TRACER: Safety and Efficacy of RAD001 + TACE in Localized Unresectable HCC

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01379521
• Collaborator: (none)
• Enrollment: 65
• Locations: 5
• Arms: 2
• Duration (Months): 48
• Patients Per Site: 13
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will evaluate the role of everolimus in combination with local Transcatheter Arterial Chemoembolization (TACE) procedure in patients with localized unresectable Hepatocellular Carcinoma (HCC).

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: everolimus; Drug: everolimus placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized, Double-blinded, Multicenter Asian Study Investigating the Combination of Transcatheter Arterial Chemoembolization (TACE) and Oral Everolimus (RAD001, Afinitor®) in Localised Unresectable Hepatocellular Carcinoma (HCC) - The TRACER Study
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: everolimus + TACE everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Drug: everolimus; Other Names: RAD001 Afinitor®)
Placebo Comparator: placebo + TACE Placebo by mouth + transcatheter arterial chemoembolization (TACE)	Drug: everolimus placebo

Outcome Measures

Primary Outcome Measures

1. Time to Progression (TTP) Based on the Modified RECIST Criteria [3, 6, 12, 18 and 24 months]

   Time to Progression (TTP) defined as the time from the date of randomization to the date of first documented radiological confirmation of disease progression based on modified RECIST criteria. Progressive Disease: >20% increase in sum of the longest diameters (SLD) of "viable" target lesion (arterial phase enhancement)

Secondary Outcome Measures

1. Overall Response Rate (ORR) and Disease Control Rate (DCR) Based on the Modified RECIST [6, 12 months, end of study]

   Overall response rate was defined as the number of patients whose best overall response was either complete response or partial response according to the modified RECIST. Complete response: Disappearance of arterial phase enhance-ment in all target lesions. Partial response: >30% decrease in sum of the longest diameters (SLD) of "viable" target lesion (arterial phase enhance-ment)Disease control rate was defined as the number of patients with a best overall response of complete response, partial response or stable disease. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.

2. Time to Progression Based on Original RECIST [6, 12 months, end of study]

   Time to Progression (TTP) defined as the time from the date of randomization to the date of first documented radiological confirmation of disease progression based on original RECIST criteria. Progressive Disease: >20% increase in sum of the longest diameters (SLD) of target lesions with an absolute increase of ≥5 mm; new lesions. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.

3. Overall Response Rate (ORR) and Disease Control Rate (DCR) Based on Original RECIST [6, 12 months, end of study]

   Overall response rate was defined as the number of patients whose best overall response was either complete response or partial response according to the Complete response: Disappearance of all target lesions or lymph nodes <10 mm in the short axis Partial response: >30% decrease in sum of the longest diameters (SLD) of target lesions Disease control rate was defined as the number of patients with a best overall response of complete response, partial response or stable disease. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.

4. Overall Survival (OS) [6, 12, 18, 24, 30 months]

   Overall survival was defined as the time from date of randomization to date of death due to any cause. If death had not occurred at the date of the analysis cut-off then OS was censored at the date of the last contact.

5. Incidences of Cumulative New Nodular Recurrence, Portal Vein Invasion and Extra Hepatic Metastases [30 months]

   Incidences of cumulative new nodular recurrence, portal vein invasion and extra hepatic metastases but incidence of portal vein invasion meant those patients without documented vascular invasion at screening/baseline. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.

6. Percentage of Participants With a Decrease in the Sum of the of Longest Diameters (SLD) of Target Lesions From Baseline to 30 Months [baseline, 30 months]

   Percentage of participants with a decrease in the sum of the of longest diameters (SLD) of target lesions from Baseline to 30 months

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Newly diagnosed hepatocellular carcinoma limited to liver and not suitable for resection, liver transplant, or radiofrequency ablation.

• Intermediate stage (stage B) (according to recognized guidelines) and suitable for TACE therapy

• At least one nodule between > 2cm and ≤ 15cm in diameter with no vascular invasion or abdominal lymph node or distant metastases.

• Must have 1 tumor which can be measured in 1 dimension according to specified criteria (RECIST and mRECIST) and has not previously been treated with any type of therapy.

• ECOG performance status < 2cm

• Cirrhotic status of Child-Pugh class A or early B

• HBV-DNA or HBsAg positive at screen or baseline: preventative treatment with anti-viral started 1-2 weeks prior to receiving study drug

Exclusion Criteria:

• Any local and/or investigational drugs within 28 days prior to randomization

• Active bleeding during the last 28 days prior to screening including variceal bleeding

• Prior therapy with mTOR inhibitors

• Tumor burden of > 60% liver involvement

• Prior systemic or local therapy including TACE except for the first TACE at Day 0), surgery or liver transplantation

• Failed first TACE at Day 0, Cycle 1 for any reason

• Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory)

• Alcohol intake of 80 grams per day

• Undergone major surgery ≤ 3 weeks prior to starting study drug or who have not recovered from surgery

• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Hong Kong		Hong Kong
2	Novartis Investigative Site	Kaohsiung		Taiwan	807
3	Novartis Investigative Site	Kaohsiung		Taiwan	83301
4	Novartis Investigative Site	Lin-Kou		Taiwan	33305
5	Novartis Investigative Site	Chiang Mai		Thailand	50200

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: NCT01379521
• Other Study ID Numbers: CRAD001OHK02
• First Posted: Jun 23, 2011
• Last Update Posted: May 3, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Novartis Pharmaceuticals: Localised; unresectable; chemoembolization
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Everolimus

Study Results

Participant Flow

Recruitment Details	Of the 65 patients who were screened they reflect the actual enrolment but 59 patients were randomized and were included in the FAS, the Safety Set and the PP Set. There were no exclusions. Post-Treatment evaluations included any patients that was treated and does not reflect the number completed in the Overall Study.

Arm/Group Title	Everolimus + TACE	Placebo + TACE
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Placebo by mouth + transcatheter arterial chemoembolization (TACE)
Period Title: Overall Study -Treatment Period
STARTED	33	26
COMPLETED	0	0
NOT COMPLETED	33	26
Period Title: Overall Study -Treatment Period
STARTED	25	21
COMPLETED	0	0
NOT COMPLETED	25	21

Baseline Characteristics

Arm/Group Title	Everolimus + TACE	Placebo + TACE	Total
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Placebo by mouth + transcatheter arterial chemoembolization (TACE)	Total of all reporting groups
Overall Participants	33	26	59
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.5 (11.29)	61.0 (10.32)	59.6 (10.85)
Sex: Female, Male (Count of Participants)
Female	4 12.1%	7 26.9%	11 18.6%
Male	29 87.9%	19 73.1%	48 81.4%

Outcome Measures

1. Primary Outcome

Title	Time to Progression (TTP) Based on the Modified RECIST Criteria
Description	Time to Progression (TTP) defined as the time from the date of randomization to the date of first documented radiological confirmation of disease progression based on modified RECIST criteria. Progressive Disease: >20% increase in sum of the longest diameters (SLD) of "viable" target lesion (arterial phase enhancement)
Time Frame	3, 6, 12, 18 and 24 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all randomized patients.

Arm/Group Title	Everolimus + TACE	Placebo + TACE
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Placebo by mouth + transcatheter arterial chemoembolization (TACE)
Measure Participants	33	26
Median (90% Confidence Interval) [months]	6.3	6.4

2. Secondary Outcome

Title	Overall Response Rate (ORR) and Disease Control Rate (DCR) Based on the Modified RECIST
Description	Overall response rate was defined as the number of patients whose best overall response was either complete response or partial response according to the modified RECIST. Complete response: Disappearance of arterial phase enhance-ment in all target lesions. Partial response: >30% decrease in sum of the longest diameters (SLD) of "viable" target lesion (arterial phase enhance-ment)Disease control rate was defined as the number of patients with a best overall response of complete response, partial response or stable disease. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Time Frame	6, 12 months, end of study

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.

Arm/Group Title	Everolimus + TACE	Placebo + TACE
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Placebo by mouth + transcatheter arterial chemoembolization (TACE)
Measure Participants	0	0

3. Secondary Outcome

Title	Time to Progression Based on Original RECIST
Description	Time to Progression (TTP) defined as the time from the date of randomization to the date of first documented radiological confirmation of disease progression based on original RECIST criteria. Progressive Disease: >20% increase in sum of the longest diameters (SLD) of target lesions with an absolute increase of ≥5 mm; new lesions. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Time Frame	6, 12 months, end of study

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.

Arm/Group Title	Everolimus + TACE	Placebo + TACE
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Placebo by mouth + transcatheter arterial chemoembolization (TACE)
Measure Participants	0	0

4. Secondary Outcome

Title	Overall Response Rate (ORR) and Disease Control Rate (DCR) Based on Original RECIST
Description	Overall response rate was defined as the number of patients whose best overall response was either complete response or partial response according to the Complete response: Disappearance of all target lesions or lymph nodes <10 mm in the short axis Partial response: >30% decrease in sum of the longest diameters (SLD) of target lesions Disease control rate was defined as the number of patients with a best overall response of complete response, partial response or stable disease. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Time Frame	6, 12 months, end of study

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.

Arm/Group Title	Everolimus + TACE	Placebo + TACE
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Placebo by mouth + transcatheter arterial chemoembolization (TACE)
Measure Participants	0	0

5. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was defined as the time from date of randomization to date of death due to any cause. If death had not occurred at the date of the analysis cut-off then OS was censored at the date of the last contact.
Time Frame	6, 12, 18, 24, 30 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered

Arm/Group Title	Everolimus + TACE	Placebo + TACE
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Placebo by mouth + transcatheter arterial chemoembolization (TACE)
Measure Participants	33	26
Median (90% Confidence Interval) [months]	29.9	21.7

6. Secondary Outcome

Title	Incidences of Cumulative New Nodular Recurrence, Portal Vein Invasion and Extra Hepatic Metastases
Description	Incidences of cumulative new nodular recurrence, portal vein invasion and extra hepatic metastases but incidence of portal vein invasion meant those patients without documented vascular invasion at screening/baseline. The study was terminated early due to slow enrollment of 4 years, higher than anticipated screen failure rate due to a higher than anticipated proportion of patients having advanced liver disease and a change in clinical practice the total of 80 patients was not reached with only 59 patients recruited in total. The study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all randomized patients. The trial results are inconclusive as the study was underpowered due to termination therefore data was not collected and the outcome measure was not analyzed.

Arm/Group Title	Everolimus + TACE	Placebo + TACE
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Placebo by mouth + transcatheter arterial chemoembolization (TACE)
Measure Participants	0	0

7. Secondary Outcome

Title	Percentage of Participants With a Decrease in the Sum of the of Longest Diameters (SLD) of Target Lesions From Baseline to 30 Months
Description	Percentage of participants with a decrease in the sum of the of longest diameters (SLD) of target lesions from Baseline to 30 months
Time Frame	baseline, 30 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) comprises all randomized patients.

Arm/Group Title	Everolimus + TACE	Placebo + TACE
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)	Placebo by mouth + transcatheter arterial chemoembolization (TACE)
Measure Participants	32	25
Number [Percentage of participants]	93.8 284.2%	88.0 338.5%

Adverse Events

Arm/Group Title	Everolimus + TACE		Placebo + TACE
Arm/Group Description	everolimus 7.5mg/day by mouth + transcatheter arterial chemoembolization (TACE)		Placebo by mouth + transcatheter arterial chemoembolization (TACE)
All Cause Mortality
	Everolimus + TACE		Placebo + TACE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Everolimus + TACE		Placebo + TACE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/33 (30.3%)		7/26 (26.9%)
Cardiac disorders
Acute myocardial infarction	1/33 (3%)		0/26 (0%)
Cardiac failure congestive	1/33 (3%)		0/26 (0%)
Gastrointestinal disorders
Abdominal pain	0/33 (0%)		1/26 (3.8%)
Intestinal ischaemia	0/33 (0%)		1/26 (3.8%)
Oesophageal haemorrhage	1/33 (3%)		0/26 (0%)
Upper gastrointestinal haemorrhage	1/33 (3%)		0/26 (0%)
General disorders
Multi-organ failure	1/33 (3%)		0/26 (0%)
Pyrexia	2/33 (6.1%)		0/26 (0%)
Infections and infestations
Liver abscess	1/33 (3%)		1/26 (3.8%)
Peritonitis bacterial	0/33 (0%)		1/26 (3.8%)
Pneumonia	1/33 (3%)		1/26 (3.8%)
Sepsis	0/33 (0%)		1/26 (3.8%)
Septic shock	1/33 (3%)		0/26 (0%)
Injury, poisoning and procedural complications
Post embolisation syndrome	1/33 (3%)		0/26 (0%)
Renal haematoma	1/33 (3%)		0/26 (0%)
Investigations
Hepatic enzyme increased	1/33 (3%)		0/26 (0%)
Metabolism and nutrition disorders
Hyperkalaemia	1/33 (3%)		0/26 (0%)
Hypoalbuminaemia	1/33 (3%)		0/26 (0%)
Renal and urinary disorders
Renal failure acute	1/33 (3%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	1/33 (3%)		0/26 (0%)
Vascular disorders
Hypertension	1/33 (3%)		0/26 (0%)
Hypotension	0/33 (0%)		1/26 (3.8%)
Hypovolaemic shock	0/33 (0%)		1/26 (3.8%)
Other (Not Including Serious) Adverse Events
	Everolimus + TACE		Placebo + TACE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/33 (100%)		25/26 (96.2%)
Blood and lymphatic system disorders
Anaemia	6/33 (18.2%)		3/26 (11.5%)
Thrombocytopenia	6/33 (18.2%)		1/26 (3.8%)
Gastrointestinal disorders
Abdominal discomfort	0/33 (0%)		2/26 (7.7%)
Abdominal pain	19/33 (57.6%)		17/26 (65.4%)
Abdominal pain upper	8/33 (24.2%)		5/26 (19.2%)
Ascites	5/33 (15.2%)		2/26 (7.7%)
Constipation	6/33 (18.2%)		8/26 (30.8%)
Diarrhoea	4/33 (12.1%)		2/26 (7.7%)
Gastritis	2/33 (6.1%)		0/26 (0%)
Gingival bleeding	2/33 (6.1%)		0/26 (0%)
Irritable bowel syndrome	2/33 (6.1%)		0/26 (0%)
Mouth ulceration	9/33 (27.3%)		2/26 (7.7%)
Nausea	6/33 (18.2%)		5/26 (19.2%)
Stomatitis	7/33 (21.2%)		0/26 (0%)
Vomiting	7/33 (21.2%)		6/26 (23.1%)
General disorders
Mucosal inflammation	2/33 (6.1%)		0/26 (0%)
Oedema peripheral	5/33 (15.2%)		0/26 (0%)
Pyrexia	12/33 (36.4%)		12/26 (46.2%)
Infections and infestations
Hepatitis b	2/33 (6.1%)		0/26 (0%)
Herpes zoster	3/33 (9.1%)		0/26 (0%)
Nasopharyngitis	2/33 (6.1%)		0/26 (0%)
Pneumonia	2/33 (6.1%)		0/26 (0%)
Skin infection	2/33 (6.1%)		0/26 (0%)
Upper respiratory tract infection	2/33 (6.1%)		0/26 (0%)
Investigations
Alanine aminotransferase increased	2/33 (6.1%)		1/26 (3.8%)
Aspartate aminotransferase increased	3/33 (9.1%)		1/26 (3.8%)
Blood alkaline phosphatase increased	0/33 (0%)		2/26 (7.7%)
Platelet count decreased	3/33 (9.1%)		1/26 (3.8%)
Weight decreased	3/33 (9.1%)		2/26 (7.7%)
Metabolism and nutrition disorders
Decreased appetite	11/33 (33.3%)		5/26 (19.2%)
Dyslipidaemia	3/33 (9.1%)		0/26 (0%)
Hyperglycaemia	4/33 (12.1%)		0/26 (0%)
Hypoalbuminaemia	2/33 (6.1%)		0/26 (0%)
Hypokalaemia	5/33 (15.2%)		1/26 (3.8%)
Hypomagnesaemia	2/33 (6.1%)		0/26 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/33 (6.1%)		1/26 (3.8%)
Back pain	4/33 (12.1%)		1/26 (3.8%)
Flank pain	2/33 (6.1%)		1/26 (3.8%)
Musculoskeletal pain	4/33 (12.1%)		2/26 (7.7%)
Myalgia	0/33 (0%)		2/26 (7.7%)
Nervous system disorders
Dizziness	2/33 (6.1%)		0/26 (0%)
Headache	4/33 (12.1%)		2/26 (7.7%)
Psychiatric disorders
Insomnia	7/33 (21.2%)		5/26 (19.2%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/33 (6.1%)		1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
Cough	6/33 (18.2%)		6/26 (23.1%)
Epistaxis	4/33 (12.1%)		0/26 (0%)
Skin and subcutaneous tissue disorders
Alopecia	1/33 (3%)		3/26 (11.5%)
Pruritus	2/33 (6.1%)		2/26 (7.7%)
Rash	4/33 (12.1%)		0/26 (0%)
Vascular disorders
Hypertension	4/33 (12.1%)		1/26 (3.8%)

Limitations/Caveats

[Not Specified]

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.