Non-small Cell Lung Cancer
Conditions
Keywords
erlotinib, tarceva, hydroxychloroquine, NSCLC
Brief summary
Erlotinib is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. EGFR is found on the surface of many types of cancer cells, including non-small cell lung cancer (NSCLC). Erlotinib is approved by the Food and Drug Administration (FDA) for the treatment of NSCLC. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treatment of malaria, rheumatoid arthritis, and several other diseases but is not currently thought of as a cancer treatment. Previous laboratory studies suggests that HCQ may have an anti-cancer effect by itself in some situations, particularly when EGFR TKI drugs have been useful in the past against the tumor. The two drugs together may be able to fight lung cancer in cases where erlotinib is no longer effective by itself. The purpose of this research study is to determine the highest dose of HCQ that can be given safely in combination with erlotinib. We will also begin to look at whether HCQ plus erlotinib helps treat cancer that have become resistant to TKI treatment after initially responding.
Detailed description
* The goal of this study is to find the highest dose of HCQ that can be given safely with erlotinib. Therefore, not all participants will receive the same dose of HCQ. Small groups of participants will be enrolled in steps in this trial. The first group will be given a certain dose of HCQ. If they have few or manageable side effects, the next small group of participants enrolled will receive a higher dose. This increase in doses will continue until the research doctors find the highest dose of HCQ that can be given without causing severe or unmanageable side effects. * Both HCQ and erlotinib are pills that are taken orally. Treatment will be divided into time periods called cycles. Each treatment cycle is 28 days. The exception to this 28 day cycle is when participants start taking the pills for the first time. Erlotinib is started first for 7 days and then HCQ is added. When the HCQ begins, the first cycle of 28 days begins. * There are several tests and procedures that will be performed at specific time periods during protocol treatment. These include: blood work, performance status assessment, questions about medical history and medications, tumor assessment with CT or MRI and, eye exams. * Participants may continue to receive study treatment as long as they do not experience unacceptable side effects or disease progression.
Interventions
DRUGerlotinib
Taken orally once a day
DRUGhydroxychloroquine
Taken orally once a day
Sponsors
Genentech, Inc.
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed diagnosis of non-small cell lung cancer * Stage IIIB with pleural effusion or Stage IV disease by the American Joint Committee on Cancer (AJCC) 6th edition staging criteria. * At least 12 weeks of prior treatment with erlotinib, gefitinib, or another EGFR small molecule TKI agent. * Age equal to or greater than 18 years * Measurable disease, defined according to RECIST criteria * Performance status of 0, 1 or 2 * At least 2 weeks since prior radiation treatment * At least 2 weeks since any prior chemotherapy or targeted therapy * Adequate organ function as outlined in the protocol * Approval for HCQ treatment by an eye doctor, based on a screening eye exam. Examples of disqualifying baseline conditions include macular degeneration and other retinal disease. * Willingness to comply with protocol procedures including the blood-sampling schedule for PK analyses and periodic eye examination
Exclusion criteria
* Current use of hydroxychloroquine for any reason * Known hypersensitivity to chloroquine, hydroxychloroquine, or any other closely related drug * Known hypersensitivity to erlotinib, gefitinib, or any closely related drug * Glucose-6-phosphate dehydrogenase (G6PD) deficiency, as HCQ may cause hemolytic anemia in patients with G6PD deficiency * Cataracts that would interfere with required funduscopic examinations, or severe baseline visual impairment including macular degeneration, retinopathy or visual field changes, or having only one functional eye. All patients must undergo a screening eye exam prior to enrollment * Pregnancy or breastfeeding. Female subjects of childbearing age and male subjects must practice acceptable method of birth control * Symptomatic CNS metastases or newly diagnosed CNS metastases that have not yet been definitively treated with radiation and/or surgery * Prior radiation therapy inclusive of all identified target lesions * Any evidence of clinically active interstitial lung disease * Malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin * Although not an absolute
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Describe the Number and Type of Observed Dose Limiting Toxcities | 2 years | HCQ doses tested included 400mg, 600mg, 800mg, and 1000mg. Dose-limiting toxicities (DLTs) were defined as CTC of grade 2 or higher retinopathy or keratitis, or CTC of grade 3 or higher hematologic, skin, CNS, neuropathic, cardiac, respiratory, gastrointestinal, or renal AEs in the first cycle considered at least possibly related to HCQ. If a DLT was observed, an additional three patients were enrolled at that dose level. The maximum tolerated dose for HCQ in each arm would be defined as one dose level below that at which two or more of 6 patients experienced a DLT, or if no DLTs were observed, the highest tested dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Pharmacokinetic (PK) Parameters of Hydroxychloroquine (HCQ) Plus Erlotinib. | 2 years | PK parameter tested was dose normalized minimum steady state concentration (Cmin SS) of HCQ in micromolar per gram. Note this outcome was only analyzed for the first 21 patients enrolled, 13 on erlotinib/HCQ and 8 on HCQ arm. |
| Objective Tumor Response Rate | 2 years | Number of Response Evaluation Criteria in Solid Tumors (RECIST) responses divided by number of patients treated. Per RECIST version 1.0 complete response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions. The objective tumor response rate is the CR + PR divided by the total number of patients |
| Correlate Epidermal Growth Factor Receptor (EGFR) Mutations and EGFR Amplification With Response to Treatment in Patients With Available Tumor Specimens. | 2 years | — |
Countries
United States
Participant flow
Recruitment details
Twenty-seven patients were enrolled between August 2007 and May 2010. They were all patients at Mass General Hospital Cancer Center
Participants by arm
| Arm | Count |
|---|---|
| Erlotinib Plus HCQ (Hydroxychloroquine) Erlotinib at 150mg QD and HCQ at escalating doses (400mg, 600mg, 800mg and 1000mg QD) | 19 |
| HCQ (Hydroxychloroquine) HCQ at escalating doses (400mg, 600mg, 800mg, and 1000mg QD) | 8 |
| Total | 27 |
Baseline characteristics
| Characteristic | HCQ (Hydroxychloroquine) | Erlotinib Plus HCQ (Hydroxychloroquine) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 10 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 9 Participants | 15 Participants |
| Age, Continuous | 61 years | 65 years | 64 years |
| Region of Enrollment United States | 8 participants | 19 participants | 27 participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 9 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 19 | 4 / 8 |
| serious Total, serious adverse events | 6 / 19 | 0 / 8 |
Outcome results
Primary
Describe the Number and Type of Observed Dose Limiting Toxcities
HCQ doses tested included 400mg, 600mg, 800mg, and 1000mg. Dose-limiting toxicities (DLTs) were defined as CTC of grade 2 or higher retinopathy or keratitis, or CTC of grade 3 or higher hematologic, skin, CNS, neuropathic, cardiac, respiratory, gastrointestinal, or renal AEs in the first cycle considered at least possibly related to HCQ. If a DLT was observed, an additional three patients were enrolled at that dose level. The maximum tolerated dose for HCQ in each arm would be defined as one dose level below that at which two or more of 6 patients experienced a DLT, or if no DLTs were observed, the highest tested dose.
Time frame: 2 years
Population: In October 2008, after enrollment of 18 patients (8 on arm A and 10 on arm B), the study was amended to limit enrollment to arm B only (HCQ plus erlotinib) given the increasing preclinical evidence supporting a role for combination therapy (but not HCQ monotherapy) and to help increase overall patient accrual.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Erlotinib Plus HCQ (Hydroxychloroquine) | Describe the Number and Type of Observed Dose Limiting Toxcities | 0 participants |
| HCQ (Hydroxychloroquine) | Describe the Number and Type of Observed Dose Limiting Toxcities | 0 participants |
Secondary
Correlate Epidermal Growth Factor Receptor (EGFR) Mutations and EGFR Amplification With Response to Treatment in Patients With Available Tumor Specimens.
Time frame: 2 years
Population: Because so few responses were observed, this exploratory outcome was not analyzed
Secondary
Determine the Pharmacokinetic (PK) Parameters of Hydroxychloroquine (HCQ) Plus Erlotinib.
PK parameter tested was dose normalized minimum steady state concentration (Cmin SS) of HCQ in micromolar per gram. Note this outcome was only analyzed for the first 21 patients enrolled, 13 on erlotinib/HCQ and 8 on HCQ arm.
Time frame: 2 years
Population: The patients participating in the randomized portion of the study were analyzed for PK parameters. When the HCQ alone arm of the study was closed, PK measurements were no longer performed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Erlotinib Plus HCQ (Hydroxychloroquine) | Determine the Pharmacokinetic (PK) Parameters of Hydroxychloroquine (HCQ) Plus Erlotinib. | 5.93 micromolar per gram | Standard Deviation 2.51 |
| HCQ (Hydroxychloroquine) | Determine the Pharmacokinetic (PK) Parameters of Hydroxychloroquine (HCQ) Plus Erlotinib. | 9.40 micromolar per gram | Standard Deviation 5.85 |
Secondary
Objective Tumor Response Rate
Number of Response Evaluation Criteria in Solid Tumors (RECIST) responses divided by number of patients treated. Per RECIST version 1.0 complete response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions. The objective tumor response rate is the CR + PR divided by the total number of patients
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Erlotinib Plus HCQ (Hydroxychloroquine) | Objective Tumor Response Rate | 5 percentage of patients |
| HCQ (Hydroxychloroquine) | Objective Tumor Response Rate | 0 percentage of patients |