RAD001 in Advanced Hepatocellular Carcinoma

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00516165
• Collaborator: Dana-Farber Cancer Institute (Other), Beth Israel Deaconess Medical Center (Other), Novartis (Industry)
• Enrollment: 28
• Locations: 3
• Arm: 1
• Duration (Months): 51
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Laboratory studies have shown that RAD001 can prevent cells from multiplying. Consequently, the study drug is being tested in medical conditions in which excessive cell multiplication (as in cancer) needs to be stopped. The main purpose of this research study is to find the highest dose of RAD001 that can be given safely (without causing severe side effects) and to learn the effects (good or bad) RAD001 has on participants with liver cancer.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: RAD001	Phase 1/Phase 2

Detailed Description

• Participants will be given a supply of the study drug RAD001 to be taken at home. They will be asked to take the study drug every morning on an empty stomach and will be given a study drug diary to record the time/date each time they take RAD001. Each 6 week period of time is called a cycle of study treatment.

• We are looking for the highest dose of RAD001 that can be given safely. Therefore not every participant will receive the same dose of RAD001.

• Participants will come to the clinic every other week. At each of these visits, a physical examination and blood tests will be performed.

• A CT and MRI will be repeated every 6 weeks during the first 3 cycles of treatment then every 12 weeks thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of RAD001 in Advanced Hepatocellular Carcinoma
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RAD001 Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death.	Drug: RAD001; Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days; Other Names: Everolimus

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose of RAD001 in Patients With Advanced Hepatocellular Carcinoma (HCC). [2 years]

2. Progression-free Survival Rate at 24 Weeks [2 years]

   Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions" This information will be collected during two years of patient participation.

Secondary Outcome Measures

1. Number of Patients With Adverse Events Who Were Treated With RAD001 for Advanced HCC [2 years]

   Everolimus given at 10 mg/day as a single agent was well tolerated in patients with advanced HCC.

2. Overall Response Rate [2 years]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

3. Time to Progression [2 years]

   3.9 months with a CI of 21-

4. Overall Survival [2 years]

   The median overall survival was 8.4 months (95% CI, 3.9-21.1 months). Only 2 ((8 %) patients were progression-free at 24 weeks. The study did not proceed to the second stage of the phase 2 portion of the study.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Unresectable of metastatic HCC. Patients must have prior core biopsy to confirm the diagnosis of HCC and have archived tissues available for correlative studies

• At least one measurable site of disease according to RECIST criteria that has not been previously irradiated. If it has had previous radiation to teh marker lesion(s), there must be evidence of progression since the radiation

• 0-2 prior systemic chemotherapy and biologic regimens for hepatocellular carcinoma

• Patients with prior chemoembolization history can participate in the study if the chemoembolization was performed more than 4 weeks ago and patients must have measurable disease outside of prior chemoembolization field

• 18 years of age or older

• Minimum of 4 weeks since any major surgery or completion of radiation

• Minimum of 4 weeks since completion of all prior systemic anticancer therapy

• ECOG performance status of 0-2

• CLIP score of equal to or less then 3

• Adequate bone marrow, liver and renal function as outlined in the protocol

Exclusion Criteria:

• Prior treatment with any investigational drug within the preceding 4 weeks

• Chronic treatment with systemic steroids or another immunosuppressive agent

• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases

• Patients with any severe and/or uncontrolled medical conditions or other condition that could affect participation in the study

• Known history of HIV seropositivity

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001

• Active, bleeding diathesis

• Women who are pregnant or breast feeding

• Patients who have received prior treatment with an mTor inhibitor

• Patients with known hypersensitivity to RAD001 or other rapamycins or its excipients

• History of non-compliance to medical regimens

• Patients with a positive dipstick for urine protein (reading of 2+ or greater) will then undergo a 24-hour urine collection for protein. If patients have a 2g or greater of protein/24hr, they will be excluded from the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Massachusetts General Hospital
• Dana-Farber Cancer Institute
• Beth Israel Deaconess Medical Center
• Novartis

Investigators

• Principal Investigator: Andrew X. Zhu, MD, PhD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Andrew X. Zhu, MD, Principal Investigator, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00516165
• Other Study ID Numbers: 06-352
• First Posted: Aug 15, 2007
• Last Update Posted: Feb 7, 2017
• Last Verified: Dec 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Andrew X. Zhu, MD, Principal Investigator, Massachusetts General Hospital: liver cancer; RAD001
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Everolimus

Study Results

Participant Flow

Arm/Group Title	RAD001
Arm/Group Description	Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death. RAD001: Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days
Period Title: Overall Study
STARTED	28
COMPLETED	28
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	RAD001
Arm/Group Description	Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death. RAD001: Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days
Overall Participants	28
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	13 46.4%
>=65 years	15 53.6%
Gender (Count of Participants)
Female	10 35.7%
Male	18 64.3%
Region of Enrollment (participants) [Number]
United States	28 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose of RAD001 in Patients With Advanced Hepatocellular Carcinoma (HCC).
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Patients with histologically confirmed measurable advanced Hepatocellular Carcinoma.

Arm/Group Title	RAD001
Arm/Group Description	Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death. RAD001: Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days
Measure Participants	25
Number [mg]	10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RAD001
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Kaplan Meier
	Comments

2. Primary Outcome

Title	Progression-free Survival Rate at 24 Weeks
Description	Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions" This information will be collected during two years of patient participation.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001
Arm/Group Description	Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death. RAD001: Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days
Measure Participants	28
Median (95% Confidence Interval) [months]	3.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RAD001
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Kaplan-Meier
	Comments

3. Secondary Outcome

Title	Number of Patients With Adverse Events Who Were Treated With RAD001 for Advanced HCC
Description	Everolimus given at 10 mg/day as a single agent was well tolerated in patients with advanced HCC.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Patients with histologically confirmed measurable advanced HCC. The primary end points were determination of a safe dosage of everolimus and progression-free survival at 24 weeks.

Arm/Group Title	RAD001
Arm/Group Description	Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death. RAD001: Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days
Measure Participants	28
Count of Participants [Participants]	28 100%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RAD001
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Kaplan-Meier
	Comments

4. Secondary Outcome

Title	Overall Response Rate
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001
Arm/Group Description	Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death. RAD001: Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days
Measure Participants	28
Number (95% Confidence Interval) [percentage of patient response]	4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RAD001
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Kaplan-Meier
	Comments

5. Secondary Outcome

Title	Time to Progression
Description	3.9 months with a CI of 21-
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001
Arm/Group Description	Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death. RAD001: Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days
Measure Participants	28
Median (95% Confidence Interval) [month]	3.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RAD001
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Kaplan-Meier
	Comments

6. Secondary Outcome

Title	Overall Survival
Description	The median overall survival was 8.4 months (95% CI, 3.9-21.1 months). Only 2 ((8 %) patients were progression-free at 24 weeks. The study did not proceed to the second stage of the phase 2 portion of the study.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001
Arm/Group Description	Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death. RAD001: Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days
Measure Participants	28
Median (95% Confidence Interval) [months]	8.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RAD001
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Kaplan-Meier
	Comments

Adverse Events

Time Frame	October 2007 and June 2009; Participants were followed for this two year time period.
Adverse Event Reporting Description	28 patients entered into the trial (9 in phase 1, 19 in phase 2) and all were evaluable for efficacy and toxicity based on intention-to-treat analysis. There were 18 men (64%) and 10 women (36%) with a median age of 65 years (range, 33-81 years).
Arm/Group Title	RAD001
Arm/Group Description	Patients will receive RAD001 10 mg/day orally (6 weeks/cycle). Patients will be continued on treatment until disease progression, limiting toxicity, patient withdrawal of consent, or death. RAD001: Oral pills taken daily in a 42-day cycle (6 weeks). Cycles will be repeated every 42 days
All Cause Mortality
	RAD001
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	RAD001
	Affected / at Risk (%)	# Events
Total	7/28 (25%)
Blood and lymphatic system disorders
Grade 4 Hypophosphatemis	1/28 (3.6%)
Grade 4 elevated SGOT	1/28 (3.6%)
Gastrointestinal disorders
Grade 4 Bilirubin	1/28 (3.6%)
General disorders
Grade 5-Death within 30 days.	4/28 (14.3%)	4
Grade 4-Hypoxia	1/28 (3.6%)
Respiratory failure	1/28 (3.6%)
Metabolism and nutrition disorders
Grade 4 Anemia	1/28 (3.6%)	1
Grade 4 Thrombocytopenia	1/28 (3.6%)	1
Nervous system disorders
Grade 3 Encephalopathy-unrelated	1/28 (3.6%)	1
Other (Not Including Serious) Adverse Events
	RAD001
	Affected / at Risk (%)	# Events
Total	28/28 (100%)
Blood and lymphatic system disorders
Anemia	11/28 (39.3%)	44
Lymphopenia	8/28 (28.6%)	32
Gastrointestinal disorders
Diarrhea	11/28 (39.3%)	44
Stomatitis	7/28 (25%)	28
Vomiting	4/28 (14.3%)	16
Nausea	4/28 (14.3%)	16
Constipation	2/28 (7.1%)	8
Pain	2/28 (7.1%)	8
General disorders
Fatigue	13/28 (46.4%)	52
Cough	2/28 (7.1%)	8
Insomnia	2/28 (7.1%)	8
Immune system disorders
Edema	3/28 (10.7%)	12
Investigations
Leukopenia	10/28 (35.7%)	40
Platelets	10/28 (35.7%)	40
Aspartate transaminase	9/28 (32.1%)	36
Alanine transaminase	6/28 (21.4%)	24
Neutropenia	5/28 (17.9%)	20
Alkaline phosphatase	4/28 (14.3%)	16
Proteinuria	4/28 (14.3%)	16
Weight loss	3/28 (10.7%)	12
Hypoalbuminemia	2/28 (7.1%)	8
Hypokalemia	2/28 (7.1%)	8
Hypertriglyceridemia	2/28 (7.1%)	8
Fever without neuropenia	2/28 (7.1%)	8
Nose bleeds	2/28 (7.1%)	8
Metabolism and nutrition disorders
Hyperglycemia	12/28 (42.9%)	48
Hyponatremia	9/28 (32.1%)	36
Anorexia	9/28 (32.1%)	36
Nervous system disorders
Taste disturbance	3/28 (10.7%)	12
Respiratory, thoracic and mediastinal disorders
Dyspnea	4/28 (14.3%)	16
Skin and subcutaneous tissue disorders
Rash	7/28 (25%)	28
Acne rash	3/28 (10.7%)	12
Pruritis	2/28 (7.1%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.