Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer.
Study Details
Study Description
Brief Summary
This was a Phase II, multicenter, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib administered as a single agent and in combination with trametinib in stage IV disease to subjects with BRAF mutant advanced non-small cell lung cancer. Central confirmation testing for the BRAF V600E mutation was performed and a sufficient number of subjects were enrolled with the intent of having at least 125 centrally confirmed subjects among the three cohorts.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
Subjects enrolled in Cohort A (Monotherapy Population) were required to have relapsed or progressed on at least one platinum based chemotherapy regimen prior to enrollment (i.e. dabrafenib was no less than second line treatment for metastatic disease). Additional lines of prior anti-cancer therapy were allowed. Subjects received dabrafenib as a single agent at the recommended dose of 150 mg twice daily. A 2 stage design with a planned sample size of 40 subjects was initially used for Cohort A.
Subjects enrolled in Cohort B (Combination Second-Line Population) were required to have relapsed or progressed on at least one platinum based chemotherapy prior to enrollment but did not receive more than 3 prior systemic anti-cancer therapies (i.e. dabrafenib/trametinib were second, third, or fourth line treatment for metastatic disease). Subjects received the recommended dose of both drugs (dabrafenib 150 mg twice daily and trametinib 2 mg once daily).
Subjects enrolled in Cohort C (Combination First-Line Population) did not receive prior systemic anti-cancer therapies for metastatic disease (i.e. dabrafenib/trametinib was first line treatment for metastatic disease). Subjects received the recommended dose of both drugs (dabrafenib 150 mg twice daily and trametinib 2 mg once daily).
Crossover: Subjects receiving and adequately tolerating dabrafenib as a single agent and who continued to meet the inclusion and exclusion criteria (including the additional criteria for combination therapy) had the option to crossover to dabrafenib (150 mg BID) and trametinib (2 mg once daily) combination treatment at the time of radiologic disease progression with prior approval from a Medical Lead. If a subject was receiving less than 150 mg BID of dabrafenib at the time of the crossover, the subject was to continue at the lower dose of dabrafenib when initiating combination therapy.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort A (Dabrafenib Monotherapy) Participants received Dabrafenib 150mg BID and continued treatment until disease progression, death, or unacceptable adverse event. Participants receiving and adequately tolerating dabrafenib as a single agent and who continue to meet the inclusion and exclusion criteria had the option to switch to Dabrafenib (150 mg BID) and Trametinib (2 mg once daily) combination treatment within 4 weeks of radiologic disease progression with prior approval from a medical monitor. |
Drug: Dabrafenib
Dabrafenib study treatment was provided as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Each capsule contains 50 mg or 75 mg of free base (present as the mesylate salt)
Other Names:
|
| Experimental: Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. |
Drug: Dabrafenib
Dabrafenib study treatment was provided as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Each capsule contains 50 mg or 75 mg of free base (present as the mesylate salt)
Other Names:
Drug: Trametinib
Trametinib study treatment was provided as 0.5 mg and 2 mg tablets. Each tablet contained 0.5 mg or 2 mg of trametinib parent (present as the dimethyl sulfoxide solvate)
Other Names:
|
| Experimental: Cohort C - Double Combination (Dabrafenib+Trametinib) naive mBRAF V600E Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. |
Drug: Dabrafenib
Dabrafenib study treatment was provided as 50 mg and 75 mg hydroxypropyl methylcellulose (HPMC) capsules. Each capsule contains 50 mg or 75 mg of free base (present as the mesylate salt)
Other Names:
Drug: Trametinib
Trametinib study treatment was provided as 0.5 mg and 2 mg tablets. Each tablet contained 0.5 mg or 2 mg of trametinib parent (present as the dimethyl sulfoxide solvate)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Overall Response Rate (ORR) [From study treatment start date until first documented complete response or partial response, assessed up to approximately 50 months]
ORR was defined as the percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR) by investigator assessment as per RECIST v1 .1 criteria. Specifically, ORR = (number of subjects with a confirmed best overall response of CR or PR) divided by the total number of subjects in the corresponding analysis population.
Secondary Outcome Measures
- Progression Free Survival (PFS) Based on Local Investigator Assessment [From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 113 months]
Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
- Duration of Response (DoR) Based on Local Investigator Assessment [From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to approximately 113 months]
Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.
- Overall Survival (OS) [From study treatment start date until date of of death from any cause, assessed up to approximately 113 months]
Overall Survival (OS) was defined as the time from first dose until death due to any cause. If a patient was not known to have died at the time of analysis cut-off, OS was censored at the date of last contact.
- Number of Participants With Treatment Emergent Adverse Events [From study treatment start date till 30 days safety follow-up, assessed up to approximately 81 months]
The distribution of adverse events (AE) was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
- Apparent Clearance (CL/F) of Dabrafenib [Week 3, Week 6, Week 12 and Week 18]
Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of dabrafenib was determined in plasma samples using the currently approved analytical methodology.
- Oral Volume of Distribution (V/F) of Dabrafenib [Week 3, Week 6, Week 12 and Week 18]
Blood samples from participants were collected for population pharmacokinetic analysis including the oral volume of distribution (V/F) following oral dosing of dabrafenib. Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of dabrafenib was determined in plasma samples using the currently approved analytical methodology.
- Apparent Clearance (CL/F) of Trametinib [Week 3, Week 6, Week 12 and Week 18]
Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of trametinib. Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of trametinib was determined in plasma samples using the currently approved analytical methodology.
- Oral Volume of Distribution (V/F) of Trametinib [Week 3, Week 6, Week 12 and Week 18]
Blood samples from participants were collected for population pharmacokinetic analysis including the oral volume of distribution (V/F) following oral dosing of trametinib. Concentrations of trametinib was determined in plasma samples using the currently approved analytical methodology.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Signed written informed consent;
-
Histologically or cytologically confirmed non-small cell cancer of the lung (NSCLC) stage IV (accordingto AJCC Staging 7th Edition);
-
For Cohorts A and B, documented tumor progression (based on radiological imaging) after receiving at least one prior approved platinum-based chemotherapy regimen for advanced stage/metastatic NSCLC. An alternate chemotherapeutic agent/regimen is an acceptable substitute in the event that the subject was intolerant to, or ineligible to receive platinum based chemotherapy. Subjects enrolled in Cohort B cannot have more than 3 prior systemic treatments for advanced stage/metastatic NSCLC (neoadjuvant and adjuvant therapies are not counted in number of prior regimens and maintenance therapy is not counted as a separate regimen). Subjects in Cohort C will be required to have not received prior systemic anti-cancer therapies for metastatic disease (i.e., dabrafenib/trametinib will be 1st line treatment for metastatic disease);
-
Measurable disease according to Response Evaluation Criteria in Solid Tumors [RECIST 1.1];
-
At least 18 years of age;
-
Anticipated life expectancy of at least three months;
-
Presence of a BRAF V600E mutation in lung cancer tissue. Mutation must be locally confirmed in a CLIA-certified laboratory (or equivalent). An adequate amount of tumor tissue (archived tumor tissue, or fresh biopsy if archived tissue is not available) must be available at the time of enrolment for central validation of BRAF mutation;
-
Able to swallow and retain oral medication;
-
Women of childbearing potential must have a negative serum pregnancy test within 14 days before the first dose of study treatment and agree to use effective contraception during the study; NOTE: Oral contraceptives are not reliable due to potential drug-drug interaction with dabrafenib.
-
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2;
-
Must have adequate organ function as defined by the following baseline values:
Absolute neutrophil count (ANC) >/=1.5x109/L Hemoglobin >/=9 g/dL Platelets >/=100x109/L Prothrombin time /International normalized ratio (INR) and partial thromboplastin time </=1.5xULN (Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to starting study treatment.) Total bilirubin </=1.5 x upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 2.5xULN Serum creatinine </=1.5 mg/dL (if serum creatinine is
1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault; creatinine clearance must be > 50 mL/min); creatinine clearance should be >/= 50 mL/min Left ventricular ejection fraction >/= institutional lower limit of normal ECHO
-
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category
-
Previously tested for presence of EGFR and ALK mutations in lung cancer tissue confirmed in a CLIA-certified laboratory (or equivalent). Subjects with EGFR or ALK mutation are eligible if they have previously received EGFR or ALK inhibitor(s) respectively.
Exclusion Criteria:
-
Previous treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, LGX818, and XL281/BMS-908662) or MEK inhibitor (including but not limited to trametinib, AZD6244, and RDEA119) prior to start of study treatment (Note: Prior treatment with dabrafenib is allowed for crossover subjects in Cohort A);
-
Anti-Cancer therapy including chemotherapy, radiation-therapy, immunotherapy, biologic therapy or major surgery within 14 days prior to start of study treatment (Note: Dabrafenib monotherapy within 14 days prior to starting combination therapy is allowed for crossover subjects in Cohort A);
-
Use of any investigational anti-cancer drug within 14 days or 5-half-lives (minimum 14 days), prior to start of study medication (Note: Dabrafenib monotherapy within 14 days prior to starting combination therapy is allowed for crossover subjects in Cohort A);
-
Current use of a prohibited medication or expected to require any of these medications during treatment with study treatment.
-
Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) Grade 2 or higher from previous anti-cancer therapy, except alopecia;
-
Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs. If clarification is needed as to whether a condition will significantly affect absorption of drugs, contact the GSK medical monitor for guidance to enrol the subject;
-
Known Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled;
-
History of another malignancy < 3 years prior to starting study treatment or any malignancy with confirmed activating RAS-mutation; Exceptions: Subjects with any of the following malignancies within 3 years (does not include malignancies with confirmed activating RAS-mutation) are eligible: (a) a history of completely resected skin cancer, (b) successfully treated in situ carcinoma, (c) chronic lymphocytic lymphoma (CLL) in stable remission, or (d) indolent prostate cancer (definition: clinical stage T1 or T2a, Gleason score <= 6, and prostate specific antigen [PSA] < 10 ng/mL) requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from lung cancer target and non-target lesions are eligible
-
Subjects with brain metastases are excluded if their brain metastases are:
-
Symptomatic OR
-
Treated (surgery, radiation therapy) but not clinically and radiographically stable 3 weeks after local therapy(as assessed by contrast enhanced magnetic resonance imaging [MRI] or computed tomography [CT]), OR
-
Asymptomatic and untreated but >1 cm in the longest dimension
-
A history or evidence of cardiovascular risk including any of the following:
Corrected QT (QTc) interval >=480 msecs History of acute coronary syndromes (including myocardial infarction or unstable angina) within 6 months prior to first dose of study treatment Coronary angioplasty, or stenting within the past 24 weeks; A history or evidence of current Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) guidelines; Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic >90 mmHg which cannot be controlled by antihypertensive therapy; Abnormal cardiac valve morphology ( >=Grade 2) documented by echocardiogram (subjects with Grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study; Patients with intra-cardiac defibrillators A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for > 30 days prior to randomization are eligible.
Uncontrolled medical conditions (i.e., diabetes mellitus, hypertension, etc.), psychological, familial, sociological, or geographical conditions that interfere with the subject's safety or obtaining informed consent or do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol;
-
Pregnant, or actively breastfeeding females.
-
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
-
Additional Exclusion Criteria for dabrafenib and trametinib combination therapy (Cohort B and C as well as subjects that crossover from monotherapy to combination therapy):
-
History of interstitial lung disease or pneumonitis
-
A history or current evidence of retinal vein occlusion (RVO).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Novartis Investigative Site | Los Angeles | California | United States | 90033 |
| 2 | Novartis Investigative Site | Orange | California | United States | 92868 |
| 3 | Novartis Investigative Site | Aurora | Colorado | United States | 80045 |
| 4 | Novartis Investigative Site | Tampa | Florida | United States | 33612 |
| 5 | Novartis Investigative Site | Baltimore | Maryland | United States | 21231 |
| 6 | Novartis Investigative Site | Boston | Massachusetts | United States | 02114 |
| 7 | Novartis Investigative Site | Boston | Massachusetts | United States | 02215 |
| 8 | Novartis Investigative Site | Ann Arbor | Michigan | United States | 48109-5848 |
| 9 | Novartis Investigative Site | Saint Louis | Missouri | United States | 63110 |
| 10 | Novartis Investigative Site | Lebanon | New Hampshire | United States | 03756 |
| 11 | Novartis Investigative Site | New York | New York | United States | 10065 |
| 12 | Novartis Investigative Site | Columbus | Ohio | United States | 43210 |
| 13 | Novartis Investigative Site | Pittsburgh | Pennsylvania | United States | 15232 |
| 14 | Novartis Investigative Site | Seattle | Washington | United States | 98109 |
| 15 | Novartis Investigative Site | Madison | Wisconsin | United States | 53792 |
| 16 | Novartis Investigative Site | Caen Cedex 9 | France | 14033 | |
| 17 | Novartis Investigative Site | Lille Cedex | France | 59037 | |
| 18 | Novartis Investigative Site | Marseille Cedex 20 | France | 13915 | |
| 19 | Novartis Investigative Site | Pierre Benite | France | 69495 | |
| 20 | Novartis Investigative Site | Saint-Herblain Cedex | France | 44805 | |
| 21 | Novartis Investigative Site | Strasbourg Cedex | France | 67091 | |
| 22 | Novartis Investigative Site | Toulouse Cedex 9 | France | 31059 | |
| 23 | Novartis Investigative Site | Villejuif | France | 94805 | |
| 24 | Novartis Investigative Site | Frankfurt/Main | Germany | 60487 | |
| 25 | Novartis Investigative Site | Grosshansdorf | Germany | 22927 | |
| 26 | Novartis Investigative Site | Heidelberg | Germany | 69126 | |
| 27 | Novartis Investigative Site | Moers | Germany | 47441 | |
| 28 | Novartis Investigative Site | Milano | Italy | 20133 | |
| 29 | Novartis Investigative Site | Milano | Italy | 20141 | |
| 30 | Novartis Investigative Site | Orbassano | Italy | 10043 | |
| 31 | Novartis Investigative Site | Osaka | Japan | 534-0021 | |
| 32 | Novartis Investigative Site | Tokyo | Japan | 104-0045 | |
| 33 | Novartis Investigative Site | Seoul | Korea, Republic of | 110-744 | |
| 34 | Novartis Investigative Site | Seoul | Korea, Republic of | 120-752 | |
| 35 | Novartis Investigative Site | Seoul | Korea, Republic of | 135-710 | |
| 36 | Novartis Investigative Site | Amsterdam | Netherlands | 1081 | |
| 37 | Novartis Investigative Site | Groningen | Netherlands | 9713 | |
| 38 | Novartis Investigative Site | Oslo | Norway | 0310 | |
| 39 | Novartis Investigative Site | Barcelona | Spain | 08025 | |
| 40 | Novartis Investigative Site | Barcelona | Spain | 08036 | |
| 41 | Novartis Investigative Site | Madrid | Spain | 28006 | |
| 42 | Novartis Investigative Site | Madrid | Spain | 28034 | |
| 43 | Novartis Investigative Site | Malaga | Spain | 29010 | |
| 44 | Novartis Investigative Site | Pamplona | Spain | 31008 | |
| 45 | Novartis Investigative Site | Sevilla | Spain | 41013 | |
| 46 | Novartis Investigative Site | Taichung | Taiwan | 40705 | |
| 47 | Novartis Investigative Site | Taipei | Taiwan | ||
| 48 | Novartis Investigative Site | London | United Kingdom | SW3 6JJ | |
| 49 | Novartis Investigative Site | Oxford | United Kingdom | OX3 7LJ | |
| 50 | Novartis Investigative Site | Sutton | United Kingdom | SM2 5PT |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 113928
- 2011-001161-41
- CDRB436E2201
Study Results
Participant Flow
| Recruitment Details | The study was conducted in 50 sites across 11 countries: Netherlands(2), United States(15), Germany(4), Spain(7), France(8), Italy(3), Taiwan(2), South Korea(3), United Kingdom(3), Japan(2), Norway(1) |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|
| Arm/Group Description | Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. |
| Period Title: Overall Study | |||
| STARTED | 84 | 57 | 36 |
| 2nd Line Plus All Treated | 78 | 57 | 0 |
| 1st Line All Treated | 6 | 2 | 34 |
| Crossover | 20 | 0 | 0 |
| COMPLETED | 70 | 49 | 27 |
| NOT COMPLETED | 14 | 8 | 9 |
Baseline Characteristics
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Total |
|---|---|---|---|---|
| Arm/Group Description | Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. | Total of all reporting groups |
| Overall Participants | 84 | 57 | 36 | 177 |
| Age (Years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [Years] |
64.8
(10.51)
|
65.1
(10.14)
|
67.8
(11.00)
|
65.5
(10.50)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
44
52.4%
|
28
49.1%
|
22
61.1%
|
94
53.1%
|
| Male |
40
47.6%
|
29
50.9%
|
14
38.9%
|
83
46.9%
|
| Race/Ethnicity, Customized (Number) [Number] | ||||
| White |
64
76.2%
|
49
86%
|
30
83.3%
|
143
80.8%
|
| Asian |
18
21.4%
|
4
7%
|
3
8.3%
|
25
14.1%
|
| African American Heritage |
2
2.4%
|
0
0%
|
0
0%
|
2
1.1%
|
| Native Hawaiian or other Pacific islander |
0
0%
|
0
0%
|
1
2.8%
|
1
0.6%
|
| Black or African American |
0
0%
|
2
3.5%
|
1
2.8%
|
3
1.7%
|
| Other |
0
0%
|
2
3.5%
|
1
2.8%
|
3
1.7%
|
| ECOG Performance Status (Count of Participants) | ||||
| Grade 0 |
20
23.8%
|
17
29.8%
|
13
36.1%
|
50
28.2%
|
| Grade 1 |
52
61.9%
|
35
61.4%
|
22
61.1%
|
109
61.6%
|
| Grade 2 |
12
14.3%
|
5
8.8%
|
1
2.8%
|
18
10.2%
|
Outcome Measures
| Title | Overall Response Rate (ORR) |
|---|---|
| Description | ORR was defined as the percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR) by investigator assessment as per RECIST v1 .1 criteria. Specifically, ORR = (number of subjects with a confirmed best overall response of CR or PR) divided by the total number of subjects in the corresponding analysis population. |
| Time Frame | From study treatment start date until first documented complete response or partial response, assessed up to approximately 50 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Treated Population (ATP). |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy) | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|---|
| Arm/Group Description | Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. | Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. |
| Measure Participants | 78 | 57 | 36 | 20 |
| Count of Participants [Participants] |
27
32.1%
|
39
68.4%
|
23
63.9%
|
4
2.3%
|
| Title | Progression Free Survival (PFS) Based on Local Investigator Assessment |
|---|---|
| Description | Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm. |
| Time Frame | From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 113 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Treated Population (ATP). Only participants with an evaluable PFS events were included in the analysis. |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy) | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|---|
| Arm/Group Description | Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. | Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. |
| Measure Participants | 65 | 48 | 28 | 18 |
| Median (95% Confidence Interval) [Months] |
5.4
|
10.2
|
10.8
|
11.0
|
| Title | Duration of Response (DoR) Based on Local Investigator Assessment |
|---|---|
| Description | Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death. |
| Time Frame | From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to approximately 113 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Treated Population (ATP). Only responders (PR or CR) were included in the analysis. |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy) | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|---|
| Arm/Group Description | Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. | Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. |
| Measure Participants | 27 | 39 | 23 | 4 |
| Median (95% Confidence Interval) [Months] |
11.8
|
9.8
|
10.2
|
13.4
|
| Title | Overall Survival (OS) |
|---|---|
| Description | Overall Survival (OS) was defined as the time from first dose until death due to any cause. If a patient was not known to have died at the time of analysis cut-off, OS was censored at the date of last contact. |
| Time Frame | From study treatment start date until date of of death from any cause, assessed up to approximately 113 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Treated Population (ATP). No separate OS analysis was conducted for cross over patient, as they were included in Cohort A (Dabrafenib Monotherapy Second-Line Plus). |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy) | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|
| Arm/Group Description | Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. |
| Measure Participants | 67 | 49 | 27 |
| Median (95% Confidence Interval) [Months] |
12.7
|
18.2
|
17.3
|
| Title | Number of Participants With Treatment Emergent Adverse Events |
|---|---|
| Description | The distribution of adverse events (AE) was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. |
| Time Frame | From study treatment start date till 30 days safety follow-up, assessed up to approximately 81 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| All Treated Population (ATP) |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|---|
| Arm/Group Description | Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. | Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. |
| Measure Participants | 84 | 57 | 36 | 20 |
| Treatment Emergent Adverse Events (TAEs) |
82
97.6%
|
54
94.7%
|
36
100%
|
20
11.3%
|
| Treatment Emergent Serious Adverse Events (TESAEs) |
37
44%
|
38
66.7%
|
24
66.7%
|
9
5.1%
|
| Deaths due to AE causally related to treatment |
2
2.4%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Apparent Clearance (CL/F) of Dabrafenib |
|---|---|
| Description | Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of dabrafenib was determined in plasma samples using the currently approved analytical methodology. |
| Time Frame | Week 3, Week 6, Week 12 and Week 18 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received at least one dose of dabrafenib in the Cohort A (Dabrafenib Monotherapy) and in the doublets combination (Dabrafenib + Trametinib) Cohort B and C and provided an evaluable PK profile. |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|
| Arm/Group Description | Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. |
| Measure Participants | 76 | 53 | 30 |
| Geometric Mean (95% Confidence Interval) [Liter/hour (L/hr)] |
30.5
|
21.4
|
23.9
|
| Title | Oral Volume of Distribution (V/F) of Dabrafenib |
|---|---|
| Description | Blood samples from participants were collected for population pharmacokinetic analysis including the oral volume of distribution (V/F) following oral dosing of dabrafenib. Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of dabrafenib was determined in plasma samples using the currently approved analytical methodology. |
| Time Frame | Week 3, Week 6, Week 12 and Week 18 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received at least one dose of dabrafenib in the Cohort A (Dabrafenib Monotherapy) and in the doublets combination (Dabrafenib + Trametinib) Cohort B and C and provided an evaluable PK profile. |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|
| Arm/Group Description | Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. |
| Measure Participants | 76 | 53 | 30 |
| Geometric Mean (95% Confidence Interval) [Liter (L)] |
50.6
|
38.1
|
48.1
|
| Title | Apparent Clearance (CL/F) of Trametinib |
|---|---|
| Description | Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of trametinib. Blood samples from participants were collected for population pharmacokinetic analysis including the apparent base clearance (CL/F) following oral dosing of dabrafenib. Concentrations of trametinib was determined in plasma samples using the currently approved analytical methodology. |
| Time Frame | Week 3, Week 6, Week 12 and Week 18 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received at least one dose of trametinib in the doublets combination (Dabrafenib + Trametinib) Cohort B and C and provided an evaluable PK profile. |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|
| Arm/Group Description | Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. |
| Measure Participants | 0 | 54 | 30 |
| Geometric Mean (95% Confidence Interval) [Liter/hour (L/hr)] |
4.9
|
5.03
|
| Title | Oral Volume of Distribution (V/F) of Trametinib |
|---|---|
| Description | Blood samples from participants were collected for population pharmacokinetic analysis including the oral volume of distribution (V/F) following oral dosing of trametinib. Concentrations of trametinib was determined in plasma samples using the currently approved analytical methodology. |
| Time Frame | Week 3, Week 6, Week 12 and Week 18 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received at least one dose of trametinib in the doublets combination (Dabrafenib + Trametinib) Cohort B and C and provided an evaluable PK profile. |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|
| Arm/Group Description | Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. |
| Measure Participants | 0 | 54 | 30 |
| Geometric Mean (95% Confidence Interval) [Liter (L)] |
91.98
|
103.48
|
| Title | All Collected Deaths |
|---|---|
| Description | On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration with dabrafenib and trametinib of 81 months (study treatment with dabrafenib and trametinib ranged from 0.3 to 80.0 months). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 9 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored. |
| Time Frame | up to 81 months (study treatment with dabrafenib and trametinib), up to approximately 9 years (study duration) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Clinical database population; all treated patients. |
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy) | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD |
|---|---|---|---|---|
| Arm/Group Description | Participants who have relapsed or progressed after receiving at least one line of prior anti-cancer therapy for metastatic disease received dabrafenib 150 mg BID. It was continued until disease progression or death or unacceptable AEs or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. | Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. |
| Measure Participants | 84 | 57 | 36 | 20 |
| On-treatment deaths |
15
17.9%
|
12
21.1%
|
5
13.9%
|
4
2.3%
|
| Post-treatment deaths |
38
45.2%
|
38
66.7%
|
21
58.3%
|
13
7.3%
|
| All deaths |
53
63.1%
|
50
87.7%
|
26
72.2%
|
17
9.6%
|
Adverse Events
| Time Frame | Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days, up to approximately 81 months (study treatment with dabrafenib and trametinib ranged from 0.3 to 80.0 months). | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Any sign or symptom that occurs during the treatment period plus 30 days post-treatment. | |||||||
| Arm/Group Title | Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD | ||||
| Arm/Group Description | Participants with or without prior systemic anti-cancer therapy received Dabrafenib 150 mg BID until disease progression, death, or unacceptable adverse event(s) (AEs) or investigator discretion to discontinue or decision to crossover from monotherapy to combination therapy. | Participants who had received 1-3 prior lines of systemic anti-cancer therapies for advanced stage/metastatic disease received Dabrafenib 150 mg BID and Trametinib 2 mg once daily (OD). Treatment continued until disease progression, death, or unacceptable AEs or investigator discretion to discontinue. | Participants who had not received any prior systemic anti-cancer for metastatic disease therapies were given Dabrafenib 150 mg BID and Trametinib 2 mg OD. Treatment continued until disease progression, death, or unacceptable AEs or at investigator discretion to discontinue. | Crossover - Double Combination (Dabrafenib+Trametinib): Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. | ||||
All Cause Mortality |
||||||||
| Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 15/84 (17.9%) | 12/57 (21.1%) | 5/36 (13.9%) | 4/20 (20%) | ||||
Serious Adverse Events |
||||||||
| Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 37/84 (44%) | 38/57 (66.7%) | 24/36 (66.7%) | 9/20 (45%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 0/84 (0%) | 3/57 (5.3%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Febrile neutropenia | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Lymphopenia | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Neutropenia | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pancytopenia | 0/84 (0%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Splenic thrombosis | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Cardiac disorders | ||||||||
| Arrhythmia | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Atrial fibrillation | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Cardiac arrest | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Cardiopulmonary failure | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pericardial effusion | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Sinus bradycardia | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Tachycardia | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Ventricular fibrillation | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Ear and labyrinth disorders | ||||||||
| Vertigo | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Vertigo positional | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Eye disorders | ||||||||
| Detachment of retinal pigment epithelium | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Macular hole | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Macular oedema | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Retinal dystrophy | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Uveitis | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Abdominal pain | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| Abdominal pain upper | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Ascites | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Colitis | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Colitis ischaemic | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Constipation | 1/84 (1.2%) | 1/57 (1.8%) | 0/36 (0%) | 1/20 (5%) | ||||
| Diarrhoea | 0/84 (0%) | 1/57 (1.8%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| Diverticulum intestinal haemorrhagic | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Duodenal ulcer haemorrhage | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Enterovesical fistula | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Gastric haemorrhage | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Gastritis | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Gastrointestinal pain | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Gastrointestinal toxicity | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Haematemesis | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Ileus | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Intestinal mass | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Intestinal obstruction | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Large intestinal obstruction | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Melaena | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Nausea | 1/84 (1.2%) | 3/57 (5.3%) | 0/36 (0%) | 0/20 (0%) | ||||
| Oesophageal stenosis | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Pancreatic duct stenosis | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pancreatitis acute | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Retroperitoneal haemorrhage | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Toothache | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Vomiting | 1/84 (1.2%) | 2/57 (3.5%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| General disorders | ||||||||
| Asthenia | 1/84 (1.2%) | 2/57 (3.5%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Chest discomfort | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Chest pain | 1/84 (1.2%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Chills | 1/84 (1.2%) | 1/57 (1.8%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Fatigue | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| General physical health deterioration | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Inflammation | 1/84 (1.2%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Malaise | 1/84 (1.2%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pyrexia | 5/84 (6%) | 10/57 (17.5%) | 4/36 (11.1%) | 1/20 (5%) | ||||
| Systemic inflammatory response syndrome | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Hepatobiliary disorders | ||||||||
| Cholecystitis acute | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Hepatocellular injury | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Malignant biliary obstruction | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Infections and infestations | ||||||||
| Bacterial infection | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Bronchitis | 0/84 (0%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Cystitis | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Device related infection | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Furuncle | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Gastritis viral | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Gastroenteritis viral | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Influenza | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Legionella infection | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pneumonia | 2/84 (2.4%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pyelonephritis | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Respiratory tract infection | 3/84 (3.6%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Respiratory tract infection bacterial | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Sepsis | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Septic shock | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Urinary tract infection | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Viral infection | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Incisional hernia | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Multiple injuries | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Stoma site haemorrhage | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Toxicity to various agents | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Investigations | ||||||||
| Alanine aminotransferase increased | 1/84 (1.2%) | 1/57 (1.8%) | 5/36 (13.9%) | 0/20 (0%) | ||||
| Aspartate aminotransferase increased | 0/84 (0%) | 1/57 (1.8%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Blood alkaline phosphatase increased | 0/84 (0%) | 1/57 (1.8%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Blood creatinine increased | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| C-reactive protein increased | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Ejection fraction decreased | 2/84 (2.4%) | 4/57 (7%) | 3/36 (8.3%) | 1/20 (5%) | ||||
| Gamma-glutamyltransferase increased | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Lymphocyte count decreased | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| White blood cell count decreased | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Decreased appetite | 1/84 (1.2%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Dehydration | 0/84 (0%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Diabetes mellitus | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Hypercalcaemia | 0/84 (0%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Hyperglycaemia | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Hyperkalaemia | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Hyponatraemia | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Hypophosphataemia | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Malnutrition | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Back pain | 0/84 (0%) | 3/57 (5.3%) | 0/36 (0%) | 0/20 (0%) | ||||
| Lumbar spinal stenosis | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Myalgia | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Basal cell carcinoma | 4/84 (4.8%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Bowen's disease | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Colon adenoma | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Endometrial adenocarcinoma | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Hepatocellular carcinoma | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Keratoacanthoma | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Lip squamous cell carcinoma | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Lung neoplasm malignant | 0/84 (0%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Neoplasm progression | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Squamous cell carcinoma | 1/84 (1.2%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Squamous cell carcinoma of skin | 7/84 (8.3%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Nervous system disorders | ||||||||
| Cerebral haemorrhage | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Cerebrovascular accident | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Dizziness | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Encephalopathy | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Facial paresis | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Haemorrhage intracranial | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Headache | 1/84 (1.2%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Hemiparesis | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Neurological decompensation | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Neuropathy peripheral | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Peripheral sensory neuropathy | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Seizure | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Subarachnoid haemorrhage | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Transient ischaemic attack | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Psychiatric disorders | ||||||||
| Anxiety | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Confusional state | 1/84 (1.2%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Disorientation | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Renal and urinary disorders | ||||||||
| Haematuria | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Renal artery thrombosis | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Renal failure | 0/84 (0%) | 3/57 (5.3%) | 0/36 (0%) | 1/20 (5%) | ||||
| Tubulointerstitial nephritis | 0/84 (0%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Urinary bladder haemorrhage | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Urinary retention | 1/84 (1.2%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Acute respiratory failure | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Cough | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Dyspnoea | 1/84 (1.2%) | 2/57 (3.5%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| Haemoptysis | 0/84 (0%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pleural effusion | 1/84 (1.2%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pneumonia aspiration | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pneumonitis | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Pneumothorax | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pneumothorax spontaneous | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Pulmonary embolism | 0/84 (0%) | 1/57 (1.8%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Respiratory arrest | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Respiratory distress | 0/84 (0%) | 2/57 (3.5%) | 0/36 (0%) | 0/20 (0%) | ||||
| Respiratory failure | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Blister | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Rash | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 1/20 (5%) | ||||
| Rash maculo-papular | 0/84 (0%) | 0/57 (0%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Transient acantholytic dermatosis | 1/84 (1.2%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Vascular disorders | ||||||||
| Circulatory collapse | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Hypotension | 0/84 (0%) | 2/57 (3.5%) | 2/36 (5.6%) | 0/20 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| Cohort A (Dabrafenib Monotherapy): Dabrafenib Monotherapy 150mg BID | Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Cohort C - Double Combination (Dabrafenib+Trametinib) Naive mBRAF V600E: DAB 150MG BID, TRA 2mG QD | Crossover - Double Combination (Dabrafenib+Trametinib): DAB 150MG BID, TRA 2mG QD | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 82/84 (97.6%) | 54/57 (94.7%) | 36/36 (100%) | 20/20 (100%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anaemia | 11/84 (13.1%) | 8/57 (14%) | 7/36 (19.4%) | 1/20 (5%) | ||||
| Leukopenia | 4/84 (4.8%) | 5/57 (8.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Lymphopenia | 6/84 (7.1%) | 2/57 (3.5%) | 2/36 (5.6%) | 2/20 (10%) | ||||
| Neutropenia | 2/84 (2.4%) | 11/57 (19.3%) | 1/36 (2.8%) | 3/20 (15%) | ||||
| Thrombocytopenia | 5/84 (6%) | 5/57 (8.8%) | 0/36 (0%) | 2/20 (10%) | ||||
| Cardiac disorders | ||||||||
| Atrial fibrillation | 1/84 (1.2%) | 4/57 (7%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Atrioventricular block | 1/84 (1.2%) | 0/57 (0%) | 1/36 (2.8%) | 2/20 (10%) | ||||
| Bradycardia | 0/84 (0%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Sinus bradycardia | 0/84 (0%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Tachycardia | 2/84 (2.4%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Ear and labyrinth disorders | ||||||||
| Vertigo | 1/84 (1.2%) | 5/57 (8.8%) | 1/36 (2.8%) | 3/20 (15%) | ||||
| Eye disorders | ||||||||
| Cataract | 2/84 (2.4%) | 2/57 (3.5%) | 1/36 (2.8%) | 2/20 (10%) | ||||
| Dry eye | 4/84 (4.8%) | 6/57 (10.5%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Eye pain | 1/84 (1.2%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Periorbital oedema | 0/84 (0%) | 0/57 (0%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Photopsia | 0/84 (0%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Vision blurred | 5/84 (6%) | 2/57 (3.5%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Visual acuity reduced | 3/84 (3.6%) | 5/57 (8.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Visual impairment | 3/84 (3.6%) | 4/57 (7%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Gastrointestinal disorders | ||||||||
| Abdominal distension | 1/84 (1.2%) | 1/57 (1.8%) | 0/36 (0%) | 2/20 (10%) | ||||
| Abdominal pain | 9/84 (10.7%) | 6/57 (10.5%) | 6/36 (16.7%) | 2/20 (10%) | ||||
| Abdominal pain upper | 4/84 (4.8%) | 8/57 (14%) | 0/36 (0%) | 1/20 (5%) | ||||
| Anal incontinence | 1/84 (1.2%) | 0/57 (0%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Constipation | 10/84 (11.9%) | 11/57 (19.3%) | 6/36 (16.7%) | 6/20 (30%) | ||||
| Diarrhoea | 17/84 (20.2%) | 18/57 (31.6%) | 15/36 (41.7%) | 5/20 (25%) | ||||
| Dry mouth | 2/84 (2.4%) | 4/57 (7%) | 3/36 (8.3%) | 2/20 (10%) | ||||
| Dyspepsia | 3/84 (3.6%) | 5/57 (8.8%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Dysphagia | 3/84 (3.6%) | 3/57 (5.3%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Gastritis | 2/84 (2.4%) | 0/57 (0%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Gastrooesophageal reflux disease | 4/84 (4.8%) | 3/57 (5.3%) | 0/36 (0%) | 2/20 (10%) | ||||
| Nausea | 24/84 (28.6%) | 24/57 (42.1%) | 21/36 (58.3%) | 9/20 (45%) | ||||
| Toothache | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 2/20 (10%) | ||||
| Vomiting | 18/84 (21.4%) | 24/57 (42.1%) | 11/36 (30.6%) | 6/20 (30%) | ||||
| General disorders | ||||||||
| Asthenia | 25/84 (29.8%) | 21/57 (36.8%) | 4/36 (11.1%) | 3/20 (15%) | ||||
| Chest pain | 4/84 (4.8%) | 5/57 (8.8%) | 0/36 (0%) | 1/20 (5%) | ||||
| Chills | 12/84 (14.3%) | 15/57 (26.3%) | 10/36 (27.8%) | 3/20 (15%) | ||||
| Fatigue | 24/84 (28.6%) | 11/57 (19.3%) | 15/36 (41.7%) | 2/20 (10%) | ||||
| Feeling cold | 1/84 (1.2%) | 0/57 (0%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Gait disturbance | 1/84 (1.2%) | 0/57 (0%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Hyperthermia | 0/84 (0%) | 3/57 (5.3%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Influenza like illness | 2/84 (2.4%) | 4/57 (7%) | 5/36 (13.9%) | 0/20 (0%) | ||||
| Malaise | 5/84 (6%) | 3/57 (5.3%) | 4/36 (11.1%) | 1/20 (5%) | ||||
| Mucosal inflammation | 6/84 (7.1%) | 6/57 (10.5%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Non-cardiac chest pain | 5/84 (6%) | 0/57 (0%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| Oedema peripheral | 3/84 (3.6%) | 22/57 (38.6%) | 13/36 (36.1%) | 5/20 (25%) | ||||
| Pain | 2/84 (2.4%) | 0/57 (0%) | 4/36 (11.1%) | 1/20 (5%) | ||||
| Pyrexia | 31/84 (36.9%) | 25/57 (43.9%) | 22/36 (61.1%) | 9/20 (45%) | ||||
| Infections and infestations | ||||||||
| Bronchitis | 6/84 (7.1%) | 6/57 (10.5%) | 0/36 (0%) | 3/20 (15%) | ||||
| Conjunctivitis | 2/84 (2.4%) | 3/57 (5.3%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| Folliculitis | 4/84 (4.8%) | 4/57 (7%) | 0/36 (0%) | 1/20 (5%) | ||||
| Gastroenteritis | 2/84 (2.4%) | 0/57 (0%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Influenza | 1/84 (1.2%) | 2/57 (3.5%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Laryngitis | 0/84 (0%) | 2/57 (3.5%) | 0/36 (0%) | 2/20 (10%) | ||||
| Nasopharyngitis | 8/84 (9.5%) | 7/57 (12.3%) | 7/36 (19.4%) | 3/20 (15%) | ||||
| Pneumonia | 2/84 (2.4%) | 6/57 (10.5%) | 5/36 (13.9%) | 0/20 (0%) | ||||
| Rhinitis | 5/84 (6%) | 7/57 (12.3%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Upper respiratory tract infection | 8/84 (9.5%) | 1/57 (1.8%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Urinary tract infection | 5/84 (6%) | 5/57 (8.8%) | 7/36 (19.4%) | 2/20 (10%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Contusion | 2/84 (2.4%) | 1/57 (1.8%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Fall | 2/84 (2.4%) | 2/57 (3.5%) | 1/36 (2.8%) | 2/20 (10%) | ||||
| Limb injury | 0/84 (0%) | 0/57 (0%) | 3/36 (8.3%) | 1/20 (5%) | ||||
| Thermal burn | 0/84 (0%) | 3/57 (5.3%) | 0/36 (0%) | 0/20 (0%) | ||||
| Investigations | ||||||||
| Alanine aminotransferase increased | 4/84 (4.8%) | 5/57 (8.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Amylase increased | 0/84 (0%) | 3/57 (5.3%) | 0/36 (0%) | 0/20 (0%) | ||||
| Aspartate aminotransferase increased | 3/84 (3.6%) | 6/57 (10.5%) | 3/36 (8.3%) | 2/20 (10%) | ||||
| Blood alkaline phosphatase increased | 5/84 (6%) | 11/57 (19.3%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Blood creatine phosphokinase increased | 0/84 (0%) | 6/57 (10.5%) | 1/36 (2.8%) | 2/20 (10%) | ||||
| Blood creatinine increased | 3/84 (3.6%) | 6/57 (10.5%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| C-reactive protein increased | 1/84 (1.2%) | 0/57 (0%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Lipase increased | 2/84 (2.4%) | 4/57 (7%) | 0/36 (0%) | 1/20 (5%) | ||||
| Weight decreased | 15/84 (17.9%) | 9/57 (15.8%) | 9/36 (25%) | 2/20 (10%) | ||||
| Weight increased | 0/84 (0%) | 8/57 (14%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Cell death | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 2/20 (10%) | ||||
| Decreased appetite | 25/84 (29.8%) | 17/57 (29.8%) | 12/36 (33.3%) | 6/20 (30%) | ||||
| Dehydration | 5/84 (6%) | 3/57 (5.3%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Hyperglycaemia | 7/84 (8.3%) | 4/57 (7%) | 2/36 (5.6%) | 2/20 (10%) | ||||
| Hypoalbuminaemia | 3/84 (3.6%) | 5/57 (8.8%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Hypokalaemia | 5/84 (6%) | 5/57 (8.8%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Hypomagnesaemia | 3/84 (3.6%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Hyponatraemia | 3/84 (3.6%) | 9/57 (15.8%) | 4/36 (11.1%) | 0/20 (0%) | ||||
| Hypophosphataemia | 6/84 (7.1%) | 5/57 (8.8%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Vitamin D deficiency | 0/84 (0%) | 1/57 (1.8%) | 0/36 (0%) | 2/20 (10%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 21/84 (25%) | 17/57 (29.8%) | 8/36 (22.2%) | 8/20 (40%) | ||||
| Back pain | 11/84 (13.1%) | 6/57 (10.5%) | 9/36 (25%) | 3/20 (15%) | ||||
| Groin pain | 0/84 (0%) | 1/57 (1.8%) | 1/36 (2.8%) | 2/20 (10%) | ||||
| Joint stiffness | 1/84 (1.2%) | 0/57 (0%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Muscle spasms | 2/84 (2.4%) | 7/57 (12.3%) | 5/36 (13.9%) | 3/20 (15%) | ||||
| Muscular weakness | 7/84 (8.3%) | 1/57 (1.8%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Musculoskeletal chest pain | 6/84 (7.1%) | 4/57 (7%) | 4/36 (11.1%) | 2/20 (10%) | ||||
| Myalgia | 10/84 (11.9%) | 6/57 (10.5%) | 4/36 (11.1%) | 3/20 (15%) | ||||
| Neck pain | 4/84 (4.8%) | 3/57 (5.3%) | 2/36 (5.6%) | 3/20 (15%) | ||||
| Pain in extremity | 17/84 (20.2%) | 6/57 (10.5%) | 4/36 (11.1%) | 2/20 (10%) | ||||
| Spinal osteoarthritis | 0/84 (0%) | 0/57 (0%) | 0/36 (0%) | 2/20 (10%) | ||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Acrochordon | 6/84 (7.1%) | 1/57 (1.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Basal cell carcinoma | 2/84 (2.4%) | 2/57 (3.5%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Keratoacanthoma | 6/84 (7.1%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Melanocytic naevus | 11/84 (13.1%) | 2/57 (3.5%) | 0/36 (0%) | 1/20 (5%) | ||||
| Seborrhoeic keratosis | 11/84 (13.1%) | 1/57 (1.8%) | 2/36 (5.6%) | 2/20 (10%) | ||||
| Skin papilloma | 26/84 (31%) | 2/57 (3.5%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Nervous system disorders | ||||||||
| Dizziness | 8/84 (9.5%) | 7/57 (12.3%) | 9/36 (25%) | 1/20 (5%) | ||||
| Dysgeusia | 3/84 (3.6%) | 5/57 (8.8%) | 0/36 (0%) | 0/20 (0%) | ||||
| Headache | 17/84 (20.2%) | 11/57 (19.3%) | 8/36 (22.2%) | 3/20 (15%) | ||||
| Memory impairment | 2/84 (2.4%) | 2/57 (3.5%) | 1/36 (2.8%) | 2/20 (10%) | ||||
| Paraesthesia | 4/84 (4.8%) | 3/57 (5.3%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Sciatica | 0/84 (0%) | 3/57 (5.3%) | 1/36 (2.8%) | 2/20 (10%) | ||||
| Taste disorder | 1/84 (1.2%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Psychiatric disorders | ||||||||
| Anxiety | 3/84 (3.6%) | 2/57 (3.5%) | 1/36 (2.8%) | 3/20 (15%) | ||||
| Confusional state | 2/84 (2.4%) | 4/57 (7%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| Depression | 3/84 (3.6%) | 3/57 (5.3%) | 2/36 (5.6%) | 2/20 (10%) | ||||
| Insomnia | 7/84 (8.3%) | 4/57 (7%) | 5/36 (13.9%) | 0/20 (0%) | ||||
| Renal and urinary disorders | ||||||||
| Urinary incontinence | 1/84 (1.2%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Cough | 27/84 (32.1%) | 18/57 (31.6%) | 10/36 (27.8%) | 5/20 (25%) | ||||
| Dysphonia | 9/84 (10.7%) | 3/57 (5.3%) | 5/36 (13.9%) | 3/20 (15%) | ||||
| Dyspnoea | 18/84 (21.4%) | 15/57 (26.3%) | 9/36 (25%) | 3/20 (15%) | ||||
| Epistaxis | 1/84 (1.2%) | 4/57 (7%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Haemoptysis | 8/84 (9.5%) | 3/57 (5.3%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Nasal congestion | 3/84 (3.6%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Oropharyngeal pain | 3/84 (3.6%) | 3/57 (5.3%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Pleural effusion | 0/84 (0%) | 3/57 (5.3%) | 0/36 (0%) | 0/20 (0%) | ||||
| Productive cough | 6/84 (7.1%) | 7/57 (12.3%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| Pulmonary embolism | 0/84 (0%) | 3/57 (5.3%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Acne | 1/84 (1.2%) | 1/57 (1.8%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Actinic keratosis | 11/84 (13.1%) | 2/57 (3.5%) | 3/36 (8.3%) | 3/20 (15%) | ||||
| Alopecia | 18/84 (21.4%) | 6/57 (10.5%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Dermal cyst | 3/84 (3.6%) | 1/57 (1.8%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Dry skin | 26/84 (31%) | 22/57 (38.6%) | 14/36 (38.9%) | 2/20 (10%) | ||||
| Eczema | 2/84 (2.4%) | 3/57 (5.3%) | 1/36 (2.8%) | 2/20 (10%) | ||||
| Erythema | 2/84 (2.4%) | 7/57 (12.3%) | 5/36 (13.9%) | 4/20 (20%) | ||||
| Erythema nodosum | 0/84 (0%) | 3/57 (5.3%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| Hair texture abnormal | 7/84 (8.3%) | 3/57 (5.3%) | 0/36 (0%) | 0/20 (0%) | ||||
| Hyperhidrosis | 3/84 (3.6%) | 4/57 (7%) | 1/36 (2.8%) | 1/20 (5%) | ||||
| Hyperkeratosis | 26/84 (31%) | 7/57 (12.3%) | 1/36 (2.8%) | 2/20 (10%) | ||||
| Madarosis | 5/84 (6%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Palmar-plantar erythrodysaesthesia syndrome | 20/84 (23.8%) | 2/57 (3.5%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Papule | 11/84 (13.1%) | 1/57 (1.8%) | 1/36 (2.8%) | 0/20 (0%) | ||||
| Pruritus | 14/84 (16.7%) | 9/57 (15.8%) | 6/36 (16.7%) | 2/20 (10%) | ||||
| Rash | 15/84 (17.9%) | 16/57 (28.1%) | 11/36 (30.6%) | 3/20 (15%) | ||||
| Rash macular | 1/84 (1.2%) | 1/57 (1.8%) | 2/36 (5.6%) | 0/20 (0%) | ||||
| Rash maculo-papular | 5/84 (6%) | 0/57 (0%) | 0/36 (0%) | 0/20 (0%) | ||||
| Rash papular | 4/84 (4.8%) | 2/57 (3.5%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Seborrhoeic dermatitis | 0/84 (0%) | 2/57 (3.5%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Skin lesion | 4/84 (4.8%) | 1/57 (1.8%) | 4/36 (11.1%) | 0/20 (0%) | ||||
| Urticaria | 3/84 (3.6%) | 3/57 (5.3%) | 3/36 (8.3%) | 0/20 (0%) | ||||
| Vascular disorders | ||||||||
| Haematoma | 1/84 (1.2%) | 1/57 (1.8%) | 2/36 (5.6%) | 1/20 (5%) | ||||
| Hypertension | 4/84 (4.8%) | 6/57 (10.5%) | 4/36 (11.1%) | 4/20 (20%) | ||||
| Hypotension | 6/84 (7.1%) | 6/57 (10.5%) | 5/36 (13.9%) | 0/20 (0%) | ||||
| Orthostatic hypotension | 0/84 (0%) | 0/57 (0%) | 2/36 (5.6%) | 1/20 (5%) | ||||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Novartis Pharmaceuticals |
| Phone | 862-778-8300 |
| Novartis.email@novartis.com |
- 113928
- 2011-001161-41
- CDRB436E2201