MACS0375: Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00751036
• Collaborator: (none)
• Enrollment: 94
• Locations: 32
• Arms: 2
• Duration (Months): 38
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study will investigate the comparative efficacy and safety of two oral inhibitors of Kit and PDGFR: nilotinib 400 mg bid, a novel agent, and imatinib 400 mg bid, an approved agent with an established efficacy.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Stromal Tumors	Drug: Nilotinib; Drug: Imatinib	Phase 3

Detailed Description

This is an international, randomized, open-label, double-arm, phase III trial that will be conducted in centers in Latin America, Asia, Europe and Canada. The study will be sponsored by Novartis Pharmaceuticals Corporation. Patient enrollment will be competitive and will have a duration of up to 30 months. An interim analysis is planned to occur when approximately 60% of the PFS events occurs. A total of 150 patients per arm will be enrolled in the study. Eligible patients will have advanced/metastatic, inoperable GIST of any anatomical location or recurrent GIST while on or post imatinib adjuvant therapy, with documented disease progression on therapy with imatinib 400 mg q.d.

Study Design

• Study Type: Interventional
• Actual Enrollment: 94 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase III Trial Comparing Nilotinib 800mg to Imatinib 800 mg for the Treatment of Patients With Advanced and/or Metastatic Gastrointestinal Stromal Tumors Refractory to Imatinib 400 mg
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nilotinib Patients who were assigned to this treatment group received 400 mg. nilotinib bid.	Drug: Nilotinib; Nilotinib hard gel capsules were supplied to the Investigators at dose strengths of 200 mg. Nilotinib is a novel agent, which has been approved for the treatment of chronic phase and accelerated phase Philadelphia-chromosome-positive CML in adult patients resistant to or intolerant to prior therapy that included imatinib.; Other Names: Tasigna
Active Comparator: Imatinib Patients who were assigned to this treatment group received 400 mg. imatinib bid.	Drug: Imatinib; Imatinib tablets were supplied at 100 mg and/or 400 mg dose strength. Imatinib is an approved agent for GIST. Efficacy of imatinib at a dose of 400 mg bid has been established in the setting of disease progression after the use of the conventional dose (400 mg qd).

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [24 months]

   Progression-free survival (PFS) is the time from date of randomization to the date of first documented progression or death due to any cause. If a participant has not had an event, progression-free survival is censored at the time of last adequate tumor assessment. Progression is defined according to modified RECIST criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions.

Secondary Outcome Measures

1. Disease Control Rate (DCR) [every 2 months until 24 months (end of study)]

   The Disease Control Rate (Complete Response(CR), Partial Response (PD) and Stable Disease (SD) rates for each treatment arm will be computed using the exact Clopper-Pearson interval estimation methodology. DCR is defined as the percentage of patients with a best overall response of • CR, i.e. at least two determinations of CR at least 4 weeks apart without loss of response between the determinations, • PR, i.e. at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) and without loss of PR between the determinations, or • SD lasting at least 24 weeks, i.e. at least one SD or better response at least 24 weeks after randomization (and not qualifying for CR or PR).

2. Time to Treatment Failure [Time from date of radomization to the earliest date of the first objective tumor, death or discontinuation, assesed until 24 months.]

   TTF, defined as the time from date of randomization to the earliest of date of the first objective tumor progression, date of death due to any cause, or date of discontinuation due to reasons other than 'Protocol deviation' or 'Administrative problems'.

3. Overall Survival (OS) [time from the date of randomization to the date of death due to any cause or the date of last contact prior to or on the date of data cutoff, assesed until 24 months.]

   . OS is defined as the time from the date of randomization to the date of death due to any cause or the date of last contact prior to or on the date of data cutoff. The median time to overall survival and its associated 95 % CI will be derived, for each treatment arm, using the time to event analysis based on Kaplan-Meier methodology.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Provide a written informed consent.

• Male or female patients ≥ 18 years of age.

• Histologically confirmed diagnosis of GIST of any anatomical location, which is unresectable and/ or metastatic or recurrent.

• Documented disease progression according to RECIST 1.0. Documentation of progression required by either 2 CT scans or 2 MRI scans within 6 months prior to randomization (one image will document the lesion and the other will document the progression by lesion(s) growth or the presence of new lesion(s)). The interval between the 2 images should be no greater than 6 months apart. Scans will be provided to the selected imaging CRO.

• Documented disease progression must occur while on imatinib 400 mg PO q.d. Imatinib therapy could be for (1) unresectable GIST; (2) metastatic GIST; or (3) recurrent GIST while on imatinib adjuvant therapy or recurrent GIST post adjuvant imatinib therapy.

• Positive immunohistochemical staining for c-KIT (CD117) or negative staining for KIT, but with either positive staining for DOG1 or an identified mutation on KIT or PDGFR genes.

• Presence of at least one measurable lesion according to RECIST 1.0, defined as a lesion that can be accurately measured in at least one dimension (longest diameter) as ≥ 20 mm with conventional techniques (conventional CT or MRI scan) or as ≥ 10 mm with spiral CT scan. Lesions in previously irradiated areas can be considered measurable only if they have demonstrated clear evidence of progression since the radiotherapy.

• A performance status of 0, 1 or 2 according to the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al 1982)(Appendix A).

• Adequate organ function, as indicated by all of the following:

• White blood cell (WBC) count ≥ 3500/mm3;

• Absolute neutrophil count (ANC) ≥1500/mm3;

• Hemoglobin ≥ 9.0 g/dL;

• Platelet count ≥ 100 x 109/L;

• Total bilirubin ≤ 1.5 X ULN (< 3.0 X ULN if related to disease);

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times the ULN, unless liver metastases present, in which case AST and ALT have to be ≤ 5 times the ULN;

• Serum creatinine ≤ 1.5 times the ULN;

• Serum amylase and lipase ≤1.5 X ULN;

• Alkaline phosphatase ≤2.5 X ULN (≤ 5.0 X ULN if related to disease);

• Serum potassium, phosphorus, magnesium and calcium ≥ LLN [lower limit of normality] or correctable with supplements prior to first dose of study drug. (Total calcium corrected for serum albumin)

• Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to registration.

• Fertile patients (female) must agree to use an acceptable method of contraception to avoid pregnancy for the duration of the study and for 3 months after study termination.

Exclusion Criteria:

• Prior use of imatinib doses higher than 400 mg q.d. or prior use of any other tyrosine-kinase inhibitor.

• Tumor progression after stopping imatinib 400 mg q.d.

• No investigational cytotoxic drug ≤ 4 weeks (6 weeks for nitrosurea or mitomycin C) prior to the Screening Visit (V100) is allowed with the exception of imatinib therapy.

• Cytotoxic, or antineoplastic treatments, such as chemotherapy, immunotherapy, biological response modifiers, or radiotherapy.

• If the only measurable lesion was previously irradiated and has not shown clear evidence of progression since the radiotherapy, the patient cannot be included.

• Serious uncontrolled concomitant medical or psychiatric illness.

• Impaired cardiac function including any one of the following:

• LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) confirmed by ECHO or Muga

• Inability to determine the QT interval on ECG

• Complete left bundle branch block

• Right bundle branch block plus left anterior or posterior hemiblock

• Use of a ventricular-paced pacemaker

• Congenital long QT syndrome or a known family history of long QT syndrome

• History of or presence of clinically significant ventricular or atrial tachyarrhythmias

• Clinically significant resting bradycardia (<50 bpm);

• QTcF >450 msec on screening ECG (using the QTcF formula). If QTc >450 and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc;

• History or clinical signs of myocardial infarction within 1 year of study entry

• History of unstable angina within 1 year of study entry

• Other clinically significant heart disease (e.g., congestive heart failureor uncontrolled hypertension).

• Treatment with strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. (Appendix B).

• Treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St John's Wort), and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.

• Patients using medication that have been documented to prolong QT interval (see Appendix B for complete list).

• Grade 3 or higher impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome).

• History of acute pancreatitis within one year of study entry or medical history of chronic pancreatitis.

• Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.

• Patients with any other clinically significant medical or surgical condition which, according to investigators' discretion, should preclude participation; (i.e.: severe renal disease unrelated to tumor, active or chronic liver disease- hepatitis B or C virus carriers with normal liver function tests, as described above, can be included). This includes patient with an acquired bleeding disorder unrelated to cancer.

• Use of any investigational agent within 28 days prior to enrollment in the study or foreseen use of an investigational agent during the study.

• History of non-compliance to medical regimens or inability to grant consent.

• Women who are pregnant, breast feeding, or of childbearing potential without a negative serum pregnancy test at baseline. Male or female patients of childbearing potential unwilling to use effective barrier contraceptives throughout the trial and for 3 months following discontinuation of study drug. Post-menopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential.

• Inability to comply with the study protocol.

• Patients with a history of CNS metastasis. Note: Patients without clinical signs and symptoms of CNS involvement are not required to have CT/MRI of the brain.

• Major surgery within 4 weeks prior to randomization or those who have not recovered from prior surgery

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1426ANZ
2	Novartis Investigative Site	Buenos Aires		Argentina	C1264AAA
3	Novartis Investigative Site	Fortaleza	CE	Brazil	60430-230
4	Novartis Investigative Site	Belo Horizonte	MG	Brazil	30130-100
5	Novartis Investigative Site	Divinopolis	MG	Brazil	35500-000
6	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	20230-130
7	Novartis Investigative Site	Natal	RN	Brazil	59040-000
8	Novartis Investigative Site	Porto Alegre	RS	Brazil	90020-090
9	Novartis Investigative Site	Porto Alegre	RS	Brazil	90610-000
10	Novartis Investigative Site	Barretos	SP	Brazil	14784-400
11	Novartis Investigative Site	São Paulo	SP	Brazil	01221-020
12	Novartis Investigative Site	São Paulo	SP	Brazil	05403-000
13	Novartis Investigative Site	Montreal	Quebec	Canada	H2L 4M1
14	Novartis Investigative Site	Chengdu	Sichuan	China	610041
15	Novartis Investigative Site	Beijing		China	100036
16	Novartis Investigative Site	Guang zhou		China	510080
17	Novartis Investigative Site	Guangzhou		China	510060
18	Novartis Investigative Site	Shanghai		China	200025
19	Novartis Investigative Site	Shanghai		China	200433
20	Novartis Investigative Site	Hwasun-gun	Jeollanam-do	Korea, Republic of	519-809
21	Novartis Investigative Site	Daegu		Korea, Republic of	705-717
22	Novartis Investigative Site	Seoul		Korea, Republic of	138-736
23	Novartis Investigative Site	Seoul		Korea, Republic of	139-706
24	Novartis Investigative Site	México	Distrito Federal	Mexico	06720
25	Novartis Investigative Site	Ekaterinburg		Russian Federation	620036
26	Novartis Investigative Site	Moscow		Russian Federation	115478
27	Novartis Investigative Site	St. Petersburg		Russian Federation	197022
28	Novartis Investigative Site	Bangkok		Thailand	10330
29	Novartis Investigative Site	Bangkok		Thailand	10700
30	Novartis Investigative Site	Khon Kaen		Thailand	40002
31	Novartis Investigative Site	Songkla		Thailand	90110
32	Novartis Investigative Site	Caracas	Distrito Capital	Venezuela	1010

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00751036
• Other Study ID Numbers: CAMN107DBR01; 2010-019806-18
• First Posted: Sep 11, 2008
• Last Update Posted: Mar 26, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by Novartis Pharmaceuticals: GIST
• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors; Imatinib Mesylate

Study Results

Participant Flow

Arm/Group Title	Nilotinib	Imatinib
Arm/Group Description	Patients who were assigned to this treatment group received 400 mg. nilotinib bid.	Patients who were assigned to this treatment group received 400 mg. imatinib bid.
Period Title: Overall Study
STARTED	48	46
COMPLETED	0	0
NOT COMPLETED	48	46

Baseline Characteristics

Arm/Group Title	Nilotinib	Imatinib	Total
Arm/Group Description	Patients who were assigned to this treatment group received 400 mg. nilotinib bid.	Patients who were assigned to this treatment group received 400 mg. imatinib bid.	Total of all reporting groups
Overall Participants	48	46	94
Age, Customized (Number) [Number]
<65 years	38 79.2%	35 76.1%	73 77.7%
≥ 65 years	9 18.8%	11 23.9%	20 21.3%
Missing	1 2.1%	0 0%	1 1.1%
Sex: Female, Male (Count of Participants)
Female	28 58.3%	19 41.3%	47 50%
Male	20 41.7%	27 58.7%	47 50%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) is the time from date of randomization to the date of first documented progression or death due to any cause. If a participant has not had an event, progression-free survival is censored at the time of last adequate tumor assessment. Progression is defined according to modified RECIST criteria as at least a 20% increase in the sum of the longest diameter of target lesions, worsening of the non-target lesions or the appearance of one or more new lesions.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all randomized patients. Following the intent to treat principle, patients were analyzed according to the treatment which they were assigned at randomization.

Arm/Group Title	Nilotinib	Imatinib
Arm/Group Description	Patients who were assigned to this treatment group received 400 mg. nilotinib bid.	Patients who were assigned to this treatment group received 400 mg. imatinib bid.
Measure Participants	48	46
Median (95% Confidence Interval) [Days]	111.00	120.00

2. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	The Disease Control Rate (Complete Response(CR), Partial Response (PD) and Stable Disease (SD) rates for each treatment arm will be computed using the exact Clopper-Pearson interval estimation methodology. DCR is defined as the percentage of patients with a best overall response of • CR, i.e. at least two determinations of CR at least 4 weeks apart without loss of response between the determinations, • PR, i.e. at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) and without loss of PR between the determinations, or • SD lasting at least 24 weeks, i.e. at least one SD or better response at least 24 weeks after randomization (and not qualifying for CR or PR).
Time Frame	every 2 months until 24 months (end of study)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): consisted of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.

Arm/Group Title	Nilotinib	Imatinib
Arm/Group Description	Patients who were assigned to this treatment group received 400 mg. nilotinib bid.	Patients who were assigned to this treatment group received 400 mg. imatinib bid.
Measure Participants	48	46
Disease Control Rate (CR, PR, or SD)	54.2	47.8
Complete Response (CR)	2.1	0
Partial Response (PR)	4.2	6.5
Stable Disease (SD)	47.9	41.3
Progressive Disease (PD)	25.0	37.0
Unknown (UNK)	20.8	15.2

3. Secondary Outcome

Title	Time to Treatment Failure
Description	TTF, defined as the time from date of randomization to the earliest of date of the first objective tumor progression, date of death due to any cause, or date of discontinuation due to reasons other than 'Protocol deviation' or 'Administrative problems'.
Time Frame	Time from date of radomization to the earliest date of the first objective tumor, death or discontinuation, assesed until 24 months.

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): consisted of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.

Arm/Group Title	Nilotinib	Imatinib
Arm/Group Description	Patients who were assigned to this treatment group received 400 mg. nilotinib bid.	Patients who were assigned to this treatment group received 400 mg. imatinib bid.
Measure Participants	48	46
Median (95% Confidence Interval) [Days]	90.00	112.00

4. Secondary Outcome

Title	Overall Survival (OS)
Description	. OS is defined as the time from the date of randomization to the date of death due to any cause or the date of last contact prior to or on the date of data cutoff. The median time to overall survival and its associated 95 % CI will be derived, for each treatment arm, using the time to event analysis based on Kaplan-Meier methodology.
Time Frame	time from the date of randomization to the date of death due to any cause or the date of last contact prior to or on the date of data cutoff, assesed until 24 months.

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): consisted of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.

Arm/Group Title	Nilotinib	Imatinib
Arm/Group Description	Patients who were assigned to this treatment group received 400 mg. nilotinib bid.	Patients who were assigned to this treatment group received 400 mg. imatinib bid.
Measure Participants	48	46
Median (95% Confidence Interval) [Days]	737	594.00

Adverse Events

Arm/Group Title	Nilotinib 800 mg		Imatinib 800 mg
Arm/Group Description	Patients who were assigned to this treatment group received 400 mg. nilotinib bid.		Patients who were assigned to this treatment group received 400 mg. imatinib bid.
All Cause Mortality
	Nilotinib 800 mg		Imatinib 800 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nilotinib 800 mg		Imatinib 800 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/48 (25%)		10/46 (21.7%)
Cardiac disorders
Acute myocardial infarction	1/48 (2.1%)		0/46 (0%)
Cardiac failure	0/48 (0%)		1/46 (2.2%)
Cardiopulmonary failure	1/48 (2.1%)		1/46 (2.2%)
Tachycardia	1/48 (2.1%)		0/46 (0%)
Gastrointestinal disorders
Abdominal mass	0/48 (0%)		1/46 (2.2%)
Abdominal pain	2/48 (4.2%)		1/46 (2.2%)
Duodenal ulcer	1/48 (2.1%)		0/46 (0%)
Duodenal ulcer haemorrhage	1/48 (2.1%)		0/46 (0%)
Enterocutaneous fistula	0/48 (0%)		1/46 (2.2%)
Gastric haemorrhage	1/48 (2.1%)		0/46 (0%)
Gastrointestinal haemorrhage	0/48 (0%)		1/46 (2.2%)
Gastrointestinal obstruction	0/48 (0%)		1/46 (2.2%)
Melaena	1/48 (2.1%)		0/46 (0%)
Rectal haemorrhage	1/48 (2.1%)		0/46 (0%)
Small intestinal haemorrhage	1/48 (2.1%)		0/46 (0%)
General disorders
Asthenia	0/48 (0%)		1/46 (2.2%)
Disease progression	2/48 (4.2%)		1/46 (2.2%)
Drug ineffective	1/48 (2.1%)		1/46 (2.2%)
Performance status decreased	0/48 (0%)		1/46 (2.2%)
Hepatobiliary disorders
Hepatitis acute	0/48 (0%)		1/46 (2.2%)
Hepatotoxicity	0/48 (0%)		1/46 (2.2%)
Hyperbilirubinaemia	0/48 (0%)		1/46 (2.2%)
Infections and infestations
Bronchopneumonia	1/48 (2.1%)		0/46 (0%)
Necrotising fasciitis	0/48 (0%)		1/46 (2.2%)
Peritonitis	1/48 (2.1%)		0/46 (0%)
Respiratory tract infection	1/48 (2.1%)		0/46 (0%)
Septic shock	0/48 (0%)		1/46 (2.2%)
Metabolism and nutrition disorders
Decreased appetite	0/48 (0%)		1/46 (2.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastrointestinal stromal tumour	2/48 (4.2%)		1/46 (2.2%)
Neoplasm	2/48 (4.2%)		0/46 (0%)
Neoplasm malignant	0/48 (0%)		1/46 (2.2%)
Nervous system disorders
Depressed level of consciousness	1/48 (2.1%)		0/46 (0%)
Renal and urinary disorders
Renal failure	1/48 (2.1%)		0/46 (0%)
Urinary retention	1/48 (2.1%)		0/46 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/48 (2.1%)		1/46 (2.2%)
Surgical and medical procedures
Tumour excision	1/48 (2.1%)		0/46 (0%)
Other (Not Including Serious) Adverse Events
	Nilotinib 800 mg		Imatinib 800 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/48 (81.3%)		41/46 (89.1%)
Blood and lymphatic system disorders
Anaemia	14/48 (29.2%)		15/46 (32.6%)
Thrombocytopenia	1/48 (2.1%)		3/46 (6.5%)
Eye disorders
Eyelid oedema	0/48 (0%)		6/46 (13%)
Gastrointestinal disorders
Abdominal distension	4/48 (8.3%)		7/46 (15.2%)
Abdominal pain	8/48 (16.7%)		11/46 (23.9%)
Abdominal pain upper	4/48 (8.3%)		4/46 (8.7%)
Ascites	0/48 (0%)		3/46 (6.5%)
Constipation	7/48 (14.6%)		2/46 (4.3%)
Diarrhoea	4/48 (8.3%)		14/46 (30.4%)
Dyspepsia	2/48 (4.2%)		6/46 (13%)
Nausea	12/48 (25%)		20/46 (43.5%)
Vomiting	10/48 (20.8%)		13/46 (28.3%)
General disorders
Asthenia	6/48 (12.5%)		5/46 (10.9%)
Face oedema	0/48 (0%)		9/46 (19.6%)
Fatigue	10/48 (20.8%)		12/46 (26.1%)
Oedema peripheral	3/48 (6.3%)		9/46 (19.6%)
Pyrexia	8/48 (16.7%)		5/46 (10.9%)
Hepatobiliary disorders
Hyperbilirubinaemia	8/48 (16.7%)		0/46 (0%)
Infections and infestations
Influenza	3/48 (6.3%)		1/46 (2.2%)
Nasopharyngitis	1/48 (2.1%)		3/46 (6.5%)
Upper respiratory tract infection	1/48 (2.1%)		3/46 (6.5%)
Urinary tract infection	3/48 (6.3%)		0/46 (0%)
Investigations
Alanine aminotransferase increased	8/48 (16.7%)		1/46 (2.2%)
Aspartate aminotransferase increased	7/48 (14.6%)		1/46 (2.2%)
Blood albumin decreased	3/48 (6.3%)		1/46 (2.2%)
Blood alkaline phosphatase increased	4/48 (8.3%)		0/46 (0%)
Blood bilirubin increased	8/48 (16.7%)		0/46 (0%)
Blood calcium decreased	0/48 (0%)		3/46 (6.5%)
Blood potassium decreased	1/48 (2.1%)		6/46 (13%)
Gamma-glutamyltransferase increased	3/48 (6.3%)		0/46 (0%)
Neutrophil count decreased	2/48 (4.2%)		4/46 (8.7%)
White blood cell count decreased	2/48 (4.2%)		8/46 (17.4%)
Metabolism and nutrition disorders
Decreased appetite	6/48 (12.5%)		10/46 (21.7%)
Hyperglycaemia	5/48 (10.4%)		1/46 (2.2%)
Hypokalaemia	0/48 (0%)		3/46 (6.5%)
Hypophosphataemia	2/48 (4.2%)		6/46 (13%)
Musculoskeletal and connective tissue disorders
Myalgia	3/48 (6.3%)		1/46 (2.2%)
Pain in extremity	2/48 (4.2%)		3/46 (6.5%)
Nervous system disorders
Dizziness	1/48 (2.1%)		3/46 (6.5%)
Headache	8/48 (16.7%)		2/46 (4.3%)
Renal and urinary disorders
Dysuria	3/48 (6.3%)		2/46 (4.3%)
Respiratory, thoracic and mediastinal disorders
Cough	3/48 (6.3%)		2/46 (4.3%)
Dyspnoea	3/48 (6.3%)		1/46 (2.2%)
Skin and subcutaneous tissue disorders
Pruritus	5/48 (10.4%)		1/46 (2.2%)
Rash	8/48 (16.7%)		2/46 (4.3%)
Vascular disorders
Hypertension	1/48 (2.1%)		3/46 (6.5%)

Limitations/Caveats

Patients were limited (planned 300, Actual 94). Early termination of study; not sufficient power to test the original primary hypothesis with respect to PFS. Only descriptive analyses were carried out for this study.

More Information

Certain Agreements

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

Principal Investigators are NOT employed by the organization sponsoring the study. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. 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 pooled data (i.e.,data from all sites) in clinical trial.