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

Primary Purpose

Non-small Cell Lung Cancer

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

erlotinib

hydroxychloroquine

About this trial

This is an interventional treatment trial for Non-small Cell Lung Cancer focused on measuring erlotinib, tarceva, hydroxychloroquine, NSCLC

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Massachusetts General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Erlotinib plus hydroxychloroquine

Hydroxychloroqine

Arm Description

erltoinib 150mg per day plus HCQ in esclating doses of 400mg, 600mg, 800mg and 1000mg per day

hydroxychloroquine given at escalating doses of 400mg, 600mg, 800mg and 1000mg per day

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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

Correlate Epidermal Growth Factor Receptor (EGFR) Mutations and EGFR Amplification With Response to Treatment in Patients With Available Tumor Specimens.

Full Information

NCT ID

NCT01026844

First Posted

December 2, 2009

Last Updated

January 27, 2017

Sponsor

Massachusetts General Hospital

Collaborators

Genentech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01026844

Brief Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2017

Overall Recruitment Status

Terminated

Why Stopped

slow enrollment

Study Start Date

July 2007 (undefined)

Primary Completion Date

November 2012 (Actual)

Study Completion Date

November 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

Collaborators

Genentech, Inc.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Non-small Cell Lung Cancer

Keywords

erlotinib, tarceva, hydroxychloroquine, NSCLC

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

27 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Erlotinib plus hydroxychloroquine

Arm Type

Experimental

Arm Description

erltoinib 150mg per day plus HCQ in esclating doses of 400mg, 600mg, 800mg and 1000mg per day

Arm Title

Hydroxychloroqine

Arm Type

Experimental

Arm Description

hydroxychloroquine given at escalating doses of 400mg, 600mg, 800mg and 1000mg per day

Intervention Type

Drug

Intervention Name(s)

erlotinib

Other Intervention Name(s)

Tarceva

Intervention Description

Taken orally once a day

Intervention Type

Drug

Intervention Name(s)

hydroxychloroquine

Other Intervention Name(s)

HCQ

Intervention Description

Taken orally once a day

Primary Outcome Measure Information:

Title

Describe the Number and Type of Observed Dose Limiting Toxcities

Description

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Determine the Pharmacokinetic (PK) Parameters of Hydroxychloroquine (HCQ) Plus Erlotinib.

Description

Time Frame

2 years

Title

Objective Tumor Response Rate

Description

Time Frame

2 years

Title

Correlate Epidermal Growth Factor Receptor (EGFR) Mutations and EGFR Amplification With Response to Treatment in Patients With Available Tumor Specimens.

Time Frame

2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Lecia Sequist, MD, MPH

Organizational Affiliation

Massachussets General Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

22878749

Citation

Goldberg SB, Supko JG, Neal JW, Muzikansky A, Digumarthy S, Fidias P, Temel JS, Heist RS, Shaw AT, McCarthy PO, Lynch TJ, Sharma S, Settleman JE, Sequist LV. A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer. J Thorac Oncol. 2012 Oct;7(10):1602-8. doi: 10.1097/JTO.0b013e318262de4a.

Results Reference

result

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

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