Non-small Cell Lung CancerPhase 1/2NCT00809237
Hydroxychloroquine and Gefitinib to Treat Lung Cancer
A Phase 1/2 study testing Gefitinib, Hydroxychloroquine in people with Non-small Cell Lung Cancer, run by National University Hospital, Singapore at 1 site in Singapore.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 21 years and older
- Conditions the study is for
- Non-small Cell Lung Cancer
- What is being tested?
- Gefitinib, Hydroxychloroquine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 71 participants
- Where
- 1 siteSingapore
- Study dates
- Nov 2008to Nov 2014
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- For the lead in phase I study:
- 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.
- Age equal to or greater than 21 years
- Measurable disease, defined according to RECIST criteria
- Performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group(ECOG) Performance Status scale.
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- 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.
- 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.
- 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.
- Willingness to comply with protocol procedures including the blood-sampling schedule for PK analyses and periodic eye examinations.
- Willingness to participate in clinical research as evidenced by their signature on the informed consent form.
- 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:
- NSCLC patients must be non-smokers and have adenocarcinomas.
- 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.
Who cannot join
- For both lead in phase I and phase II study:
- Current use of hydroxychloroquine for any reason.
- Known hypersensitivity to chloroquine, hydroxychloroquine, or any 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.
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- 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.
- 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.
- 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.
- Any evidence of clinically active interstitial lung disease. Note that patients with chronic, stable radiographic changes who are asymptomatic need not be excluded.
- 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 prophyria or non-light-sensitive psoriasis, as HCQ can significantly exacerbate both of these conditions.
- 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 investigator.
- 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.
- Concommitant use of anti-convulsants is not allowed.
Trial locations and contacts
1 site in 1 country.
Singapore1 site, 1 recruiting
- Recruiting
National University Hospital
Singapore, 119074
Tan Min Chin, MD, 65-67724140, Tan_Min_CHIN@nuhs.com.sg
Boon Cher Goh, MD, 65-67724140, Boon_Cher_GOH@nuhs.com.sg
About this study
Official title: 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.
Read the detailed description
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.
- Conditions
- Non-small Cell Lung Cancer
- Being tested
- Gefitinib, Hydroxychloroquine
- Keywords
- Non-small cell lung cancer, Gefitinib, Hydroxychloroquine
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gefitinib, HydroxychloroquineDrug
Also called Iressa
Gefitinib 250 mg om Hydroxychloroquine at maximally tolerated dose
| Study group | Role | What they receive |
|---|---|---|
| Gefitinib, Hydroxychloroquine | Experimental | For the lead in phase I study, recruited patients will receive one week of 250 mg of Gefitinib, before HCQ at the assigned dose is introduced in addition to Gefitinib 250 mg om.
After the MTD of HCQ is determined, the phase II study will proceed with the combination of 250 mg of Gefitinib and the MTD dose of HCQ. Receives: Drug: Gefitinib, Hydroxychloroquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 2 years
For the phase II study: To determine the response rates to HCQ and Gefitinib.
Measured: 2 years
Secondary outcomes (2)
For the phase I lead in study: To determine the PK (pharmacokinetic) parameters of HCQ plus gefitinib.
Measured: 2 years
For the phase II study: To determine the time to progression for patients treated with HCQ and Gefitinib.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Dec 2008 (estimated)
- Study startNov 2008
- Primary completionNov 2014 (estimated)
- Study completionNov 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-small Cell Lung CancerStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 71 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- Massachusetts General Hospital, AstraZeneca
- Responsible party
- Principal investigator, Haematology-Oncology, National University Hospital, Singapore
- Investigators
- Tan Min Chin, MD, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00809237
- Sponsor's protocol ID
- NS 01/03/08
- Other IDs
- 2008/00196, 2008
- Status last verified
- Dec 2013
- First submitted
- 16 Dec 2008
- Last updated
- 10 Dec 2013
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 10 Dec 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT00809237
- Acronym / sponsor ID
- NS 01/03/08
- Conditions
- Non-small Cell Lung Cancer
- Keywords
- Non-small cell lung cancer, Gefitinib, Hydroxychloroquine
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 71 participants (estimated)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Collaborators
- Massachusetts General Hospital, AstraZeneca
- Study start
- Nov 2008
- Primary completion
- Nov 2014 (estimated)
- Study completion
- Nov 2014 (estimated)
- First posted
- 17 Dec 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Gefitinib, Hydroxychloroquine | Experimental | Drug: Gefitinib, HydroxychloroquineFor the lead in phase I study, recruited patients will receive one week of 250 mg of Gefitinib, before HCQ at the assigned dose is introduced in addition to Gefitinib 250 mg om. After the MTD of HCQ is determined, the phase II study will proceed with the combination of 250 mg of Gefitinib and the MTD dose of HCQ. |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- 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.
- Age equal to or greater than 21 years
- Measurable disease, defined according to RECIST criteria
- Performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group(ECOG) Performance Status scale.
Key exclusion criteria (16 listed)
- Current use of hydroxychloroquine for any reason.
- Known hypersensitivity to chloroquine, hydroxychloroquine, or any 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Gefitinib, HydroxychloroquineAlso: IressaGefitinib 250 mg om Hydroxychloroquine at maximally tolerated dose | Drug | Gefitinib, Hydroxychloroquine |
Primary outcome
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.
Time frame: 2 years
For the phase II study: To determine the response rates to HCQ and Gefitinib.
Time frame: 2 years
2 secondary outcomes
For the phase I lead in study: To determine the PK (pharmacokinetic) parameters of HCQ plus gefitinib.
Time frame: 2 years
For the phase II study: To determine the time to progression for patients treated with HCQ and Gefitinib.
Time frame: 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Dec 2013.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tan Min Chin, MD principal investigator
National University Hospital, Singapore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Gefitinib, Hydroxychloroquine in people with Non-small Cell Lung Cancer, run by National University Hospital, Singapore at 1 site in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 10 Dec 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Tan Min Chin, MD (65-67724140, Tan_Min_CHIN@nuhs.com.sg), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary 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. (time frame: 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Dec 2013.