Hydroxychloroquine With or Without Erlotinib in Advanced Non-small Cell Lung Cancer (NSCLC)

Official Title: “A Phase I Study of Hydroxychloroquine With or Without Erlotinib in Advanced NSCLC”

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.

- 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.

Intervention(s) in this Clinical Trial

• Drug: erlotinib
  • Taken orally once a day
• Drug: hydroxychloroquine
  • Taken orally once a day

Primary Measures

• Identify the dose limiting toxicities and maximum tolerated dose of HCQ plus erlotinib in patients with advanced NSCLC and to determine the overall safety profile.
  • Time Frame: 2 years
    Safety Issue?: Yes

Secondary Measures

• To determine the PK parameters of HCQ plus erlotinib.
  • Time Frame: 2 years
    Safety Issue?: No
• To determine the objective tumor response rate to treatment with HCQ plus erlotinib.
  • Time Frame: 2 years
    Safety Issue?: No
• To correlate EGFR mutations and EGFR amplification with response to treatment in patients with available tumor specimens.
  • Time Frame: 2 years
    Safety Issue?: 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 exclusion criteria, caution should be exercised in patients with a diagnosis of porphyria or non-light sensitive psoriasis, as HCQ can significantly exacerbate both of those conditions
• Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study
• Use of any non-FDA approved or investigational agent within 2 weeks 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Massachusetts General Hospital Other

Overall Clinical Trial Officials and Contacts

Lecia Sequist, MD, MPH Principal Investigator Massachussets General Hospital  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01026844

Study ID Number: 07-037

ClinicalTrials.gov Identifier: NCT01026844

Health Authority: United States: Institutional Review Board