Trial of RAD001 in Patients With Operable Non-Small Cell Lung Cancer (NSCLC)

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00401778
• Collaborator: (none)
• Enrollment: 33
• Location: 1
• Arms: 3
• Duration (Months): 85
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This is a Phase 1b pre-operative lung cancer trial wherein patients with operable lung cancer will be treated with RAD001 to evaluate the target effects of this compounds on relevant molecular pathways and on the 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (FDG) uptake of the tumor by a positron emission tomography (PET) scan at baseline and immediately prior to surgery. The safety profile of RAD001 will also be evaluated.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Drug: RAD001	Phase 1

Detailed Description

This is a Phase 1b pre-operative lung cancer trial wherein patients with operable lung cancer will be treated with RAD001 for 3-4 weeks to study the effects of the novel agent in relevant molecular pathways. The study will also assess the FDG uptake of the tumor at baseline and upon completion of therapy (before surgery) with a PET scan. The safety profile of RAD001 will also be evaluated.

New agents and regimens are urgently needed for lung cancer treatment. With the development of novel agents and small molecules designed to curtail the aggressive aspects of this disease, some progress has been realized. However, much more effort and insight will be required for further real gains to be made. We propose that studying the mammalian target of rapamycin (mTOR) axis, known to be abnormal in non-small cell lung cancer (NSCLC), and translating that knowledge into therapeutic adjustments can lead to meaningful advances in lung cancer treatment.

Approximately 35 patients will participate at Winship Cancer Institute of Emory University in Atlanta, Georgia.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Trial of RAD001 in Patients With Operable Non-Small Cell Lung Cancer (NSCLC)
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 RAD001 5 mg/day for 21 days sequentially.	Drug: RAD001; Patients will be assigned to one of three treatment arms with RAD001 doses of 5, and 10 mg/day for 21-28 days sequentially taken orally in tablet form.; Other Names: Everolimus
Active Comparator: 3 RAD001 10 mg/day for 21 days sequentially.	Drug: RAD001; Patients will be assigned to one of three treatment arms with RAD001 doses of 5, and 10 mg/day for 21-28 days sequentially taken orally in tablet form.; Other Names: Everolimus
No Intervention: Control Patients who are eligible for the study but choose not to receive RAD001 treatment.

Outcome Measures

Primary Outcome Measures

1. Clinical Response as Assessed Metabolically by Changes in Positron Emission Tomography (PET) Scan Between Baseline and Immediately Prior to Surgery. [Day 21]

   All patients had baseline imaging in a fasted state with 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (18FDG)-PET scan and a repeat scan at 3 to 4 weeks later using routine clinical protocol for patient preparation, radiotracer administration and data acquisition. The repeat imaging occurred no longer than 24 hours before surgical resection.

2. Effects of RAD001 on the Regulation of Key Proteins Involved With the Mammalian Target of Rapamycin (mTOR) Axis in Tumor Specimens and Buccal Mucosa in Patients With Operable Non-small Cell Lung Cancer (NSCLC). [6 months]

   Changes in the expression of key signaling proteins in the mTOR/phosphatidylinositol 3-kinase (PI3K) pathway were determined by immunohistochemistry using previously published protocols and manufacturers' recommendations for antigen retrieval and antibody dilution along with positive and negative controls. Two investigators assessed protein expression jointly by light microscopy. The degree of expression was assessed by intensity (0, 1+, 2+, 3+) and percentage of cell staining in line with published algorithm. A derivative score (immunoscore) ranging between 0 and 300 was calculated as the product of intensity and percent cell staining.

3. Inhibition of Proliferation (Ki67) and Induction of Apoptosis (TUNEL Assay) in Tumor Specimens and Buccal Mucosa. [6 months]

Secondary Outcome Measures

1. Safety and Tolerability of RAD001 as Pre-operative Therapy. [6 months]

2. Duration of Hospital Stay Following Surgery. [6 months]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patient must have histologically confirmed Stage I-IIIA non-small cell lung cancer (NSCLC) which is accessible to biopsy.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.

• Life-expectancy greater than 6 months.

• Adequate bone marrow, renal, hepatic, pulmonary and cardiac function as defined in the protocol.

• Patient must be at least 18 years of age.

• Must meet pre-entry requirements for timing of study parameters as specified in section 7.0.

• Female patients of child-bearing potential must have a negative serum pregnancy test within 48 hours of study initiation and be non-lactating.

• Patients of child-bearing potential must agree to use an effective form of contraception while on study and for 3 months following completion of study treatment.

• The use of granulocyte-colony stimulating factor (G-CSF) will be permitted in study participants.

• Final eligibility for a clinical trial is determined by the health professionals conducting the trial.

Exclusion Criteria:

• Patient has received previous treatment for NSCLC.

• Known hypersensitivity to everolimus, sirolimus, or any of its excipients.

• Patient is pregnant or breast-feeding.

• Patient has incurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Patient is unable to swallow RAD001 tablet.

• History of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of the malignancy being present within the past five years.

• History of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80. Symptoms may include any reaction such as bronchospasm, generalized urticaria, systolic BP ≤ 80mm Hg, and angioedema.

• Final eligibility for a clinical trial is determined by the health professionals conducting the trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University

Investigators

• Principal Investigator: Suresh Ramalingam, MD, Emory University Winship Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Suresh S. Ramalingam, Principal Investigator, Emory University
• ClinicalTrials.gov Identifier: NCT00401778
• Other Study ID Numbers: IRB00024810
• First Posted: Nov 22, 2006
• Last Update Posted: Dec 21, 2016
• Last Verified: Nov 1, 2016

• Keywords provided by Suresh S. Ramalingam, Principal Investigator, Emory University: Lung Cancer
• Additional relevant MeSH terms: Lung Neoplasms; Everolimus

Study Results

Participant Flow

Recruitment Details	All enrolled patients were recruited through the multidisciplinary thoracic oncology clinics of Emory Clinic of Emory University.
Pre-assignment Detail	Eligible patients were enrolled concurrently on the active and control arms. Patient preference for a specific arm was entertained until the control cohort was completely filled after which all patients were competitively enrolled on the active treatment arm of the study.

Arm/Group Title	Control	Everolimus 5 mg	Everolimus 10 mg
Arm/Group Description	No everolimus taken.	Everolimus dose of 5 mg/day for 21-28 days sequentially taken orally in tablet form.	Everolimus dose of 10 mg/day for 21-28 days sequentially taken orally in tablet form.
Period Title: Overall Study
STARTED	10	12	11
COMPLETED	9	11	10
NOT COMPLETED	1	1	1

Baseline Characteristics

Arm/Group Title	Control	Everolimus 5 mg	Everolimus 10 mg	Total
Arm/Group Description	No everolimus taken.	Everolimus dose of 5 mg/day for 21-28 days sequentially taken orally in tablet form.	Everolimus dose of 10 mg/day for 21-28 days sequentially taken orally in tablet form.	Total of all reporting groups
Overall Participants	10	12	11	33
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63	58	70	64
Gender (Count of Participants)
Female	6 60%	6 50%	7 63.6%	19 57.6%
Male	4 40%	6 50%	4 36.4%	14 42.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	3 30%	2 16.7%	4 36.4%	9 27.3%
White	7 70%	10 83.3%	7 63.6%	24 72.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	12 100%	11 100%	33 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Response as Assessed Metabolically by Changes in Positron Emission Tomography (PET) Scan Between Baseline and Immediately Prior to Surgery.
Description	All patients had baseline imaging in a fasted state with 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (18FDG)-PET scan and a repeat scan at 3 to 4 weeks later using routine clinical protocol for patient preparation, radiotracer administration and data acquisition. The repeat imaging occurred no longer than 24 hours before surgical resection.
Time Frame	Day 21

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Everolimus 5 mg	Everolimus 10 mg
Arm/Group Description	No everolimus taken.	Everolimus dose of 5 mg/day for 21-28 days sequentially taken orally in tablet form.	Everolimus dose of 10 mg/day for 21-28 days sequentially taken orally in tablet form.
Measure Participants	9	11	10
Stable metabolic disease (SMD)	78	64	50
Progressive metabolic disease (PM)	22	36	50

2. Primary Outcome

Title	Effects of RAD001 on the Regulation of Key Proteins Involved With the Mammalian Target of Rapamycin (mTOR) Axis in Tumor Specimens and Buccal Mucosa in Patients With Operable Non-small Cell Lung Cancer (NSCLC).
Description	Changes in the expression of key signaling proteins in the mTOR/phosphatidylinositol 3-kinase (PI3K) pathway were determined by immunohistochemistry using previously published protocols and manufacturers' recommendations for antigen retrieval and antibody dilution along with positive and negative controls. Two investigators assessed protein expression jointly by light microscopy. The degree of expression was assessed by intensity (0, 1+, 2+, 3+) and percentage of cell staining in line with published algorithm. A derivative score (immunoscore) ranging between 0 and 300 was calculated as the product of intensity and percent cell staining.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Everolimus 5 mg	Everolimus 10 mg
Arm/Group Description	No everolimus taken.	Everolimus dose of 5 mg/day for 21-28 days sequentially taken orally in tablet form.	Everolimus dose of 10 mg/day for 21-28 days sequentially taken orally in tablet form.
Measure Participants	9	11	10
S6	-36.06 (100.02)	-13.69 (144.05)	-77.03 (16.02)
pS6	-41.25 (65.62)	-61.57 (35.8)	-47.21 (44.96)
pS6/S6	-85.75 (20.15)	-100 (NA)	128.57 (219.26)
pMTOR	-6.58 (138.88)	30 (153.95)	-63.82 (51.3)
p4E-BP1	-95.37 (4.24)	150 (NA)	-78.75 (14.36)
p70s6k	25 (176.78)	137.14 (442.07)	-78.62 (22.79)
p70s6k Cytoplasmic	-19.17 (73.16)	0.56 (14.93)	305.37 (686.3)
p70s6k Nuclear	-3.33 (100.17)	135 (49.5)	223.43 (437.7)
pe1f4e	-50 (86.6)	2.78 (5.56)	-27.13 (42.17)
PAKT Nuclear	-33.33 (57.74)	NA (NA)	0 (0)
PAKT Cytoplasmic	200 (469.04)	NA (NA)	-25 (50)
Bim	-11.76 (NA)	NA (NA)	-21.76 (60.07)

3. Primary Outcome

Title	Inhibition of Proliferation (Ki67) and Induction of Apoptosis (TUNEL Assay) in Tumor Specimens and Buccal Mucosa.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Safety and Tolerability of RAD001 as Pre-operative Therapy.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Duration of Hospital Stay Following Surgery.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Everolimus 5 or 10 mg
Arm/Group Description	No everolimus taken.	Everolimus dose of 5 or 10 mg/day for 21-28 days sequentially taken orally in tablet form.
Measure Participants	10	20
Median (Full Range) [days]	5	5

Adverse Events

Time Frame	4 weeks
Arm/Group Title	Control		Everolimus 5 & 10 mg
Arm/Group Description	No everolimus taken.		Everolimus dose of 5 or 10 mg/day for 21-28 days sequentially taken orally in tablet form.
All Cause Mortality
	Control		Everolimus 5 & 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Control		Everolimus 5 & 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		1/23 (4.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Symptomatic Progression of Lung Cancer	0/10 (0%)		1/23 (4.3%)
Other (Not Including Serious) Adverse Events
	Control		Everolimus 5 & 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		21/23 (91.3%)
Blood and lymphatic system disorders
Hyperglycemia	0/10 (0%)		21/23 (91.3%)
Elevated ALT	0/10 (0%)		9/23 (39.1%)
Elevated AST	0/10 (0%)		10/23 (43.5%)
Elevated Alkaline Phosphatase	0/10 (0%)		9/23 (39.1%)
Hypocalcemia	0/10 (0%)		12/23 (52.2%)
Hyponatremia	0/10 (0%)		10/23 (43.5%)
Hypokalemia	0/10 (0%)		10/23 (43.5%)
Anemia	0/10 (0%)		12/23 (52.2%)
Hypophosphatemia	0/10 (0%)		4/23 (17.4%)
Hypoalbuminemia	0/10 (0%)		12/23 (52.2%)
Hypertriglyceridemia	0/10 (0%)		15/23 (65.2%)
Low Platelets	0/10 (0%)		2/23 (8.7%)
Edema	0/10 (0%)		5/23 (21.7%)
Hyperbilirubinemia	0/10 (0%)		1/23 (4.3%)
Hypercalcemia	0/10 (0%)		1/23 (4.3%)
Thrombocytopenia	0/10 (0%)		2/23 (8.7%)
Leukopenia	0/10 (0%)		1/23 (4.3%)
Ear and labyrinth disorders
Vertigo	0/10 (0%)		1/23 (4.3%)
Tinnitus	0/10 (0%)		1/23 (4.3%)
Ear Ache	0/10 (0%)		1/23 (4.3%)
Endocrine disorders
Hot Flashes	0/10 (0%)		1/23 (4.3%)
Eye disorders
Conjuctivitis	0/10 (0%)		1/23 (4.3%)
Gastrointestinal disorders
Diarrhea	0/10 (0%)		3/23 (13%)
Heartburn	0/10 (0%)		2/23 (8.7%)
Mucositis	0/10 (0%)		4/23 (17.4%)
Constipation	0/10 (0%)		6/23 (26.1%)
Reflux	0/10 (0%)		2/23 (8.7%)
General disorders
Fatigue	0/10 (0%)		14/23 (60.9%)
Night Sweats	0/10 (0%)		3/23 (13%)
Fever	0/10 (0%)		3/23 (13%)
Insomnia	0/10 (0%)		5/23 (21.7%)
Hoarseness	0/10 (0%)		2/23 (8.7%)
Nausea	0/10 (0%)		8/23 (34.8%)
Pain in Lower Flank	0/10 (0%)		1/23 (4.3%)
Intermittent Discomfort in Left Leg	0/10 (0%)		1/23 (4.3%)
Malaise	0/10 (0%)		1/23 (4.3%)
Dizziness	0/10 (0%)		2/23 (8.7%)
Restlessness	0/10 (0%)		1/23 (4.3%)
Confusion	0/10 (0%)		1/23 (4.3%)
Loss of Energy	0/10 (0%)		1/23 (4.3%)
Difficulty in Walking	0/10 (0%)		1/23 (4.3%)
Loss of Balance	0/10 (0%)		1/23 (4.3%)
Photosensitivity	0/10 (0%)		1/23 (4.3%)
Cramping Feet	0/10 (0%)		1/23 (4.3%)
Immune system disorders
Low Leukocytes	0/10 (0%)		3/23 (13%)
Infections and infestations
Bronchitis	0/10 (0%)		1/23 (4.3%)
MRSA Bacteremia	0/10 (0%)		1/23 (4.3%)
Upper Respiratory Infection	0/10 (0%)		2/23 (8.7%)
Metabolism and nutrition disorders
Weight-loss	0/10 (0%)		5/23 (21.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/10 (0%)		1/23 (4.3%)
Myalgia	0/10 (0%)		3/23 (13%)
Sinusitis	0/10 (0%)		5/23 (21.7%)
Nervous system disorders
Headache	0/10 (0%)		3/23 (13%)
Pain	0/10 (0%)		6/23 (26.1%)
Neuropathy	0/10 (0%)		2/23 (8.7%)
Psychiatric disorders
Depression	0/10 (0%)		2/23 (8.7%)
Anxiety	0/10 (0%)		1/23 (4.3%)
Renal and urinary disorders
Elevated Creatinine	0/10 (0%)		8/23 (34.8%)
Burning with Urination	0/10 (0%)		1/23 (4.3%)
Acute Renal Failure	0/10 (0%)		1/23 (4.3%)
Urinary Frequency	0/10 (0%)		1/23 (4.3%)
Respiratory, thoracic and mediastinal disorders
Cough	0/10 (0%)		10/23 (43.5%)
Dyspnea	0/10 (0%)		8/23 (34.8%)
Productive Cough	0/10 (0%)		3/23 (13%)
Difficulty in Breathing	0/10 (0%)		1/23 (4.3%)
Chest Pain	0/10 (0%)		5/23 (21.7%)
Sore Throat	0/10 (0%)		3/23 (13%)
Hemoptysis	0/10 (0%)		1/23 (4.3%)
Respiratory Failure	0/10 (0%)		2/23 (8.7%)
Odynophagia	0/10 (0%)		1/23 (4.3%)
Skin and subcutaneous tissue disorders
Mouth Sores	0/10 (0%)		5/23 (21.7%)
Eczema	0/10 (0%)		1/23 (4.3%)
Rash	0/10 (0%)		7/23 (30.4%)
Erythema	0/10 (0%)		1/23 (4.3%)
Vascular disorders
Elevated Cholesterol	0/10 (0%)		13/23 (56.5%)

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.