
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Brigatinib
CAS Number: 1197953-54-0
Current Sponsor code: AP26113
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 90-

Product Name: Brigatinib
Product Code: AP26113
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Brigatinib
CAS Number: 1197953-54-0
Current Sponsor code: AP26113
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 180-

Criteria for participation in trial

Inclusion criteria:
All patients must meet all the following eligibility criteria for study entry:
1. Have histologically or cytologically confirmed locally advanced or
metastatic NSCLC that is ALK+.
2. Must meet one of the following two criteria:
a. Have documented ALK rearrangement by a positive result from the
Vysis® ALK Break-Apart fluorescence in situ hybridization (FISH)
Probe Kit; or
b. Have documented ALK positivity by a different test and tissue available for the Vysis® FISH test. Tissue should be derived preferably from abiopsy taken after progression with crizotinib. If such a sample is not available, testing may be performed with archived tumor tissue.
3. Had progressive disease while on crizotinib, as assessed by the investigator or treating physician.
4. No longer a required criterion as of Amendment 2
8. Are a male or female patient =18 years old.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 109
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 109

Exclusion criteria

Exclusion criteria:
Patients meeting any of the criteria below are ineligible for the study:
1. Received any prior ALK-targeted TKI other than crizotinib.
2. Received crizotinib within 3 days of the first dose of AP26113 (Day 1, Cycle1).
3. Received cytotoxic chemotherapy, investigational agents, or radiation within 14 days, except SRS or stereotactic body radiosurgery.
4. Received monoclonal antibodies or had major surgery within 30 days of the first dose of AP26113 (Day 1, Cycle 1).