LOGIC: LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma

• Sponsor: Array BioPharma (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01820364
• Collaborator: (none)
• Enrollment: 15
• Locations: 6
• Arm: 1
• Duration (Months): 15.9
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary purpose of the Phase II CLGX818X2102 study is to assess the anti-tumor activity of LGX818 in combination with selected agents.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: LGX818	Phase 2

Detailed Description

This is a phase II two part multi-center, open-label study. Part I: LGX818 single agent treatment until progression Part II: Combination treatments of LGX818 + MEK162, or BKM120, or BGJ398, or INC280, or LEE01 to assess the clinical efficacy, to further evaluate the safety of the drug combinations in patients with locally advanced or metastatic BRAF mutant melanoma after relapse on LGX818, and to determine the maximum tolerated dose of the combinations (when not established previously). These drug combinations are selected and assigned to patients based on documentation of molecular resistance mechanism.

Patients with BRAF mutant melanoma treated by LGX818 single agent in other studies can be enrolled directly in Part II of CLGX818X2102 after relapse.

Dose-escalations in the combination arms for which no MTD has been established will be based on the recommendations of a Bayesian logistic regression model guided by an escalation with overdose control criterion.

After careful evaluation of slow enrollment and the BRAF-mutant melanoma treatment landscape, recruitment was permanently halted on 26-Jul-2014.

This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II, Multi-center, Open-label Study of Single-agent LGX818 Followed by a Rational Combination With Agents After Progression on LGX818, in Adult Patients With Locally Advanced or Metastatic BRAF V600 Melanoma
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LGX818 single agent Patients had to have written documentation of a BRAFV600 mutation, which was to have been obtained locally on a fresh tumor biopsy (preferred) or on the most recent archival tumor sample available.	Drug: LGX818; BRAF inhibitor. LGX818 was administered QD orally on a daily schedule (21-day cycles) as a flat-fixed dose and not by body weight or body surface area. LGX818 100 mg capsules and 50 mg capsules.; Other Names: encorafenib

Outcome Measures

Primary Outcome Measures

1. Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II) [Baseline through study completion (approximately 2 years)]

   Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Secondary Outcome Measures

1. Incidence of Dose Limiting Toxicities (DLTs) (Part II) [Baseline through study completion (approximately 2 years)]

   Incidence of DLTs in Part II of the study was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.

2. Plasma Concentration and Derived Pharmacokinetic Parameters [Baseline through study completion (approximately 2 years)]

   Assessment of pharmacokinetic (PK) parameters and plasma concentration was not done due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.

3. Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I) [Baseline through completion of Part I of the study (approximately 2 years)]

   Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

4. Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II) [Entry to Part II of the study through study completion (approximately 22 days)]

   Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. One patient with documented PD at study Day 146 entered into Part II of the study and received combination treatment of LGX818 450 mg plus MEK162 45 mg for two weeks. The patient experienced disease progression on Day 22 of Part II and discontinued the study.

5. Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways [Baseline and at progression with LGX818 single agent treatment]

   Molecular status was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• locally advanced or metastatic melanoma

• confirmed BRAF V600 mutation

• patients naïve to a selective BRAF inhibitor

• fresh tumor biopsy at baseline, and patient agrees for a mandatory biopsy at the time of relapse

• life expectancy ≥ 3 months

• World Health Organization (WHO) Performance Status ≤ 2.

Exclusion Criteria:

• Previous treatment with RAF-inhibitor

• Symptomatic or untreated leptomeningeal disease

• Symptomatic brain metastases.

• Known acute or chronic pancreatitis

• Clinically significant cardiac disease

• AST/SGOT and ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral interventional drug

• Previous or concurrent malignancy.

• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation

Specific exclusion criteria for each treatment arm:

LGX818/MEK162:

History or current evidence of retinal disease History of Gilbert's syndrome.

LGX818/BKM120:

Patients with diabetes mellitus requiring insulin treatment Patient has mood disorders

LGX818/BGJ398:

History and/or current evidence of ectopic mineralization/ calcification Current evidence of corneal disorder/ keratopathy Patients with current evidence of endocrine alteration of calcium/phosphate homeostasis.

History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade ≥ 3 and/or magnesium levels below the clinically relevant lower limits before study entry.

Ionized (i) calcium (Ca) > ULN Serum inorganic phosphorus (Pi) > ULN

LGX818/LEE011 History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade ≥ 3 and/or magnesium levels below the clinically relevant lower limits before study entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sarah Cannon Research Institute Onc Dept	Nashville	Tennessee	United States	37203
2	Novartis Investigative Site	East Melbourne	Victoria	Australia	3002
3	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 1Z2
4	Novartis Investigative Site	Heidelberg		Germany	69120
5	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
6	Novartis Investigative Site	Zuerich		Switzerland	8091

Sponsors and Collaborators

• Array BioPharma

Investigators

• Study Director: Array BioPharma, 303-381-6604

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Array BioPharma
• ClinicalTrials.gov Identifier: NCT01820364
• Other Study ID Numbers: CLGX818X2102; 2012-004798-17
• First Posted: Mar 28, 2013
• Last Update Posted: Jan 9, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by Array BioPharma: open-label study; BRAF inhibitor; LGX818; MEK1620; MAPK1/2 inhibitor; Pi3K inhibitor; FGFR; c-Met; CDK4/6; metastatic melanoma; BRAF; V600
• Additional relevant MeSH terms: Melanoma

Study Results

Participant Flow

Recruitment Details	The study began on 04-Nov-2013 (First Subject First Visit) to the CLGX818X2102 (LOGIC 1) study. A total of 15 subjects were enrolled. The last subject's last visit occurred on 23-Mar-2015. Not completed subjects represents subjects that stopped treatment early, due to the corresponding reason.
Pre-assignment Detail	After careful evaluation of slow enrollment and the BRAF-mutant melanoma treatment landscape, recruitment was permanently halted on 26-Jul-2014. This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.

Arm/Group Title	Part I: LGX818 - Single Agent	Part II: CLGX818 + MEK162
Arm/Group Description	Subjects in Part I of the study received LGX818 as a single agent.	As per the original study design, Part II was to have five arms corresponding to the five potential combination treatments; however, only one patient was treated in this part of the study and received LGX818 in combination with MEK162.
Period Title: Part I: LGX818
STARTED	15	0
COMPLETED	1	0
NOT COMPLETED	14	0
Period Title: Part I: LGX818
STARTED	0	1
COMPLETED	0	0
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Part I: LGX818 - Single Agent
Arm/Group Description	Subjects in Part I of the study received LGX818 as a single agent.
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 80%
>=65 years	3 20%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.3 (16.53)
Gender (Count of Participants)
Female	7 46.7%
Male	8 53.3%
Region of Enrollment (participants) [Number]
United States	2 13.3%
Australia	3 20%
Switzerland	6 40%
Germany	1 6.7%
Spain	3 20%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	80.3 (19.11)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	171.8 (9.51)
WHO/ ECOG performance status (participants) [Number]
0	14 93.3%
1	1 6.7%

Outcome Measures

1. Primary Outcome

Title	Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II)
Description	Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time Frame	Baseline through study completion (approximately 2 years)

Outcome Measure Data

Analysis Population Description

This analysis is comprised of the Full Analysis Set, which consists of all patients who received at least one dose of LGX818.

Arm/Group Title	Part I: LGX818 - Single Agent	Part II: CLGX818 + MEK162
Arm/Group Description	Subjects in Part I of the study received LGX818 as a single agent.	As per the original study design, Part II was to have five arms corresponding to the five potential combination treatments; however, only one patient was treated in this part of the study and received LGX818 in combination with MEK162.
Measure Participants	15	1
Complete Response	1 6.7%	0 NaN
Partial Response	8 53.3%	0 NaN
Progressive Disease	1 6.7%	1 NaN
Stable Disease	2 13.3%	0 NaN
Unknown	3 20%	0 NaN

2. Secondary Outcome

Title	Incidence of Dose Limiting Toxicities (DLTs) (Part II)
Description	Incidence of DLTs in Part II of the study was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Time Frame	Baseline through study completion (approximately 2 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part II: CLGX818 + MEK162
Arm/Group Description	As per the original study design, Part II was to have five arms corresponding to the five potential combination treatments; however, only one patient was treated in this part of the study and received LGX818 in combination with MEK162.
Measure Participants	0

3. Secondary Outcome

Title	Plasma Concentration and Derived Pharmacokinetic Parameters
Description	Assessment of pharmacokinetic (PK) parameters and plasma concentration was not done due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Time Frame	Baseline through study completion (approximately 2 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part I: LGX818 - Single Agent	Part II: CLGX818 + MEK162
Arm/Group Description	Subjects in Part I of the study received LGX818 as a single agent.	As per the original study design, Part II was to have five arms corresponding to the five potential combination treatments; however, only one patient was treated in this part of the study and received LGX818 in combination with MEK162.
Measure Participants	0	0

4. Secondary Outcome

Title	Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I)
Description	Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Time Frame	Baseline through completion of Part I of the study (approximately 2 years)

Outcome Measure Data

Analysis Population Description

This analysis is comprised of the Full Analysis Set, which consists of all patients who received at least one dose of LGX818.

Arm/Group Title	Part I: LGX818 - Single Agent
Arm/Group Description	Subjects in Part I of the study received LGX818 as a single agent.
Measure Participants	15
Complete Response	1 6.7%
Partial Response	8 53.3%
Progressive Disease	1 6.7%
Stable Disease	2 13.3%
Unknown	3 20%

5. Secondary Outcome

Title	Tumor Response (Overall Response Rate) Via Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part II)
Description	Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define the status of tumors in cancer patients during a specific treatment. The Overall Response Rate was calculated according to the RECIST criteria, as per investigator assessment. Per RECIST guidelines: Complete Response (CR) is the Disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of diameters of target lesions. Progressive Disease (PD) is the at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. One patient with documented PD at study Day 146 entered into Part II of the study and received combination treatment of LGX818 450 mg plus MEK162 45 mg for two weeks. The patient experienced disease progression on Day 22 of Part II and discontinued the study.
Time Frame	Entry to Part II of the study through study completion (approximately 22 days)

Outcome Measure Data

Analysis Population Description

This analysis group is comprised of the Full Analysis Set, which consists of all patients who received at least one dose of LGX818.

Arm/Group Title	Part II: CLGX818 + MEK162
Arm/Group Description	As per the original study design, Part II was to have five arms corresponding to the five potential combination treatments; however, only one patient was treated in this part of the study and received LGX818 in combination with MEK162.
Measure Participants	1
Complete Response	0 0%
Partial Response	0 0%
Progressive Disease	1 6.7%
Stable Disease	0 0%
Unknown	0 0%

6. Secondary Outcome

Title	Molecular Status of Markers Relevant to the RAP/MEK/ERK and PI3K/AKT Pathways
Description	Molecular status was not evaluated due to an inadequate number of patients enrolled in Part II prior to the permanent recruitment halt of this study.
Time Frame	Baseline and at progression with LGX818 single agent treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part I: LGX818 - Single Agent	Part II: CLGX818 + MEK162
Arm/Group Description	Subjects in Part I of the study received LGX818 as a single agent.	As per the original study design, Part II was to have five arms corresponding to the five potential combination treatments; however, only one patient was treated in this part of the study and received LGX818 in combination with MEK162.
Measure Participants	0	0

Adverse Events

Time Frame	Adverse Events (AEs), Serious Adverse Events (SAEs), and Non-serious AEs were collected throughout the duration of the study, approximately 2 years. An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after patient's signed informed consent has been obtained. This analysis group is the Safety Set, which is all patients from the Full Analysis Set who had at least one post-baseline safety assessment.
Adverse Event Reporting Description	Due to slow enrollment, the study was terminated on 26-July-2014, at which time 15 patients were enrolled of Phase I of the study. The last patient last visit date occurred on 23-March-2015. One patient with documented PD at study Day 146 entered into Part II of the study and received combination treatment of LGX818 450 mg plus MEK162 45 mg for two weeks. The patient experienced disease progression on Day 22 of Part II and discontinued the study.
Arm/Group Title	Part I: LGX818 - Single Agent
Arm/Group Description	Subjects in Part I of the study received LGX818 as a single agent.
All Cause Mortality
	Part I: LGX818 - Single Agent
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Part I: LGX818 - Single Agent
	Affected / at Risk (%)	# Events
Total	3/15 (20%)
Blood and lymphatic system disorders
Coagulopathy	1/15 (6.7%)
Cardiac disorders
Atrial Fibrillation	1/15 (6.7%)
Infections and infestations
Pneumonia	1/15 (6.7%)
Metabolism and nutrition disorders
Dehydration	1/15 (6.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases To Central Nervous System	1/15 (6.7%)
Metastatic Pain	1/15 (6.7%)
Psychiatric disorders
Panic Attack	1/15 (6.7%)
Renal and urinary disorders
Renal Failure Acute	1/15 (6.7%)
Urinary Retention	1/15 (6.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/15 (6.7%)
Vascular disorders
Hypotension	1/15 (6.7%)
Other (Not Including Serious) Adverse Events
	Part I: LGX818 - Single Agent
	Affected / at Risk (%)	# Events
Total	15/15 (100%)
Blood and lymphatic system disorders
Anaemia	5/15 (33.3%)
Leukocytosis	2/15 (13.3%)
Eosinophilia	1/15 (6.7%)
Thrombocytopenia	1/15 (6.7%)
Cardiac disorders
Atrial Fibrillation	1/15 (6.7%)
Long Qt Syndrome	1/15 (6.7%)
Ear and labyrinth disorders
Ear Pain	1/15 (6.7%)
Endocrine disorders
Hypothyroidism	2/15 (13.3%)
Eye disorders
Cataract	1/15 (6.7%)
Conjunctival Hyperaemia	1/15 (6.7%)
Ophthalmoplegia	1/15 (6.7%)
Vision Blurred	1/15 (6.7%)
Gastrointestinal disorders
Nausea	3/15 (20%)
Vomiting	3/15 (20%)
Constipation	2/15 (13.3%)
Abdominal Pain Upper	1/15 (6.7%)
Dyspepsia	1/15 (6.7%)
Gingival Bleeding	1/15 (6.7%)
Haemorrhoidal Haemorrhage	1/15 (6.7%)
Haemorrhoids	1/15 (6.7%)
Inguinal Hernia	1/15 (6.7%)
Rectal Haemorrhage	1/15 (6.7%)
Tongue Coated	1/15 (6.7%)
General disorders
Fatigue	9/15 (60%)
Asthenia	4/15 (26.7%)
Oedema Peripheral	3/15 (20%)
Face Oedema	1/15 (6.7%)
Pyrexia	1/15 (6.7%)
Infections and infestations
Anal Abscess	1/15 (6.7%)
Folliculitis	1/15 (6.7%)
Lower Respiratory Tract Infection	1/15 (6.7%)
Oral Candidiasis	1/15 (6.7%)
Upper Respiratory Tract Infection	1/15 (6.7%)
Urinary Tract Infection	1/15 (6.7%)
Injury, poisoning and procedural complications
Procedural Pain	1/15 (6.7%)
Toxicity To Various Agents	1/15 (6.7%)
Investigations
Gamma-Glutamyltransferase Increased	2/15 (13.3%)
Alanine Aminotransferase Increased	1/15 (6.7%)
Amylase Increased	1/15 (6.7%)
Blood Alkaline Phosphatase Increased	1/15 (6.7%)
Blood Cholesterol Increased	1/15 (6.7%)
Blood Creatinine Increased	1/15 (6.7%)
Electrocardiogram Qt Prolonged	1/15 (6.7%)
Haemoglobin Increased	1/15 (6.7%)
Lipase Increased	1/15 (6.7%)
Weight Decreased	1/15 (6.7%)
Metabolism and nutrition disorders
Decreased Appetite	4/15 (26.7%)
Hyperglycaemia	3/15 (20%)
Dehydration	2/15 (13.3%)
Hyperkalaemia	1/15 (6.7%)
Hypertriglyceridaemia	1/15 (6.7%)
Hypoalbuminaemia	1/15 (6.7%)
Hypokalaemia	1/15 (6.7%)
Hypophosphataemia	1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/15 (40%)
Myalgia	4/15 (26.7%)
Back Pain	3/15 (20%)
Muscular Weakness	3/15 (20%)
Musculoskeletal Pain	2/15 (13.3%)
Joint Swelling	1/15 (6.7%)
Musculoskeletal Chest Pain	1/15 (6.7%)
Pain In Extremity	1/15 (6.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic Naevus	2/15 (13.3%)
Skin Papilloma	2/15 (13.3%)
Acrochordon	1/15 (6.7%)
Blepharal Papilloma	1/15 (6.7%)
Pyogenic Granuloma	1/15 (6.7%)
Seborrhoeic Keratosis	1/15 (6.7%)
Nervous system disorders
Headache	4/15 (26.7%)
Dysgeusia	3/15 (20%)
Aphasia	1/15 (6.7%)
Convulsion	1/15 (6.7%)
Dizziness	1/15 (6.7%)
Hypogeusia	1/15 (6.7%)
Neuralgia	1/15 (6.7%)
Paraesthesia	1/15 (6.7%)
Peripheral Sensorimotor Neuropathy	1/15 (6.7%)
Tremor	1/15 (6.7%)
VIIth Nerve Paralysis	1/15 (6.7%)
Insomnia	10/15 (66.7%)
Renal and urinary disorders
Dysuria	1/15 (6.7%)
Haematuria	1/15 (6.7%)
Proteinuria	1/15 (6.7%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia	1/15 (6.7%)
Breast Pain	1/15 (6.7%)
Menstruation Irregular	1/15 (6.7%)
Vaginal Haemorrhage	1/15 (6.7%)
Dyspnoea	2/15 (13.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/15 (6.7%)
Skin and subcutaneous tissue disorders
Hyperkeratosis	12/15 (80%)
Alopecia	10/15 (66.7%)
Palmar-Plantar Erythrodysaesthesia Syndrome	9/15 (60%)
Dry Skin	5/15 (33.3%)
Rash	4/15 (26.7%)
Rash Maculo-Papular	4/15 (26.7%)
Erythema	3/15 (20%)
Rash Papular	2/15 (13.3%)
Granuloma Skin	1/15 (6.7%)
Palmar Erythema	1/15 (6.7%)
Papule	1/15 (6.7%)
Rash Macular	1/15 (6.7%)
Skin Hypertrophy	1/15 (6.7%)
Vascular disorders
Flushing	3/15 (20%)
Hypotension	1/15 (6.7%)

Limitations/Caveats

Recruitment halted on 26-Jul-2014, which led to small numbers of subjects analyzed. This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of the sponsor's agreements with its investigators may vary. However, the sponsor does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in the clinical trial.