Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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Hydroxychloroquine is approved for the treatment of non-cancerous illnesses such as rheumatoid arthritis and systemic lupus erythematous. Researchers in the laboratory have tested tumors from patients with pancreatic cancer and have discovered that they have certain pathways inside the cells that promote growth and survival of the tumor. Hydroxychloroquine may inactivate these pathways and results in the death of pancreatic cancer cells.

Detailed Description
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Primary Objective To determine the efficacy of single-agent hydroxychloroquine in patients with metastatic pancreatic cancer previously treated with one or two prior chemotherapy regimens as measured by progression-free survival at two months Secondary Objectives To assess tumor response rate, biochemical response rate (i.e. decrease in serum CA19-9 by > 30%), and overall survival Translational/Exploratory Objectives To investigate predictors of response to anti-autophagy therapy with hydroxychloroquine To explore the kinetics of in vivo autophagy inhibition using peripheral blood WBCs to monitor autophagic activity among patients receiving hydroxychloroquine

Official Title
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Phase II Study of Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed unresectable pancreatic adenocarcinoma that is metastatic to distant sites Measurable disease, defined as at least one lesion that can accurately be measured in at least one dimension Patients must have been treated with one or two previous lines of chemotherapy for metastatic disease with documented tumor progression or intolerance due to toxicity Minimum of two weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy 18 years of age or older Life expectancy of greater than 12 weeks ECOG performance status of 0, 1 or 2 Normal organ and marrow function as outlined in the protocol Patients must be able to swallow pills Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Exclusion Criteria: Participants who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. More than two previous chemotherapy regimens for the treatment of metastatic pancreatic cancer Uncontrolled brain or leptomeningeal metastases History of macular degeneration, visual field changes, retinal disease, or cataracts that would interfere with funduscopic eye examinations History of allergic reactions attributed to compounds of similar chemical or biologic composition to hydroxychloroquine Previous treatment with chloroquine or hydroxychloroquine for other indications, such as rheumatoid arthritis, SLE or malaria prophylaxis Prior treatment with any investigational drug within the preceding 4 weeks Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter absorption of hydroxychloroquine. Patients who have undergone a Whipple procedure for localized pancreatic cancer are not excluded from enrollment History of non-compliance to medical regimens Known diagnosis of glucose-6-phosphate deficiency, porphyria or psoriasis Penicillamine use for Wilson's disease or any other indication Uncontrolled intercurrent illness including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant or breastfeeding women Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3-years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past three years: cervical cancer in situ, and basal cell or squamous cell carcinoma HIV-positive individuals on combination antiretroviral therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: There were 2 arms in this study because the study was amended to evaluate a second cohort of patients treated at a higher dose using the same two-stage statistical design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine 400 mg b.i.d.<br>Patients received 400 mg hydroxychloroquine orally twice per day. Cycle duration was 4 weeks. Patients remained on treatment indefinitely without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision. | Drug: Hydroxychloroquine<br> <br> * Other names: Plaquenil;|
| Experimental: Hydroxychloroquine 600 mg b.i.d.<br>Patients received 600 mg hydroxychloroquine orally twice per day. Cycle duration was 4 weeks. Patients remained on treatment indefinitely without the occurrence of disease progression, unacceptable adverse events, patient withdrawal, or discontinuation per MD decision. | Drug: Hydroxychloroquine<br> <br> * Other names: Plaquenil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-month Progression-Free Survival Rate | 2-month progression-free survival rate was defined as the percentage of patients absent progression (PD) or death before 2 months. Patients were considered to have experienced PD if they demonstrated either clinical deterioration resulting in withdrawal or PD per RECIST 1.0 criteria: At least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. | Disease was evaluated radiologically at baseline and at the first restaging at 2 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Response Rate | Biochemical response rate was defined as the percentage of patients achieving on treatment a decrease in serum CA 19-9 by > 30% from baseline. | Disease was evaluated radiologically at baseline and every 2 months on treatment. Median duration of treatment for this study cohort was 34 days. | 
| Tumor Response Rate | Tumor response rate is the percentage of patients achieving complete or partial response on treatment based on RECIST 1.0 criteria. For target lesions, complete response (CR) is disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR for the evaluation of non-target lesions is the disappearance of non-target lesions and normalization of tumor marker level. Appearance of one or more new lesions is classified as progression of non-target lesions. CR or PR confirmation is required >/= 4 weeks. | Disease was evaluated radiologically at baseline and every 2 months on treatment. Median duration of treatment for this study cohort was 34 days. | 
| Overall Survival | Overall survival estimated using Kaplan-Meier (KM) methods is defined as the time from study entry to death or date last known alive. | All patients were followed until death. Median survival follow-up in this study cohort was 60 days (95% CI: 40-184). | 
| Progression-Free Survival | Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to time of objective progression on CT scan or the time of death for patients with clinical deterioration resulting in withdrawal from the trial. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Patients without an event were censored at date of last disease evaluation. | Disease was evaluated radiologically at baseline and every 2 months on treatment. Median PFS follow-up in this study cohort was 46.5 days (95% CI 33-61). | 
| Grade 4-5 Treatment-Related Toxicity | All grade 4-5 adverse events with treatment attribution of possibly, probably or definite based on CTCAEv3 as reported on case report forms. | Adverse events were assessed each cycle throughout treatment. Participants were followed for the duration of treatment, an average of 34 days for this study population. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic pancreatic cancer, hydroxychloroquine