Erlotinib With or Without Hydroxychloroquine in Chemo-Naive Advanced NSCLC and (EGFR) Mutations

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00977470
Recruitment Status : Active, not recruiting
First Posted : September 15, 2009
Results First Posted : June 6, 2017
Last Update Posted : June 6, 2017
Stanford University
Yale University
University of Maryland
Genentech, Inc.
Information provided by (Responsible Party):
Lecia V. Sequist, Massachusetts General Hospital

September 11, 2009
September 15, 2009
March 22, 2017
June 6, 2017
June 6, 2017
October 2009
May 2015   (Final data collection date for primary outcome measure)
  • Median Progression Free Survival [ Time Frame: From start of treatment until report of disease progression, assessed up to 10 years. ]
    A measure of progression-free survival in patients with advanced non small-cell lung cancer (NSCLC) and EGFR mutations treated with erlotinib as compared with patients treated with erlotinib plus hydroxychloroquine (HCQ). Disease progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, as seen on CT scan, or the appearance of one or more new lesions on CT scan.
  • Nine-month Progression-free Survival Rate [ Time Frame: Nine months ]
    This trial can detect a difference in proportions alive without progression at 9 months from 50% in the erlotinib arm to 77% in the erlotinib plus hydroxychloroquine (HCQ) arm, using an alpha of 0.15 and power of 85%, using the two-sided Likelihood Ratio test. Progression is defined as at least a 20% increase in the size of existing lesions or the appearance of one or more new lesions.
To demonstrate a difference in progression-free survival in patients with advanced NSCLC and EGFR mutations treated with erlotinib as compared with patients treated with erlotinib plus HCQ. [ Time Frame: 2 years ]
Complete list of historical versions of study NCT00977470 on Archive Site
  • Treatment Related Toxicity, > 10% Frequency, Any Grade [ Time Frame: 2 years ]
    To evaluate the safety of treatment with erlotinib with and without hydroxychloroquine (HCQ). All participants receiving study treatment were evaluated for safety. Parameters included laboratory tests, hematological abnormalities, physical exam findings and spontaneous reports of adverse events reported by participants. Toxicities were evaluated and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = fatal.
  • Objective Tumor Response Rate Following Treatment With Erlotinib and With Erlotinib/HCQ. [ Time Frame: 2 years ]

    Response is assessed via spiral CT scan, done at baseline and after every 2 cycles of study treatment. Standard RECIST (Response Evaluation Criteria in Solid Tumors) was used. Complete Response (CR) = disappearance of all target lesions; Partial Response (PR) = at least a 30% decrease in the size of target lesions, as compared to baseline; Progressive Disease (PD) = at least at 20% increase in the size of target lesions, or the appearance of one or more new lesions; Stable Disease (SD) = neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease.

    Response rate = CR + PR. Disease control rate = CR + PR + SD

  • Overall Survival of Patients Treated With Erlotinib and With Erlotinib/HCQ [ Time Frame: Until death ]
  • To evaluate teh safety of treatment with erlotinib with and without HCQ. [ Time Frame: 2 years ]
  • To describe the objective tumor response rate following treatment with erlotinib and with erlotinib/HCQ. [ Time Frame: 2 years ]
  • To describe the median overall survival of patients treated with erlotinib and with erlotinib/HCQ [ Time Frame: 2 years ]
  • To collect serial circulating tumor cell (CTC) analyses from peripheral blood and associate tumor response via CTC quantification with outcome, and describe changing molecular genotypes from the isolated CTCs. [ Time Frame: 2 years ]
  • To correlate genetic characteristics of tumors with response. Mutations in EGFR, KRAS, ALK and other genetic abnormalities will be analyzed. [ Time Frame: 2 years ]
  • Circulating Tumor Cell Quantification [ Time Frame: Until disease progression (median of 10.8 months) ]
    Serial circulating tumor cell (CTC) analyses will be performed on peripheral blood and correlated with disease response.
  • EGFR Mutational Status [ Time Frame: 2 years ]
    Correlation of molecular and genetic tumor characteristics with disease response. Genomic DNA will be extracted from tumor tissue and direct sequencing analysis will be performed to identify additional mutations.
  • Percent of Participants in Which FMISO-PET ([18F]-Fluoromisonidazole-positron Emission Tomography) is Able to Detect and Quantify Changes in Tumor Hypoxia After Erlotinib. [ Time Frame: 12 weeks ]
    [18F]-FMISO-PET/CT was performed on a 64-slice PET/CT scanner and tracer uptake was assessed using SUV (standardized uptake value), normalizing the radioactivity measured in tissue by the injected dose and the body weight of the patient. Mean and maximum SUV and threshold volume of FMISO uptake were measured to quantify the extent of hypoxia in the primary tumor. Imaging was performed before and after initiation of therapy with erlotinib.
Not Provided
Erlotinib With or Without Hydroxychloroquine in Chemo-Naive Advanced NSCLC and (EGFR) Mutations
Phase II Study of Erlotinib With or Without Hydroxychloroquine in Patients With Previously Untreated Advanced NSCLC and EGFR Mutations
The purpose of this research study is to learn if adding hydroxychloroquine (HCQ) to erlotinib helps treat non-small cell lung cancer (NSCLC). Another goal of this research study is to learn more about NSCLC and how it may respond to study treatment. Erlotinib (Tarceva) is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called the epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. However, although TKI drugs can work for some lung cancer patients for a period of time, eventually the tumor finds a way to resist or counteract the TKI treatment and it begins to grow again. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treating malaria, rheumatoid arthritis, and several other diseases. Laboratory research suggests that when HCQ is given with a TKI, it may help delay or prevent TKI resistance from developing.
  • Because no one knows which of the study options are best, participants will be randomized into of the study groups: Group A (erlotinib) or Group B (erlotinib and HCQ). Study treatment will be divided into time periods called cycles. Each study treatment cycle is 28 days.
  • Erlotinib (Group A and Group B) will be taken orally once a day. Hydroxychloroquine (Group B) will be taken orally once a day after taking erlotinib.
  • The following tests and procedures will be performed day 1 of each cycle: physical examination, performance status assessment, questions about any symptoms or side effects, blood for routine tests. The following procedures will be performed at certain study visits: Research blood tests (cycle 1, cycle 2, then every other even cycle); eye exam (cycle 4, cycle 7, and then every 3 months); assessment of the tumor with CT or MRI scan (done at the end of even cycles.
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Non-small Cell Lung Cancer
  • Drug: Erlotinib
    150 mg taken orally once daily
    Other Name: Tarceva
  • Drug: Hydroxychloroquine
    1000 mg taken orally once daily after erlotinib
    Other Name: HCQ
  • Experimental: Erlotinib
    Erlotinib 150 mg oral daily
    Intervention: Drug: Erlotinib
  • Experimental: Erlotinib and Hydroxychloroquine
    Erlotinib 150 mg oral daily plus Hydroxychloroquine (HCQ) 1000 mg oral daily
    • Drug: Erlotinib
    • Drug: Hydroxychloroquine
Arvold ND, Heidari P, Kunawudhi A, Sequist LV, Mahmood U. Tumor Hypoxia Response After Targeted Therapy in EGFR-Mutant Non-Small Cell Lung Cancer: Proof of Concept for FMISO-PET. Technol Cancer Res Treat. 2016 Apr;15(2):234-42. doi: 10.1177/1533034615574386. Epub 2015 Mar 10.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Active, not recruiting
Same as current
December 2017
May 2015   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Pathologically confirmed diagnosis of non-small cell lung cancer
  • Stage IV disease by the American Joint Committee on Cancer/IASLC 7th edition proposed edition staging criteria
  • An EGFR sensitizing mutation must be detected in tumor tissue. Specifically, patients harboring the most common mutations, deletions in exon 19 or the L858R mutation in exon 21 are eligible. Presence of the known resistance mutation T790M as detected by direct tumor sequencing is not allowed. Other rare EGFR mutations may be eligible after discussion with the overall principal investigator
  • Age equal to or greater than 18 years
  • Measurable disease by RECIST criteria, defined as the presence of at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as 10mm or greater with spiral CT scan
  • ECOG Performance status of 0, 1 or 2
  • Since prior radiation or surgery, 14 days or more must have elapsed before starting protocol treatment
  • No prior treatment with erlotinib, gefitinib, or other small molecule EGFR-TKIs. Prior treatment in the adjuvant setting is allowed if at least 1 year has elapsed since TKI course.
  • Adequate organ function as outlined in the protocol
  • Patients must undergo a screening eye exam to obtain approval for HCQ treatment, which establishes the absence of baseline conditions include macular degeneration, visual field changes, other retinal disease, and cataracts that interfere with required funduscopic examinations
  • No G6PD deficiency, as HCQ may cause hemolysis in patients with G6DP

Exclusion Criteria:

  • Symptomatic CNS metastases or newly diagnosed CNS metastases that have not yet been definitively treated with radiation and/or surgery. Note that patients with a history of CNS metastases or cord compression are allowed if they have been definitively treated and are clinically stable. Maintenance steroids are allowed but maintenance seizure medication with an EIAED is not allowed
  • Prior radiation therapy inclusive of all identified target lesions. Note that prior palliative radiation to bony disease, CNS disease, or a limited thoracic area is allowed, provided that there is measurable disease outside the field and radiation is completed at least two weeks prior to starting treatment and the patient has fully recovered from all side effects
  • Current use of hydroxychloroquine for any reason
  • Known hypersensitivity to chloroquine, hydroxychloroquine, or any closely related drug: erlotinib, gefitinib, or any closely related drug
  • Patients who are pregnant or breastfeeding. Female subjects of childbearing potential and male subjects must practice acceptable methods of birth control
  • Any evidence of clinically active interstitial lung disease. Note that patients with chronic, stable radiographic changes who are asymptomatic are eligible
  • Invasive malignancies within the past 3 years except for adequately treated carcinoma of the cervix, basal or squamous cell carcinomas of the skin
  • Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study, including a prior diagnosis of porphyria or non-light-sensitive psoriasis, as HCQ can significantly exacerbate both of these conditions
  • Use of any non-FDA approved or investigational agent in 30 days or less of enrolling onto the trial, or failure to recover from the side effects of any of these agents
  • Penicillamine use for Wilson's disease or any other indication, as concomitant use with HCQ can increase toxicity to penicillamine
  • Life expectancy of less than 12 weeks
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
Contact information is only displayed when the study is recruiting subjects
United States
OSI4620s ( Other Identifier: OSI )
Not Provided
Plan to Share IPD: No
Lecia V. Sequist, Massachusetts General Hospital
Massachusetts General Hospital
  • Stanford University
  • Yale University
  • University of Maryland
  • Genentech, Inc.
Principal Investigator: Lecia Sequist, MD Massachusetts General Hospital
Massachusetts General Hospital
May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP