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A Phase II With a Lead in Phase I Study to Examine the Tolerability, Safety Profile and Efficacy of Hydroxychloroquine and Gefitinib in Advanced Non-Small Cell Lung Cancer

Phase 1/Phase 2
21 Years
Open (Enrolling)
Non-small Cell Lung Cancer

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Trial Information

A Phase II With a Lead in Phase I Study to Examine the Tolerability, Safety Profile and Efficacy of Hydroxychloroquine and Gefitinib in Advanced Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the most common cause of cancer mortality in men and
women in Singapore.Chemotherapy and biologically targeted agents can extend survival only
modestly for these patients; therefore, discovery of novel ways to prolong the disease
course is a top research priority.

The epidermal growth factor receptor (EGFR) signaling pathway plays a central role in the
neoplastic transformation of NSCLC and promotes cancer cell survival, metastasis, and
angiogenesis. The predominance of EGFR signaling in NSCLC makes the pathway an attractive
candidate for the development of targeted therapeutics. Over the last three years, the FDA
has approved two drugs for salvage treatment of NSCLC, gefitinib (Iressa ®, formerly known
as ZD1839) and erlotinib (Tarceva ®, formerly known as OSI-774). Both are small molecule
orally-bioavailable tyrosine kinase inhibitors (TKIs) of the EGFR TK domain, and have been
shown to improve survival compared to placebo in asian patients when administered after
failure of first or second line chemotherapy for advanced NSCLC.

Recently, it was found that somatic mutations in the EGFR gene sensitize NSCLC tumors to
TKIs. These mutations are present in approximately 50 % of asian patients with NSCLC.
Retrospective studies suggest that patients harboring a mutation may derive greater clinical
benefit from treatment with TKIs than patients without a mutation.

Nevertheless, all patients that benefit from TKI treatment ultimately develop resistance to
therapy manifesting as progression of their cancer, after which there remains few, if any
treatment options. Hence, there would be vast clinical utility in understanding the
mechanisms of TKI resistance and developing strategies to reverse or prevent it.

We have preliminary data which shows that the combination of hydroxychloroquine and
gefitinib results in delayed acquired resistance to gefitinib in cell lines that harbour the
EGFR mutation. In addition, the addition of hydroxychloroquine to gefitinib can result in
reversal of acquired resistance to gefitinib. Much parallel has been observed in resistance
mechanisms between NSCLC cell lines and molecular changes observed in patients thus far.

The long term aim therefore is to examine the efficacy of this combination in delaying
acquired resistance to gefitinib in NSCLC patients.

First, however, the MTD and DLT of each drug when used in combination therapy will be
examined in this study. The other aim is to examine the pharmacokinetic effect and
interactions of hydroxychloroquine on gefitinib, and vice versa. Gefitinib is usually well
tolerated, with main toxicities of rash and diarrhoea. Hydroxychloroquine is also FDA
approved and widely used and generally well-tolerated for rheumatological conditions.

Inclusion Criteria:

For the lead in phase I study:

1. Pathologically confirmed diagnosis of non-small cell lung cancer.

2. Stage IIIB with pleural effusion or stage IV disease by the American Joint Committee
on Cancer (AJCC) 6th edition staging criteria.

3. Age equal to or greater than 21 years

4. Measurable disease, defined according to RECIST criteria

5. Performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group(ECOG)
Performance Status scale.

6. At least 2 weeks since prior radiation treatment, chemotherapy or targeted therapy
(from the day that protocol treatment begins).

Patients who had been on gefitinib should have a wash out period of two weeks prior
to commencement of treatment drugs for this study.

7. Adequate organ function including the following:

- Adequate bone marrow reserve:

- Total white blood cell count (WBC) > 3.0 x 109/L

- Platelet count >100 x 109/L

- Hemoglobin >8 g/dL

- Hepatic:

- Bilirubin: = 1.25 times the upper limit of normal (ULN)

- Alanine transaminase (ALT): = <5 times the ULN

- Aspartate transaminase (AST): = <5 times the ULN

- Renal: Serum creatinine =< 1.5 times the ULN, or creatinine clearance
=>60mL/minute as calculated by the standard Cockcroft Gault formula.

8. 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, see exclusion criteria.

9. Willingness to comply with protocol procedures including the blood-sampling schedule
for PK analyses and periodic eye examinations.

10. Willingness to participate in clinical research as evidenced by their signature on
the informed consent form.

11. Tumor block from subject's biopsy or surgical resection specimen should ideally be
available but is not a mandatory requirement for study entry.

For the phase II study:

Inclusion criteria as above, except that:

1. NSCLC patients must be non-smokers and have adenocarcinomas.

2. Patients who had been on gefitinib should have a wash out period of two weeks prior
to commencement of treatment drugs for this study. They must have responded to
Gefitinib previously (either CR, PR or SD) for more than twelve weeks to be eligible.

Exclusion Criteria:

For both lead in phase I and phase II study:

1. Current use of hydroxychloroquine for any reason.

2. Known hypersensitivity to chloroquine, hydroxychloroquine, or any closely related

3. Known hypersensitivity to erlotinib, gefitinib, or any closely related drug.

4. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, as HCQ may cause hemolytic
anemia in patients with G6PD deficiency.

5. 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.

6. Pregnant or breastfeeding. HCQ crosses the placenta and use is not recommended during
pregnancy except for life-threatening malaria. The effects of gefitinib on a fetus
are unknown. For these reasons, female subjects of childbearing age must practice
acceptable methods of birth control to avoid pregnancy. Male subjects must also
practice acceptable methods of birth control to prevent pregnancy of a partner.

7. 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 allowable if they have been definitively
treated and are clinically stable. Maintenance steroids are allowed but maintenance
seizure medication is not allowed.

8. 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.

9. Any evidence of clinically active interstitial lung disease. Note that patients with
chronic, stable radiographic changes who are asymptomatic need not be excluded.

10. Malignancies within the past 3 years except for adequately treated carcinoma of the
cervix or basal or squamous cell carcinomas of the skin.

11. Although not an absolute exclusion criteria, caution should be exercised in patients
with a diagnosis of prophyria or non-light-sensitive psoriasis, as HCQ can
significantly exacerbate both of these conditions.

12. Evidence of any other significant clinical disorder or laboratory finding that makes
it undesirable for the patient to participate in the study, in the opinion of the

13. 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.

14. Penicillamine use for Wilson's disease or any other indication, as concomitant use
with HCQ can increase toxicity to penicillamine.

15. Concommitant use of anti-convulsants is not allowed.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

For the phase I lead in study: To identify the tolerability, the dose limiting toxicity (DLT) and the general safety profile of HCQ and gefitinib when used in combination.

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Tan Min Chin, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

National University Hospital, Singapore


Singapore: Domain Specific Review Boards

Study ID:

NS 01/03/08



Start Date:

November 2008

Completion Date:

November 2013

Related Keywords:

  • Non-Small Cell Lung Cancer
  • Non-small cell lung cancer
  • Gefitinib
  • Hydroxychloroquine
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms