Lung Cancer
Conditions
Keywords
Lung Cancer
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.
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.
Interventions
DRUGRAD001
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.
Sponsors
Emory University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Inhibition of Proliferation (Ki67) and Induction of Apoptosis (TUNEL Assay) in Tumor Specimens and Buccal Mucosa. | 6 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Safety and Tolerability of RAD001 as Pre-operative Therapy. | 6 months |
| Duration of Hospital Stay Following Surgery. | 6 months |
Countries
United States
Participant flow
Recruitment details
All enrolled patients were recruited through the multidisciplinary thoracic oncology clinics of Emory Clinic of Emory University.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Control No everolimus taken. | 10 |
| Everolimus 5 mg Everolimus dose of 5 mg/day for 21-28 days sequentially taken orally in tablet form. | 12 |
| Everolimus 10 mg Everolimus dose of 10 mg/day for 21-28 days sequentially taken orally in tablet form. | 11 |
| Total | 33 |
Baseline characteristics
| Characteristic | Control | Everolimus 5 mg | Everolimus 10 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 63 years | 58 years | 70 years | 64 years |
| Gender Female | 6 Participants | 6 Participants | 7 Participants | 19 Participants |
| Gender Male | 4 Participants | 6 Participants | 4 Participants | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 10 Participants | 7 Participants | 24 Participants |
| Region of Enrollment United States | 10 participants | 12 participants | 11 participants | 33 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 21 / 23 |
| serious Total, serious adverse events | 0 / 10 | 1 / 23 |
Outcome results
Primary
Clinical Response as Assessed Metabolically by Changes in Positron Emission Tomography (PET) Scan Between Baseline and Immediately Prior to Surgery.
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Control | Clinical Response as Assessed Metabolically by Changes in Positron Emission Tomography (PET) Scan Between Baseline and Immediately Prior to Surgery. | Stable metabolic disease (SMD) | 78 percentage of patients |
| Control | Clinical Response as Assessed Metabolically by Changes in Positron Emission Tomography (PET) Scan Between Baseline and Immediately Prior to Surgery. | Progressive metabolic disease (PM) | 22 percentage of patients |
| Everolimus 5 mg | Clinical Response as Assessed Metabolically by Changes in Positron Emission Tomography (PET) Scan Between Baseline and Immediately Prior to Surgery. | Stable metabolic disease (SMD) | 64 percentage of patients |
| Everolimus 5 mg | Clinical Response as Assessed Metabolically by Changes in Positron Emission Tomography (PET) Scan Between Baseline and Immediately Prior to Surgery. | Progressive metabolic disease (PM) | 36 percentage of patients |
| Everolimus 10 mg | Clinical Response as Assessed Metabolically by Changes in Positron Emission Tomography (PET) Scan Between Baseline and Immediately Prior to Surgery. | Stable metabolic disease (SMD) | 50 percentage of patients |
| Everolimus 10 mg | Clinical Response as Assessed Metabolically by Changes in Positron Emission Tomography (PET) Scan Between Baseline and Immediately Prior to Surgery. | Progressive metabolic disease (PM) | 50 percentage of patients |
Primary
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).
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Control | 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). | pMTOR | -6.58 % change in immunoscore | Standard Deviation 138.88 |
| Control | 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). | PAKT Cytoplasmic | 200 % change in immunoscore | Standard Deviation 469.04 |
| Control | 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). | Bim | -11.76 % change in immunoscore | — |
| Control | 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). | p4E-BP1 | -95.37 % change in immunoscore | Standard Deviation 4.24 |
| Control | 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). | p70s6k | 25 % change in immunoscore | Standard Deviation 176.78 |
| Control | 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). | p70s6k Cytoplasmic | -19.17 % change in immunoscore | Standard Deviation 73.16 |
| Control | 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). | p70s6k Nuclear | -3.33 % change in immunoscore | Standard Deviation 100.17 |
| Control | 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). | pe1f4e | -50 % change in immunoscore | Standard Deviation 86.6 |
| Control | 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). | PAKT Nuclear | -33.33 % change in immunoscore | Standard Deviation 57.74 |
| Control | 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). | S6 | -36.06 % change in immunoscore | Standard Deviation 100.02 |
| Control | 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). | pS6 | -41.25 % change in immunoscore | Standard Deviation 65.62 |
| Control | 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). | pS6/S6 | -85.75 % change in immunoscore | Standard Deviation 20.15 |
| Everolimus 5 mg | 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). | pS6/S6 | -100 % change in immunoscore | — |
| Everolimus 5 mg | 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). | PAKT Nuclear | NA % change in immunoscore | — |
| Everolimus 5 mg | 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). | S6 | -13.69 % change in immunoscore | Standard Deviation 144.05 |
| Everolimus 5 mg | 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). | pe1f4e | 2.78 % change in immunoscore | Standard Deviation 5.56 |
| Everolimus 5 mg | 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). | p4E-BP1 | 150 % change in immunoscore | — |
| Everolimus 5 mg | 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). | PAKT Cytoplasmic | NA % change in immunoscore | — |
| Everolimus 5 mg | 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). | pMTOR | 30 % change in immunoscore | Standard Deviation 153.95 |
| Everolimus 5 mg | 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). | p70s6k | 137.14 % change in immunoscore | Standard Deviation 442.07 |
| Everolimus 5 mg | 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). | p70s6k Nuclear | 135 % change in immunoscore | Standard Deviation 49.5 |
| Everolimus 5 mg | 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). | pS6 | -61.57 % change in immunoscore | Standard Deviation 35.8 |
| Everolimus 5 mg | 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). | p70s6k Cytoplasmic | 0.56 % change in immunoscore | Standard Deviation 14.93 |
| Everolimus 5 mg | 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). | Bim | NA % change in immunoscore | — |
| Everolimus 10 mg | 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). | p70s6k Cytoplasmic | 305.37 % change in immunoscore | Standard Deviation 686.3 |
| Everolimus 10 mg | 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). | p70s6k Nuclear | 223.43 % change in immunoscore | Standard Deviation 437.7 |
| Everolimus 10 mg | 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). | pMTOR | -63.82 % change in immunoscore | Standard Deviation 51.3 |
| Everolimus 10 mg | 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). | pe1f4e | -27.13 % change in immunoscore | Standard Deviation 42.17 |
| Everolimus 10 mg | 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). | PAKT Nuclear | 0 % change in immunoscore | Standard Deviation 0 |
| Everolimus 10 mg | 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). | PAKT Cytoplasmic | -25 % change in immunoscore | Standard Deviation 50 |
| Everolimus 10 mg | 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). | Bim | -21.76 % change in immunoscore | Standard Deviation 60.07 |
| Everolimus 10 mg | 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). | pS6/S6 | 128.57 % change in immunoscore | Standard Deviation 219.26 |
| Everolimus 10 mg | 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). | S6 | -77.03 % change in immunoscore | Standard Deviation 16.02 |
| Everolimus 10 mg | 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). | p4E-BP1 | -78.75 % change in immunoscore | Standard Deviation 14.36 |
| Everolimus 10 mg | 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). | p70s6k | -78.62 % change in immunoscore | Standard Deviation 22.79 |
| Everolimus 10 mg | 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). | pS6 | -47.21 % change in immunoscore | Standard Deviation 44.96 |
Primary
Inhibition of Proliferation (Ki67) and Induction of Apoptosis (TUNEL Assay) in Tumor Specimens and Buccal Mucosa.
Time frame: 6 months
Secondary
Duration of Hospital Stay Following Surgery.
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control | Duration of Hospital Stay Following Surgery. | 5 days |
| Everolimus 5 mg | Duration of Hospital Stay Following Surgery. | 5 days |
Secondary
Safety and Tolerability of RAD001 as Pre-operative Therapy.
Time frame: 6 months